CA2045327A1 - Pyrimidine derivatives which are angiotensin ii receptor antagonists, their methods of preparation and pharmaceutical compositions in which they are present - Google Patents
Pyrimidine derivatives which are angiotensin ii receptor antagonists, their methods of preparation and pharmaceutical compositions in which they are presentInfo
- Publication number
- CA2045327A1 CA2045327A1 CA002045327A CA2045327A CA2045327A1 CA 2045327 A1 CA2045327 A1 CA 2045327A1 CA 002045327 A CA002045327 A CA 002045327A CA 2045327 A CA2045327 A CA 2045327A CA 2045327 A1 CA2045327 A1 CA 2045327A1
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- Prior art keywords
- group
- methyl
- formula
- propyl
- lower alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
- C07D239/40—One sulfur atom as doubly bound sulfur atom or as unsubstituted mercapto radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/58—Two sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
PATENT APPLICATION
entitled: Novel pyrimidine derivatives which are angio-tensin II receptor antagonists, their methods of preparation and pharmaceutical composi-tions in which they are present in the names of: Nicole BRU-MAGNIEZ
Jean-Marie TEULON
Eric NICOLAI
Assignee: Laboratoires UPSA
ABSTRACT OF THE DISCLOSURE
The present invention relates to the deriva-tives of the formulae Formula (I) Formula (I') in which:
R1 is a lower alkyl radical having 1 to 6 carbon atoms or a lower alkylene radical having 2 to 6 carbon atoms, R2 is a lower alkyl radical, an aromatic, a functional group, the hydrogen atom or a halogen atom, X can be a bond, an oxygen or sulfur atom, a radical NH or a halogen, R3 or R'3 can be a functional group, a hydrogen atom, a lower alkyl radical, an aromatic ring or a heterocycle, and R4 can be a 2-sulfobenzoylamino, 2-carboxy-3,6-dichlorobenzoylamino, 2-carboxyphenyl, 2-sulfoxyphenyl or 2-(tetrazol-5-yl)phenyl group, and their addition salts, and to their use in thera-peutics, especially for the treatment of cardiovascular diseases and in particular for the treatment of hyper-tension and cardiac insufficiency.
PATENT APPLICATION
entitled: Novel pyrimidine derivatives which are angio-tensin II receptor antagonists, their methods of preparation and pharmaceutical composi-tions in which they are present in the names of: Nicole BRU-MAGNIEZ
Jean-Marie TEULON
Eric NICOLAI
Assignee: Laboratoires UPSA
ABSTRACT OF THE DISCLOSURE
The present invention relates to the deriva-tives of the formulae Formula (I) Formula (I') in which:
R1 is a lower alkyl radical having 1 to 6 carbon atoms or a lower alkylene radical having 2 to 6 carbon atoms, R2 is a lower alkyl radical, an aromatic, a functional group, the hydrogen atom or a halogen atom, X can be a bond, an oxygen or sulfur atom, a radical NH or a halogen, R3 or R'3 can be a functional group, a hydrogen atom, a lower alkyl radical, an aromatic ring or a heterocycle, and R4 can be a 2-sulfobenzoylamino, 2-carboxy-3,6-dichlorobenzoylamino, 2-carboxyphenyl, 2-sulfoxyphenyl or 2-(tetrazol-5-yl)phenyl group, and their addition salts, and to their use in thera-peutics, especially for the treatment of cardiovascular diseases and in particular for the treatment of hyper-tension and cardiac insufficiency.
Description
~ovel pyrimidine derivatives which a~e anaiotensin II
receptor an~aonists. their m~thods of preparation and E~harmaceutical compositions in which they ~re present 05 The present invention relates, by way of novel products, to the pyrimidine derivatives of general formulae (I) and (I') below and, if appropriate, their addition salts, in particular the pharmaceutically acceptable addition salts.
The compounds in question have a very valuable pharmacological profile insofar as they possess anta-gonistic properties towards angiotensin II receptors.
They are therefore especially indicated for the treat-ment of cardiovascular diseases and in particular for the treatment of hypertension and the treatment of cardiac insufficiency.
~he present invention further relates to the method of preparing said products and to their appli-cations in therapeutics.
These pyrimidine derivatives have general formulae (I) and (I'):
N N N~N~R 3 R1J~x_R3 R1~0 R~ ~ H2 R ~ H2 Formula (I) Formula (I') In fo~mula (I), R1 is a lower alkyl radical having 1 to 6 carbon atoms or a lower alkenyl radical having 2 to 6 carbon atoms;
R2 is the hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower 05 halogenoalkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group OH, SH or NH2, a group OR5, SR5 or NHRs, R5 being a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or a group NHCOR6, R6 being defined in the same way as R5 except that it can also be an aromatic ring, a substituted or unsubstituted methanebiphenyl or a heterocycle: R2 can also be an aromatic ring or a heterocycle;
X can be a bond, an oxygen or sulfur atom, a radical NH or a halogen;
R3 will be absent when X is a halogen, or can be a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical or else a group -(CH21n-CN, a group -(CH2)n-COOR7, a group -(CH2) n~
OR7, a group --(CH~)n--~H--~CH2 0~0 ~ \
a group -(CH,)n-O-COR7, a group ~(CH2)n~ o or a group -(CH2)n-SR7, n being an integer from 0 to 5 and R7 being a hydrogen atom or a lower alkyl radical ::
receptor an~aonists. their m~thods of preparation and E~harmaceutical compositions in which they ~re present 05 The present invention relates, by way of novel products, to the pyrimidine derivatives of general formulae (I) and (I') below and, if appropriate, their addition salts, in particular the pharmaceutically acceptable addition salts.
The compounds in question have a very valuable pharmacological profile insofar as they possess anta-gonistic properties towards angiotensin II receptors.
They are therefore especially indicated for the treat-ment of cardiovascular diseases and in particular for the treatment of hypertension and the treatment of cardiac insufficiency.
~he present invention further relates to the method of preparing said products and to their appli-cations in therapeutics.
These pyrimidine derivatives have general formulae (I) and (I'):
N N N~N~R 3 R1J~x_R3 R1~0 R~ ~ H2 R ~ H2 Formula (I) Formula (I') In fo~mula (I), R1 is a lower alkyl radical having 1 to 6 carbon atoms or a lower alkenyl radical having 2 to 6 carbon atoms;
R2 is the hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower 05 halogenoalkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group OH, SH or NH2, a group OR5, SR5 or NHRs, R5 being a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or a group NHCOR6, R6 being defined in the same way as R5 except that it can also be an aromatic ring, a substituted or unsubstituted methanebiphenyl or a heterocycle: R2 can also be an aromatic ring or a heterocycle;
X can be a bond, an oxygen or sulfur atom, a radical NH or a halogen;
R3 will be absent when X is a halogen, or can be a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical or else a group -(CH21n-CN, a group -(CH2)n-COOR7, a group -(CH2) n~
OR7, a group --(CH~)n--~H--~CH2 0~0 ~ \
a group -(CH,)n-O-COR7, a group ~(CH2)n~ o or a group -(CH2)n-SR7, n being an integer from 0 to 5 and R7 being a hydrogen atom or a lower alkyl radical ::
- 3 ~
having 1 to 6 carbon atoms; R~ can also be a group -~CH2)p-CONR8Rg or -(CH2)p-NR8Rg, p being an integer from 0 to 5 and R8 and R9 independently being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon 05 atoms, or it being possible for R8 and ~ to form, together with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by a lower alkyl, an aromatic ring or a heterocycle; R3 can also be a group ~(CH2)q~NH~(CH~)r~COORlo, ~(CH2)g~NH~CO~NHRl1 or ~(CH,)q~NH~CS~NH~Rll, q and r being integers from 0 to 5 and Rlo and Rll independently being a lower alkyl radical having 1 to 6 carbon atoms, it also being possible for Rll to be an aromatic ring, a heterocycle or else a group -(CH2)n-COOR7, n and R7 being as defined above; R3 can also be the group S03H, one of its esters or one of its amides; R3 can also be an amino acid group : ~NH2 ~(CH2)n-CH~
or one of its amides ~ NH-COR6 (CH2)n-CH ~
~o n, R~ and R7 being as defined above; finally, R3 can be a radical -(CH2)n-aromatic ring or -(CH2)n-heterocycle, n being as de~ined above; and R~ can be a nitro or amino group or a group -COORl2, Rl2 being a hydrogen atom, a lower alkyl ' radical having 1 to 6 carbon atoms or a benzyl; R~ can also be the following radicals:
R~200C~ ' N~, H~3 o2N~3 ~N,N Y
~3 ~ NH-CO~
H03S CF3SO2NH H2N R1200C~
-NH-CO~ -NH-CO ~3 -C-N H~
H03S~ ' CF3SO2NH R1200C
~ S , ~ S H ~ S
R120(X ~ ~ N
N~
in which R12 is as defined above and Y and Z can inde-pendently be a hydrogen atom, a lower alkyl radical, a : halogen atom, a lower alkoxy radical or a tri~luoro- -~:
methyl radical.
In formula (I'), ~, R~ and R~ are as defined in formula ~I), R'3 is defined in the same way as R3 except that, unlike the latter, it may not be a group SO3H, one of its esters or one of its amides and that also, in the case of R'3, the number q may not be less than 2, the number p may not be equal to 0 and the number n may not be equal to 0, except in the case of a group -(CH2)n-~, :
, ' . ' ' .
-- 5 -- f~
C00~, an aromatic ring or a heterocycle.
The afore-mantioned derivatives can take the form of addition salts, in particular pharmaceutically acceptable addition salts.
05 In the description and the claims, lower alkyl is understood as meaning a linear or branched hydro-carbon chain having from 1 to 6 carbon atoms. A lower alkyl radical is-, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, iso-lo pentyl, hexyl or isohexyl radical.
Lower alkenyl is understood as meaning a linear or branched hydrocarbon chain having from 2 to 6 carbon atoms and one unit of unsaturation. A lower alkenyl radical is, for example, an ethene, propene, iso-propene, butene, isobutene, pentene, isopentene, hexeneor isohexene radical.
Lower halogenoalkyl radical is understood as meaning an alkyl radical having 1 to 6 carbon atoms in which 1 to 7 hydrogen atoms have been substituted by 1 to 7 halogen ato~s. A lower halogenoalkyl radical is, for example, a trifluoromethyl radical, a 2,2,2-tri-fluoroethyl radical, a pentafluoroethyl radical, a 2,2-difluoro-3,3,3-trifluoropropyl radical or a hepta-fluoropropyl radical.
C3-C7 cycloalkyl radical is understood as meaning a saturated cyclic hydrocarbon radical, pre-ferably a cyclopropane, cyclobutane, cyclohexane or cycloheptane radical.
Lower alkoxy is understood as meaning an 0-lower alkyl group, lower alkyl being as de~ined above.
Lower thioalkyl is understood as meaning an S-lower alkyl group, lower alkyl being as de~ined above.
Halogen is understood as meaning a chlorine, bromine, iodine or fluorine atom.
Aromatic ring is understood as meaning a phenyl ~ 6 ~ r~ ~` ~ ,1 or naphthyl ring, it being possible for the phenyl or naphthyl to be unsubstituted or substituted by a lower alkyl group, a halogen, a lower halogenoalkyl group, a lower alkoxy, a lower thioalkyl or a nitro.
05 Heterocycle is understood as meaning an aro-matic ring having 5 to 7 atoms and containing at least one heteroatom such as nitrogen, oxygen or sulfur, it being possible for the heterocycle to be unsubstituted or substituted by a lower alkyl radical, a halogen, a lower halogenoalkyl group, a lower alkoxy, a lower thioalkyl, a nitro or an aromatic ring.
A heterocycle is, for example, pyridine, thio-phene, furan, pyrimidine, piperazine, pyridazine, a diazepine, a thiazole, an imidazole, an oxazole, a thiazepine, an oxazepine, a triazole or a tetrazole.
According to one embodiment, Rl is an n-propyl group.
According to another embodiment, Rl is an n-butyl group.
According to one embodiment, R2 is a methyl group.
According ;to another embodiment, R2 is the hydrogen atom.
According to another embodiment, R2 is a methylthiO group.
According to one embodiment, X is the oxygen atom.
According to another embodiment, X is the ~ulfur atom.
According to one embodiment, R3 is an ethoxy-carbonylmethyl group.
According to another embodiment, R'3 is an ethoxycarbonylmethyl group.
A¢cording to another embodiment, R3 is a 2-hydroxyethyl group.
`? `7 According to another em~odiment, R'3 is a 2-hydroxyethyl group.
According to another embodiment, R3 is a methyl radical.
05 According to another embodiment, R3 or R'3 is the hydrogen atom.
According to one embodiment, R, is a 2-sulfoxy-benzoylamino group.
According to another embodiment, R, is a 2-carboxyphenyl group.
According to another embodiment, R, is a 2-(tetrazol-5-yl)phenyl group.
The particularly preferred compounds of the invention are those selected from the products of the formulae N ~ N ~ COOC2H5 ~0 ~ N
HN~N
::
~: .
-- 8 -- f~ ` !7 N~N
05 1 ll ~S~COOC2H5 .~
0 ~N
HN~ ~N
N~N
--_~OCH3 ~1 1~
~N~
2s HN~N
:: N~ ~N
` ~S ~OH
~NJ~
; -- ,;. ~ ' ` ` `
.. ~. ~` . ~, ` .
N~N
'--J~O~COOC2H5 N
H N~N"
N~N
~OH
~J
~N
N
H N~N"
qH3 N~N
J~SH
~N
HN_N' . .
N~N~OH
~0 0 ~sN
HN~N"
N~N
/\J~SCH3 ~N~N
HN_N'~
N~N
----~S ~OH
:; ~N~
I N
HN "
N~N
os ~S~
~N J3--N~N
-- ~OCH3 ~ :' ~s ~ ~ HN_N~
~H3 N N
~; ~ ~OCH3 ~ .
~N
HN~
3s ~: :
'~
, . :
. :, -' . .
' . ':
N~N
05 ~ OH
o ~N
H N_N
According to the invention, the compounds of formula (I) or (I') may be synthesized by the following reaction sequence:
Methods known per se, such as, for example, the Claisen reaction or the method using Meldrum's acid, some of which can be found in the following literature references:
- OIKAWA Y.; SUGANO K.; YONEMITSU O.; J. org. Chem., 1978, 43(10), 2087-88, - WIERENGA W.; SKULNICX H.I.; J. org. Chem., 1979, 44, 310, - HOUGHTON R.; LAPHAM D.; SYNTHESIS, 1982, , 451-2, 25 - BRAM G.; VILKAS M.; Bull. Soc. Chim. France, 1964(5), 945-51, - BALYAKINA M.V.; Z~DANOVIC~ E.S.; PREOBRAZHENSKII
N.A.; Tr. Vses. Nauchn. Issled. Vitam in. Inst., 1961, 7, 8-16, - RENARD M.; ~AQUINAY A~; Bull. Soc. Chim. Belg., 1946, 55, 98-105, - BRUCE F.W.; COOVER H.W.; J. Am. Chem. Soc., 1944, 66, 2092-94, and - EBY C.J. and HAUSER C.R.; J. Am. Chem. Soc., 1957, 79, 723-5, , ' ~ ' . ~ '`
- .
.
. .
:.... . . . . .
.
- 13 - ~, 3~.. 7 will be used to prepare - the alkyl 3-oxoalkanoates of formula ( II ):
R1 -C CH2 CCX~R13 05 ll o Formula (II) in which Rl is as defined above and Rl3 is a lower alkyl radical, preferably methyl or ethyl, - the 3-oxonitriles of formula (III):
ll Formula ~III) in which R~ is as defined above, and - the 1,3-diketones of formula (IV):
Rl-~C,~-CH2-~-(CH2),-U-Rl~
: Formula (~V) in which Rl is a8 defined above, s i8 an integer rrom 1 to 5, U can be an oxygen or sulfur atom or a methylene and Rl~ i8 a hydrogen atom or a lower alkyl, preferably methyl or et~yl.
~: The compounds of the formulae .
- 14 - f ~ ., 3 )~ cOOR13 R~ ~/
V
Formula (VI) O ~.
R
~ 0 ~
Formula (VII) O O
R~)~(CH2)S--U--Rl4 V
~ Formula (VIII) :: 30 will be obtained by benzylating the compounds o~ for-mulae ~II), (III~ and tIV) with compounds o$ formula ~: (V) : -~ .
.
- ~ - .
:
.
' - 15 - ~
W
C~2 05 V ~
Formula (V) in the presence of a base such as sodium or potassium carbonate in acetone, a sodium or potassium alcoholate in an alcohol, or sodium or lithium hydride in solvents such as tetrahydrofuran, dioxane or dimethylformamide, for example, at a temperature of between 50 and 100 C, or else in the presence of one equivalent of lithium chloride or bromide and two equivalents of diisopropyl-ethylamine in tetrahydrofuran under reflux, according to the following reference:
- SUNG-EUN Y00; KYU YANG YI; Bull. Korean Chem. Soc., 1989, 10(1), 112.
These compounds of formulae (VI), (VII) and (VIII) can also be obtained by condensation of an : aldehyde of formula (IX):
:~ 25 ~ V
Formula (IX) with the compounds of formulae (II), (III) and (IV), followed by hydrogenation in the presence of a catalyst such as Raney nickel, palladium-on-charcoal or platinum oxite, in a solvent such as an alcohol or tetrahydro-;
. - '.: . . , :.-- . :
.
2 ~ `; ) furan, under pressure or at ordinary pressure if the substituents present allow it~
In more general terms, methods of preparing the compounds of formulae (VI), (VII) and (VIII) will be 05 found in the following references:
- DURGESHWARI P.; CHAUDHURY N.D.: J. Ind. Chem. Soc., 1962, 3~, 735-6, - HEINZ P.; KREGLEWSKI A.; J. Prakt. Chem., 1963, ~1(3-4), 186-197, - ZAUGG H.E.; DUNNIGAN D.A.; MICHAELS R.J.; SWETT L.R.;
J. Org. Chem., 1961, 26, 644-51, - KAGAN H.B.; HENG SUEN Y.; Bull. Soc. Chim. France, 1966(6), 1819-22, - RATHKE M.W.; DEITCH J.; Tetrahedron Lett., 1971(31), 2953-6, - BORRIES KUBEL; Liebigs Ann. Chem., 1980, 1392-1401, - MARQUET J.; MORENO-MANAS M.; Chem. Lett., 1981, 2, 173-6, - IOFFE T.; POPOV E.M.; VATSURO K.V.; TULIKOVA E.K.;
KABACHNIK M.I.; Tetrahedron, 1962, 18, 923-940, and - SHEPHERD T.M.; Chem. Ind. (London), l9?0, 1~, 567.
In formula (V), W is a halogen atom, preferably chlorine or bromine.
In the same formula:
V can be a nitro group, in which case the derivative of formula (V) is commercially available.
V can be a group COORl5, R~5 being a lower alkyl or benzyl radical, in which case the derivative of formula (V) will be prepared by chlorinating or bromi-nating a commercially available p-methylbenzoic acid ester with N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromo-ethane, according to the following reference:
- JULIA M.; CHASTRETTE F.; Bull. Soc. Chim. France, 1962(~), 2247.
.
V can be a group Rl6 being a lower alkyl or benzyl radical, in which case the compounds of formula (V) are prepared by reacting a maqnesium compound of p-bromotoluene with a compound of the formula C~130 ><,~
to give a compound of the formula ~: N
~ 25 >~a whioh i8 then hydrolyzed to give the compound of tne Pormula ~ ~ 35 HOOC
.. ; ......................... .
- 18 - ,~.
, ~, . " . i Procedures for the three steps described above w.;ll be found in the following reference:
- MEYERS A.I.; MIHELICH E.D.; J. Am. Chem. Soc., 1975, 97, 7383.
05 The acid is then esterified with an alcohol of the formula Rl60H, Rl6 being as defined above. These derivatives are then brominated or chlorinated, for example with N-bromosuccinimide, N-chlorosuccinimide or bromine, in a solvent such as carbon tetrachloride, dibromoethane or dichloroethane, to give the compounds of formula (V) in which V is the group R,6ooc~3 V can be the group NC
in which case the compound ~3 HXC
prepared above will be converted to the primary amide by reacting the acid chloride, obtained with thionyl chloride or phosphorus oxychloride, with aqueous ammonia and this amide will be converted to the nitrile -- 19 -- . ::
by reaction with phosphorus oxychloride in dimethyl-formamide or with thionyl chloride. The nitrile obtained:
~0 will then be brominated or chlorinated under the same conditions as the above ester to give the compounds of formula (V) in which V is the group NC~ .
V can be the group in which case the compound Cl CH2~
I ll ~3 will be prepared by chloromethylating co~mercially 2 0 ~
available 2-nitrobiphenyl according to the following references:
-- CA : 70(25) : 114837 d, and -- CA : 69(2) : 3704.
05 V can be a group HO S~
in which case the compounds of formula (V) are prepared in the following manner: A Wurtz reaction between para-iodotoluene and orthonitroiodobenzene in the presence of copper, with heating at between 180 and 210C, will give CHq~
02N ~
Hydrogenation of the nitro group to the amine and diazotization with NaN02 in concentrated hydrochloric acid, followed by treatment with S02 in the presence of CuCl2 in acetic acid, will give the compound Cl 02SJ~
which will be treated with methanol in the presence of ~' . . ~ . .
`
pyridine to give the ester CH~
CH~
This derivative is then brominated or chlori-nated, for example with N-bromosuccinimide or N-chloro-succinimide, in a solvent such as carbon tetrachloride or dibromoethane, to lead to the compounds of formula (V) in which V is the group ) and, by hydrolysisl to the compounds of formula (V) in which V is the group ~ , ".
The bromination or chlorination may also ke carried out on the compound Cl O2S
~ 35 conversion to the su}fonic acid then being ef~ected by .:, .:
: .
.
.
. :
hydrolysis of the sulfonyl chloride group.
v can be a group 05 ~ 3 R16C S `.
R16 being a lower alkyl or benzyl radical, in which case the corresponding compounds of formula (IV) are obtained in the following manner:
The compounds of the formula CH
R,6C~C
will be obtained from the compour.d CH3~ , , :: ~ ~S
whose preparation can be found in the following reference:
- FISSELMANN H.; HABITCH H.; Ger. Of~en.: l,os2,sas (1960); CA : ~ : 5894 g, by esterlfication with an alcohol of the formula R~60H, Rl6 being as defined above, using classical methods known to those skilled in the art.
- These compounds are then treated with N-ahloro-succinimide or N-bromosuccinimlde, in a solvent such as ':
;''"''"`''`' ' ~ .
- ' ' ', . - ~.
..
- 23 - :
carbon tetrachloride or dibromoethane, for example, to c;ive the compounds of formula tIV) in which V is the group 05~ 3 R16OOc S
Rl6 being as defined above.
10V can be the group \, NC S
in which case the corresponding compounds of formula (IV) will be prepared in the following manner:
Treatment of the compound 3-(p-methylphenyl)-` thiophene-2-carboxylic acid, whose preparation is given above, with thionyl chloride and then ammonia gives the amide compound, which is then dehydrated with thionyl chloride or phosphorus oxychloride, without a solvent or in dimethylformamide, to give the nitrile compound 25C ~ ~
~S
N~
This nitrile compound is then halogenated with N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, to give the compounds o~ formula (IV) in which V is the group .
.
','' ' ' ~ .
.
- 24 - `~
NC
05 V can be the group NC~3 in which case the corresponding compounds of formula (IV) are synthesized in the following manner:
~ reatment of 4-chloro-4'-methylbutyrophenone of the formula CH3~3Co--CH2--CH2--CH2--Cl whose preparation can be found in Belgian patent 577,977 of 15 May 1959, CA : 54, 4629 c, with phospho-rus oxychloride and dimethylformamide, under the condi-tions described in the fo~lowing reference:
- VOLODINA M.A.; TENENT'EV A.P.; KUDRYASHOVA V.A.;
KXBOSHINA L.N.; Khim. Geterosikl. Soedim, 1967, 5-8, will give the compound of the formula C11,~C--C~CH~CH2--C I
This compound is then treated with sodium 8ul-fide, under reflux in a solvent such as tetrahydro-furan, to give the derivative ~: 3S
.. ..... ,~
- : :
.
:
. ~ "' ': ' 05 ~
which is then converted in two steps to the nitrile derivative by dehydration of the oxime formed from the aldehyde and hydroxylamine. This dehydration may be effected, for example, with acetic anhydride to give the nitrile compound CH3~, l 11 ~S
NC~
which may then be aromatized by treatment with bromine in carbon tetrachloride and then with potassium tert-butylate in tetrahydrofuran to give the compound CH3~, l~
2s This compound can then be chlorinated or bromi-nated with halogenating agents such as N-chlorosuccini-mide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, to give the compounds of formula ~IV) in which V is the group ;~ 35 ~;
'~
N~ .
05 v can be the group ~S
/1 \
R1600C~
Rl6 being as defined above, in which case the corres-ponding compounds of formula (IV) may be prepared from the compound of the formula ~S
by classical hydrolysis of the nitrile group followed : by esterification of the acid obtained, or by direct conversion of the nitri}e group to the ester group by the methods known to those skilled in the art, followed by chlorination or bromination of the ester with N-chlorosuccinimide or N-bromosuccinimide, in carbon :tetrachloride or dibromoethane, for example.
In the formulae tVI), (VII) and (VIII), R" R", 8, U and Rl~ are as defined above and V is A8 defined 0 in formula ~V).
~:~ In formula (IX), V is as defined in formula :(V), but this aondensation method will only be used in cases where V aontains a funational qroup which is unaffected by hydrogenation. Otherwise, these benzyli-~dene compounds, obtained by aondensation of the alde-' -hydes, may be converted to the pyrimidine of formula (XI), without hydrogenation, by condensation with an aldehyde of the formula R2-CHO in the case where R2 is a lower alkyl having 1 to 6 carbon atoms or an aromatic 05 ring, in the presence of aqueous ammonia, according to the method described in the following literature reference:
- KROHNKE, SCHMIDT and ZECHER, Chem. Ber., 1964, '~7, 1163.
Reaction of a urea, a thiourea, an amidine or a guanidine, i.e. reaction of a compound of formula (X):
R2--C~
Formula (X) in which R, is as defined above, with the compounds of formula (VI), ~VII) or (VIII) will give the compounds of formula (XI):
N~N
1 ll R1~T
~ ~;H2 Formula (XI) by condensation in an alcohol, in the presence of a sodium or potassium alcoholate, at a temperature which . ~ .
, - 28 - ~ ~
can range from room temperature to the boiling point of the solvent, in which formula Rl, R2 and V are as defined above and it being possible for T to be OH when the condensation reaction is carried 05 out with the compounds of formula (VI), ~H2 when starting from the compounds of formula (VII), or (CH2)U-U-Rl~ when starting from the compunds of formula (VIII), s, U and Rl,ibeing as defined above.
This condensation reaction may be found in the following literature references:
- AROYAN A.A.; KRAMER M.S.; Arm. Khim. Zk., 1969, ~(9), 835-41, and - KRAMER M.S.; AROYAN A.A.; Arm. Khim. Zk., 1970, 23(1), 69-73.
The compounds of formula (XI) in which R2 is a hydrogen atom, a lower alkyl radical or a substituted or unsubstituted phenyl and T is (CH2)~URl~, in which s, U and Rl~ are as deined above, can also be prepared in the following manner:
Reaction of an aldehyde of formula (IX) with a derivative of formula (IV) gives the following deri-vatives of formula (IV'):
O O
Jl ~
Rl ~¢ (CH2)s U Rl4 ~ V
Formula (IV') in which Rl, s, U, Rl, and V are as defined above.
Reaction of these compounds of formula (IV'~
- 29 ~ 204~3~7 with aldehydes of the formula R2CHO, R2 being as defined above, in the presence of ammonium acetate and acetic acid, according to the following reference:
- KROHNKE F.; SCHMIDT E.: ZECHER W.; Chem. Ber., 1964, 05 97, 1163-1178, makes it possible to obtain the derivatives of formula (XI) in which T is -(CH2).-U-R1" in which s, U and R~
are as defined above.
The compounds of formulae (XII) and (XII'):
N~N N~N~R'3 R J~X,R3 R J~O
VJ3, H2 vJ~
Formula (XII) Formula (XII') in which Rl, R2, R3, X and V for formula (XII) and R1, R2, R'3 and V for formula (XII') are as defined above, may be obtained from the compounds of formula (XI) in the following manner:
The derivative of formula (XI) in which T is a group OH may be metalated. According to the metalation conditions, substitution Will be directed towards the oxygen atom to give the oompounda of ~ormula tXII) or towards the nitrogen atom to give the compounds of formula (XII'). In particular, the use of sodium or potassium carbonate or of a base such as sodium or potassiu~ hydroxide in an aqueous, alcoholic, aceto-nitrile or toluene medium, or in a ketone such as acetone or methyl ethyl ketone, in the presence or 3~ absence of a quaternary ammonium salt, will favor O-- 30 ~ 20~a3 27 substitution to give the compounds of formula (XII) preferentially, whereas the use of a metalating agent such as sodium or lithium hydride in dimethylformamide or tetrahydrofuran, for example, will favor the for-05 mation of the N-substituted derivatives of formula (XII').
Reaction with halogenated derivatives of the formula A-( CH2 ) n~CH3 A-(CH2)n-aromatic A-(CH2)n-heterocycle A~(CH2)n~CN
A-(CH2)n-cOoR7 A-( CH2 ) n~O~R7 A-(CH2)n-SR7 A-(CH2)p-CONR8R9 A-(CH2)p-NR8R9 in which A is a halogen atom, more particularly chlo-rine or bromine, and n, p, R7 ~ Ra and ~ are as defined above, will give the derivatives of formula (XII) in which XR3 is _o-(cH2)n-cH3 -O-(CH2)n-aromatic -O-(CH,)n-heterocycle --O--(CH2)n--CN
--O--( CH2 ) n~COOR7 -O-lCH2)n-OR7 _O~ ( CHa ) n - sR7 -O--( CH2 ) p-CONRaRg -O- ( CH2 ) p-NR8R9 or the compounds of formula (XII') in which R'3 is - 31 - 204'~327 --( CH2 ) n~CH3 -(CH2)n-aromatic -(CH2)n-heterocycle --(CH2)n--CN
05 -(CH2)n-COOR7 --( CHZ ) n--OR7 ~(CH2)n~SR7 --( CH2 ) p--CONRARg --( CH2 ) p~NRaR9 Heating of the derivatives of formula (XI) in which T is OH, in POCl3, will give the derivatives of formula (XII) in which XR3 is chlorine. Reaction of :
compounds of the formulae HB-(CH2)n-CN
HB-(CH2)n-cOoR7 HB-(CH2)n-OR7 HB-~CH2)n-OcOR7 HB-(CH~) n~ ~oJ
HB-(CH2)n-SR7 ~:~ HB-(CH2)p-CONR~R9 HB-(CH,)p-NR,R~
HB~(CH,)q~NH~(CH,)r~COORlo HB~(CH~)q~NH~CO~NHR
~: 30 NH2-NH-COOR7 NH2-NR8Rg ~ ~ HB CH ~
.. . . . .
'~
-- 32 - 2 ~ ~ ~ 3 2 7 which have been metalated beforehand if necessary and in which n, p, q, r, R7, R8, Rg, Rlo and Rll are as defined above and B is an oxygen or sulfur atom or a group NH, with said chlorinated derivative, according 05 to methods known per se, which can be found in the fol-lowing references:
- KRAMER M.S.; AROYAN A.A.; Arm. Khim. Zk., 1970, 23(1), 69-73, - AROYAN A.A.: KRAMER M.S.; GARIBDZHANYAN B.T.: Arm.
Khim. Zk., 1969, 22t7), 617-22, and - SUNLEY R.L., SNOWLING G.D.; Ger. Offen. 2,533,710, will give the compounds of formula (XII) in which XR3 is -B-(CH2)n-CN
-B-(CH2)n-cOoR7 --B--(CH2)n~OR7 -B-(CH2)n-Oc-R7 ~B--(CH2)n-O ~ ) -B-(CH2)n-SR7 -B-(CH2)p-CONR~R9 -B-(CH~)p-NR,R9 -B-(CH~)q~NH~(CH~)r~COOR
-B-(CH~)q~NH~CO~NHR
-NH-NR~R9 -N-R~R9 O /
B'CH2--~, y--O
' _ 33 _ 2~-~`)32~
On treatment of the compounds of formula (XII) in which XR3 is chlorine with thiourea, followed by basic hydrolysis of the intermediate obtained, the com-pounds of formula (XII) in which X~3 iS a group SH will 05 be synthesized. Alkylation of these mercapto compounds with alkyl halides of the formula Y'R7, in which Y' is a halogen, preferably bromine or iodine, and ~ is as defined above, will give derivatives of formula (XII) in which XR3 is a group SR7.
This reaction sequence is described in the fol-lowing publication:
- AROYAN, A.A.; KRAMER, M.S.; Arm. Khim. Zk., 1973, 26(5~, 402-405.
If the derivatives of formula (XI) in which T
is NH2 are subjected to a Sandmeyer reaction, i.e.
diazotization with NaNO2 and then treatment with the appropriate copper salt, according to the following references:
- H.H. HODGSON, Chem. Revs., 1947, 40, 251, and - W.A. COWDR~Y and D.S. DAVIES, Quart. Revs~ (London), 1952, 6, 358, it will be possible to obtain the derivatives of formula (XII) in which XR3 is the iodine, bromine, chlorine or fluorine atom or else the group CN, which may be hydrolyzed to give a group COOH, which in turn may be esterified to COO~, in which ~ is as defined above, or converted via the acid chloride to the amide CONR.R9, in which R~ and R9 are as defined above.
Hydrogenation of the CN group may give the derivatives in which XR3 is CH2NH2, which, when treated with an iso-cyanate or an isothiocyanate, would make it possible to obtain the compounds in which XR3 is -CH2-NH-CONHRl~ or -CH2-NH-CS-NHR1~ where R,l is as defined above.
The derivatives of formula tXI) in which T is -(CH2)~-O-CH3 or -tCH2),-OC2H5 may be converted to the .
_ 34 _ 204~327 -tCH2)~-Br derivative by heating in hydrobromic acid.
These brominated compounds may be converted by reaction with sodium or potassium cyanide, in a solvent such as an alcohol or dimethyl sulfoxide, at a temperature of 0520 to 100 C, to derivatives of formula (XII) in which XR3 is -(CH2)~-CN; as previously, these compounds may be converted by hydrolysis and then by esterification to compounds of formula (XII) in which XR3 is -(CH2)~-COOR7. Catalytic hydrogenation of these nitriles may also give the compounds in which XR3 is -(CH~)n-CH2-NH~, which, by reaction with isocyanate or isothiocyanate, will give the compounds in which XR3 is the group -(CH2)~-CH2-NH-CO-NH-Rll or the group -(CH2)~-CH2-NH-CS-NH-Rll .
15Likewise, condensation of the brominated deri-vatives with ethyl acetamidomalonate, metalated before-hand with a sodium or potassium alcoholate in an alcohol under reflux, will give the compounds of formula (XII) in which XR3 will be ~ NH-COCH3 -(CH2)s C ~
¦ COOEt COOEt Hydrolysis and then decarboxylation of these compounds will make it possible to obtain the amino acids of formula (XII) in which XR3 is 30~NH2 -(CH2)s-CH
COOH
which may be esterified and/or converted to the amide according to methods known to those skilled in the art, ~ 35 ~ 20~327 for example by heating in an alcohol in the presence of thionyl chloride, or by reaction with an acid chloride, to give the derivatives of formula (XII) in which XR3 iB
~ NH2 , NH-COR6 -(CH2)s-CH or -(CH2)s-cH
CCX~R~ ~COOR7 The same reaction sequences may be applied to the derivatives of formula (XII') in which R'3 is a group -(CH2)n-OH, n being as defined above but other than zero, to give the derivatives in which R'3 is the same amino acid, amino ester or amido acid groups, it being possible here for the treatment of the alcohol to be carried out with thionyl chloride, leading to the chlorinated derivative, which will react like the above brominated derivatives with metalated ethyl acetamido-malonate.
In certain cases, the amine or acid groups may be protected by benzyloxycarbonyl groups for the amines or tert-butoxy groups for the acids, and then freed, if necessary, ~y hydrogenolysis or by treatment with tri-~luoroacetic acid according to the classical methods known to those skilled in the art.
The compounds of formulae (XII) and (XII') in which V is a nitro group may be sub~ected to catalytic hydrogenation, for example in the presence of Raney nickel, in an alcohol, at atmospheric pressure or under pressure, to give the compounds of formulae (XII) and (XII') in which V is an amino group.
Reaction of an appropriately substituted phthalic anhydride with this amine derivative will give the compounds of general formulae (I) and (I') in which R, is the group - , . : .
.-: '' ., ~ - -. . ' - 36 - 20~327 o Y
HN~
~DOC~
Y and Z being as defined above, it then heing possible for the acid obtained to be esterified to give the group O Y
HN~
R,2(X~
Likewise, reaction of a benzosulfonic anhydride with these amine compounds will give the compounds of general formulae (I) and (I') in which R4 is the group HO3S~
Likewise, reaction of N (trifluoromethylsul-fonyl)anthranilic acid chloride, whose preparation canbe found in the following references:
: - CA 96(I3) : 103~51Z, and - CA 97(7) : 55500W, ~ with these amine compounds will give the compounds of : 35 general formulae (I) and (I') in which R4 is the group _ 37 _ 204~327 - HN ~
The compounds of formulae (XII) and (XII') in which V is a group -COORl, may be hydrolyzed in an acid or basic medium, or hydrogenated in the case where R
is a benzyl so as not to affect the other ester groups present, to give the compounds of formulae (I) and (I') in which R, is a group -COO~.
After these acid derivatives have been conver-ted to the acid chloride with thionyl chloride or to a : 15 mixed anhydride with ethyl chloroformate, reaction with anthranilic acid derivatives of the formula y H2N~
,~_ R,2~0C
in which Y, Z and Rl2 are as defined above, will give the compounds of general fo~mulae (I) and (I') in which R~ is the group .
O Y
NH~, 30:
Z
The compounds o~ formulae ( XII ) and ( XII ' ) in : 35 which V is the group , ~ .
: ::
.... ,., ,. ,.,. . . . . : ~ .
.' .:
" - ' ' , . ~ , . , - . .
` ~ ' '' ' ': " ""' ' - 38 - ~0~1327 R,600C~
05 will likewise be hydrolyzed, or hydrogenated in the presence of a catalyst, such as palladium, in the case where Rl2 is a benzyl, to give the compounds of formu-lae tI) and (I') in which R~ is a group ~1 ~OC
The compounds of formulae (XII) and (XII') in which V is a group may react with one equivalent of sodium nitride in a solvent such as dimethylformamide, in the presence of an ammonium salt such as ammonium chloride, or by : . heating in toluene with trimethyltin nitride followed by treatment with gaseous hydrogen chloride in tetra-hydrofuran, to give the compounds of general formula (I) or (I') in which R4 is a group . ~ .
H
N~
,N
To carry out this reaction in the case where R3 or R'3 - -~ - , 20~:~327 contains an aliphatic alcohol group, it can be desira-ble to protect said group, according to the methods known to those skilled in the art, with an acetate or a t;etrahydropyran and then to free it, if necessary, 05 after formation of the tetrazole.
The compounds of formulae (XII) and (XII') in which V is a group ~3 ' ' may undergo catalytic hydrogenation, for example in the presence of Raney nickel, in an alcohol, at atmospheric pressure or under pressure, to give compounds of gene-ral formula (I) or (I') in which R4 is a group H2N ~
Reaction of trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride with the latter compounds in a solvent such as chloroform or in an aromatic solvent such as toluene, in the presence of a base such as triethylamine or pyridine, or in pyridine, will give the compounds of general formula (I) or (I') in which R~ is a group CF3SOzHNJ~
The compounds of formulae (XII) and (XII') in which V is the ~roup . .. . ..
20~327 N ~ S
may be treated with a trialkyltin nitride under reflux 05 in toluene, and then with gaseous hydrogen chloride in tetrahydrofuran, to give the derivatives of formula (I) or (I') in which R. is the group o N~
H
To carry out this reaction in the case where R3 or R'3 contains an aliphatic alcohol group, it can be desi-rable to protect said group, according to the methodsknown to those skilled in the art, with an acetate or a tetrahydropyran and then to free it, if necessary, after formation of the tetrazole.
The compounds of formulae (XII) and (XII') in which V is the group R.6 Ct s :~ 25 may be hydrolyzed, or hydrogenated in the presence of a catalyst, such as palladium-on-charcoal, in the case where Rl6 is a benzyl, to give the compounds of formula (I) in which R, is the group ~
HOOC~S
It is possible to obtain addition salts of some ~ ~o~ the compounds o~ formulae (I) and (I'), especially ;~ 35 pharmaceutically acceptable addition salts. In parti-..... ~ ;
'' 2~327 cular, when R2, R3, R'3 or R4 contains an acid group, there may be mentioned the salts of sodium, potassium, calcium, an amine such as dicyclohexylamine or an amino acid such as lysine. When R2, R3, R' 3 or R4 contains an 05 amine group, there may be mentioned the salts of a mineral or organic acid, such as the hydrochloride, methanesulfonate, acetate, maleate, succinate, fuma-rate, sulfate, lactate or citrate.
The novel compounds according to the invention lo possess remarkable pharmacological properties as angio-tensin II receptor antagonists and can be used in therapeutics for the treatment of cardiovascular diseases and in particular for the treatment of hyper-tension and cardiac insufficiency.
Thus the invention covers the pharmaceutical compositions which contain, as the active principle, the drugs consisting of a pharmaceutically effective amount of at least one compound of formula (I) or (I') as defined above, as well as its pharmaceutically acceptable addition salts if appropriate.
These compositions can be administered by the buccal, rectal, parenteral, percutaneous or ocular route.
These compositions can be solid or liquid and can take the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, gelatin capsules, granules, suppositories, injectable preparations, percutaneous systems and eye lotions. ~hey are prepared by the customary m~thods.
In said compositions, the active principle, consisting of a pharmaceutically effective amount of at least one compound o~ formula (I) or (I') as defined above, or one of its pharmaceutically acceptable addition salts, can be incorporated with excipients normally employed in these pharmaceutical compositions, such as talc, gum . ................ .
.
- 42 - 204~327 arabic, lactose, starch, magnesium stearate, polyvi-done, cellulose derivatives, cocoa butter, semisyn-thetic glycerides, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, glycols, various 05 wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavorings and colors.
The invention also covers a pharmaceutical com-position with antagonistic activity towards angiotensin II receptors, which makes it possible especially to favorably treat cardiovascular diseases, in particular hypertension and cardiac insufficiency, said composi-tion comprising a pharmaceutically effective amount of at least one compound of formula (I) or (I') mentioned above, or one of its pharmaceutically acceptable addition salts, which may be incorporated in a pharma-ceutically acceptable excipient, vehicle or carrier~
The dosage varies especially according to the route of administration, the complaint treated and the subject in question.
For example, for an adult with an average weight of 60 to 70 kg, it can vary between 1 and 400 mg of active principle, administered orally in one or more daily doses, or from 0.01 to 50 mg, administered paren-terally in one or more daily doses.
The invention also covers a method of preparinga pharmaceutical composition, which comprises incor-porating a pharmaceutically effective amount of at least one compound of formula (I) or (I') as defined above, or one of its pharmaceutically acceptable addition salts, into a pharmaceutically acceptable excipient, vehicle or carrier, this pharmaceutical composition being formulated for example as gelatin capsules or tablets containing from 1 to 400 mg of active ingredien~, or as injectable preparations - 43 ~ 20 4~327 containing from 0.01 to 50 mg of active ingredient.
The invention also covers a method of thera-peutic treatment for mammals, which comprises adminis-tering to this mammal a therapeutically effective 05 amount of at least one compound of formula (I) or (I') as defined above, or one of its pharmaceutically acceptable addition salts.
In animal therapeutics, the daily dose which can be used should normally be between 1 and lO0 mg per kg.
Further characteristics and advantages of the invention will be understood more clearly from the following description of some Preparatory Examples, which in no way imply a limitation but are given by way of illustration.
: 35 - 44 - 204~327 ~Example 1: Ethyl 3-oxohexanoate Pormula (II): R~ = n-propyl, RL3 = ethyl 05 176 g of 2,2-dimethyl-4,6-dioxo-1,3-dioxane (Meldrum's acid) are dissolved in 550 ml of methylene chloride and 188 ml of pyridine. The mixture is cooled to 0C with a bath of water and ice and 133 ml of butyryl chloride are added dropwise. When the addition is complete, the mixture is stirred for three hours at room temperature. The solution is washed with a dilute solution of hydrochloric acid, dried over magnesium sulfate and evaporated under vacuum to give an oil.
This oil is dissolved in 700 ml of ethanol and the mixture is refluxed for six hours. The ethanol is evaporated off under vacuum and the residue obtained is distilled to give 145.4 g of ethyl 3-oxohexanoate in the form of a liquid of b.p.20 = 98-100 C.
Example 2: ~thyl 3-oxoheptanoate Formula (II): R, = n-butyl, ~13 = ethyl Prepared by the procedure of Example 1.
Li~uid of b.p.20 = 115-120C.
E8~LDiL~: Ethyl 2-(4-nitrobenzyl)-3-oxohexanoate Formula (Yl): Rl = n-propyl, V = N02, R,3 =
ethyl 127.7 g of ethyl 3-oxohexanoate are dissolved in 700 ml of tetrahydrofuran. 174.5 g of 4-nitrobenzyl bromide and 35 g of lithium chloride are added and the mixture is stirred at room temperature. 286 ml of ~ 45 ~ 204~327 diisopropylethylamine are then added dropwise, causing a slight exothermic effect. The mixture is subse-quently stirred for three hours at room temperature and then for ten hours under reflux. The solvents are 05 evaporated off under vacuum and the residue is taken up with water and then extracted with chloroform. The organic phase is decanted and then washed with a dilute solution of hydrochloric acid, dried over magnesium sulfate and evaporated under vacuum. The oily residue obtained is taken up with isopropyl ether and the crys-tals formed are filtered off. The mother liquors are concentrated under vacuum and the residue is heated under 20 mm of mercury at 130C in order to eliminate the residual starting materials. This gives 174 g of ethyl 2-(4-nitrobenzyl)-3-oxohexanoate in the form of an oil, which is used as such for the next step.
Example 4: Ethyl 2-(4-nitrobenzyl)-3-oxoheptanoate Formula (YI): R1 = n-butyl, V = NO2, Rl3 =
ethyl Prepared by the procedure of Example 3.
Oil used as such for the next step.
ExamDle 5: ~thyl 2-(2'-methoxycarbonylbiphenyl-4-yl)-methyl-3-oxohexanoate Formula ~VI): Rl = n-propyl, V - ~ , MeO2C
Rl3 = ethyl Prepared by the procedure of Example 3 from ethyl 3-oxohexanoate, prepared in Example 1, and methyl , .. ..... . .
.
' _ 46 - 20~)327 (4'-bromomethylbiphenyl-2-yl)carboxylate.
Oil used as such for the next step.
Preparation of methyl (4'-bromomethylbiphenyl-2-yl)car-05 boxylate A) Methyl (4'-methylbiphenyl-2-yl)carboxylate 15 ml of acetyl chloride are added to 300 ml of methanol cooled to 0C. The mixture is stirred for 10 minutes at this temperature and 15 g of (4'-methylbi-phenyl-2-yl)carboxylic acid, prepared according to MEYERS A.I.; MIHELICH E.D., J. Am. Chem. Soc., 1975, 97(25), 7383, by reacting (4-methylphenyl)magnesium bromide with 2-(2-methoxyphenyl)-4,4-dimethyloxazo-lidine, are then added. The mixture is subsequentlyrefluxed for 4 hours and the solvents are evaporated off under vacuum to give 16 g of methyl (4'-methylbi-phenyl-2-yl)carboxylate in the form of an oil, which is used as such for the next step.
B) Methyl (4'-bromomethylbiphenyl-2-yl)carboxylate 16 g of methyl (4'-methylbiphenyl-2-yl)car-boxylate, prepared in A), are dissolved in 120 ml of carbon tetrachloride in the presence of 12.6 g of N-bromosuccinimide and 0.5 g of benzoyl peroxide. Themixture is refluxed for 6 hours, the crystals are fil-tered off and the remaining solution is washed with a solution of sodium bicarbonate and then evaporated under vacuum. The residue is taken up with ether and the solution is then filtered on charcoal and evapo-rated under vacuum to give 14.5 g of methyl (4'-bromo-methylbiphenyl-2-yl)carboxylate in the form of an oil, which is used as such for the next step.
2 ~J ~ r~) 3 2 7 E,xample 6: Ethyl 2-(2'-cyanobiphenyl-4-yl)methyl-3-oxohexanoate Formula (VI): R1 = n-propyl, R13 = ethyl, V= ~3 Prepared by the procedure of Example 3 from 4'-bromomethyl-2-cyanobiphenyl.
Oil used as such for the next step.
Preparation of 4'-bromomethyl-2-cyanobiphenyl A) 4'-Methyl-2-cyanobiphenyl 18.5 g of (4'-methylbiphenyl-2-yl)carboxylic acid, prepared as in Example 5A), are refluxed in 60 ml of thionyl chloride for two hours. The thionyl chlo-ride is concentrated under vacùum, the residue ispoured into a 28~ solution of ammonium hydroxide, the mixture is stirred for 30 minutes and the crystals obtained are filtered off, washed with ether and then dried to give 14.5 g of (4'-methylbiphenyl-2-yl)car-boxamide in the form of crystals melting at 128 C.
: These crystals are taken up in 50 ml of thionyl chlo-ride and the mixture is refluxed for 3 hours and then concentrated under vacuum to give 9 g of 4'-methyl-2-cyanobiphenyl in the form of crystals melting at 45-46C.
~ B) 4'-Bromomethyl-2-cyanobiphenyl : 7.9 g of 4'-methyl-2-cyanobiphenyl, prepared in A), are dissolved in 100 ml of carbon tetrachloride in tne presence of 7.3 g of N-bromosuccinimide and 0.3 g `
':
.
204a327 of benzoyl peroxide. The mixture is refluxed for 6 hours, the crystals are filtered off, the remaining solution is concentrated under vacuum and the residue is crystallized from ether to give 6.6 g of 4'-bromo-05 methyl-2-cyanobiphenyl in the form of crystals melting at 115-118C.
Example 7: 6-n-Propyl-2-methyl-4-hydroxy-5-(4-nitro-benzyl)pyrimidine Formula (XI): Rl = n-propyl, R2 = methyl, T = OH, V = NO2 3.5 g of sodium are dissolved in 175 ml of ethanol. 9.5 g of acetamidine hydrochloride are added to this solution and the mixture is stirred for five minutes at room temperature. 20 g of ethyl 2-(4-nitro-benzyl)-3-oxohexanoate, prepared in Example 3, are then added and the mixture is stirred for four days at room temperature. The solvents are then evaporated off under vacuum and the residue is taken up with a solu-tion of hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated under vacuum to give an oily residue, which crystallizes from an acetone/ether mixture. The crystals are filtered off and dried to give 10.9 g of 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of orystals melting at 200C.
Exam~le 8: 6-n-Butyl-2-methyl-4-hydroxy-5-(4-nitro-benzyl)pyrimidine Formula (XI): R1 = n-butyl, R2 = methyl, T = OH, V = NO2 ~ 49 - 204~32~
Prepared by the procedure of Example 7.
Crystals melting at 205C.
Example 9: 6-n-Propyl-2-methyl-4-hydroxy-s-(2~-methoxy-05 carbonylbiphenyl-4-yl)methylpyrimidine ~, Formula (XI): R~ = n-propyl, V = ~ , MeO2C
R2 = methyl, T = OH
Prepared by the procedure of Example 7.
Crystals melting at 206C.
Example 10: 6-n-Propyl-2-methyl-4-hydroxy-5-(2'-cyano-biphenyl-4-yl)methylpyri~idine Formula (XI): Rl = n-propyl, R2 = methyl, T = OH, V =
: Prepared by the procedure of Example 7.
Crystals melting at 206C.
Exam~le 11: Ethyl [4-n-propyl-2-methyl-5-(4-nitro-kenzyl)-6-oxopyrimidin-1(6H~-yl]acetate Formula (XII')~ Rl = n-propyl, R2 = methyl, R' 3 = CH2cOzEt ~ V = N2 4 g of 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 7, are dis-solved in 30 ml of anhydrous N,N-dimethylformamide.
- 50 - 20~327 0.6 g of 60% sodium hydride is added and the mixture is stirred for thirty minutes at room temperature. 2 ml of ethyl bromoacetate are then added and the mixture is subsequently heated at 60C for one hour. After cool-05 ing, 200 ml of water are added, the solution is extrac-ted with ether and the organic phase is dried over mag-nesium sulfate and evaporated under vacuum to give a residue, which crystallizes from an ether/pentane mix-ture to give 2 g of ethyl ~4-n-propyl-2-methyl-5-(4-lo nitrobenzyl)-6-oxopyrimidin-1(6H)-yl]acetate in the form of crystals melting at 120C.
Example 12: Ethyl [4-n-propyl-2-methyl-5-(4-amino-benzyl)-6-oxopyrimidin-1(6H)-yl~acetate Formula (XII'): Rl = n-propyl, R2 = methyl, R' 3 = CH2C02Et ~ V = NH2 2 g of ethyl [4-n-propyl-2-methyl-5-(4-nitro-benzyl)-6-oxopyrimidin-1(6H)-yl]acetate, prepared in Example 11, are dissolved in 25 ml of ethanol in the presence of 0.5 g of Raney nickel and hydrogenated under atmospheric pressure and at room temperature.
When the uptake of hydrogen has ceased, the catalyst is filtered off and the ethanol is evaporated off under vacuum to give 1.8 g of ethyl [4-n-propyl-2-methyl-5-(4-aminobenzyl)-6-oxopyrimidin-1(6H)-yl]acetate in the form of an oil, which is used as such for the next step.
Ex~m~le 13: Ethyl [4-n-propyl-2-methyl-6-oxo-5-t4-~2-sulfoxyphenyl)carbonyla~inophenylmethyl]-pyrimidin-1(6H)-yl]acetate Formula (I'): R~ = n-propyl, R2 = methyl, .
, .
:
- 51 ~ 20~327 R' 3 = CH2C02Et, o R~ = N H~
1 g of ethyl [4-n-propyl-2-methyl-5-(4-amino-benzyl)-6-oxopyrimidin-1(6H)-yl]acetate, prepared in Example 12, is dissolved in lO ml of acetonitrile. A
solution of 0.6 g of sulfobenzoic anhydr~de in 5 ml of acetonitrile is added and the mixture is left to stand for one day at room temperature. ~he crystals formed are filtered off, washed with acetonitrile and then with ether and dried to give 0.9 g of ethyl t4-n-propyl-2-methyl-6-oxo-5-[4-(2-sulfoxyphenyl)carbonyl-aminophenylmethyl]pyrimidin-1(6H)-yl]acetate in the form of crystals melting at 268-269C.
Example 14: ~4-n-Propyl-2-methyl-6-oxo-5-t4-12-carboxy-~: 3,6-dichlorophenyl)carbonylaminophenyl-methyl]pyrimidin-1(6H)-yl~acetic acid Foroula (I'): R~ = n-propyl, R2 = methyl, R'3 = CH2C02H, ~, O C l : R~ = N H~
::::
1.1 g o~ ethyl ~4-n-propyl-2-methyl-5-(4-amino-~ benzylj-6-oxopyrimidin-1(6H)-yl]acetate, prepared in :~ ~ 35 :Example 12, are dissolved in 10 ml of acetonitrile in :~ :
~ ' .
. .
- 52 - 20~.~327 the presence of 0.7 g of 3,6-dichlorophthalic anhy-dride. The mixture is left to stand at room tempera-ture overnight and the acetonitrile is evaporated off under vacuum without excessive heating. The residue 05 obtained is taken up in water in the presence of 0.6 g of sodium hydroxide pellets and stirred for 30 minutes at 45 C. The solution is then neutralized with concen-trated hydrochloric acid and the crystals obtained are filtered off, washed with water and then dried to give 0.6 g of [4-n-propyl-2-methyl-6-oxo-5-[4-~2-carboxy-3,6-dichlorophenyl)carbonylaminophenylme~hyl]pyrimidin-1(6H)-yl]acetic acid in the form of crystals melting at 167-168 c.
Example 15: 6-n-Propyl-2-methyl-4-hydroxyethoxy-s-(2~-methoxycarbonylbiphenyl-4-yl3methylpyri-midine ~ormula (I): Rl = n-propyl, R2 = methyl, R3 - CH2CH20H, X = 0, R. =
MeO2C
having 1 to 6 carbon atoms; R~ can also be a group -~CH2)p-CONR8Rg or -(CH2)p-NR8Rg, p being an integer from 0 to 5 and R8 and R9 independently being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon 05 atoms, or it being possible for R8 and ~ to form, together with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by a lower alkyl, an aromatic ring or a heterocycle; R3 can also be a group ~(CH2)q~NH~(CH~)r~COORlo, ~(CH2)g~NH~CO~NHRl1 or ~(CH,)q~NH~CS~NH~Rll, q and r being integers from 0 to 5 and Rlo and Rll independently being a lower alkyl radical having 1 to 6 carbon atoms, it also being possible for Rll to be an aromatic ring, a heterocycle or else a group -(CH2)n-COOR7, n and R7 being as defined above; R3 can also be the group S03H, one of its esters or one of its amides; R3 can also be an amino acid group : ~NH2 ~(CH2)n-CH~
or one of its amides ~ NH-COR6 (CH2)n-CH ~
~o n, R~ and R7 being as defined above; finally, R3 can be a radical -(CH2)n-aromatic ring or -(CH2)n-heterocycle, n being as de~ined above; and R~ can be a nitro or amino group or a group -COORl2, Rl2 being a hydrogen atom, a lower alkyl ' radical having 1 to 6 carbon atoms or a benzyl; R~ can also be the following radicals:
R~200C~ ' N~, H~3 o2N~3 ~N,N Y
~3 ~ NH-CO~
H03S CF3SO2NH H2N R1200C~
-NH-CO~ -NH-CO ~3 -C-N H~
H03S~ ' CF3SO2NH R1200C
~ S , ~ S H ~ S
R120(X ~ ~ N
N~
in which R12 is as defined above and Y and Z can inde-pendently be a hydrogen atom, a lower alkyl radical, a : halogen atom, a lower alkoxy radical or a tri~luoro- -~:
methyl radical.
In formula (I'), ~, R~ and R~ are as defined in formula ~I), R'3 is defined in the same way as R3 except that, unlike the latter, it may not be a group SO3H, one of its esters or one of its amides and that also, in the case of R'3, the number q may not be less than 2, the number p may not be equal to 0 and the number n may not be equal to 0, except in the case of a group -(CH2)n-~, :
, ' . ' ' .
-- 5 -- f~
C00~, an aromatic ring or a heterocycle.
The afore-mantioned derivatives can take the form of addition salts, in particular pharmaceutically acceptable addition salts.
05 In the description and the claims, lower alkyl is understood as meaning a linear or branched hydro-carbon chain having from 1 to 6 carbon atoms. A lower alkyl radical is-, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, iso-lo pentyl, hexyl or isohexyl radical.
Lower alkenyl is understood as meaning a linear or branched hydrocarbon chain having from 2 to 6 carbon atoms and one unit of unsaturation. A lower alkenyl radical is, for example, an ethene, propene, iso-propene, butene, isobutene, pentene, isopentene, hexeneor isohexene radical.
Lower halogenoalkyl radical is understood as meaning an alkyl radical having 1 to 6 carbon atoms in which 1 to 7 hydrogen atoms have been substituted by 1 to 7 halogen ato~s. A lower halogenoalkyl radical is, for example, a trifluoromethyl radical, a 2,2,2-tri-fluoroethyl radical, a pentafluoroethyl radical, a 2,2-difluoro-3,3,3-trifluoropropyl radical or a hepta-fluoropropyl radical.
C3-C7 cycloalkyl radical is understood as meaning a saturated cyclic hydrocarbon radical, pre-ferably a cyclopropane, cyclobutane, cyclohexane or cycloheptane radical.
Lower alkoxy is understood as meaning an 0-lower alkyl group, lower alkyl being as de~ined above.
Lower thioalkyl is understood as meaning an S-lower alkyl group, lower alkyl being as de~ined above.
Halogen is understood as meaning a chlorine, bromine, iodine or fluorine atom.
Aromatic ring is understood as meaning a phenyl ~ 6 ~ r~ ~` ~ ,1 or naphthyl ring, it being possible for the phenyl or naphthyl to be unsubstituted or substituted by a lower alkyl group, a halogen, a lower halogenoalkyl group, a lower alkoxy, a lower thioalkyl or a nitro.
05 Heterocycle is understood as meaning an aro-matic ring having 5 to 7 atoms and containing at least one heteroatom such as nitrogen, oxygen or sulfur, it being possible for the heterocycle to be unsubstituted or substituted by a lower alkyl radical, a halogen, a lower halogenoalkyl group, a lower alkoxy, a lower thioalkyl, a nitro or an aromatic ring.
A heterocycle is, for example, pyridine, thio-phene, furan, pyrimidine, piperazine, pyridazine, a diazepine, a thiazole, an imidazole, an oxazole, a thiazepine, an oxazepine, a triazole or a tetrazole.
According to one embodiment, Rl is an n-propyl group.
According to another embodiment, Rl is an n-butyl group.
According to one embodiment, R2 is a methyl group.
According ;to another embodiment, R2 is the hydrogen atom.
According to another embodiment, R2 is a methylthiO group.
According to one embodiment, X is the oxygen atom.
According to another embodiment, X is the ~ulfur atom.
According to one embodiment, R3 is an ethoxy-carbonylmethyl group.
According to another embodiment, R'3 is an ethoxycarbonylmethyl group.
A¢cording to another embodiment, R3 is a 2-hydroxyethyl group.
`? `7 According to another em~odiment, R'3 is a 2-hydroxyethyl group.
According to another embodiment, R3 is a methyl radical.
05 According to another embodiment, R3 or R'3 is the hydrogen atom.
According to one embodiment, R, is a 2-sulfoxy-benzoylamino group.
According to another embodiment, R, is a 2-carboxyphenyl group.
According to another embodiment, R, is a 2-(tetrazol-5-yl)phenyl group.
The particularly preferred compounds of the invention are those selected from the products of the formulae N ~ N ~ COOC2H5 ~0 ~ N
HN~N
::
~: .
-- 8 -- f~ ` !7 N~N
05 1 ll ~S~COOC2H5 .~
0 ~N
HN~ ~N
N~N
--_~OCH3 ~1 1~
~N~
2s HN~N
:: N~ ~N
` ~S ~OH
~NJ~
; -- ,;. ~ ' ` ` `
.. ~. ~` . ~, ` .
N~N
'--J~O~COOC2H5 N
H N~N"
N~N
~OH
~J
~N
N
H N~N"
qH3 N~N
J~SH
~N
HN_N' . .
N~N~OH
~0 0 ~sN
HN~N"
N~N
/\J~SCH3 ~N~N
HN_N'~
N~N
----~S ~OH
:; ~N~
I N
HN "
N~N
os ~S~
~N J3--N~N
-- ~OCH3 ~ :' ~s ~ ~ HN_N~
~H3 N N
~; ~ ~OCH3 ~ .
~N
HN~
3s ~: :
'~
, . :
. :, -' . .
' . ':
N~N
05 ~ OH
o ~N
H N_N
According to the invention, the compounds of formula (I) or (I') may be synthesized by the following reaction sequence:
Methods known per se, such as, for example, the Claisen reaction or the method using Meldrum's acid, some of which can be found in the following literature references:
- OIKAWA Y.; SUGANO K.; YONEMITSU O.; J. org. Chem., 1978, 43(10), 2087-88, - WIERENGA W.; SKULNICX H.I.; J. org. Chem., 1979, 44, 310, - HOUGHTON R.; LAPHAM D.; SYNTHESIS, 1982, , 451-2, 25 - BRAM G.; VILKAS M.; Bull. Soc. Chim. France, 1964(5), 945-51, - BALYAKINA M.V.; Z~DANOVIC~ E.S.; PREOBRAZHENSKII
N.A.; Tr. Vses. Nauchn. Issled. Vitam in. Inst., 1961, 7, 8-16, - RENARD M.; ~AQUINAY A~; Bull. Soc. Chim. Belg., 1946, 55, 98-105, - BRUCE F.W.; COOVER H.W.; J. Am. Chem. Soc., 1944, 66, 2092-94, and - EBY C.J. and HAUSER C.R.; J. Am. Chem. Soc., 1957, 79, 723-5, , ' ~ ' . ~ '`
- .
.
. .
:.... . . . . .
.
- 13 - ~, 3~.. 7 will be used to prepare - the alkyl 3-oxoalkanoates of formula ( II ):
R1 -C CH2 CCX~R13 05 ll o Formula (II) in which Rl is as defined above and Rl3 is a lower alkyl radical, preferably methyl or ethyl, - the 3-oxonitriles of formula (III):
ll Formula ~III) in which R~ is as defined above, and - the 1,3-diketones of formula (IV):
Rl-~C,~-CH2-~-(CH2),-U-Rl~
: Formula (~V) in which Rl is a8 defined above, s i8 an integer rrom 1 to 5, U can be an oxygen or sulfur atom or a methylene and Rl~ i8 a hydrogen atom or a lower alkyl, preferably methyl or et~yl.
~: The compounds of the formulae .
- 14 - f ~ ., 3 )~ cOOR13 R~ ~/
V
Formula (VI) O ~.
R
~ 0 ~
Formula (VII) O O
R~)~(CH2)S--U--Rl4 V
~ Formula (VIII) :: 30 will be obtained by benzylating the compounds o~ for-mulae ~II), (III~ and tIV) with compounds o$ formula ~: (V) : -~ .
.
- ~ - .
:
.
' - 15 - ~
W
C~2 05 V ~
Formula (V) in the presence of a base such as sodium or potassium carbonate in acetone, a sodium or potassium alcoholate in an alcohol, or sodium or lithium hydride in solvents such as tetrahydrofuran, dioxane or dimethylformamide, for example, at a temperature of between 50 and 100 C, or else in the presence of one equivalent of lithium chloride or bromide and two equivalents of diisopropyl-ethylamine in tetrahydrofuran under reflux, according to the following reference:
- SUNG-EUN Y00; KYU YANG YI; Bull. Korean Chem. Soc., 1989, 10(1), 112.
These compounds of formulae (VI), (VII) and (VIII) can also be obtained by condensation of an : aldehyde of formula (IX):
:~ 25 ~ V
Formula (IX) with the compounds of formulae (II), (III) and (IV), followed by hydrogenation in the presence of a catalyst such as Raney nickel, palladium-on-charcoal or platinum oxite, in a solvent such as an alcohol or tetrahydro-;
. - '.: . . , :.-- . :
.
2 ~ `; ) furan, under pressure or at ordinary pressure if the substituents present allow it~
In more general terms, methods of preparing the compounds of formulae (VI), (VII) and (VIII) will be 05 found in the following references:
- DURGESHWARI P.; CHAUDHURY N.D.: J. Ind. Chem. Soc., 1962, 3~, 735-6, - HEINZ P.; KREGLEWSKI A.; J. Prakt. Chem., 1963, ~1(3-4), 186-197, - ZAUGG H.E.; DUNNIGAN D.A.; MICHAELS R.J.; SWETT L.R.;
J. Org. Chem., 1961, 26, 644-51, - KAGAN H.B.; HENG SUEN Y.; Bull. Soc. Chim. France, 1966(6), 1819-22, - RATHKE M.W.; DEITCH J.; Tetrahedron Lett., 1971(31), 2953-6, - BORRIES KUBEL; Liebigs Ann. Chem., 1980, 1392-1401, - MARQUET J.; MORENO-MANAS M.; Chem. Lett., 1981, 2, 173-6, - IOFFE T.; POPOV E.M.; VATSURO K.V.; TULIKOVA E.K.;
KABACHNIK M.I.; Tetrahedron, 1962, 18, 923-940, and - SHEPHERD T.M.; Chem. Ind. (London), l9?0, 1~, 567.
In formula (V), W is a halogen atom, preferably chlorine or bromine.
In the same formula:
V can be a nitro group, in which case the derivative of formula (V) is commercially available.
V can be a group COORl5, R~5 being a lower alkyl or benzyl radical, in which case the derivative of formula (V) will be prepared by chlorinating or bromi-nating a commercially available p-methylbenzoic acid ester with N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromo-ethane, according to the following reference:
- JULIA M.; CHASTRETTE F.; Bull. Soc. Chim. France, 1962(~), 2247.
.
V can be a group Rl6 being a lower alkyl or benzyl radical, in which case the compounds of formula (V) are prepared by reacting a maqnesium compound of p-bromotoluene with a compound of the formula C~130 ><,~
to give a compound of the formula ~: N
~ 25 >~a whioh i8 then hydrolyzed to give the compound of tne Pormula ~ ~ 35 HOOC
.. ; ......................... .
- 18 - ,~.
, ~, . " . i Procedures for the three steps described above w.;ll be found in the following reference:
- MEYERS A.I.; MIHELICH E.D.; J. Am. Chem. Soc., 1975, 97, 7383.
05 The acid is then esterified with an alcohol of the formula Rl60H, Rl6 being as defined above. These derivatives are then brominated or chlorinated, for example with N-bromosuccinimide, N-chlorosuccinimide or bromine, in a solvent such as carbon tetrachloride, dibromoethane or dichloroethane, to give the compounds of formula (V) in which V is the group R,6ooc~3 V can be the group NC
in which case the compound ~3 HXC
prepared above will be converted to the primary amide by reacting the acid chloride, obtained with thionyl chloride or phosphorus oxychloride, with aqueous ammonia and this amide will be converted to the nitrile -- 19 -- . ::
by reaction with phosphorus oxychloride in dimethyl-formamide or with thionyl chloride. The nitrile obtained:
~0 will then be brominated or chlorinated under the same conditions as the above ester to give the compounds of formula (V) in which V is the group NC~ .
V can be the group in which case the compound Cl CH2~
I ll ~3 will be prepared by chloromethylating co~mercially 2 0 ~
available 2-nitrobiphenyl according to the following references:
-- CA : 70(25) : 114837 d, and -- CA : 69(2) : 3704.
05 V can be a group HO S~
in which case the compounds of formula (V) are prepared in the following manner: A Wurtz reaction between para-iodotoluene and orthonitroiodobenzene in the presence of copper, with heating at between 180 and 210C, will give CHq~
02N ~
Hydrogenation of the nitro group to the amine and diazotization with NaN02 in concentrated hydrochloric acid, followed by treatment with S02 in the presence of CuCl2 in acetic acid, will give the compound Cl 02SJ~
which will be treated with methanol in the presence of ~' . . ~ . .
`
pyridine to give the ester CH~
CH~
This derivative is then brominated or chlori-nated, for example with N-bromosuccinimide or N-chloro-succinimide, in a solvent such as carbon tetrachloride or dibromoethane, to lead to the compounds of formula (V) in which V is the group ) and, by hydrolysisl to the compounds of formula (V) in which V is the group ~ , ".
The bromination or chlorination may also ke carried out on the compound Cl O2S
~ 35 conversion to the su}fonic acid then being ef~ected by .:, .:
: .
.
.
. :
hydrolysis of the sulfonyl chloride group.
v can be a group 05 ~ 3 R16C S `.
R16 being a lower alkyl or benzyl radical, in which case the corresponding compounds of formula (IV) are obtained in the following manner:
The compounds of the formula CH
R,6C~C
will be obtained from the compour.d CH3~ , , :: ~ ~S
whose preparation can be found in the following reference:
- FISSELMANN H.; HABITCH H.; Ger. Of~en.: l,os2,sas (1960); CA : ~ : 5894 g, by esterlfication with an alcohol of the formula R~60H, Rl6 being as defined above, using classical methods known to those skilled in the art.
- These compounds are then treated with N-ahloro-succinimide or N-bromosuccinimlde, in a solvent such as ':
;''"''"`''`' ' ~ .
- ' ' ', . - ~.
..
- 23 - :
carbon tetrachloride or dibromoethane, for example, to c;ive the compounds of formula tIV) in which V is the group 05~ 3 R16OOc S
Rl6 being as defined above.
10V can be the group \, NC S
in which case the corresponding compounds of formula (IV) will be prepared in the following manner:
Treatment of the compound 3-(p-methylphenyl)-` thiophene-2-carboxylic acid, whose preparation is given above, with thionyl chloride and then ammonia gives the amide compound, which is then dehydrated with thionyl chloride or phosphorus oxychloride, without a solvent or in dimethylformamide, to give the nitrile compound 25C ~ ~
~S
N~
This nitrile compound is then halogenated with N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, to give the compounds o~ formula (IV) in which V is the group .
.
','' ' ' ~ .
.
- 24 - `~
NC
05 V can be the group NC~3 in which case the corresponding compounds of formula (IV) are synthesized in the following manner:
~ reatment of 4-chloro-4'-methylbutyrophenone of the formula CH3~3Co--CH2--CH2--CH2--Cl whose preparation can be found in Belgian patent 577,977 of 15 May 1959, CA : 54, 4629 c, with phospho-rus oxychloride and dimethylformamide, under the condi-tions described in the fo~lowing reference:
- VOLODINA M.A.; TENENT'EV A.P.; KUDRYASHOVA V.A.;
KXBOSHINA L.N.; Khim. Geterosikl. Soedim, 1967, 5-8, will give the compound of the formula C11,~C--C~CH~CH2--C I
This compound is then treated with sodium 8ul-fide, under reflux in a solvent such as tetrahydro-furan, to give the derivative ~: 3S
.. ..... ,~
- : :
.
:
. ~ "' ': ' 05 ~
which is then converted in two steps to the nitrile derivative by dehydration of the oxime formed from the aldehyde and hydroxylamine. This dehydration may be effected, for example, with acetic anhydride to give the nitrile compound CH3~, l 11 ~S
NC~
which may then be aromatized by treatment with bromine in carbon tetrachloride and then with potassium tert-butylate in tetrahydrofuran to give the compound CH3~, l~
2s This compound can then be chlorinated or bromi-nated with halogenating agents such as N-chlorosuccini-mide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, to give the compounds of formula ~IV) in which V is the group ;~ 35 ~;
'~
N~ .
05 v can be the group ~S
/1 \
R1600C~
Rl6 being as defined above, in which case the corres-ponding compounds of formula (IV) may be prepared from the compound of the formula ~S
by classical hydrolysis of the nitrile group followed : by esterification of the acid obtained, or by direct conversion of the nitri}e group to the ester group by the methods known to those skilled in the art, followed by chlorination or bromination of the ester with N-chlorosuccinimide or N-bromosuccinimide, in carbon :tetrachloride or dibromoethane, for example.
In the formulae tVI), (VII) and (VIII), R" R", 8, U and Rl~ are as defined above and V is A8 defined 0 in formula ~V).
~:~ In formula (IX), V is as defined in formula :(V), but this aondensation method will only be used in cases where V aontains a funational qroup which is unaffected by hydrogenation. Otherwise, these benzyli-~dene compounds, obtained by aondensation of the alde-' -hydes, may be converted to the pyrimidine of formula (XI), without hydrogenation, by condensation with an aldehyde of the formula R2-CHO in the case where R2 is a lower alkyl having 1 to 6 carbon atoms or an aromatic 05 ring, in the presence of aqueous ammonia, according to the method described in the following literature reference:
- KROHNKE, SCHMIDT and ZECHER, Chem. Ber., 1964, '~7, 1163.
Reaction of a urea, a thiourea, an amidine or a guanidine, i.e. reaction of a compound of formula (X):
R2--C~
Formula (X) in which R, is as defined above, with the compounds of formula (VI), ~VII) or (VIII) will give the compounds of formula (XI):
N~N
1 ll R1~T
~ ~;H2 Formula (XI) by condensation in an alcohol, in the presence of a sodium or potassium alcoholate, at a temperature which . ~ .
, - 28 - ~ ~
can range from room temperature to the boiling point of the solvent, in which formula Rl, R2 and V are as defined above and it being possible for T to be OH when the condensation reaction is carried 05 out with the compounds of formula (VI), ~H2 when starting from the compounds of formula (VII), or (CH2)U-U-Rl~ when starting from the compunds of formula (VIII), s, U and Rl,ibeing as defined above.
This condensation reaction may be found in the following literature references:
- AROYAN A.A.; KRAMER M.S.; Arm. Khim. Zk., 1969, ~(9), 835-41, and - KRAMER M.S.; AROYAN A.A.; Arm. Khim. Zk., 1970, 23(1), 69-73.
The compounds of formula (XI) in which R2 is a hydrogen atom, a lower alkyl radical or a substituted or unsubstituted phenyl and T is (CH2)~URl~, in which s, U and Rl~ are as deined above, can also be prepared in the following manner:
Reaction of an aldehyde of formula (IX) with a derivative of formula (IV) gives the following deri-vatives of formula (IV'):
O O
Jl ~
Rl ~¢ (CH2)s U Rl4 ~ V
Formula (IV') in which Rl, s, U, Rl, and V are as defined above.
Reaction of these compounds of formula (IV'~
- 29 ~ 204~3~7 with aldehydes of the formula R2CHO, R2 being as defined above, in the presence of ammonium acetate and acetic acid, according to the following reference:
- KROHNKE F.; SCHMIDT E.: ZECHER W.; Chem. Ber., 1964, 05 97, 1163-1178, makes it possible to obtain the derivatives of formula (XI) in which T is -(CH2).-U-R1" in which s, U and R~
are as defined above.
The compounds of formulae (XII) and (XII'):
N~N N~N~R'3 R J~X,R3 R J~O
VJ3, H2 vJ~
Formula (XII) Formula (XII') in which Rl, R2, R3, X and V for formula (XII) and R1, R2, R'3 and V for formula (XII') are as defined above, may be obtained from the compounds of formula (XI) in the following manner:
The derivative of formula (XI) in which T is a group OH may be metalated. According to the metalation conditions, substitution Will be directed towards the oxygen atom to give the oompounda of ~ormula tXII) or towards the nitrogen atom to give the compounds of formula (XII'). In particular, the use of sodium or potassium carbonate or of a base such as sodium or potassiu~ hydroxide in an aqueous, alcoholic, aceto-nitrile or toluene medium, or in a ketone such as acetone or methyl ethyl ketone, in the presence or 3~ absence of a quaternary ammonium salt, will favor O-- 30 ~ 20~a3 27 substitution to give the compounds of formula (XII) preferentially, whereas the use of a metalating agent such as sodium or lithium hydride in dimethylformamide or tetrahydrofuran, for example, will favor the for-05 mation of the N-substituted derivatives of formula (XII').
Reaction with halogenated derivatives of the formula A-( CH2 ) n~CH3 A-(CH2)n-aromatic A-(CH2)n-heterocycle A~(CH2)n~CN
A-(CH2)n-cOoR7 A-( CH2 ) n~O~R7 A-(CH2)n-SR7 A-(CH2)p-CONR8R9 A-(CH2)p-NR8R9 in which A is a halogen atom, more particularly chlo-rine or bromine, and n, p, R7 ~ Ra and ~ are as defined above, will give the derivatives of formula (XII) in which XR3 is _o-(cH2)n-cH3 -O-(CH2)n-aromatic -O-(CH,)n-heterocycle --O--(CH2)n--CN
--O--( CH2 ) n~COOR7 -O-lCH2)n-OR7 _O~ ( CHa ) n - sR7 -O--( CH2 ) p-CONRaRg -O- ( CH2 ) p-NR8R9 or the compounds of formula (XII') in which R'3 is - 31 - 204'~327 --( CH2 ) n~CH3 -(CH2)n-aromatic -(CH2)n-heterocycle --(CH2)n--CN
05 -(CH2)n-COOR7 --( CHZ ) n--OR7 ~(CH2)n~SR7 --( CH2 ) p--CONRARg --( CH2 ) p~NRaR9 Heating of the derivatives of formula (XI) in which T is OH, in POCl3, will give the derivatives of formula (XII) in which XR3 is chlorine. Reaction of :
compounds of the formulae HB-(CH2)n-CN
HB-(CH2)n-cOoR7 HB-(CH2)n-OR7 HB-~CH2)n-OcOR7 HB-(CH~) n~ ~oJ
HB-(CH2)n-SR7 ~:~ HB-(CH2)p-CONR~R9 HB-(CH,)p-NR,R~
HB~(CH,)q~NH~(CH,)r~COORlo HB~(CH~)q~NH~CO~NHR
~: 30 NH2-NH-COOR7 NH2-NR8Rg ~ ~ HB CH ~
.. . . . .
'~
-- 32 - 2 ~ ~ ~ 3 2 7 which have been metalated beforehand if necessary and in which n, p, q, r, R7, R8, Rg, Rlo and Rll are as defined above and B is an oxygen or sulfur atom or a group NH, with said chlorinated derivative, according 05 to methods known per se, which can be found in the fol-lowing references:
- KRAMER M.S.; AROYAN A.A.; Arm. Khim. Zk., 1970, 23(1), 69-73, - AROYAN A.A.: KRAMER M.S.; GARIBDZHANYAN B.T.: Arm.
Khim. Zk., 1969, 22t7), 617-22, and - SUNLEY R.L., SNOWLING G.D.; Ger. Offen. 2,533,710, will give the compounds of formula (XII) in which XR3 is -B-(CH2)n-CN
-B-(CH2)n-cOoR7 --B--(CH2)n~OR7 -B-(CH2)n-Oc-R7 ~B--(CH2)n-O ~ ) -B-(CH2)n-SR7 -B-(CH2)p-CONR~R9 -B-(CH~)p-NR,R9 -B-(CH~)q~NH~(CH~)r~COOR
-B-(CH~)q~NH~CO~NHR
-NH-NR~R9 -N-R~R9 O /
B'CH2--~, y--O
' _ 33 _ 2~-~`)32~
On treatment of the compounds of formula (XII) in which XR3 is chlorine with thiourea, followed by basic hydrolysis of the intermediate obtained, the com-pounds of formula (XII) in which X~3 iS a group SH will 05 be synthesized. Alkylation of these mercapto compounds with alkyl halides of the formula Y'R7, in which Y' is a halogen, preferably bromine or iodine, and ~ is as defined above, will give derivatives of formula (XII) in which XR3 is a group SR7.
This reaction sequence is described in the fol-lowing publication:
- AROYAN, A.A.; KRAMER, M.S.; Arm. Khim. Zk., 1973, 26(5~, 402-405.
If the derivatives of formula (XI) in which T
is NH2 are subjected to a Sandmeyer reaction, i.e.
diazotization with NaNO2 and then treatment with the appropriate copper salt, according to the following references:
- H.H. HODGSON, Chem. Revs., 1947, 40, 251, and - W.A. COWDR~Y and D.S. DAVIES, Quart. Revs~ (London), 1952, 6, 358, it will be possible to obtain the derivatives of formula (XII) in which XR3 is the iodine, bromine, chlorine or fluorine atom or else the group CN, which may be hydrolyzed to give a group COOH, which in turn may be esterified to COO~, in which ~ is as defined above, or converted via the acid chloride to the amide CONR.R9, in which R~ and R9 are as defined above.
Hydrogenation of the CN group may give the derivatives in which XR3 is CH2NH2, which, when treated with an iso-cyanate or an isothiocyanate, would make it possible to obtain the compounds in which XR3 is -CH2-NH-CONHRl~ or -CH2-NH-CS-NHR1~ where R,l is as defined above.
The derivatives of formula tXI) in which T is -(CH2)~-O-CH3 or -tCH2),-OC2H5 may be converted to the .
_ 34 _ 204~327 -tCH2)~-Br derivative by heating in hydrobromic acid.
These brominated compounds may be converted by reaction with sodium or potassium cyanide, in a solvent such as an alcohol or dimethyl sulfoxide, at a temperature of 0520 to 100 C, to derivatives of formula (XII) in which XR3 is -(CH2)~-CN; as previously, these compounds may be converted by hydrolysis and then by esterification to compounds of formula (XII) in which XR3 is -(CH2)~-COOR7. Catalytic hydrogenation of these nitriles may also give the compounds in which XR3 is -(CH~)n-CH2-NH~, which, by reaction with isocyanate or isothiocyanate, will give the compounds in which XR3 is the group -(CH2)~-CH2-NH-CO-NH-Rll or the group -(CH2)~-CH2-NH-CS-NH-Rll .
15Likewise, condensation of the brominated deri-vatives with ethyl acetamidomalonate, metalated before-hand with a sodium or potassium alcoholate in an alcohol under reflux, will give the compounds of formula (XII) in which XR3 will be ~ NH-COCH3 -(CH2)s C ~
¦ COOEt COOEt Hydrolysis and then decarboxylation of these compounds will make it possible to obtain the amino acids of formula (XII) in which XR3 is 30~NH2 -(CH2)s-CH
COOH
which may be esterified and/or converted to the amide according to methods known to those skilled in the art, ~ 35 ~ 20~327 for example by heating in an alcohol in the presence of thionyl chloride, or by reaction with an acid chloride, to give the derivatives of formula (XII) in which XR3 iB
~ NH2 , NH-COR6 -(CH2)s-CH or -(CH2)s-cH
CCX~R~ ~COOR7 The same reaction sequences may be applied to the derivatives of formula (XII') in which R'3 is a group -(CH2)n-OH, n being as defined above but other than zero, to give the derivatives in which R'3 is the same amino acid, amino ester or amido acid groups, it being possible here for the treatment of the alcohol to be carried out with thionyl chloride, leading to the chlorinated derivative, which will react like the above brominated derivatives with metalated ethyl acetamido-malonate.
In certain cases, the amine or acid groups may be protected by benzyloxycarbonyl groups for the amines or tert-butoxy groups for the acids, and then freed, if necessary, ~y hydrogenolysis or by treatment with tri-~luoroacetic acid according to the classical methods known to those skilled in the art.
The compounds of formulae (XII) and (XII') in which V is a nitro group may be sub~ected to catalytic hydrogenation, for example in the presence of Raney nickel, in an alcohol, at atmospheric pressure or under pressure, to give the compounds of formulae (XII) and (XII') in which V is an amino group.
Reaction of an appropriately substituted phthalic anhydride with this amine derivative will give the compounds of general formulae (I) and (I') in which R, is the group - , . : .
.-: '' ., ~ - -. . ' - 36 - 20~327 o Y
HN~
~DOC~
Y and Z being as defined above, it then heing possible for the acid obtained to be esterified to give the group O Y
HN~
R,2(X~
Likewise, reaction of a benzosulfonic anhydride with these amine compounds will give the compounds of general formulae (I) and (I') in which R4 is the group HO3S~
Likewise, reaction of N (trifluoromethylsul-fonyl)anthranilic acid chloride, whose preparation canbe found in the following references:
: - CA 96(I3) : 103~51Z, and - CA 97(7) : 55500W, ~ with these amine compounds will give the compounds of : 35 general formulae (I) and (I') in which R4 is the group _ 37 _ 204~327 - HN ~
The compounds of formulae (XII) and (XII') in which V is a group -COORl, may be hydrolyzed in an acid or basic medium, or hydrogenated in the case where R
is a benzyl so as not to affect the other ester groups present, to give the compounds of formulae (I) and (I') in which R, is a group -COO~.
After these acid derivatives have been conver-ted to the acid chloride with thionyl chloride or to a : 15 mixed anhydride with ethyl chloroformate, reaction with anthranilic acid derivatives of the formula y H2N~
,~_ R,2~0C
in which Y, Z and Rl2 are as defined above, will give the compounds of general fo~mulae (I) and (I') in which R~ is the group .
O Y
NH~, 30:
Z
The compounds o~ formulae ( XII ) and ( XII ' ) in : 35 which V is the group , ~ .
: ::
.... ,., ,. ,.,. . . . . : ~ .
.' .:
" - ' ' , . ~ , . , - . .
` ~ ' '' ' ': " ""' ' - 38 - ~0~1327 R,600C~
05 will likewise be hydrolyzed, or hydrogenated in the presence of a catalyst, such as palladium, in the case where Rl2 is a benzyl, to give the compounds of formu-lae tI) and (I') in which R~ is a group ~1 ~OC
The compounds of formulae (XII) and (XII') in which V is a group may react with one equivalent of sodium nitride in a solvent such as dimethylformamide, in the presence of an ammonium salt such as ammonium chloride, or by : . heating in toluene with trimethyltin nitride followed by treatment with gaseous hydrogen chloride in tetra-hydrofuran, to give the compounds of general formula (I) or (I') in which R4 is a group . ~ .
H
N~
,N
To carry out this reaction in the case where R3 or R'3 - -~ - , 20~:~327 contains an aliphatic alcohol group, it can be desira-ble to protect said group, according to the methods known to those skilled in the art, with an acetate or a t;etrahydropyran and then to free it, if necessary, 05 after formation of the tetrazole.
The compounds of formulae (XII) and (XII') in which V is a group ~3 ' ' may undergo catalytic hydrogenation, for example in the presence of Raney nickel, in an alcohol, at atmospheric pressure or under pressure, to give compounds of gene-ral formula (I) or (I') in which R4 is a group H2N ~
Reaction of trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride with the latter compounds in a solvent such as chloroform or in an aromatic solvent such as toluene, in the presence of a base such as triethylamine or pyridine, or in pyridine, will give the compounds of general formula (I) or (I') in which R~ is a group CF3SOzHNJ~
The compounds of formulae (XII) and (XII') in which V is the ~roup . .. . ..
20~327 N ~ S
may be treated with a trialkyltin nitride under reflux 05 in toluene, and then with gaseous hydrogen chloride in tetrahydrofuran, to give the derivatives of formula (I) or (I') in which R. is the group o N~
H
To carry out this reaction in the case where R3 or R'3 contains an aliphatic alcohol group, it can be desi-rable to protect said group, according to the methodsknown to those skilled in the art, with an acetate or a tetrahydropyran and then to free it, if necessary, after formation of the tetrazole.
The compounds of formulae (XII) and (XII') in which V is the group R.6 Ct s :~ 25 may be hydrolyzed, or hydrogenated in the presence of a catalyst, such as palladium-on-charcoal, in the case where Rl6 is a benzyl, to give the compounds of formula (I) in which R, is the group ~
HOOC~S
It is possible to obtain addition salts of some ~ ~o~ the compounds o~ formulae (I) and (I'), especially ;~ 35 pharmaceutically acceptable addition salts. In parti-..... ~ ;
'' 2~327 cular, when R2, R3, R'3 or R4 contains an acid group, there may be mentioned the salts of sodium, potassium, calcium, an amine such as dicyclohexylamine or an amino acid such as lysine. When R2, R3, R' 3 or R4 contains an 05 amine group, there may be mentioned the salts of a mineral or organic acid, such as the hydrochloride, methanesulfonate, acetate, maleate, succinate, fuma-rate, sulfate, lactate or citrate.
The novel compounds according to the invention lo possess remarkable pharmacological properties as angio-tensin II receptor antagonists and can be used in therapeutics for the treatment of cardiovascular diseases and in particular for the treatment of hyper-tension and cardiac insufficiency.
Thus the invention covers the pharmaceutical compositions which contain, as the active principle, the drugs consisting of a pharmaceutically effective amount of at least one compound of formula (I) or (I') as defined above, as well as its pharmaceutically acceptable addition salts if appropriate.
These compositions can be administered by the buccal, rectal, parenteral, percutaneous or ocular route.
These compositions can be solid or liquid and can take the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, gelatin capsules, granules, suppositories, injectable preparations, percutaneous systems and eye lotions. ~hey are prepared by the customary m~thods.
In said compositions, the active principle, consisting of a pharmaceutically effective amount of at least one compound o~ formula (I) or (I') as defined above, or one of its pharmaceutically acceptable addition salts, can be incorporated with excipients normally employed in these pharmaceutical compositions, such as talc, gum . ................ .
.
- 42 - 204~327 arabic, lactose, starch, magnesium stearate, polyvi-done, cellulose derivatives, cocoa butter, semisyn-thetic glycerides, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, glycols, various 05 wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavorings and colors.
The invention also covers a pharmaceutical com-position with antagonistic activity towards angiotensin II receptors, which makes it possible especially to favorably treat cardiovascular diseases, in particular hypertension and cardiac insufficiency, said composi-tion comprising a pharmaceutically effective amount of at least one compound of formula (I) or (I') mentioned above, or one of its pharmaceutically acceptable addition salts, which may be incorporated in a pharma-ceutically acceptable excipient, vehicle or carrier~
The dosage varies especially according to the route of administration, the complaint treated and the subject in question.
For example, for an adult with an average weight of 60 to 70 kg, it can vary between 1 and 400 mg of active principle, administered orally in one or more daily doses, or from 0.01 to 50 mg, administered paren-terally in one or more daily doses.
The invention also covers a method of preparinga pharmaceutical composition, which comprises incor-porating a pharmaceutically effective amount of at least one compound of formula (I) or (I') as defined above, or one of its pharmaceutically acceptable addition salts, into a pharmaceutically acceptable excipient, vehicle or carrier, this pharmaceutical composition being formulated for example as gelatin capsules or tablets containing from 1 to 400 mg of active ingredien~, or as injectable preparations - 43 ~ 20 4~327 containing from 0.01 to 50 mg of active ingredient.
The invention also covers a method of thera-peutic treatment for mammals, which comprises adminis-tering to this mammal a therapeutically effective 05 amount of at least one compound of formula (I) or (I') as defined above, or one of its pharmaceutically acceptable addition salts.
In animal therapeutics, the daily dose which can be used should normally be between 1 and lO0 mg per kg.
Further characteristics and advantages of the invention will be understood more clearly from the following description of some Preparatory Examples, which in no way imply a limitation but are given by way of illustration.
: 35 - 44 - 204~327 ~Example 1: Ethyl 3-oxohexanoate Pormula (II): R~ = n-propyl, RL3 = ethyl 05 176 g of 2,2-dimethyl-4,6-dioxo-1,3-dioxane (Meldrum's acid) are dissolved in 550 ml of methylene chloride and 188 ml of pyridine. The mixture is cooled to 0C with a bath of water and ice and 133 ml of butyryl chloride are added dropwise. When the addition is complete, the mixture is stirred for three hours at room temperature. The solution is washed with a dilute solution of hydrochloric acid, dried over magnesium sulfate and evaporated under vacuum to give an oil.
This oil is dissolved in 700 ml of ethanol and the mixture is refluxed for six hours. The ethanol is evaporated off under vacuum and the residue obtained is distilled to give 145.4 g of ethyl 3-oxohexanoate in the form of a liquid of b.p.20 = 98-100 C.
Example 2: ~thyl 3-oxoheptanoate Formula (II): R, = n-butyl, ~13 = ethyl Prepared by the procedure of Example 1.
Li~uid of b.p.20 = 115-120C.
E8~LDiL~: Ethyl 2-(4-nitrobenzyl)-3-oxohexanoate Formula (Yl): Rl = n-propyl, V = N02, R,3 =
ethyl 127.7 g of ethyl 3-oxohexanoate are dissolved in 700 ml of tetrahydrofuran. 174.5 g of 4-nitrobenzyl bromide and 35 g of lithium chloride are added and the mixture is stirred at room temperature. 286 ml of ~ 45 ~ 204~327 diisopropylethylamine are then added dropwise, causing a slight exothermic effect. The mixture is subse-quently stirred for three hours at room temperature and then for ten hours under reflux. The solvents are 05 evaporated off under vacuum and the residue is taken up with water and then extracted with chloroform. The organic phase is decanted and then washed with a dilute solution of hydrochloric acid, dried over magnesium sulfate and evaporated under vacuum. The oily residue obtained is taken up with isopropyl ether and the crys-tals formed are filtered off. The mother liquors are concentrated under vacuum and the residue is heated under 20 mm of mercury at 130C in order to eliminate the residual starting materials. This gives 174 g of ethyl 2-(4-nitrobenzyl)-3-oxohexanoate in the form of an oil, which is used as such for the next step.
Example 4: Ethyl 2-(4-nitrobenzyl)-3-oxoheptanoate Formula (YI): R1 = n-butyl, V = NO2, Rl3 =
ethyl Prepared by the procedure of Example 3.
Oil used as such for the next step.
ExamDle 5: ~thyl 2-(2'-methoxycarbonylbiphenyl-4-yl)-methyl-3-oxohexanoate Formula ~VI): Rl = n-propyl, V - ~ , MeO2C
Rl3 = ethyl Prepared by the procedure of Example 3 from ethyl 3-oxohexanoate, prepared in Example 1, and methyl , .. ..... . .
.
' _ 46 - 20~)327 (4'-bromomethylbiphenyl-2-yl)carboxylate.
Oil used as such for the next step.
Preparation of methyl (4'-bromomethylbiphenyl-2-yl)car-05 boxylate A) Methyl (4'-methylbiphenyl-2-yl)carboxylate 15 ml of acetyl chloride are added to 300 ml of methanol cooled to 0C. The mixture is stirred for 10 minutes at this temperature and 15 g of (4'-methylbi-phenyl-2-yl)carboxylic acid, prepared according to MEYERS A.I.; MIHELICH E.D., J. Am. Chem. Soc., 1975, 97(25), 7383, by reacting (4-methylphenyl)magnesium bromide with 2-(2-methoxyphenyl)-4,4-dimethyloxazo-lidine, are then added. The mixture is subsequentlyrefluxed for 4 hours and the solvents are evaporated off under vacuum to give 16 g of methyl (4'-methylbi-phenyl-2-yl)carboxylate in the form of an oil, which is used as such for the next step.
B) Methyl (4'-bromomethylbiphenyl-2-yl)carboxylate 16 g of methyl (4'-methylbiphenyl-2-yl)car-boxylate, prepared in A), are dissolved in 120 ml of carbon tetrachloride in the presence of 12.6 g of N-bromosuccinimide and 0.5 g of benzoyl peroxide. Themixture is refluxed for 6 hours, the crystals are fil-tered off and the remaining solution is washed with a solution of sodium bicarbonate and then evaporated under vacuum. The residue is taken up with ether and the solution is then filtered on charcoal and evapo-rated under vacuum to give 14.5 g of methyl (4'-bromo-methylbiphenyl-2-yl)carboxylate in the form of an oil, which is used as such for the next step.
2 ~J ~ r~) 3 2 7 E,xample 6: Ethyl 2-(2'-cyanobiphenyl-4-yl)methyl-3-oxohexanoate Formula (VI): R1 = n-propyl, R13 = ethyl, V= ~3 Prepared by the procedure of Example 3 from 4'-bromomethyl-2-cyanobiphenyl.
Oil used as such for the next step.
Preparation of 4'-bromomethyl-2-cyanobiphenyl A) 4'-Methyl-2-cyanobiphenyl 18.5 g of (4'-methylbiphenyl-2-yl)carboxylic acid, prepared as in Example 5A), are refluxed in 60 ml of thionyl chloride for two hours. The thionyl chlo-ride is concentrated under vacùum, the residue ispoured into a 28~ solution of ammonium hydroxide, the mixture is stirred for 30 minutes and the crystals obtained are filtered off, washed with ether and then dried to give 14.5 g of (4'-methylbiphenyl-2-yl)car-boxamide in the form of crystals melting at 128 C.
: These crystals are taken up in 50 ml of thionyl chlo-ride and the mixture is refluxed for 3 hours and then concentrated under vacuum to give 9 g of 4'-methyl-2-cyanobiphenyl in the form of crystals melting at 45-46C.
~ B) 4'-Bromomethyl-2-cyanobiphenyl : 7.9 g of 4'-methyl-2-cyanobiphenyl, prepared in A), are dissolved in 100 ml of carbon tetrachloride in tne presence of 7.3 g of N-bromosuccinimide and 0.3 g `
':
.
204a327 of benzoyl peroxide. The mixture is refluxed for 6 hours, the crystals are filtered off, the remaining solution is concentrated under vacuum and the residue is crystallized from ether to give 6.6 g of 4'-bromo-05 methyl-2-cyanobiphenyl in the form of crystals melting at 115-118C.
Example 7: 6-n-Propyl-2-methyl-4-hydroxy-5-(4-nitro-benzyl)pyrimidine Formula (XI): Rl = n-propyl, R2 = methyl, T = OH, V = NO2 3.5 g of sodium are dissolved in 175 ml of ethanol. 9.5 g of acetamidine hydrochloride are added to this solution and the mixture is stirred for five minutes at room temperature. 20 g of ethyl 2-(4-nitro-benzyl)-3-oxohexanoate, prepared in Example 3, are then added and the mixture is stirred for four days at room temperature. The solvents are then evaporated off under vacuum and the residue is taken up with a solu-tion of hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated under vacuum to give an oily residue, which crystallizes from an acetone/ether mixture. The crystals are filtered off and dried to give 10.9 g of 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of orystals melting at 200C.
Exam~le 8: 6-n-Butyl-2-methyl-4-hydroxy-5-(4-nitro-benzyl)pyrimidine Formula (XI): R1 = n-butyl, R2 = methyl, T = OH, V = NO2 ~ 49 - 204~32~
Prepared by the procedure of Example 7.
Crystals melting at 205C.
Example 9: 6-n-Propyl-2-methyl-4-hydroxy-s-(2~-methoxy-05 carbonylbiphenyl-4-yl)methylpyrimidine ~, Formula (XI): R~ = n-propyl, V = ~ , MeO2C
R2 = methyl, T = OH
Prepared by the procedure of Example 7.
Crystals melting at 206C.
Example 10: 6-n-Propyl-2-methyl-4-hydroxy-5-(2'-cyano-biphenyl-4-yl)methylpyri~idine Formula (XI): Rl = n-propyl, R2 = methyl, T = OH, V =
: Prepared by the procedure of Example 7.
Crystals melting at 206C.
Exam~le 11: Ethyl [4-n-propyl-2-methyl-5-(4-nitro-kenzyl)-6-oxopyrimidin-1(6H~-yl]acetate Formula (XII')~ Rl = n-propyl, R2 = methyl, R' 3 = CH2cOzEt ~ V = N2 4 g of 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 7, are dis-solved in 30 ml of anhydrous N,N-dimethylformamide.
- 50 - 20~327 0.6 g of 60% sodium hydride is added and the mixture is stirred for thirty minutes at room temperature. 2 ml of ethyl bromoacetate are then added and the mixture is subsequently heated at 60C for one hour. After cool-05 ing, 200 ml of water are added, the solution is extrac-ted with ether and the organic phase is dried over mag-nesium sulfate and evaporated under vacuum to give a residue, which crystallizes from an ether/pentane mix-ture to give 2 g of ethyl ~4-n-propyl-2-methyl-5-(4-lo nitrobenzyl)-6-oxopyrimidin-1(6H)-yl]acetate in the form of crystals melting at 120C.
Example 12: Ethyl [4-n-propyl-2-methyl-5-(4-amino-benzyl)-6-oxopyrimidin-1(6H)-yl~acetate Formula (XII'): Rl = n-propyl, R2 = methyl, R' 3 = CH2C02Et ~ V = NH2 2 g of ethyl [4-n-propyl-2-methyl-5-(4-nitro-benzyl)-6-oxopyrimidin-1(6H)-yl]acetate, prepared in Example 11, are dissolved in 25 ml of ethanol in the presence of 0.5 g of Raney nickel and hydrogenated under atmospheric pressure and at room temperature.
When the uptake of hydrogen has ceased, the catalyst is filtered off and the ethanol is evaporated off under vacuum to give 1.8 g of ethyl [4-n-propyl-2-methyl-5-(4-aminobenzyl)-6-oxopyrimidin-1(6H)-yl]acetate in the form of an oil, which is used as such for the next step.
Ex~m~le 13: Ethyl [4-n-propyl-2-methyl-6-oxo-5-t4-~2-sulfoxyphenyl)carbonyla~inophenylmethyl]-pyrimidin-1(6H)-yl]acetate Formula (I'): R~ = n-propyl, R2 = methyl, .
, .
:
- 51 ~ 20~327 R' 3 = CH2C02Et, o R~ = N H~
1 g of ethyl [4-n-propyl-2-methyl-5-(4-amino-benzyl)-6-oxopyrimidin-1(6H)-yl]acetate, prepared in Example 12, is dissolved in lO ml of acetonitrile. A
solution of 0.6 g of sulfobenzoic anhydr~de in 5 ml of acetonitrile is added and the mixture is left to stand for one day at room temperature. ~he crystals formed are filtered off, washed with acetonitrile and then with ether and dried to give 0.9 g of ethyl t4-n-propyl-2-methyl-6-oxo-5-[4-(2-sulfoxyphenyl)carbonyl-aminophenylmethyl]pyrimidin-1(6H)-yl]acetate in the form of crystals melting at 268-269C.
Example 14: ~4-n-Propyl-2-methyl-6-oxo-5-t4-12-carboxy-~: 3,6-dichlorophenyl)carbonylaminophenyl-methyl]pyrimidin-1(6H)-yl~acetic acid Foroula (I'): R~ = n-propyl, R2 = methyl, R'3 = CH2C02H, ~, O C l : R~ = N H~
::::
1.1 g o~ ethyl ~4-n-propyl-2-methyl-5-(4-amino-~ benzylj-6-oxopyrimidin-1(6H)-yl]acetate, prepared in :~ ~ 35 :Example 12, are dissolved in 10 ml of acetonitrile in :~ :
~ ' .
. .
- 52 - 20~.~327 the presence of 0.7 g of 3,6-dichlorophthalic anhy-dride. The mixture is left to stand at room tempera-ture overnight and the acetonitrile is evaporated off under vacuum without excessive heating. The residue 05 obtained is taken up in water in the presence of 0.6 g of sodium hydroxide pellets and stirred for 30 minutes at 45 C. The solution is then neutralized with concen-trated hydrochloric acid and the crystals obtained are filtered off, washed with water and then dried to give 0.6 g of [4-n-propyl-2-methyl-6-oxo-5-[4-~2-carboxy-3,6-dichlorophenyl)carbonylaminophenylme~hyl]pyrimidin-1(6H)-yl]acetic acid in the form of crystals melting at 167-168 c.
Example 15: 6-n-Propyl-2-methyl-4-hydroxyethoxy-s-(2~-methoxycarbonylbiphenyl-4-yl3methylpyri-midine ~ormula (I): Rl = n-propyl, R2 = methyl, R3 - CH2CH20H, X = 0, R. =
MeO2C
5.5 g of 6-n-propyl-2-methyl-4-hydroxy-5-(2'-methoxycarbonylbiphenyl-4-yl)methylpyrimidine, prepared in Example 9, are dissolved in 50 ml of acetonitrile in the presence of 3 g o~ potassium car~onate and 0.3 g o~
triethylbenzylamine hydrochloride. 2 ml of 2-bromo-ethanol are added and the mixture is refluxed for ten hours. The solvent is evaporated off to dryness and the residue is taken up with water and then extracted with ether. The organic phase is dried and then eva-porated to dryness and the oily residue obtained is _ 53 - 20~327 chromatographed on silica in ether to give 3 g of 6-n-propyl-2-methyl-4-hydroxyethoxy-5-(2'-methoxyGarbo-nylbiphenyl-4-yl)methylpyrimidine in the form of a colorless oil, which is used as such for the next step.
Example 16: 4'-[6-n-Propyl-2-methyl-4-hydroxyethoxy-pyrimidin-5-yl]methylbiphenyl-2-carboxylic acid Formula (I): Rl = n-propyl, R2 = methyl, R3 = CH2CH,OH, X = 0, ~.= 1 11 1.8 g of 6-n-propyl-2-methyl-4-hydroxyethoxy-5-(2'-methoxycarbonylbiphenyl-4-yl)methylpyrimidine, pre-pared in Example 15, are dissolved in 20 ml of ethanol.
A solution of 1 g of sodium hydroxide in 10 ml of dis-tilled water is added and the mixture is heated at 50 C
for two hours. The solvents are evaporated off to dry-ness and the residue is taken up with water and washed with ethyl acetate. The aqueous phase is acidified by having sulfur dioxide bubbled through it, and is extracted with chloroform. ~he organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. ~he residue obtained crystallizes Prom i~o-propyl ether to give 1.2 g of 4'-[6-n-propyl-2-methyl-4-hydroxyethoxypyrimidin-5-yl]methylbiphenyl-2-carboxy-lic acid in the form of crystals melting at 143-144C.
_ 54 _ 2 ~4a3 Example 17: [4-n-Propyl-2-methyl-6-oxo-5-(4-nitro-benzyl)pyrimidin-1(6H)-yl]acetylmorpholine Formula (XII'~: Rl = n-propyl, R2 = methyl, R'3 = CH2 CON~ O
Prepared by the procedure of Example 11 from N-(chloroacetyl)morpholine and 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 7.
Crystals melting at 174C.
Example 18: [4-n-Propyl-2-methyl-6-oxo-5-(4-amino-benzyl)pyrimidin-1(6H)-yl]acetylmorpholine Formula (XII'): R~ = n-propyl, R2 = methyl, R'3 - CH2 CON~O
V = NH~
Prepared by the procedure of Example 12 Crystals melting at 160DC.
Exam~le 19: 6-n-Propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine Formula (XII): Rl = n-propyl, R, = methyl, ' . :
,.
_ 55 _ 20~327 XR3 = Cl, V = NO2 32 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-hydroxypyrimidine, prepared in Example ?, are suspen-05 ded in 45 ml of phosphorus oxychloride. The mixture isrefluxed for 6 hours and then concentrated under vacuum. The residue is taken up with water and extrac-ted with methylene chloride. The organic phase is washed with a solution of potassium carbonate and then dried over magnesium sulfate and evaporated to dryness to give 24 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine in the form of crystals melting at 65 C.
Example 20: 6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine Formula (XII): Rl = n-butyl, R2 = methyl, XR3 = Cl, ~ = NO2 Prepared by the procedure of Example 19.
Crystals melting at 45C.
Example 21: 6-n-Propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-chloropyrimidine Formula (XII): Rl = n-propyl, R~ - methyl, XR, = C1, V =
Prepared by the procedure of Example 19.
Crystals melting at 95C.
, ' ,, ' ~ , .
- 56 - 2 0 ~3 3 2 7 Example 22: ~thyl 16-n-propyl-2-methyl-5-~4-nitro-~enzyl)pyrimidin-4-yl]mercaptoacetate Formula (XII): Rl = n-propyl, R2 = methyl, 05 X = S, R3 = CH2CO2Et, V =
4 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine and 1.9 g of ethyl mercaptoacetate are dissolved in 50 ml Or ethanol. 1.2 g of anhydrous sodium acetate are added and the mixture is stirred for 6 hours at room temperature and then for 6 hours under reflux. The ethanol is evaporated off under vacuum and the residue is taken up with water and then extracted with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum to give an oil, which crystallizes from a pen-tane/isopropyl ether mixture to give 2.9 g of ethyl [6-n-propyl-2-methyl-5-(4-nitrobenzyl)pyrimidin-4-yl~-mercaptoacetate in the form of crystals melting at 66-67C.
xample 23: Ethyl [6-n-propyl-2-methyl-5-(4-amino-benzyl)pyrimidin-4-yl]mercaptoacetate Formula (XII): R~ = n-propyl, R2 ~ methyl, X - S, R3 - CH,CO,Et, V -NH, Prepared by the procedure of Example 12.
Oil used aB such for the next step.
.
, . . .
~. . .
, _ 57 _ 20~;~3 2 Exa~ple 24: 2-[[6-n-Propyl-2-methyl-4-(ethoxycarbonyl-methylmercapto)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid 05Formula (I): Rl - n-propyl, R2 = methyl, R3 = CH2C02Et, X = S, O
R, = NH ~
0 HO3SJ~J
Prepared by the procedure of Example 13.
Crystals melting at 252-253C.
Example 25: 6-n-Propyl-2-~ethyl-4-(N,N-dimethyla~ino-carkonyloxy)-5-(4-nitrobenzyl)pyrimidine Form~la (XII): Rl = n-propyl, R~ = methyl, X = o, R3 = C~-N'cH3 V = NO2 g of 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 7, are dissolved in 100 ml of methylene ahloride in the presenae of 2.6 ml of triethylamine. 1.7 ml of N,N-dimethylcarbamoyl chloride are added and the mixture isrefluxed for 12 hours. After cooling, the solution is washed with a dilute solution of hydrochloric acid, dried over magnesiu~ sulfate and evaporated to dryness.
The residue is chromatographed on silica gel, in ~he eluent methylene chloride 9/acetone 1, to give 3.1 g of : '' ' . . ' :
.`
- 58 - 20~32 7 6-n-propyl-2-methyl-4-(N,N-dimethylaminocarbonyloxy)-5-~4-nitrobenzyl)pyrimidine in the form of crystals melt'ng at 110C.
05 xample 26: 6-n-Propyl-2-methyl-4-(N,N-dimethylamino-carbonyloxy)-5-(4-aminobenzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, o CH3 X = O, R3 = C~ ~CH3 V = NH2 Prepared by the procedure of Example 12.
oi 1 used as such for the next step.
ExamDle 27: 2-[[6-n-Propyl-2-methyl-4-(N,N-dimethyl-aminocarbonyloxy)pyrimidin-5-yl]methyl-phenyl-4-yl]a~inocarbonylbenzenesulfonic acid Formula (I): R~ = n-propyl, R2 = methyl, X = O, R = C~-R, =
Prepared by the procedure of Example 13.
Crystals melting at 215-218C.
, . .. . .
.
' - 59 - 20~ ~327 F.xample 28: Ethyl [4-n-propyl-2-methyl-6-oxo-5-(2'-cyanobiphenyl-4-yl)~ethylpyri~idin-1(6H)-yl]acetate 05 Formula (XII'): R1 = n-propyl, R2 ~ methyl, R' 3 = CH2C02Et ~
~, V=
~
Prepared by the procedure o~ Example 11.
Crystals melting at 98C.
Example 29: Ethyl ~6-n-propyl-2-methyl-5-(2'-cyanobi-phenyl-4-yl)methylpyrimidin-4-yl]mercapto-acetate Formula (XII): R, = n-propyl, R2 = methyl, R3 = CH2C02Et, X = S, V=
Nt;~
Prepared by the procedure of Example 22.
oi 1 used as such ~or the next step.
Example 30: 6-n-Propyl-2-methyl-4-methoxy-5-(2'-cyano-biphenyl-4-yl)methylpyrimidine Formula (XII): R, = n-propyl, R2 = methyl, R3 = methyl, X = 0, ~ ' ', 20~ :~3 2 7 V= I IJ
05 12 g of 6-n-propyl-2-methyl-4-chloro-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, prepared in Example 21, are dissolved in 100 ml of methanol. 1.2 g of sodium dissolved in 20 ml of methanol are added and the mixture is stirred for 3 hours at room temperature, then for one hour at 40C and finally for one hour under reflux. The reaction mixture is concentrated, water is then added and the resulting mixture is extracted with isopropyl ether. The organic phase is dried and then evaporated under vacuum and the residue obtained crystallizes from an isopropyl ether/pentane mixture to give 8.9 g of 6-n-propyl-2-methyl-4-methoxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine in the form of crystals melting at 108C.
Example 31: 6-n-Propyl-2-methyl-4-methoxy-5-[2'-(tetrazol-s-yl)biphenyl-4-yl]methylpyri~i-dine : Formula (I): R~ = n-propyl, R2 = methyl, R3 = methyl, X = 0, R~ ~ H~
~N
:
8.9 g of 6-n-propyl-2-methyl-4-methoxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, prepared in Example 30, and 6.3 g of trimethyltin nitride are .
2~ .327 refluxed for 12 hours in 100 ml of toluene. The crys-tals obtained are filtered off hot to give 6.6 g of 6-n-propyl-2-methyl-4-methoxy-5-[2'-(1-trimethylstannyl-tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine in the 05 form of crystals melting at 235C. These crystals are dissolved in a toluene/THF mixture (60 ml/10 ml) and treated with gaseous hydrogen chloride for one hour at room temperature. The mixture is concentrated, taken up with chloroform and then washed with water. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give an oil, which crystal-lizes from an ether/acet.,ne mixture to give 4.2 g of 6-n-propyl-2-methyl-4-methoxy-5-[2'-(tetrazol-5-yl)-biphenyl-4-yl]methylpyrimidine melting at 132-4 C.
~xam~le 32: Ethyl [4-n-propyl-2-methyl-6-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyri-midin-1(6~)-yl]acetate Formula (I'): R1 = n-propyl, R2 = methyl, R' 3 = CHzC02Et, R~ = H~
~N' Prepared by the procedure of Example 31.
Crystals melting at 164-5C.
Exam~l~ 33: ~thyl [6-n-propyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-7-yl]~ethylpyrimidin-4-yl]-mercaptoacetate Formula (I): Rl = n-propyl, R~ - methyl, 62 -- 2 0 Ll ~ 3 2 7 X = S, R3 = CH~C02Et, ~ ' .
R. = H~
~N,N
Prepared by the procedure of Example 31.
Crystals melting at 137-8C.
~3m~1e 34: 2-[6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]mercaptoethanol .
Formula (XII): Rl - n-butyl, R2 = methyl, X = S, R3 = CH2CH20H, V =
10 g of 6-n-butyl-2-methyl-5-t4-nitrobenzyl)-4-chloropyrimidine, prepared in Example 20, are dissolved in 150 ml of butan-2-one. 7 g of potassium carbonate and 3.7 g of 2-mercaptoethanol are added and the mixture is refluxed for 6 hours. After concentration of the solvent under vacuum, the residue is ~aken up .
:~ with water and then extracted with ether and the ; 25 organic phase is washed wi~h water and then dried over magnesium sulfate and evaporated to dryness to give a residue, which crystallizes from isopropyl ether to give 5.5 g o~ 2-[6-n-butyl-2-methyl-5-t4-nitrobenzyl)-pyrimidin-4-yl]meroaptoethanol melting at 65C.
~0 ~:~ Exàmple 35: 2-16-n-Propyl-2-methyl-5-(~-nitr~enzyl)- .
pyri~idin-4-yl]mercaptoethanol For~ula (XII): R1 = n-propyl, R2 = methyl, X = S, R3 = CH2CH20H, `,~: .
.~,.,.,.. , ....... ~ :
.
- 63 - 20 4 ~)327 V = NO2 Prepared by the procedure of Example 34.
Crystals melting at 110C.
Example 36: ~thyl [6-n-butyl-2-methyl-5-(4-nitro-benzyl)pyrimidin-4-yl]mercaptoa~etate Pormula (XII): R~ = n-butyl, R2 = methyl, X = S, ~ = CH2C02Et, V =
N0~
Prepared by the procedure of Example 22.
Oil used as such for the next step.
Example 37: 6-n-Butyl-2-methyl-4-amino-5-(4-nitro-benzyl)pyrimidine Formula (XII): R1 = n-butyl, R2 = methyl, XR3 = NH2, V = N02 25.4 g of 6-n-butyl-2-methyl-4-chloro-5-(4-nitrobenzyl)pyrimidine, prepared in Example 20, are heated in 400 ml of ammoniacal methanol at 170C for 12 : 25 hours in an autoclave. After cooling, the solution is evaporated under vacuum and the residue obtained is ; taken up with water and then extracted with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated under vacuum. ~he res~due obtained crystallizes from ether to give 15.4 g of 6-n-butyl-2-methyl-4-amino-5-(4-nitrobenzyl)pyrimidine in the form or crystals melting at 135C.
`~ 35 . . .
.
, - 64 - 20~1327 Ex,ample 38: 6-n-Propyl-2-methyl-4-amino-5-(4-nitro-benzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, 05 XR3 = NH2, V = N02 Prepared by the procedure of Example 37.
Crystals melting at 152~C.
ExamDle 3~: N-[6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]morpholine Formula (XII): Rl = n-butyl, R2 = methyl, V = N02, XR3 = ~ O
8 g of 6-n-butyl-2-methyl-4-chloro-5-(4-nitro-benzyl)pyrimidine, prepared in Example 20, are dis-solved in 100 ml of xylene. 10 ml of morpholine are added and the,mixture is refluxed for 16 hours. After cooling, the xylene is evaporated off under vacuum and the residue is taken up with ether and washed with a dilute solution of sodium hydroxide and then with water. The ether phase is dried over magnesium sulfate and evaporated under vacuum to give a residue, which crystallizes from isopropyl ether to give 5 ~ of N-C6-n-butyl-2-methyl-5-(4-nitrobenzyl)pyrimidin-4-yl~-morpholine in the form of crystals melting at 124C.
Exam~le 40: N-l6-n-Propyl-~-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]~orpholine Formula (XII): Rl = n-propyl, R2 = methyl, V = NOz, , . . .
- 65 - 20~327 XR3 = N~O
05 Prepared by the procedure of Example 39.
Crystals melting at 125C.
Example 41: N-~6-n-Propyl-2-methyl-5-(4-nitrobenzyl)-pyri~idin-4-yl]thiomorpholine Formula (XII): R1 = n-propyl, R2 = methyl, V = NO2, XR3 = N~ S
Prepared by the procedure of Example 39.
Crystals melting at 133C.
Exam~le 42: 4-t6-n-Propyl-2-methyl-5-(4-nitrobenZyl)-pyrimidin-4-yl]-1-(2-methoxyphenyl)pipera-zine Formula (XII): Rl = n-propyl, R2 = methyl, : 25 V = N02, XR3 =
Cl-bO
Prepared by the procedure of Example 39.
Crystals melting at 110C.
:~:
... , . ,, ~
' . . .~
.
- 66 - 20453~7 E~am~le 43: 6-n-Propyl-2-methyl-5-(4-nitrobenzyl)-4-mercaptopyri~i~ine Formula (XII): R~ = n-propyl, R2 = methyl, 05 XR3 = SH, V = N02 24 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine, prepared in Example 19, and 5.5 g of thiourea are refluxed for 6 hours in 75 ml of ace-tone in the presence of 0.05 ml of concentrated hydro-chloric acid. The crystals obtained are filtered off, washed with acetone and then taken up in a mixture com-posed of 150 ml of ethanol, 150 ml of water and 25 g of sodium hydroxide pellets. The mixture is refluxed for 5 hours, the solvents are then evaporated off under vacuum, the residue is taken up with water and then acidified with concentrated hydrochloric acid and the crystals obtained are fi tered off and washed with water to give 12 g of 6-n-propyl-2-methyl-5-(4-nitro-benzyl)-4-mercaptopyrimidine melting at 212 C.
Exam~le 44: 6-n-Propyl-2-methyl-4-methylthio-5-(4-nitrobenzyl)pyrimidine Fornula (XII): Rl = n-propyl, R~ = methyl, XR3 = SCH3, V = N0, 4 g of 6-n-propyl-2-methyl-4-mercapto-5-~4-nitrobenzyl)pyrimidine, prepared in Example 43, are dissolved in 75 ml of ethanol. 0.6 g of sodium hydrox-ide dissolved in 10 ml of water is added and the mixture is stirred at room temperature for a few mlnutes. 1.5 ml o~ methyl iodide are then added to the reaction medium and tha solution is stirred for 2 hours ;~ 35 at room temperature and then for 2 hours under reflux.
., .. "~,., . , . . - :
- ' ' . , ., . . ~ .
, - 67 - 20~ ~327 After evaporation of the solvents under vacuum, the rlesidue is taken up with water and then extracted with ether; the ether phase is dried over magnesium sulfate and then evaporated to dryness to give 3.7 g of 6-05 n-propyl-2-methyl-4-methylthio-5-(4-nitrobenzyl)pyrimi-dine in the form of an oil, which is used as such for the next step.
~xample 45: 2-t6-n-Propyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yl]mercaptoethanol Formula (XII): Rl = n-propyl, R2 = methyl, R3 = CH2CH2OH, X = S, V =
Prepared by the procedure of Example 12.
Oil used as such for the next step.
Example 46: N-[6-n-Propyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yl]morpholine Pormula (XII): R, = n-propyl, R2 = methyl, V = NH2, XR3 = N O
Prepared by the procedure of Example 12.
Oil used as such for the next step.
Exam~le 47: N-[6-n-Propyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yl;thio~orpholine Formula (XII): R1 = n-propyl, R2 = methyl, - 68 - 20 ~ e~2~
V = NH2, XR3 = N S
05 Prepared by the procedure of Example 12.
Oil used as such for the next step.
Example 48: 4-[6-n-Propyl-2-methyl-s-(4-aminobenzyl)-pyrimidin-4-yl]-l-(2-methoxyphenyl)pipera lo zine Formula (XII): R1 = n-propyl, R2 = methyl, V = NH2, XR3 = N N~
\ \=:/
Prepared by the procedure of Example 12.
Oil used as such for the next step.
Exam~le 49: B~hyl ~6-n-butyl-2-methyl-5-[4-amino-benzyl)pyrimidin-4-yl]mer~aptoacetate Formula (XII): R, = n-butyl, R2 = methyl, V = NH2, R3 = CH~CO~Et, X - S
Prepared by the procedure o~ Example 12.
Oil used as such for the next step.
Exam~le:50: 2-16-n-Butyl-2-methyl-5-(4-aminoben~yl)-pyrimidin-4-yl]mercaptoethanol Formula (XII): R1 - n-butyl, R2 = methyl, ~,~
, . ~
~ .
69 20~ ~327 V = NHz, R3 = CH2CH20H, X = ~
Prepared by the procedure of Bxample 12.
05 Oil used as such for the next step.
Example 51: 6-n-Propyl-2-methyl-4-thiomethyl-5-(4-aminobenzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, V = NH2, XR3 = SCH3 Prepared by the procedure of Example 12.
Oil used as such for the next step.
Example 52: 6-n-Butyl-2-methyl-4-amino-5-(4-amino-kenzyl)pyrimidine Formula ~XII): Rl = n-butyl, R2 = methyl, V = NH2, XR3 = NH2 Prepared by the procedure of Example 12.
Oil used as such for the next step.
Xxample S3: 6-n-Propyl-2-methyl-4-amino-5-(4-amino-benzyl)pyrimidine Formula (XII): R~ = n-propyl, R, = methyl, V = NHz, XR3 = NH2 Prepared by the procedure of Example 12.
Oil used as such for the next step.
.:
~ 70 - 20~327 E~ L~-~: 2-[(6-n-Propyl-2-methyl-4-hydroxyethyl-mercaptopyrimidin-5-yl)methylphenyl-4-yl]-aminocarbonylbenzenesulfonic acid 05 Formula (I): R~ = n-propyl, R2 = methyl, R3 = CH2CH20H, X = S, N~OO~
R~
HO3S~
Prepared by the procedure of Example 13.
Crystals melting at 226-8C.
15 Example 55: 2-[(6-n-Butyl-2-methyl-4-hydroxyethyl~er-captop~rimidin-5-yl)methylphenyl-4-yl]-a~inocarbonylbenzenesulfonic acid Formula (I): Rl = n-butyl, R2 = methyl, R3 = CH2CH20H, X = S, N~OO~, R4 =
~03 Prepared by the procedure of Example 13.
Crystals melting at 198-9C.
~x~m~le 56: 2-~[6-n-propyl-2-methyl-4-(morpholin-l-yl) pyrimidin-s-yl]methylphenyl-4-yl]amino-carbonyl~enzenesulfonic acid Formula (I): Rl - n-propyl, R2 = methyl, .
20~ :~?32 7 XR3 = ~ 0, R4 =
Prepared by the procedure of Example 13.
Crystals melting at 213-6C.
Example 57: 2-[~6-n-Butyl-2-methyl-4-aminopyri~idin-5-yl)methylphenyl-4-yl]aminocarbonylbenzene-sulfonic acid Formula tI~: Rl = n-butyl, R2 = methyl, XR3 = NH2, R~
HO3S~
Prepared by the procedure of Example 13.
Crystals melting at 239-240Co lç_g~: 2-[~6-n-propyl-2-methyl-4-t(2-methoxy-phenyl)piperazin-4-yl)pyrimidin-5-yll-: ~ethy}phenyl-~-yl]aoinocarbonylbenzenesul-fonic acid ,:
Formula (I): Rl ~ n-propyl, R~ ~ methyl, XR3 = ~N~, ~; OCH3 R, =
.
-` ' ' -;, . .
. . ' .
- 72 - 20~327 Prepared by the procedure of Example 13.
Crystals melting at 215-7C.
Exam~le S~: 2-[[6-n-Propyl-2-methyl-4-methylthiopyrimi-05 din-5-yl]methylphenyl-4-yl]aminocarbonyl-benzenesulfonic acid Formula (I): Rl = n-propyl, R2 = methyl, N~OO
XR3 = SC~3, R, =
Prepared by the pr~cedure of Example 13.
Crystals melting at 254-7C.
ExamDle 60: 2-t[6-n-Propyl-2-methyl-4-(thiomorpholin-4-yl)pyrimidin-5-yl]methylphenyl-4-yl]amino-carbonylbenzenesulfonic acid Formula (I): Rl = n-propyl, R2 = methyl, x~ = N/ \S . R~
Prepared by the procedure of Example 13.
Cry tal~ melting at 207-210C.
Exam~le 61: 2-tt6-n-Butyl-2-methyl-4-(ethoxycarbonyl-~ethylthio)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rl = n-butyl, Rl = methyl, 20~327 X = S, R3 = CH2CO~Et, N~CO~
R~
05 HO3$~
Prepared by the procedure of Example 13.
Crystals melting at 262-3C.
Exam~le 62: 2-[t6-n-Propyl-2-methyl-4-(ethoxycarkonyl-methylthio)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonyl-3-methylkenzenesulfonic acid Formula (I): R1 = n-propyl, R2 = methyl, X = S, R3 = CH2CO2Et, R, =
Prepared by the procedure of Example 13 from 3-methylsulfobenzoic anhydride.
Crystals meltin~ at 224-227C.
:
Preparation of 3-methylsulfobenzoic anhydride A) ~thyl 6-methyLanthranilate 16.2 g of 6-methylanthranilic acid are dis-solved in 150 ml of tetrahydrofuran. 17.5 g of N,N-carbonyldiimidazole are added and the mixture is stirred for one hour at room temperature and then for 6 hours under reflux. The mixture is concentrated under ~' .
- . - s '~ :
, .
- 74 ~ 20 4~327 vacuum, 200 ml of ethanol are added and the mixture is refluxed for 6 hours. After evaporation of the solvent ~mder vacuum, the residue is taken up with isopropyl ether, the crystals are filtered off and the filtrate 05 is treated with charcoal and then evaporated to give 9.5 g of ethyl 6-methylanthranilate in the form of an oil, which is used as such for the next step.
B) 3-Methyl-~-etho~ycarbonylbenzenesulfonyl chloride 10.4 g of ethyl 6-methylanthranilate are added at -5C to 40 ml of concentrated hydrochloric acid. A
solution of 4.4 g of sodium nitrite in 10 ml of water is added dropwise at -5C and the mixture i5 stirred for 30 minutes at this temperature.
In a separate procedure, 8 g of sulfur dioxide are dissolved in 50 ml of acetic acid, and 1.~ g of copper(IIl chloride are added. The solution obtained is added dropwise to the reaction mixture, still at -5C. After having been stirred for one hour at 20 C
and then for one hour at 4n C, thè mixture is pou~ed on to ice and extracted with ether. The organic phase is dried over magnesium sulfate to give 6.7 g of 3-methyl-2-ethoxycarbonylbenzenesulfonyl chloride in the form of an oil, which is used as such for the next step.
C) 3-Methylsulfobenzoic anh~lde 6.7 g of 3-methyl-2-ethoxycarbonylbenzene-sulfonyl chloride are re~luxed for 3 hours in 60 ml of dlstilled water and 5 ml o~ concentrated hydrochloric acid. The solution obtained is filtered on active charcoal and then evaporated to dryness. The residue obtained is refluxed for 3 hours in 50 ml of acetic anhydride. The solution is evaporated to dryness under vacuum and the residue obtained crystallizes from an ether/pentane mixture. The crystals obtained are 20~327 fi.ltered off and dried to give 3.2 g of 3-methyl-sulfobenzoic anhydride in the form of crystals melting at 130C.
05 Example 63: 6-n-Butyl-2-isopropyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine Formula (XI): Rl = n-butyl, R~ = isopropyl, T = OH, V = NO2 1~
2.8 g of sodium are dissolved in 150 ml of ethanol and the solution is cooled to 5C. 15.1 g of isobutyramidine hydrochloride are added and the mixture is stirred for fifteen minutes. 25 g of ethyl 2-(4-nitrobenzyl)-3-oxoheptanoate, prepared in Example 4, are added and the mixture is stirred for 3 hours at room temperature and then poured into water and acidi-fied with concentrated hydrochloric acid. The crystals obtained are filtered off and washed with water and then with isopropyl ether and acetone to give 16.1 g of 6-n-butyl-2-isopropyl-4-hydroxy-5-(4-nitrobenzyl)pyri-midine in the form of crystals melting at 143 C.
Examle 64: 6-n-Butyl-2-phenyl-4-hydroxy-5-(4-nitro-b~nzyl)pyrimidine Formula (XI): R~ - n-butyl, R, = phenyl, T - OH, V = NO~
Prepared by the procedure of Example 63 from benzamidinQ hydrochloride.
Crystals melting at 2~0C.
.
- 76 - 20~327 Exam~le 65: 6-n-Butyl-2-isopropyl-4-chloro-5-(4-nitrobenzyl)pyrimidine Formula (XII): Rl = n-butyl, R2 = iso-05 propyl, XR3 = Cl, V = N02 Prepared by the precedure of Example 19.
Oil used as such for the next step.
Ex~me~ 6: 6-n-Butyl-2-phenyl-4-chloro-5-(4-nitro-benzyl)pyrimidine Formula (XII): Rl = n-butyl, R2 = phenyl, XR3 = Cl, ~ = N02 Prepared by the procedure of Example 19.
Crystals melting at 85C.
Exam~le 67: ~thyl ~6-n-butyl-2-phenyl-5-(4-nitro-benzyl)pyrimidin-4-yl]mercaptoace~ate Formula (XII): Rl = n-butyl, R2 = phenyl, X = S, R3 = CH2C02Et, V =
: Prepared by the procedure of Example 22.
Cry6tals melting at 102C.
~x~m~l~ 68: Ethyl [6-n-butyl-2-isopropyl-5-~4-nitro-benzyl)pyrimidin-4-yllmercaptoacetate For~ula (XII): R~ = n-butyl, R2 = iso-propyl, X = S, R3 =
CHaco2Et ~ V = N02 , 204~327 Prepared by the procedure of Example 22.
Oil used as such for the next step.
Example 69: 2-~6-n-Butyl-2-phenyl-5-(4-nitrobenzyl)-05 pyrimidin-4-yl]mercaptoethanol Formula (XII): Rl = n-butyl, R2 = phenyl, X = S, ~3 = CH2CH20H ~ V =
Prepared by the procedure of Example 3~.
Crystals melting at 98C.
Example 70: 2-[6-n-Butyl-2-isopropyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]mercaptoethanol Forcula (XII): Rl = n-butyl, R2 = iso-propyl, X = S, R3 =
CH2CH20H, V = N2 Prepared by the procedure of Example 34.
Oil used as such ~or the next step.
The following were prepared by the procedure of Example 12:
~X~19L~1: Ethyl ~6-n-butyl-2-phenyl-5-(4-amino-bensyl)pyrimidin-4-yl~mercaptoacetate For~ula (XII): Rl = n-butyl, R2 = phenyl, X = S, R3 = CH2CO2Et, V =
Oil used as such for the next step.
..... . , , .
- ~ ' . ' ' . ' - ~
,. - . -. ~
. . .
- 78 - 20~327 E~mple 7~: Ethyl [6-n-butyl-2-i~opropyl-5-(4-amino-benzyl)pyrimidin-4-yl]mercaptoacetate Formula ~XII): R~ = n-butyl, R2 = iso-05 propyl, X = S, ~ =
CH2CO2Et, V = NH2 Oil used as such for the next step.
Example 73: 2-[6-n-Butyl-2-phenyl-5-(4-aminobenzyl)-pyrimidin-4-yl]mercaptoethanol For~ula (XII): Rl = n-butyl, R2 ~ phenyl, X = S, R3 = CH2CH2OH, V =
Crystals melting at 103C.
Examle 74: 2-t6-n-Butyl-2-isopropyl-5-(4-aminobenzyl3-pyrimidin-4-yl]mercaptoethanol : Formula (XII): Rl = n-butyl, R2 = iso-: propyl, X = S, R3 =
CH2CH20H, V = NH2 ; : Oil used as such for the next step.
The ~ollowing compounds were prepared by the procedure o~ Example 13:
m~le 75: 2-t~6-n-Butyl-2-phenyl-4-~ethoxycarbonyl-methylthio)pyrimidin-5-yl~methylphenyl-4-yl]a~inocarbonylbenzenesulfonic acid ,~ .
~: 35 Formula ~ Rl = n-butyl, R2 = phenyl, .: .....
, - ., : -.
204~327 X = S, R3 = CH2CO2Et, N ICO ~
R4 = I 11 HO3S~/
Crystals melting at 241-242C. .
~xample ~Ç: 2-[[6-n-Butyl-2-isopropyl-4-(ethoxycarbo-nylmethylthio)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid For~ula (I): Rl = n-butyl, R2 = isopropyl, X = S, R3 = CH2CO2Et, N~OO~, R =
Crystals melting at 227-229~C.
~ xample 77: 2-t[6-n-Butyl-2-phenyl-4-~hydroxyethyl-: ~ 25 thio)pyrimidin-5-yl]methylphenyl-4-yl]-: aminocarbonylb~nzenesulfonic acid For~ula (I): Ra ' n-butyl, R, - phenyl, X = S, R3 - CH~CH~OH, CO~
R~
Crystals melting at 220-221C.
.
. .
: . . . .
- ~ . ; - . .
,' ': ' ' . ,' ~ , - : - ~, - . : , ~ .
, - 80 - 20~327 Ex~m~le 78: 2-[[6-n-Butyl-2-isopropyl-4-(hydroxy-ethylthio)pyrimidin-5~yl]methylphenyl-4-yl]a~inocarbonylbenzenesulfonic acid 05 Formula (I): Rl = n-butyl, R2 = isopropyl, X = S, R3 = CH2CH20H, N~CO~, R4 = l ll o HO3S
Crystals melting at 240-241C.
Exam~ 79: 1-Methoxy-4-oxoheptan-2-one Formula (IV): R~ = n-propyl, s = 1, U = O, Rl4 = CH3 A solution of 127.5 ml of methyl methoxyacetate and 214.5 ml of pentan-2-one in 100 ml of toluene is added dropwise to 33.5 g of finely divided sodium in 600 ml of hot toluene, the temperature being kept at between 60C and 70C. When the addition is complete, the mixture is heated for 2 hours at 55-60C, 30 ml of methanol are then added dropwise, the mixture obtained is taken up with water and washed with ether and the : aqueous phase is acidified with concentrated hydro-chloric acid and then extracted with ether. The orga-nic phase is dried over magnesium sulfate and evapora-ted under vaauum. The oily residue is distilled under reduced pressure to give 103.8 g of 1-methoxy-4-oxo-heptan-2-one boiling at 100-110C.
.:
.... . . . .
. ' : '.
- 81 - 20~327 ~am~le 80: 3-(4-Aceta~idobenzylidene)-l-methoxy-4-oxoheptan-2-one Formula (IV'): R1 = n-propyl, s = 1, U =
05 O, R14 = methyl, V = NHCOCH3 63.2 g of 1-methoxy-4-oxoheptan-2-one and 65.2 g of 4-acetamidobenzaldehyde are dissolved in 480 ml of toluene in the presence of 20 ml of acetic acid and 4 ml of piperidine. The mixture is refluxed for 5 hours and 10.5 ml of water are removed via a Dean-Stark apparatus. The crystals obtained after cooling are filtered off and washed with water, methylene chloride and isopropanol and then recrystallized from 200 ml of methanol to give 43 g of 3-(4-acetamidobenzylidene)-1-methoxy-4-oxoheptan-2-one in the form of crystals melting at 160~C.
Example 81: 6-n-Propyl-2-phenyl-4-methoxymethyl-5-(4-acetamidobenzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = phenyl, XR3 = CH20CH" V = NHCOCH3 42 g of 3-(4-acetamidobenzylidene)-1-methoxy-4-oxoheptan-2-onej prepared in Example 80, are dissolved in 1250 ml of acetic acid. 128.7 g of dry ammonium acetate are added and the mixture is heated at 60-70 C
for 10 minutes. 30 ml of benzaldehyde are added at 60C and the mixture is stirred for 2 hours at this temperature. 500 ml o~ benzene are added and the mix-ture is then refluxed, 9.5 ml o~ water being removed via a Dean-Stark apparatus. The solvents are concen-trated under vacuum and the residue is taken up with water and extracted with ethyl acetate. The organic ~::
.
,., .. ,,.. ~........... ~
- 82 - 20~'?3 2 7 phase is washed with water, dried over magnesium sul-fate and evaporated under vacuum. The residue obtained is chromatographed on silica gel in the eluent chloro-form 95/acetone 5 to giv~ 3.5 g of 6-n-propyl-4-meth-05 oxymethyl-2-phenyl-5-(4-acetamidobenzyl)pyrimidine in the form of crystals melting at 135C.
Example 82: 6-n-Propyl-2-phenyl-4-methoxymethyl-5-(4-aminobenzyl)pyrimidine Formula (XII): R1 = n-propyl, R2 = phenyl, XR3 = CH2OCH3, V = NH2 1.8 g of 6-n-propyl-2-phenyl-4-methoxymethyl-5-(4-acetamidobenzyl)pyrimidine, prepared in Example 81, are dissolved in a mixture composed of 25 ml of ethanol and 25 ml of water. 2 g of sodium hydroxide pellets are added and the mixture is refluxed for 15 hours and then taken up with water and extracted with ether. The organic phase is dried and then evaporated under vacuum. The residue obtained is chromatographed on silica gel with ether as the eluent to give 1.2 g of 6-n-propyl-2-phenyl-4-methoxymethyl-5-(4-aminobenzyl)-pyrimidine in the form of crystals melting at 115 C.
25~ample ~3: 2-[[6-n-Propyl-4-methoxymethyl-2-phenyl-pyrimidin-5-yl]methylphenyl-4-yl]amino-carbonylbenzenesulfonic acid Formula (I): Rl = n-propyl, R~ = phenyl, XR3 = CH~OCH3, NHCO~
H
.. :
- 83 - 2 0 ~ r~ 3 2 7 Prepared by the procedure of Example 13.
Crystals melting at 186-187C.
Example 84: 2-[(6-n-Propyl-2-methyl-2-aminopyrimidin-05 5-yl)methylphenyl-4-yl]aminocarbonyl-benzenesulfonic acid Formula (I): Rl = n-propyl, R2 = methyl, XR3 = NH2, R
Prepared by the procedure of Example 13.
Crystals melting at 310-312C.
~xample ~5: N-[6-n-Butyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yll.morpholine Formula (XII): Rl = n-butyl, R2 = methyl A
V = NH2, XR3 = N~O
Prepared by the procedure of Example 12.
Oil used as such for the next step.
~Y~m~ 2-l(6-n-Butyl-2-methyl-4-(morpholin-1-yl)-pyrimidin-5-yl)methylphenyl-4-yl]amino-carbonylbenzenesulfonic acid Formula (I): Rl z n-butyl, R2 = methyl, ~
~' '.
,.. ,. , . - ~
~.
- 84 - 2 0~ ~3 2 7 R4 = I
Prepared by the procedure of Example 13.
Crystals melting at 213 6C.
~xample 87: 6-n-Propyl-2-methyl-4-hydroxy-5-[2'-(tetra-zol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): Rl = n-propyl, R2 = methyl, XR3 = OH, R4 N~
`N_N
Prepared by the procedure of Example 31 from 6-n-propyl-2-methyl-4-hydroxy-5-(2'-cyanobiphenyl-4-yl)-methylpyrimidine, prepared in Example 10.
; Crystals melting at 204-6C.
Exam~ 88: 6-n-Propyl-2-methyl-4-(2-hydroxyethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XII~: Rl = n-propyl, R2 = methyl, X = O, R3 = CH,CH2OH, : 30 ~
~ 35 8 g of 6-n-propyl-2-methyl-4-hydroxy-5-(2'-.,~,.. .
- 85 - 20~327 cyanobiphenyl-4-yl)methylpyrimidine, prepared in Exam-ple 10, are dissolved in 80 ml of acetonitrile in the presence of 4 g of potassium carbonate, and 3 ml of 2-bromoethanol are added. The mixture is brought to the 05 reflux temperature and hea~ed for 8 hours; the solvents are concentrated under vacuum and the residue is taken up with water and then extracted with methylene chlo-ride. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give an oily residue, which is chromatographed on silica gel.
Elution with an 80/20 methylene chloride/acetone mix-ture gives 2.1 g of pure 6-n-propyl-2-methyl-4-(2-hydroxyethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimi-dine in the form of crystals melting at 103 c.
If elution is continued with a 60/40 methylene chloride/acetone mixture, 2.8 g of 6-n-propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-3-(2-hydroxyethyl)-3,4-dihydro-4-oxopyrimidine are recovered in the form of an oil, which is used as such for the next step.
Example 89: 6-n-Propyl-2-methyl-4-(2-hydroxyethyl)oxy-5-12'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidine Formula (I): R, = n-propyl, R2 = methyl, X = O, R3 = CH2cH20H, ~, R, =
o N
N
H
3.8 g of 6-n-propyl-2-methyl-4-(2-hydroxy-ethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, prepared in Example 88, are dissolved in 80 ml of toluene. 2.7 g of trimethyltin nitride are added and '' ';.
2 0 4 r~ 3 2 7 the mixture is refluxed for 35 hours, cooled and extracted with a dilute solution of potassium hydro-xide, which is washed with ethyl acetate. The aqueous phase is then acidified by having sulfur dioxide 05 bubbled through it, and is extracted with chloroform.
After drying and evaporation of the solvent, the residue obtained is chromatographed on silica gel in an 85/15 chloroform/ethanol eluent to give 2 g of 6-n-propyl-2-methyl-4-(2-hydroxyethyl)oxy-5-[2'-ttetrazol-5-yl~biphenyl-4-yl]methylpyrimidine in the form of cry~tals melting at 154-155C.
Example 90: 6-n-Propyl-2-methyl-3-(2-hydroxyethyl)-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxopyrimidine hydrochloride Formula (I'): R = n-propyl, R2 = methyl, R' 3 = CH,CH~OH, N
~I_N
Prepared by the procedure of Example 89 from 6-n-propyl-2-methyl-3-(2-hydroxyethyl)-5-(2'-cyanobi-phenyl-4-yl)methyl-3,4-dihydro-4-oxopyrimidine, pre-pared in Example 88. The hydrochloride i8 obta1ned by bubbling hydrochloric acid into a tetrahydrofuran solu-tion o~ the compound in the form o~ the base.
Crystals melting at 240-1C.
. . ' ~ ' , .
.
20~327 Example 21: 6-n-Propyl-2-methyl-4-(prop-2-yl)oxy-S-(2'-cyano~iphenyl-4-yl)methylpyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, XR3 = ~ , V =
Prepared by the procedure of Example 30.
Oil used as such for the next step.
Example ~2: 6-n-Propyl-2-methyl-4-(prop-2-yl)oxy-5-t2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyri-midine Formula (I): Rl = n-propyl, R2 = methyl, ~1 XR3 = ~ , R~ = ~ ;~, ~ _N
Prepared by the procedure of Example 89.
Crys~als melting at 190-1C.
Example 93: N-t6-n-Propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methylpyri~idin-4-yl]thiomorpholine Formula (XII): R1 = n-propyl, R~ = methyl, XR, = ~ S , V =
' ,. . , ~ .
.
20~327 Prepared by the procedure of Example 39.
Crystals melting at 153-4C.
~Kample 94: N-[6~n-Propyl-2-~ethyl-5-[2'-(tetrazQl-5-05 yl)biphenyl-4-yl]methylpyrimidin-4-yl]-thiomorpholine hydrochloride Formula (I)O Rl = n-propyl, R2 = methyl, XR3 = ~ S , R4 =
N ~ N
Prepared by the procedure of Example 89. The hydrochloride is obtained by dissolving the compound in the form of the base in an acetone/ether mixture and bubbling hydrochloric acid.
Crystals melting at 240-241C.
~x~m~le 95: 6-n-Propyl-2-methyl-4-mercapto-5-(2'-cyanobiphenyl-4-yl)methylpyri~idine Formula (XII): Rl = n-propyl, R~ = methyl, XR3 = SH, V =
N~
Prepared by the procedure o~ Example 43.
Crystals melting at 202-3C.
.
,. ~ . . .
' ' ~ ' .
-.
: - , . ~ :
. .
- 89 - 20~327 ~cample 96: 6-n-Propyl-2-methyl-4-mercapto-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyri midine O 5 FGrmU1a ( I ): R~ = n-propyl, R2 = methyl, ~, XR3 = SH, R4 = l ll ,N~/
N_N
Prepared by the procedure of Example 89.
Crystals melting at 247-248C.
Example ~: 6-n-Propyl-2-methyl-4-methylthio-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XII): R1 = n-propyl, R2 = methyl, XR3 = SCH3, V =
Prepared by the procedure of Example 44.
Crystals melting at 134C.
:~ Exam~le ~: 6-n-Propyl-2-methyl-4-methylthio-5-t2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyri-~idine Formula (I): Rl - n-propyl, R, = methyl, ~; 35 . ~, ..
' - go - 20~327 XR3 = SCH3, R~ = N~
N~N - H
Prepared by the procedure of Example 89.
Crystals melting at 173-174~C.
Exam~le 99: 6-n-Propyl-2-methyl-4-(2~hydroxyethyl)-mercapto-5-(2'-cyanobiphenyl-4-yl)methyl-pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, ~ = S, R3 = CH2CH20H, V= ~3 Prepared by the procedure of Example 34.
Crystals melting at 97-C.
Exam~Ie 100: 6-n-Propyl-2-methyl-4-(2-acetoxyethyl)-~:~ mercapto-5-(2'-cyanobiphenyl-4-yl)methyl-~:~;: 25 pyrimidine ~ ;
Formula (XII)~: Rl = n-propyl, Rl = methyl, X = S, R, = CH2CH20COCH"
V ~ ~
~ 6.7 g of 6-n-propyl-2-methyl-4-(2-hydroxy-~:
.. - . .
, 91 - 2Q4-~327 ethyl)mercapto-5-(2'-cyanobiphenyl-4-yl)methylpyrimi-dine, prepared in Example 99, are refluxed in 35 ml of acetic anhydride for 3 hours. The acetic anhydride is evaporated off under vacuum, the residue is taken up 05 with ether and the ether solution is filtered on animal charcoal and then evaporated under vacuum to give 5.9 g of 6-n-propyl-2-methyl-4-(2-acetoxyethyl)mercapto-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine in the form of an oil, which is used as such for the next step.
Example 101: 6-n-Propyl-2-methyl-4-(2-hydroxyethyl)-mercapto-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): R, = n-propyl, R2 = methyl, X = S, R3 = CH2CH20H, R4 =
N~
N' 5.9 g of 6-n-propyl-2-methyl-4-(2-acetoxy-ethyl)mercapto-5-(2'-cyanobiphenyl-4-yl)methylpyrimi-dine, prepared in Example 100, are dissolved in 100 ml of toluene, and 3.7 g of trimethyltin nitride are added. The mixture is refluxed for 12 hours, cooled, taken up with ether and extracted with a dilute solu-tion of potassium hydroxide~ The aqueous phase i~acidified by having sulfur dioxide bubbled through it, and i8 then extracted with chloroform. The chloroform phase is dried over magnesium sulfate and evaporated under vacuum; the residue obtained is chromatographed on silica gel with an 85/15 chloroform/methanol eluent - 92 - 20~`~327 to give 2.5 g of a residue composed of a mixture of the expected alcohol and the acetylated derivative. This mixture is taken up in a dilute solution of potassium hydroxide and left to stand overnight at room tempera-05 ture. The aqueous solution is washed with ether andthen acidified by having sulfur dioxide bubbled through it, and the crystals obtained are filtered off and washed with ether to give 2.3 g of 6-n-propyl-2-methyl-4-(2-hydroxyethyl)mercapto-5-[2'-~tetrazol-5-yl)bi-phenyl-4-yl]methylpyrimidine in the form of crystals melting at 186-189~C.
~Y9~5LsLiQ2: Ethyl 2-(2'-cysnobiphenyl-4-yl)methyl-3-oxoheptanoate 5 Formula (VI): Rl = n-butyl, R3 = ethyl, V= I 11 NC~
Prepared by the procedure of Example 6.
Oil used as such for the next step.
Exampl~ 103: 6-n-Butyl-2-methyl-4-hydroxy-5-(2'-cyano-biphenyl-4-yl)methylpyrimidine Formula (XI): R~ = n-butyl, R, = methyl, ~, ~ = O~, V =
N~
Prepared by the procedure of Example 7.
Crystals meltin~ at 173C.
- 93 - 204~327 ~xample lQ~: 6-n-Butyl-2-methyl-4-chloro-5-(2'-cyano-biphenyl-4-yl)methylpyrimidine Formula (XII): Rl = n-butyl, R2 = methyl, 05 ,~
XR3 = Cl, V =
Prepared by the procedure of Example 19.
Crystals melting at 75C.
Example 105: 6-n-Butyl-2-~ethyl-4-methoxy-5-(2'-cyano-biphenyl-4-yl)methylpyrimidine Formula (XII): R1 - n-butyl, R2 = methyl, XR3 = OCH3, V =
Prepared by the procedure of EXample 30.
Oil used as such for the next step.
Exam~le 106: 6-n-Butyl-2-methyl-4-methoxy-5-[2~-(tetra zol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): Rl - n-butyl, R~ ~ methyl, XR3 - OCH3, R~ ' N
N~
94 _ 204.~327 Prepared by the procedure of Example 89.
Crystals melting at 148-149C.
Example 107: 6-n-Butyl-2-methyl-4-hydroxy-5-[2'-(tetra-05 zol-5-yl)biphenyl-4-yl]methylpyri~idine For~ula (I): R~ = n-butyl, R2 = methyl, XR, = ON, R. = N
Prepared by the procedure of Example 31.
Crystals melting at 248-249C.
Example 108: 6-n-Propyl-2-methyl-4-(2-methoxyethyl)-oxy-5-(2'-cyanobiphenyl-4-yl)methylpyri-midine Formula (XII): Rl = n-propyl, R2 = methyl, X = O, R3 = CH2CH2O
V = ~ 3 Prepared by the procedure oP Example 30 from 2-methoxyethanol.
Oil used as such for the next step.
.~
, , .
_ 95 - 20~-~327 Exa~le 10~: 6-n-Propyl-2-methyl-4-(2-methoxyethyl)oxy-5-~2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidine 05 Formula (I): Rl = n-propyl, R2 = methyl, X - 0, R3 = CH2CH2~CH3, ~, ,N~
o N N
Prepared by the procedure of Example 89.
Crystals melting at 169-170C.
Exa~m~le 110: 6-n-Propyl-2-methyl-4-(2-dimethylamino-ethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methyl-pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, : X = 0, R3 ~
V=
NC~
: 6 g of 6-n-propyl-2-methyl-5-(2~-cyanobiphenyl-4-yl)methyl-4-chloropyrimidine, prepared in Example ~1, ~: are added to a solution obtained by adding 1 g of 60~
sodium hydride to 75 ml of THF containing 2.7 g of 2-.
- 96 - 20~327 dimethylaminoethanol. The mixture is stirred for 4 hours under reflux, the solvent is then concentrated under vacuum and the residue is taken up with water and extracted with ether. The organic phase is washed with 05 water and then dried over magnesium sulfate to give 5.1 g of 6-n-propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-(2-dimethylaminoethyl)oxypyrimidine in the form of an oil, which is used as such for the next step.
E~aLlÇL~ 6-n-Propyl-2-methyl-4-(2-dimethylamino-ethyl)oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): Rl = n-propyl, R2 = methyl, X = O, R3 = CH2CH2 N~
R4 =
~`N_N
H
Prepared by the procedure of Example 89.
Crystals melting at 175-176C.
~89~l9~1lZ: 6-n-Propyl-2-methyl-4-~2-morpholinoethyl)-amino-5-(2'-cyanobiphenyl-4-yl)methylpyri-midine Formula (XII): Rl = n-propyl, R2 = methyl, ` .
-_ 97 - 20~327 X = NH, R3 = CH2CH2 N~O, 05 v= I 11 Prepared by the procedure of Example 39 from N-(2-aminoethyl)morpholine.
Oil used as such for the next step.
Example 113: 6-n-Propyl-2-methyl-4-(2-morpholinoethyl)-amino-S-[2'-(tetrazol-5-yl)biphenyl-4-yl~-methylpyrimidine For~ula (I): R, = n-propyl, R2 = methyl, X = NH, R3 = CH2CH2 N~O, R =
~`N_N
~ Prepared by the procedure of ~xample 89.
:- Crystals melting at 270-2 C.
Example 114: 6-n-Propyl-2-~ethyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-(2-hydroxyethyl)aminopyri-midine :~
:~: For-Nla (XII): R, = n-propyl, R2 = methyl, X = NH, R3 = CH2CH2OH, ~: : 35 ~ .
: .
', . . . . .
.. ~ . . .
.
,- ~ , .
. ' ' .
- 98 - 204.~327 ,~, V=
~/
Prepared by the procedure of Example 39 from ethanolamine.
Crystals melting at 135~C.
~m~le 115: 6-n-Propyl-2-methyl-5-[2'-(tetrazol-5-yl)-biphenyl-4-yl]methyl-4-(2-hydroxyethyl)-aminopyrimidine FQrmula (I): R~ = n-propyl, R2 = methyl, X = NH, R~ = CH2CH20H, R4 = _ ~` NH
Prepared by the procedure of Example 89.
Crystals melting at 149-150C.
E~9~RlgL~Lk: 6-n-propy}-2-methyl-4-(2-~ethylthioethyl)-oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimi-dine :
Formula (XII~: R~ = n-propyl, Rl ~ methyl, X - 0, R3 = CH,CH2SCH3, :
::
.,,, . . ~ - .
. ~ . ~ ....
, ~ ~ . . .
- - ' ~
: , 2~4~327 Prepared by the procedure of Example llo from 2-methylthioethanol.
Oil used as such for the next step.
05 Exam~le lL7: 6-n-Propyl-2-methyl-4-(2-methylthioethyl)-oxy-5-t2'-(tetrazol-5-ylIbiphenyl-4-yl]-~ethylpyrimidine Formula (I): R1 = n-propyl, R2 = methyl, X = 0, R3 = CH~CH2SCH3, R4 = N~
N -Prepared by the procedure of Example 89.
Crystals melting at 121-122C.
Example 118: 6-n-Butyl-2-methyl-4-(2-methoxyethyl)-oxy-5-(2'-cyanobiphenyl-4-yl)methylpyri-midine Formula (XII): Rl = n-butyl, R2 = methyl, X = 0, R~ = CH2CH20CH3, V= 1 1.1 N~
Prepared by the procedure o~ Example 30.
Oil used as such for the next step.
- ' :
lOO- 20~.~327 Example 119: 6-n-Butyl-2-methyl-4-(2-methoxyethyl)oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidine 05 Formula (I): Rl = n-butyl, R2 = methyl, X = 0, R3 = CH2CH20CH3, R4 =
N
lo ~ N
N~H
Prepared by the procedure of Example 89.
Crystals melting at 128-129C.
~xample 120: 6-n-Butyl-2-methyl-4-(2-dimethylamino-ethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methyl-pyri~idine Formula (XII): Rl = n-butyl, R2 = methyl, X = 0, R3 = CH2CH2 ~C
V = ~
NC
Prepared by the procedure of Example 110.
Oil used as suah ~or the next step.
:
' ' ' `: ' ' - :~ ' .. ~ `.
' :
.
2oL~327 Exam~le 121: 6-n-Butyl-2-methyl-4-(2-dimethylamino-ethyl)oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine 05 For~ula (I): R, = n-butyl, R2 = methyl, X = O, R3 = CH2CH2 ~CH
R4 =
~ _N
N H
Prepared by the procedure of Example 89.
Crystals melting at 166-167C.
Example 122: Ethyl 3-oxooctanoate For~ula (II): Rl = n-pentyl, R,3 = ethyl Prepared by the procedure of Example 1.
25Oil of b.p.,5 = 110-115 C.
Exam~le 123: Ethyl 2-(2'-cyanobiphenyl-4-yl)methyl-3-oxooctanoate ~
Foruula (VI): R, = n-pentyl, V = ~ J .
CN
R,3 = ethyl Prepared by the procedure of Example 3.
.
, - 102 - 204~327 Oil used as such for the next step.
xample 124: 6-n-Pentyl-2-methyl-4-hydroxy-5-(2'-cyanobiphenyl-4-yl)methylpyr~midine Formula (XI): Rl = n-pentyl, R2 = methyl, T = OH, V =
Prepared by the procedure of Example 7.
Crystals melting at 162C.
Exam~le 125: 6-n-Pentyl-2-methyl-4-hydroxy-5-[2'-(tet-razol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): R1 = n-pentyll R2 = methyl, XR3 = OH, R4 = N~
N'~N--N
H
Prepared by the procedure of Example 31.
Crystals melting at 195-196C.
mpLe 126: 6-n-Penty}-2,3-dimethyl-5-(2'-cyanobi-phenyl-4-yl)methyl-3,4-dihydro-4-oxopyri-midine Formula (XII'): Rl = n-pentyl, R2 =
methyl, R'3 = methyl, - 103 - 20~327 ,~
V = -W
05 7 g of 6-n-pentyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-hydroxypyrimidine, prepared in Example 124, are dissolved in 70 ml of dimethylformamide.
After the addition of 0.8 g of 60% sodium hydride, the mixture is stirred for 30 minutes at room temperature.
2 ml of methyl iodide are added and the solution is heated for 2 hours at 80C. The solvent is evaporated off under vacuum and the residue is taken up with water and extracted with ether. The ether phase is dried over magnesium sulfate and evaporated under vacuum and the residue is chromatographed on silica gel in a 90/lO
chloroform/acetone eluent to give 5.8 g of 6-n-pentyl-2,3-dimethyl-5-(2'-cyanobiphenyl-4-yl)methyl-3,4-di-hydro-4-oxopyrimidine in the form of an oil, which is used as such for the next step.
ExamDl e 127: 6-n-Pentyl-2,3-dimethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-pyrimidine hydrochloride Formula (I'): Rl = n-pentyl, R2 = methyl, R'3 = methyl, R~ = N~
N--H
Prepared by the procedure of Example 90.
Crystals melting at 215~217C.
,. ~, ., . . ~
- 104 - 2 ~ ~ ~ 3 2 7 Example ~8: 6-n-pentyl-2-methyl-4-chloro-s-(2~-cyan biphenyl-4-yl)methylpyrimidine Formula (XII): Rl = n-pentyl, R2 = methyl, XR3 = Cl, V =
~/
loPrepared by the procedure of Example 19.
Oil used as such for the next step.
~x~m~le 129: Ethyl 2-t6-n-pentyl-2-methyl-5-(2'-cyano-biphenyl-4-yl)methylpyrimidin-4-yl]oxy-15acetate Formula (XII); Rl = n-pentyl, R, = methyl, X = 0, R3 = CH2C02Et, ~ .
20V = l 11 ~ .
3 g of ethyl 2-hydroxyacetate are dissolved in 2550 ml of anhydrous tetrahydrofuran. 1.1 g of 60%
sodium hydride are added and the mixture is stirred for 30 minutes at 50-60C. 5.4 q of 6-n-pentyl-2-methyl-4-chloro-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, pre-pared in Example 128, are added and the mixture i8 re~luxed ~or 8 hours. ~he solvent is evaporsted o~
under vacuum and the residue is taken up with water and extracted with ethyl acetate. The organic phase i9 dried over magnesium sulfate and concentrated under vacuum to give an oil, which crystallizes from iso-35propyl ether to give 3.4 g of ethyl 2-[6-n-pentyl-2-, ..... .
2 0 4 -~ 3 2 7 methyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-4-yl]-oxyacetate in the form of crystals melting at 68C.
Example 130: ~thyl 2-[6-n-pentyl-2-methyl-5-t2'-05 (tetrazol-5-yl~biphenyl-4-yl]methylpyri-midin-4-yl]oxyacetate Formula (I): Rl = n-pentyl, R2 = methyl, X = O, R3 = CH2CO2Et, R4 =
N
N--Prepared by the procedure of Example 89.
Crystals melting at }46-148C.
~mDle 131: Ethyl 2-[6-n~propyl-2-methyl-5-t2'-cyano-biphenyl-4-yl)methylpyrimidin-4-yl]oxy-acetate For~ula (XII): R1 = n-propyl, R2 = methyl, X = O, R3 = cH2co2Et~
V= 1 11 ~/
Prepared by the procedure of Example 129.
Oil used as such for the next step.
.... ~ . :
~' , - 106 - 2Q~327 Example 132: Ethyl 2-t6-n-propyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyri-midin-4-yl]oxyacetate 05 Formula ( I ): Rl = n-propyl, R2 = methyl, X = o, R3 = CHzCO2Et, R =
~ ~,N
~ H
Prepared by the procedure of Example 89.
Crystals melting at 149-150C.
Example 133: 6-n-Propyl-2-mercapto-4-hydroxy-5-(4-nitrobenzyl)pyrimidine Formula (XI): Rl = n-propyl, R, = SH, T =
OH, V = NO2 5.7 g of sodium are dissolved in 150 ml of methanol, and 19 g of thiourea are added. The mixture is stirred for 5 minutes at room temperature and 55 g of ethyl 3-oxohexanoate, prepared in Example 1, are ~;: added. After refluxing for 8 hours, the solvent is concentrated to half its volume under vacuum and the : resldue is taken up with water and neutralized by the addition o~ dilute hydrochloric acid. The mixture i9 le~t to stand overnight at room temperature and the ¢rystals formed are filtered off, washed with ether and ethanol and dried to give 29 g of 6-n-propyl-2-mer-: capto-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of crystals melting at 240C.
.
204~327 E~ample 134: 6-n-Propyl-2-methylthio-4-hydroxy-5-(4-nitrobenzyl)pyrimidine Formula (XI): R, = n-propyl, R2 = SCH3, 05 T = OH, V = N02 26 g of 6-n-propyl-2-mercapto-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 133, and 8.3 g of potassium hydroxide are dissolved in 200 ml of methanol. The mixture is stirred ~or lo minutes at room temperature and 5.3 ml of methyl iodide are added.
The mixture is then refluxed for 2 hours. The solvent is evaporated of~ under vacuum and the residue is taken up with water. After acidification with a dilute solu-tion of hydrochloric acid, the aqueous phase is extrac-ted with chloroform. The organic phase is dried over magnesium sulfate and then evaporated under vacuum and the residue crystallizes from a chloroform/methanol mixture to give 13.4 g of 6-n-propyl-2-methylthio-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of crystals melting at 223C.
Example 1~5: 6-n-Propyl-2-methylthio-4-chloro-5-(4-nitrobenzyl)pyrimidine For~ula (XII): Rl = n-propyl, R2 = SCH3, XR3 = Cl, V = NO2 Prepared by the procedure of Example 19.
Crystals melting at 108C.
Example 136: 2-t6-n-propyl-2-methylthio-5-(4-nitr benzyl)pyrimidin-4-yl]mercaptoethanol Formul~ (XII): R~ = n-propyl, R2 = SCH3, l ~
- -' -' ~
20~i327 X = S, R3 = CH2CH20H, V =
Prepared by the procedure of Example 34.
05 Crystals melting at 97C.
Example 137: 2-[6-n-Propyl-2-methylthio-5-(4-ami-lo-benzyl)pyrimidin-4-yllmercaptoethanol Formula (XII): R~ = n-propyl, R2 = SCH3, X = S, R3 = CH2CH20H, V =
Prepared by the procedure of Example 12.
Oil used as such for the next step.
Example 1~: 2-[t6-n-Propyl-2-methylthio-4-(2-hydroxy-ethyl)~ercaptopyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid For~ula (I): R~ = n-propyl, R2 = SCH3, X = S, R3 = CH2CH20H, R, =
HO3S~
Prepared by the procedure of Example 13.
Crystals melting at 198-201aC.
:~ 35 .
' ' ' ~'' ,, :
- , lOg- 20~327 ExamPle 139: 3-t6-n-Propyl-2-methyl-5-(2'-cyanobi-phenyl-4-yl)methylpyrimidin-4-yl]mercapto-propanol 05 Formula (XII): R = n-propyl, R2 = methyl, X = S, R3 = CH2CHzCH2OH, V= 1~ 1~
NC~ ~
5 g of 6-n-propyl-2-methyl-4-mercapto-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, prepared in Exam-ple 95, are dissolved in 50 ml of ethanol. 0.4 g of sodium discolved in 10 ml of ethanol is added and the mixture is stirred for 10 minutes at room temperature.
2.5 g of 3-bromopropanol are added and the reaction mixture is refluxed for 6 hours. ~he solvent is then evaporated off under vacuum and the residue is taken up with water and extracted with ether. The ether phase is dried over magnesium sulfate and evaporated under vacuum to give 5 g of 3-[6-n-propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-4-yl]mercaptopropa-nol in the form of an oil, which is used as such for the next step~
Example 140: 6-n-Propyl-2-~ethyl-4-(3-acetoxypropyl)-mercapto-S-(2'-cyanobiphenyl-4-yl)methyl-pyrimidine Forcula (XII): Rl = n-propyl, Rz = methyl, X = S, R3 = CH2CH2CH2OCOCH3, ~ V= ~0 ~ 3 NC
;:
.
: .
. . . ..
- llO - 2 0 ~ ~ 3 2 7 Prepared by the procedure of Example 100.
Oil used as such for the next step.
~Kample 141: 6-n-Propyl-2-methyl-4-(3-acetoxypropyl)-05 mercapto-5-t2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): Rl = n-propyl, R2 = methyl, X = S, R3 = CH2CH2CH20COCH3, R4 =
N~
Prepared by the procedure of Example 89.
Oil used as such for the next step.
Example 142: 3-t6-n-Propyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]-mercaptopropanol For~ula (I): R~ = n-propyl, R2 = methyl, X - S, R3 = CH2CH~CH20H, R4 =
3 g of 6-n-propyl-2-methyl-4-(3-acetoxypropyl)-~: mercapto-5-~2~-(tetrazol-5-yl)biphenyl-4-yl]methyl W ri-: midine, prepared in Example 141, are dissolved in 30 ml of ethanol in the presence of 1 g of sodium hydroxide pellets. The mixture i~ heated for one hour at 50 C.
:
2~327 The alcohol is evaporated off under vacuum, the residue is taken up with warm water, the solution is acidified by having sulfur dioxide bubbled through it, and is extracted with chloroform, the organic phase is concen-05 trated under vacuum and the residue obtained crystalli-æes from acetone to give 2.2 g of 3-[6-n-propyl-2-methyl-5-~2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimi-din-4-yl]mercaptopropanol in the form of crystals melting at 157-158C.
Example 143: 6-n-Propyl-4-hydroxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XI): Rl = n-propyl, R2 = H, T = OH, V = l ll 13 g of ethyl 2~(2'-cyanobiphenyl-4-yl)methyl-3-oxohexanoate, prepared in Example 6, are dissolved in 100 ml of diglyme. 8 g of formamidine acetate are added and the mixture is heated for 8 hours at 200 C
and then taken up with water and extracted with ethyl acetate. The organic phase is washed several times with a dilute solution of sodium hydroxide and the aqueous extracts are neutralized with hydrochloric acid to give 2.6 g of 6-n-propyl-4-hydroxy-5-(2'-cyanobi-phenyl-4-yl)methylpyrimidine in the form o~ crystals melting at 152C.
Exa~k~ 144: 6-n-Propyl-4-chloro-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine For~ula IXII): Rl = n-propyl, R2 ~ H, - 112 - 20~327 XR3 = Cl, V =
05 Prepared by the procedure of Example 19.
Crystals melting at 58C.
Example 145: 6-n-Propyl-4-methoxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XII): Rl = n-propyl, R2 = H, XR3 = OCH" V =
Prepared by the procedure of Example 30.
Crystals melting at 110C.
Example 146: 6-n-Propyl-4-methoxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl~methylpyrimidine Formula (I): Rl - n-propyl, Ra = H
X = O, R3 = CH3, N~
N`N'N
H
:~ Prepared by the procedure of Example 89.
Crystals melting at 148-149C.
.. .. .
2 0 ~ 2 7 xam~le 147: 6-n-Propyl-2-amino-4-hydroxy-5-(4-ni~ro-benzyl)pyrimidine Formula (XI): Rl = n-propyl, R2 = NH2, T =
05 OH, V = NO2 18.8 g of guanidine hydrochloride are added to a solution of sodium ethylate obtained by adding 4.5 g of sodium to 150 ml of ethanol. The mixture is stirred for 5 minutes and 50 g of ethyl 3-oxo-2-(4-nitro-benzyl)hexanoate, prepared in Example 3, are added.
After 4 hours at room temperature and 4 hours under reflux, the mixture is taken up with water and the crystals are filtered off and washed with ether and acetone to give 22.1 g of 6-n-propyl-2-amino-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of crystals melting at 245-8C.
Example 148: 6-n-Propyl-2-amino-4-chloro-5-(4-nitro-benzyl)pyrimidine Formula (XII): R1 = n-propyl, R2 = NH2, XR3 = Cl, V = NO2 .
Prepared by the procedure of Example 19.
Crystals melting at 140C.
EY9~ 2: 2-~6-n-Propyl-2-amino-5-(4-nitrobenzyl)-pyrimidln-4-yl percaptoethanol Formula (XII): R = n-propyl, R2 = NH~, X = S, R3 = CH2CH2OH, V =
Prepared by the procedure of Example 34.
` '~
204~327 Crystals melting at 110C.
E~am~le 150: 2-t6-n-propyl-2-amino-5-(4-amino~enzyl) pyrimidin-4-yl]mercaptoethanol Formula (XII): Rl = n-propyl, R2 = NH2, X = S, R3 = CH2CH20H, V =
Prepared by the procedure of Example 12.
Crystals melting at 138C.
Exam~le 151: 2-[16-n-Propyl-2-amino-4-(2-hydroxyethyl)-mercaptopyrimidin-5-yl~methylphenyl-4-yl]-aminocarbonylbenzenesulfonic acid Formula (I): Rl = n-propyl, R2 = NH2, X =
S, R3 = CH2CH20H, R~ =
Prepared by the procedure of Example 13.
Crystals melting at 228-230C.
Examlple 152: N-2-[6-n-Butyl-2-meth~1-5-(2'-cyanobi-phenyl-4-yl)methylpyrimidin-4-yl]oxyethyl-phthalimide For~ula (XII): R~ = n-butyl, R2 = methyl, o X = 0, R3 = CH2CH2N ~ , ~
.. .-- 115 - 20~327 ~, V= ~
05 Prepared by the procedure of Example 110 from 2-phthalimidoethanol.
Crystals melting at 110C.
E~m~le 15~: N-2-[6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-1o yl)biphenyl-4-yl]methylpyri~idin-4-yl]oxy-ethylphthalimide For~ula (I): R~ = n-butyl, R2 - methyl, X = 0, R, = CH2CH2N ~ , R~ =
N'~/
Prepared by the procedure of Example 89.
Crystals melting at 200-201C.
15 1~: 6-n-Butyl-2-methyl-4-(Z-dimethylaoino-ethyl)mercapto-5-(2'-cyanobiphenyl-4-yl)-methylpyrimidine FormNla ~ Rl = n-butyl, R2 = methyl, :: CH3 X = ~, R3 =
.
.. - - ,.. . .
': - : -- 116 - 20~5327 ~, V= 1 11 ~/
05 Prepared by the procedure of Example 22 from N-2-mercaptoethyl-N,N-dimethylamine.
Oil used as such for the next step.
~am~le 155: 6-n-Butyl-2-methyl-4-(2-dimethylamino-ethyl)~ercapto-5-[2'-(tetrazol-5-yl)bi-phenyl-4-yl]~ethylpyrimidine Formula (I): R1 = n-butyl, R, = methyl, X = S, R3 = CH2CH2 ~ , R. =
; I H
Prepared by the procedure of ~xample 89.
Crystals melting at 187-188C.
~xample 1~: 6-n-~utyl-2-~eth~1-4-(2-methylthioethyl)-oxy-5-~2'-cyanobiphenyl-4-yl)methylpyrlmi-dine For~ula (XII): Rl = n-butyl, R, = m~thyl, X = O, R3 = CH2cH2scH
:~: V= l I
~ 35 . . .: ~ , ' 2 0 4 e~i 3 2 7 Prepared by the procedure of Example 110 from 2-methylthioethanol.
Oil used as such for the next step.
05 ~xam~le 157: 6-n-Butyl-2-methyl-4-(2-methylthioethyl)-oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]-methylpyrimidine Formula (I): Rl = n-butyl, R2 = methyl, X = O ~ R3 = CH2CH
,N~
"N_N
Prepared by the procedure of Example 89.
Crystals melting at 121-122C.
~xam~le 1~: 2-[6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-4-yl]mercaptoethanol For~ula (XII): Rl = n-butyl, R2 = methyl, 2 5 X = S, R3 = CH2CH20H, V=
Prepared by the procedure of Example 22.
Oil used as such for tha next step.
'' , .
.
' - 118 - 20~ ~327 E~ample 159: 2-[6-n-Butyl-2-~ethyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-~-yl]mercaptoethyl acetate 05 Formula (XII): Rl = n-butyl, R2 = methyl, X = S, R3 = CH2CH20COCH3, ~ .
V= 1 11 NC~
Prepared by the procedure of Example 100.
oi l used as such for the next step.
Exam~le 160: 2-t6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]-mercaptoethyl acetate Formula (I): Rl - n-butyl, R2 = methyl, X = S, R, = CHzCH~OCOCH
: R" = ~ 3 ~ N
H
Prepared by the procedure Or Example 89.
Crystals melting at 112-114C~
~le 161: 2-l6-n-Butyl-2-~ethyl-5-~2~-(tetrazol-5 yl)biphenyl-4-yl pethylpyrimidin-4-yl]-~ercaptoethanol Forcula (I): R~ = n-butyl, R2 = methyl, . .
- ' : . . ... .
. . , -. . .
.
.. ' ~' . ' .
, . ~ , .
204~327 X = S, R3 = CH2CH20H, 05 ~ ~
3.7 g of 2-[6-n-butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]mercaptoethyl acetate, prepared in Example 160, are dissolved in 300 ml of ethanol and 100 ml of water in the presence of 1 g of sodium hydroxide pellets. The mixture is stirred for 48 hours at room t~mperature, the solvents are concentrated, 200 ml of water are added, the aqueous phase is washed with ethyl acetate and then with ether and acidified by having sulfur dioxide bubbled through it, and the crystals obtained are filtered off, washed with water and ether and chromato-graphed on silica gel with a 9/1 methylene chloride/
methanol eluent to give 1.7 g of 2-[6-n-butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl~mercaptoethanol in the form of crystals melting at 161-162C.
Exam~le 1~2: Ethyl 2-t6-n-butyl-2-~ethyl-5-(2'-cyano-biphenyl-4-yl)msthylpyri~idin-4-yl~oxy-acetate Formula tXII): Rl = n-butyl, R~ ~ methyl, X - 0, R3 8 CH2CO~Et ~
~ ~ v= ~1 ~ 35 .~ ~ ~ .. . . . . .
.
-. . , .. -.
- : .. . .
.
- . . ~: . .
- -20~5327 Prepared by the procedure of Example 129.
Oil used as such for the next step.
~xample 163: Ethyl 2-[6-n-butyl-2-methyl-5-[2'-(tetra-05 zol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]oxyacetate Formula ~ Rl = n-butyl, R2 = methyl, X = O, R3 = CH2CO2Et, Prepared by the procedure of Example 89.
Crystals melting at 133-135C.
Example 164: 4-l6-n-Propyl-2-methyl-5-(2'-cyanobi-phenyl-4-yl)methylp~ri~idin-4-yl~oxy-methyl-2,2-dimethyl-1,3-dioxolane Formula (XII): R1 = n-propyl, R2 = methyl, ~ CH2 X s o, R3 = ~ o ~<
. ~
V~
N~
Prepared by the procedure of Example 110.
Oil used as such for the next step.
: . ' ' ' .
- 121 - 204~327 ~ample 165: Sodium salt of 4-~6-n-propyl-2-methyl-5-[2'-(tetrazol-5-yllbiphenyl-4-yl]~ethyl-pyrimidin-4-yl]o~ymethyl-2,2-dimethyl-1,3-dioxolane Formula (I): Rl = n-propyl, R2 = methyl, CH2~
R~ =
~N--~1 Na Prepared by the procedure of Example 89, the sodium salt being obtained by treatment of the tetra-zole derivative with 0.9 equivalent of sodium hydroxide in alcoholic solution.
Crystals melting at 224-225~C.
Example ~66: Ethyl 2-t4-t3-cyanothien-2-yl)benzyl]-3-oxohexanoate Formula (VI): Rl = n-propyl, Rl3 = ethyl, ~S
V = ~ ~
NC
Prepared by the procedure of Example 3 from 4-(3-cyanothien-2-yl)benzyl bromide.
~;~ Oil used as such for the next step.
,~.,, . . :
:' -, ' 204~327 Preparation of 4-(3-cyanothien-2-yl)benzyl bromide A) 4'-Methyl-4-chlorobutyrophenone 53 ml of toluene and 70.5 g of 4-chlorobutyroyl 05 hloride are dissolved in 100 ml of methylene chloride and the solution is added at 10 D C to a suspension of 74 g of aluminum chloride in 200 ml of methylene chloride. The temperature is then allowed to rise for a quarter of an hour and the mixture is treated with iced water. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give 96.9 g of 4'-methyl-4-chlorobutyrophenone in the form of an oil, which is used as such for the next step.
B) ~-Chloro-~-(2-chloroethyl)-4'-methylcinnamaldehyde 130 ml of phosphorus oxychloride are added slowly, at 0 C, to 130 ml of dimethylformamide, and 117.5 g of 4'-methyl-4-chlorobutyrophenone, prepared in A), dissolved in 50 ml of dimethylformamide are then added dropwise. The mixture is subsequently stirred at room temperature for one hour and then at 50 C for 2 hours and at 70 C for 1 hour. The mixture is then poured on to ice and taken up with ether and the ether phase is washed with a saturated solution of sodium bicarbonate, dried over sodium sulfate and evaporated under vacuum to give 133.8 g of ~-chloro-~-(2-chloro-ethyl)-4'-methylcinnamaldehyde in the form of an oil, which is used as such for the next step.
C) 2-(4-Methylphenyl)-4,5-dihydrothiophene-3-carboxal-dehyde 15.9 g of ~-chloro-~-(2-chloroethyl)-4'-methyl-cinnamaldehyde, prepared in B), and 22 g of sodium sulfide (9H20) are added to 200 ml of THF. Water is added in a sufficient amount for the sodium sulfide to :
.
20~327 pass completely into solution, after which the mixture is refluxed for 3 hours, cooled and then taken up with ether. The organic phase is decanted, washed with water and then dried over magnesium sulfate and evapo-05 rated under vacuum to give 13.5 g of 2-(4-methyl-phenyl)-4,5-dihydrothiophene-3-carboxaldehyde in the form of an oil, which is used as such for the next step.
D) 2-(4-Methylphenyl)-3-cyano-4l5-dihydrothiophene 15 g of 2-(4-methylphenyl)-4,5-dihydrothio-phene-3-carboxaldehyde, prepared in C), and 6.5 g of hydroxylamine hydrochloride are mixed in 40 ml of ethanol and 10 ml of water. A solution of 4.7 g of sodium carbonate in 10 ml of water is added. The mix-ture is stirred at room temperature for half an hour and then extracted with ether. The ether phase is washed with water and then dried over sodium sulfate and evaporated under vacuum to give 15.2 g of a gummy yellow residue. This residue is added to 13 ml of acetic anhydride and the mixture warms up slightly, turns brown and becomes liquid. The mixture is sub-sequently refluxed for 1 hour and then poured on to ice, extracted with methylene chloride and washed with a saturated solution of sodium bicarbonate, the organic phase is then dried over magnesium sulfate and evapora-ted under vacuum and the residue obtained is chromato-graphed on silica gel in methylene chloride to give 10 g of 2-(4-methylphenyl)-3-cyano-4,5-dihydrothlophene in the ~orm of an oil, which is used a~ such ~or the next step.
E) 2-(4-Methylphenyl)-3-cyanothiophene 49.9 q of 2-(4-methylphenyl)-3-cyano-4,5-dihydrothiophene, prepared in D), are dissolved in 200 .j,.,. ,.. ,. . ~ . . .
~: - . ' ' ' '' ' ' ' ,' - 124 - 20~'327 ml of carbon tetrachloride, the mixture is heated to the reflux temperature and, after two hours, 11 g of bromine dissolved in 200 ml of carbon tetrachloride are added dropwise. Reflux is continued until the evolu-05 tion of hydrogen bromide has ceased, and the solvent isthen evaporated off under vacuum. The residue is taken up in 200 ml of anhydrous tetrahydrofuran, and 28 g of potassium tert-butylate are added. The mixture is refluxed for one hour and then cooled, water and sodium chloride are added and the resulting mixture is extrac-ted with ether. The organic phase is evaporated under vacuum to give 31.8 g of 2-(4-methylphenyl)-3-cyano-thiophene in the form of an oil, which is used as such for the next step.
F) 4-(3-Cyanothien-2-yl)benzyl bromide 24.5 g of 2-(4-methylphenyl)-3-cyanothiophene, prepared in E), are dissolved in 200 ml of carbon tetrachloride. 21.9 g of N-bromosuccinimide and 0.1 g of benzoyl peroxide are added. The mixture is refluxed for 24 hours. The crystals of succinimide are filtered off and the solvent is evaporated off under vacuum.
The residue is taken up in a mixture of hexane and ethyl acetate and the solution is kept for 24 hours in a refrigerator. The crystals formed are filtered off to give 14 g of 4-(3-cyanothien-2-yl)benzyl bromide in the form of crystals melting at 80C.
Example 167: 6-n-Propyl-2-methyl-4-hydroxy-5-[4-(3-cyanothien-2-yl)benzyl]pyrimidine Formula (XI): R~ = n-propyl, R2 = methyl, T = OH, V = ~ S
NC
- 125 - 204~327 Prepared by the procedure of Example 7.
Crystals melting at 180C.
Example 168: 6-n-propyl-2-methyl-4-chloro-s-[4-( 05 ~yanothien-2-yl)benzyl]pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, XR3 = Cl, V =
lo NC
Prepared by the procedure of Example 19.
Oil used as such f or the next step.
Example 169: 6-n-Propyl-2-methyl-4-methoxy-5-[4-l3-cyanothien-2-yl)benzyl]pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, XR3 = OCH3, V =
NC
Prepared by the procedure of Example 30.
Oil used as such for the next step.
Example 170: 6-n-Propyl-2-methyl-4-methoxy-5-~4-t3~
(tetrazol-S-yl)thien-2-yl]benzyl]pyrimi-dine Formula lI): R~ = n-propyl, R2 = methyl, : 35 ~:
,..... . .
20~327 XR3 = OCH3, R~
Prepared by the procedure of Example 89.
Crystals melting at 155C.
10Example 171: Ethyl 2-(2'-methoxycar~onylbiphenyl-4-yl)-methyl-3-oxoheptanoate For~ula (VI): R, = n-butyl, Rl3 = ethyl, --15V = ~ 3 MeO2C
Prepared by the procedure of Example 5.
20Oil used as such for the next step.
Example 172: 6-n-Butyl-2-methyl-4-hydroxy-5-(2'-methoxycarbonylbiphenyl-4-yl)methylpyrimi-dine : 25 : ~ Formula (XI): Rl - n-butyl, R2 = methyl, T - OH, V =
MeO2C
Prepared by the procedure of Example 7.
Crystals melting at ~09-210C.
' , - 127 - 20~327 Example 173: 6-n-Butyl-2-methyl-4-chloro-5-(2'-methoxy-carbonylbiphenyl-4-yl)methylpyrimidine Formula (XII): R1 = n-butyl, R, = methyl, XR3 = Cl, V = I ll MeO2C~~/
Prepared by the procedure of Example 19.
O11 used as such for the next step.
~xample 174: 6-n-Butyl-2-methyl-4-methoxy-5-(2'-methoxycarbonylbiphenyl-4-yl)methylpyrimi-dine Formula (XII): R1 = n-butyl, R2 = methyl, XR3 = OCH3, V =
M~2C
Prepared by the procedure of Example 30.
Oil used as such for the next step.
~: ~x~pl~ 175: 4'-[6-n-Butyl-2-methyl-4-methoxypyrîmidin-5-yl]methylbiphenyl-2-carboxylic acid Formula (I~: Rl = n-butyl, R, = methyl, XR3 = OCH3, V =
~2C
'~, 2.1 g of 6-n-butyl-2-methyl-4-methoxy-5-(2'-:
::
~,.,"..,~,,,, ~
- 128 - 20~.~327 methoxycarbonylbiphenyl-4-yl)methylpyrimidine, prepared in Example 174, and 0.35 g of sodium hydroxide pellets are dissolved in 15 ml of methanol and 10 ml of water.
I'he solution is heated at 60C for 10 hours, the sol-05 vents are evaporated off under vacuum, the residue istaken up with water and the aqueous phase is aci~ified with dilute hydrochloric acid. The crystals are fil-tered off, washed several times with water and dried to give 1.8 g of 4'-[6-n-butyl-2-methyl-4-methoxypyri-midin-5-yl]methylbiphenyl-2-carboxylic acid in the form of crystals melting at 168C.
Example 176: 6-n-Propyl-2-methyl-4-methoxy-5-(4-nitro-benzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, XR3 = OCH3, V = NO2 Prepared by the procedure of Example 30.
Oil used as such for the next step.
Example 177: 6-n-Propyl-2-methyl-4-methoxy-5-(4-amino-benzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, XR3 = OMe, V = NH~
5.3 g of 6-n-propyl-2-methyl-4-methoxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 176, are dissolved in 70 ml of diglyme. 1.15 g of lithium boro-hydride are added and the mixture is heated to the reflux temperature. 8 ml of methanol are added drop-wise over two hours and the mixture is subsequently refluxed for a further 2 hours and then taken up with water. The crystals are filtered off and dissolved in - 129 - 2~ ~ 32 7 isopropyl ether. The ether solution is dried over mag-nesium sulfate and evaporated under vacuum to give 3.8 g of 6-n-propyl-2-methyl-4-methoxy-5-(4-amino-benzyl)pyrimidine in the form of crystals melting at 05 179-181 C.
Exam~le 178: 2-[(6-n-Propyl-2-methyl-4-methoxypyrimi-din-5-yl)methylphenyl-4-yl]aminocar~onyl-benzenesulfonic acid Formula (I): R, = n-propyl, R2 = methyl, XR3 = OMe, R~ =
Prepared by the procedure of Example 13.
Crystals melting at 200-204C.
Exam~le 179: 6-n-Butyl-2-methyl-5-(~-nitrobenzyl)-4-(2-propionyloxyethyl)oxypyrimidine Formula (XII): R~ = n-butyl, Rz = methyl, X = O, R3 = CH2CH2OCOCH2CH3, v = NO2 Prepared by the procedure of Example 100 from 2-hydroxyethyl propionate, obtained by the catalytic hydrogenation of commercial 2-hydroxyethyl acrylate in the presence of Raney nickel.
Oil used as such for the next step.
, ' ~ ' -:
'~
.. ~ ' ~ .
.
- 130 - 2~ 3 2 7 Ex~ 180: 2-t6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]oxyethanol Formula (XII): Rl = n-butyl, Rz = methyl, 05 X = O, R3 = CH2CH20H, V = NO2 Prepared by the procedure of Example 142.
Oil used as such for the next step.
E~b1~ 2-t6-n-Butyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yl]oxyethanol Formula (XII): Rl = n-butyl, R2 = methyl, X = O, R3 = CH2CH20H, V = NH2 Prepared by the procedure of Example 12.
Oil used as ~uch for the next step.
E~xample 182: 2-[[6-n-Butyl-2-~ethyl-4-(2-hydroxy2thyl)-oxypyrimidin-5-yl]methylphenyl-4-yl]a~ino-carbonylbenzenesul~onic acid ~: 25 Formula (I): Rl = n-butyl, Rl = methyl, ' X 5 O, R3 = CH2CH20H, ~:: R~ =
;~ HO3S
~: Prçpared by the procedure of Example 13.
:~:: Crystals melting at 238-9C.
~: 35 ::
.,.,, .......... . . : . .
- : . --. .:
.
. -' .
- 131 - 2 ~ ~32 Example 183: Ethyl t6-n-butyl-2-methyl-5-(2'-cyanobi-phenyl-4-yl)methyl-3~4-dihydro-4-oxo-pyrimidin-3-yl]acetate 05 Formula (XII'): R, = n-butyl, R2 = methyl, R' 3 = CH2C02Et, V = . ¦ ll NC~
Prepared by the procedure of Example 88.
Oil used as such for the next step.
~x~LDl9LL~: Ethyl [6-n-butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxopyrimidin-3-yl]acetate Formula (I'): R~ = n-butyl, Ra = methyl, R' 3 = CH2C02Et, R4 = N~
~` N
N--H
: Prepared by the procedure of Example 89.
Cryætals melting at 170-1C.
ExamDle 185: 6-n-Butyl-2,3-dimethyl-5-(2'-cyanobi-phenyl-4-yl)methyl-3,~-dlhydro-4-oxopyri-midine :~ Formula (XII'): R~ = n-butyl, R2 = methyl, ~ 35 .... ,, .. .: .
' , ' - ' . .
: -- 132 - 2Q~327 R~3 = methyl, v =
05 Prepared by the procedure of Example 126.
Oil used as such for the next step.
Example 186: 6-n-Butyl-2,3-dimethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-pyri~idine Formula (I'): R1 = n-butyl, R2 = methyl, R'3 = methyl, R~
N~/
~N'~
Prepared by the procedure of Example 127.
Example 187: 6-n-Butyl-2-methyl-3-(2-chlorobenzyl)-5-(2'-cyanobiphenyl-4-yl)methyl-3,4-dihydro-4-oxopyrimidine : 25 :
: Formula (XII'): R1 = n-butyl, R, = methyl, ~: Cl ::
3 CH2-~3 N
~ 35 :
... , ............. . : - :
' .
- 133 - 20~3 2 7 Prepared by the procedure of Example 88.
Oil used as such for the next step.
~xample 188: 6-n-Butyl-2-methyl-3-(2-chlorobenzyl)-5-05 [2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxopyrimidine Formula (I'): Rl = n-butyl, R2 = methyl, Prepared by the procedure of Example 89.
Ex~m~le 189: 6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-oxo-3,4-dihydro-3-(2-acetoxy-ethyl)pyrimidine Formula (XII'): R1 = n-butyl, R, = methyl, R' 3 = CH2CH20COCH3 ~
V =
NC/~
:
Prepared by the procedure of Example 88.
Crystals melting at 107C.
:: :
- 134 - 2~ 327 Ex~m~lç 190: 6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-yl)-biphenyl-4-yll~ethyl-3,4-dihydro-4-oxo-3-(2-acetoxyethyl)pyrimidine 05 Formula (I~): Rl = n-butyl, R~ = methyl, R' 3 = CH2CHzOCOCH3 ~
R4 = l ll N~
o ~N' H
Prepared by the procedure of Example 89.
Example 191: 3-t6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-4-yl]oxypropyl acetate Formula (XII): R~ = n-butyl, R2 ~ methyl, X = O, R3 = CH2CH2CH2OCOCH3, V= ~3 ; 25 : Prepared by the procedure of Example 88 ~elu-ent: 5/5 ethyl acetate/cyclohexane).
oi 1 used as such for the next step.
.. , :, , ~
.
, ,, , , .; . , 204~i32~1 E,xam~le 192: 6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-3,4-dihydro-4-oxo-3-(3-acetoxy-propyl)pyrimidine 05 Formula (XII'): Rl = n-butyl, R2 = methyl, R' 3 = CH~CH2CH20COCH3 1 V= 1 11 N~/
Prepared by the procedure of Example 88 (elu-ent: 7/3 ethyl acetate/cyclohexane).
Crystals melting at 108C.
Example 193: 6-n-Butyl-2-methyl-5-t2'-(tetrazol-5-yl)-biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-3-(3-acetoxypropyl)pyrimidine For~ula (I'): Rl = n-butyl, R2 = methyl, R' 3 = CH2CH2CHzOCOCH3 ~
R4 =
~N
25 ~ N~ N
, : Prepared by the procedure of Example 89.
~ 35 :
",., . ,~, , .
, ' - 136 - 2Q~.~327 Exam~le 194: 3-[6-n-Butyl-2-methyl-5- r 2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]-oxypropyl acetate 05 Formula (I): Rl = n-butyl, R2 = methyl, X = O, R3 = CH2CH2CH20COCH3, R4 = ~
r~
o N~N,N
Prepared by the procedure of Example 89.
Example 195: 3-[6-n-Butyl-2-methyl-5-[2'-(tetrazol-S-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-pyrimidin-3-yl]propanol Formula (I'): Rl = n-butyl, R2 = methyl, R'3 = CH2CH2CH20H, R. = ~
N ~ .
N~ ,N
~: 25 H
Prepared by the procedure of Example 142 Crystals melting at 181-2C.
Exam~le L~6: 2-t6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylp~rimidin-4-yl]-oxyethanol Formula (I): Rl = n-butyl, R2 = methyl, X = O, R3 = CH~CH20H, ... . . . . .
', ~ - ' ~ '''~
.
-20~ ~2 R4 =
N~ _N
Prepared by the procedure of Example 142.
Crystals melting at 173-4C.
Example 197: 2-[6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-pyrimidin-3-yl]ethanol Formula (I'): Rl = n-butyl, R2 = methyl, R' 3 = CB2CH20H, R4 =
N
N~ ~N
N H
Prepared by the procedure of Example 142.
Crystals melting at lgS-6~C.
~DLlgL12~; 6-n-Propyl-2-mercapto-4-hydroxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine For~ula ~XI): Rl = n-propyl, R, = 5H, T =
OH, V =
NC
;~ Prepared by the procedure of Example 133.
: 35 Crystals melting at l91~C.
:
- :', - '~ .;
' , :
- :
- 138 - 20~a327 The following products may be prepared by the procedures described above:
~ 6-n-Propyl-2,4-dihydroxy-5-[2'-(tetrazol-5-yl)bi-05 phenyl-4-yl]methylpyrimidine - 6-n-Butyl-2,4-dihydroxy-5-[2'-(tetrazol-5-yl)bi-phenyl-4-yl]methylpyrimidine - 6-n-Propyl-2,4-dichloro-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Butyl-2,4-dichloro-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Propyl-2-chloro-4-methoxy-5-(2'-carboxybiphenyl-4-yl)methylpyrimidine - 6-n-Butyl-2-chloro-4-methoxy-5-(2'-carboxybiphenyl-4-yl)methylpyrimidine - 6-n-Propyl-2-chloro-4-hydroxy-5-(2'-carboxybiphenyl-4-yl)methylpyrimidine - 6-n-Butyl-2-chloro-4-hydroxy-5-(2'-carboxybiphenyl-4-yl)methylpyrimidine - 6-n-Propyl-2,4-dimethoxy-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Butyl-2,4-dimethoxy-5-(2'-carboxybiphenyl-4~yl)-methylpyrimidine - 6-n-Propyl-2,4-dihydroxy-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Butyl-2,4-dihydroxy-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Propyl-2,4-dimethoxy-5-E2'-(tetrazol-5-yl)bi-phenyl-4-yl]methylpyrimidine - 6-n-Butyl-2,4-dimethoxy-5-[2'-(tetrazol-5-yl)bi-phenyl-4-yl]methylpyrimidine - 6-n-Propyl-2-mercapto-4-hydroxy-5-E2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-mercapto-4-hydroxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine . ~ .. ..
~ ' .: ~
' ' ~ ' '~' . ' ~ ' . ' ,, :
.
, - 139 - 2~ ~ ~327 ~ 6-n-Propyl-2-methylthio-4-hydroxy-s-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methylthio-4-hydroxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine 05 - 6-n-Propyl-2-methylthio-4-methoxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methylthio-4-methoxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-2-methyl-3-phenyl-3,4-dihydro-4-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methyl-3-phenyl-3,4-dihydro-4-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-2 methyl-3-(2-chlorophenyl)-3,4-dihydro-4-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methyl-3-(2-chlorophenyl)-3,4-dihydro-4-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-2-methyl-4-methoxymethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methyl-4-methoxymethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-2-methyl-4-hydroxymethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methyl-4-hydroxymethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-4-hydroxymethyl-5-[2'-(tetr~zol-5-yl)bi-phenyl-4-yl~methylpyrimidine - 6-n-Butyl-4-hydroxymethyl-5-[2'-(tetrazol-5-yl)bi-phenyl-4-ylImethylpyrimidine - 6-n-Propyl-4-methoxymethyl-5-~2'-(tetrazol-5-yl)bi-phenyl-4-yl]methylpyrimidine - 6-n-Butyl-4-methoxymethyl-5-[2'-(tetrazol-5-yl)bi-phenyl- 4-yl]methylpyrimidine - 6-n-Propyl-2-methyl-4-carboxy-5-[2'-(tetrazol-5-yl)-biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methyl-4-carboxy-5-[2'-(tetrazol-5-yl)-' .
~0~27 biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-4-carboxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-4-carboxy-s-[2'-(tetrazol-5-yl)biphenyl-4-05 yl]methylpyrimidine- 6-n-Propyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine-4-carbaldehyde - 6-n-Butyl-2-methyl-5-~2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine-4-carbaldehyde - 6-n-Propyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidine-4-carbaldehyde - 6-n-Butyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidine-4-carbaldehyde - .
. , ' - ' ' ': , -, :. : -. ~ , ' ,, ' ' ' , '; '' ' ,~
. . ,. , : .
20'~ 327 PHAR ~COLOGY
I. Principle 05 The affinity of the products of the Examples for angiotensin II receptors is evaluated by the tech-nique of displacing a radioligand specifically bound to rat adrenal angiotensin II receptors.
II. Procedure An aliquot of a rat adrenal gland homogenate incubates in the presence of a single concentration of [l2sI]-SIAII (Sar1,Tyr~,Ile~-angiotensin II), which is an angiotensin II receptor antagonist, and two concentra-tions of competing agents (10-5 M, I0-7 M) for 60 min at 25 C.
The reaction is completed by the addition of a buffer, followed by rapid filtration through glasspaper filters. The non-specific binding is determined in the presence of angiotensin II.
III. Expression of ~he resul~s The results are expressed, for the concentra-tions tested, as the percentage displacement of the radioligand specifically bound to the adrenal angio-tensin II receptors.
~:
.
, ' .:
- 142 - 2Q4-~327 IV. Results Product of % displacement of the labeled ligand lE-7M lE-5M
Example 13 64 96 Example 14 38 81 Example 16 31 65 10 Example 24 62 93 Example 27 20 76 Example 31 51 71 Example 32 67 94 15 Example 33 62 69 Example 54 65 84 Example 55 60 86 Example 56 59 86 ~0 Example 57 69 80 Example 58 53 78 Example 59 57 89 Example 61 63 96 25 Example 75 0 72 : Example 76 37 93 Example 77 4 63 30 Example 7~ 41 74 -,, . , ~ . , . , - ~ - ' .. . .
. .
, -. : : ~.-:
.
. ' ~ ': ' '- - , :
:: : ' -:
.
20~-~327 TOXICOLOGY
The products of the Examples described have an excellent tolerance after oral administration.
05Their 50% lethal dose in rats was found to be greater than 300 mg/kg.
CONCLUSION
10The products of the Examples described have a good affinity for angiotensin II receptors. In this respect, they may be used beneficially for the various patholoqical conditions in which angiotensin II is involved, in particular for the treatment of arterial hypertension and cardiac insufficiency, in dosages of 1 to 400 mg by oral administration and 0.01 to 50 mg by intravenous administration, in one or more dosage units per day.
~ ~ .
... .
.
triethylbenzylamine hydrochloride. 2 ml of 2-bromo-ethanol are added and the mixture is refluxed for ten hours. The solvent is evaporated off to dryness and the residue is taken up with water and then extracted with ether. The organic phase is dried and then eva-porated to dryness and the oily residue obtained is _ 53 - 20~327 chromatographed on silica in ether to give 3 g of 6-n-propyl-2-methyl-4-hydroxyethoxy-5-(2'-methoxyGarbo-nylbiphenyl-4-yl)methylpyrimidine in the form of a colorless oil, which is used as such for the next step.
Example 16: 4'-[6-n-Propyl-2-methyl-4-hydroxyethoxy-pyrimidin-5-yl]methylbiphenyl-2-carboxylic acid Formula (I): Rl = n-propyl, R2 = methyl, R3 = CH2CH,OH, X = 0, ~.= 1 11 1.8 g of 6-n-propyl-2-methyl-4-hydroxyethoxy-5-(2'-methoxycarbonylbiphenyl-4-yl)methylpyrimidine, pre-pared in Example 15, are dissolved in 20 ml of ethanol.
A solution of 1 g of sodium hydroxide in 10 ml of dis-tilled water is added and the mixture is heated at 50 C
for two hours. The solvents are evaporated off to dry-ness and the residue is taken up with water and washed with ethyl acetate. The aqueous phase is acidified by having sulfur dioxide bubbled through it, and is extracted with chloroform. ~he organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum. ~he residue obtained crystallizes Prom i~o-propyl ether to give 1.2 g of 4'-[6-n-propyl-2-methyl-4-hydroxyethoxypyrimidin-5-yl]methylbiphenyl-2-carboxy-lic acid in the form of crystals melting at 143-144C.
_ 54 _ 2 ~4a3 Example 17: [4-n-Propyl-2-methyl-6-oxo-5-(4-nitro-benzyl)pyrimidin-1(6H)-yl]acetylmorpholine Formula (XII'~: Rl = n-propyl, R2 = methyl, R'3 = CH2 CON~ O
Prepared by the procedure of Example 11 from N-(chloroacetyl)morpholine and 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 7.
Crystals melting at 174C.
Example 18: [4-n-Propyl-2-methyl-6-oxo-5-(4-amino-benzyl)pyrimidin-1(6H)-yl]acetylmorpholine Formula (XII'): R~ = n-propyl, R2 = methyl, R'3 - CH2 CON~O
V = NH~
Prepared by the procedure of Example 12 Crystals melting at 160DC.
Exam~le 19: 6-n-Propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine Formula (XII): Rl = n-propyl, R, = methyl, ' . :
,.
_ 55 _ 20~327 XR3 = Cl, V = NO2 32 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-hydroxypyrimidine, prepared in Example ?, are suspen-05 ded in 45 ml of phosphorus oxychloride. The mixture isrefluxed for 6 hours and then concentrated under vacuum. The residue is taken up with water and extrac-ted with methylene chloride. The organic phase is washed with a solution of potassium carbonate and then dried over magnesium sulfate and evaporated to dryness to give 24 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine in the form of crystals melting at 65 C.
Example 20: 6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine Formula (XII): Rl = n-butyl, R2 = methyl, XR3 = Cl, ~ = NO2 Prepared by the procedure of Example 19.
Crystals melting at 45C.
Example 21: 6-n-Propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-chloropyrimidine Formula (XII): Rl = n-propyl, R~ - methyl, XR, = C1, V =
Prepared by the procedure of Example 19.
Crystals melting at 95C.
, ' ,, ' ~ , .
- 56 - 2 0 ~3 3 2 7 Example 22: ~thyl 16-n-propyl-2-methyl-5-~4-nitro-~enzyl)pyrimidin-4-yl]mercaptoacetate Formula (XII): Rl = n-propyl, R2 = methyl, 05 X = S, R3 = CH2CO2Et, V =
4 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine and 1.9 g of ethyl mercaptoacetate are dissolved in 50 ml Or ethanol. 1.2 g of anhydrous sodium acetate are added and the mixture is stirred for 6 hours at room temperature and then for 6 hours under reflux. The ethanol is evaporated off under vacuum and the residue is taken up with water and then extracted with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated to dryness under vacuum to give an oil, which crystallizes from a pen-tane/isopropyl ether mixture to give 2.9 g of ethyl [6-n-propyl-2-methyl-5-(4-nitrobenzyl)pyrimidin-4-yl~-mercaptoacetate in the form of crystals melting at 66-67C.
xample 23: Ethyl [6-n-propyl-2-methyl-5-(4-amino-benzyl)pyrimidin-4-yl]mercaptoacetate Formula (XII): R~ = n-propyl, R2 ~ methyl, X - S, R3 - CH,CO,Et, V -NH, Prepared by the procedure of Example 12.
Oil used aB such for the next step.
.
, . . .
~. . .
, _ 57 _ 20~;~3 2 Exa~ple 24: 2-[[6-n-Propyl-2-methyl-4-(ethoxycarbonyl-methylmercapto)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid 05Formula (I): Rl - n-propyl, R2 = methyl, R3 = CH2C02Et, X = S, O
R, = NH ~
0 HO3SJ~J
Prepared by the procedure of Example 13.
Crystals melting at 252-253C.
Example 25: 6-n-Propyl-2-~ethyl-4-(N,N-dimethyla~ino-carkonyloxy)-5-(4-nitrobenzyl)pyrimidine Form~la (XII): Rl = n-propyl, R~ = methyl, X = o, R3 = C~-N'cH3 V = NO2 g of 6-n-propyl-2-methyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 7, are dissolved in 100 ml of methylene ahloride in the presenae of 2.6 ml of triethylamine. 1.7 ml of N,N-dimethylcarbamoyl chloride are added and the mixture isrefluxed for 12 hours. After cooling, the solution is washed with a dilute solution of hydrochloric acid, dried over magnesiu~ sulfate and evaporated to dryness.
The residue is chromatographed on silica gel, in ~he eluent methylene chloride 9/acetone 1, to give 3.1 g of : '' ' . . ' :
.`
- 58 - 20~32 7 6-n-propyl-2-methyl-4-(N,N-dimethylaminocarbonyloxy)-5-~4-nitrobenzyl)pyrimidine in the form of crystals melt'ng at 110C.
05 xample 26: 6-n-Propyl-2-methyl-4-(N,N-dimethylamino-carbonyloxy)-5-(4-aminobenzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, o CH3 X = O, R3 = C~ ~CH3 V = NH2 Prepared by the procedure of Example 12.
oi 1 used as such for the next step.
ExamDle 27: 2-[[6-n-Propyl-2-methyl-4-(N,N-dimethyl-aminocarbonyloxy)pyrimidin-5-yl]methyl-phenyl-4-yl]a~inocarbonylbenzenesulfonic acid Formula (I): R~ = n-propyl, R2 = methyl, X = O, R = C~-R, =
Prepared by the procedure of Example 13.
Crystals melting at 215-218C.
, . .. . .
.
' - 59 - 20~ ~327 F.xample 28: Ethyl [4-n-propyl-2-methyl-6-oxo-5-(2'-cyanobiphenyl-4-yl)~ethylpyri~idin-1(6H)-yl]acetate 05 Formula (XII'): R1 = n-propyl, R2 ~ methyl, R' 3 = CH2C02Et ~
~, V=
~
Prepared by the procedure o~ Example 11.
Crystals melting at 98C.
Example 29: Ethyl ~6-n-propyl-2-methyl-5-(2'-cyanobi-phenyl-4-yl)methylpyrimidin-4-yl]mercapto-acetate Formula (XII): R, = n-propyl, R2 = methyl, R3 = CH2C02Et, X = S, V=
Nt;~
Prepared by the procedure of Example 22.
oi 1 used as such ~or the next step.
Example 30: 6-n-Propyl-2-methyl-4-methoxy-5-(2'-cyano-biphenyl-4-yl)methylpyrimidine Formula (XII): R, = n-propyl, R2 = methyl, R3 = methyl, X = 0, ~ ' ', 20~ :~3 2 7 V= I IJ
05 12 g of 6-n-propyl-2-methyl-4-chloro-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, prepared in Example 21, are dissolved in 100 ml of methanol. 1.2 g of sodium dissolved in 20 ml of methanol are added and the mixture is stirred for 3 hours at room temperature, then for one hour at 40C and finally for one hour under reflux. The reaction mixture is concentrated, water is then added and the resulting mixture is extracted with isopropyl ether. The organic phase is dried and then evaporated under vacuum and the residue obtained crystallizes from an isopropyl ether/pentane mixture to give 8.9 g of 6-n-propyl-2-methyl-4-methoxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine in the form of crystals melting at 108C.
Example 31: 6-n-Propyl-2-methyl-4-methoxy-5-[2'-(tetrazol-s-yl)biphenyl-4-yl]methylpyri~i-dine : Formula (I): R~ = n-propyl, R2 = methyl, R3 = methyl, X = 0, R~ ~ H~
~N
:
8.9 g of 6-n-propyl-2-methyl-4-methoxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, prepared in Example 30, and 6.3 g of trimethyltin nitride are .
2~ .327 refluxed for 12 hours in 100 ml of toluene. The crys-tals obtained are filtered off hot to give 6.6 g of 6-n-propyl-2-methyl-4-methoxy-5-[2'-(1-trimethylstannyl-tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine in the 05 form of crystals melting at 235C. These crystals are dissolved in a toluene/THF mixture (60 ml/10 ml) and treated with gaseous hydrogen chloride for one hour at room temperature. The mixture is concentrated, taken up with chloroform and then washed with water. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give an oil, which crystal-lizes from an ether/acet.,ne mixture to give 4.2 g of 6-n-propyl-2-methyl-4-methoxy-5-[2'-(tetrazol-5-yl)-biphenyl-4-yl]methylpyrimidine melting at 132-4 C.
~xam~le 32: Ethyl [4-n-propyl-2-methyl-6-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyri-midin-1(6~)-yl]acetate Formula (I'): R1 = n-propyl, R2 = methyl, R' 3 = CHzC02Et, R~ = H~
~N' Prepared by the procedure of Example 31.
Crystals melting at 164-5C.
Exam~l~ 33: ~thyl [6-n-propyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-7-yl]~ethylpyrimidin-4-yl]-mercaptoacetate Formula (I): Rl = n-propyl, R~ - methyl, 62 -- 2 0 Ll ~ 3 2 7 X = S, R3 = CH~C02Et, ~ ' .
R. = H~
~N,N
Prepared by the procedure of Example 31.
Crystals melting at 137-8C.
~3m~1e 34: 2-[6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]mercaptoethanol .
Formula (XII): Rl - n-butyl, R2 = methyl, X = S, R3 = CH2CH20H, V =
10 g of 6-n-butyl-2-methyl-5-t4-nitrobenzyl)-4-chloropyrimidine, prepared in Example 20, are dissolved in 150 ml of butan-2-one. 7 g of potassium carbonate and 3.7 g of 2-mercaptoethanol are added and the mixture is refluxed for 6 hours. After concentration of the solvent under vacuum, the residue is ~aken up .
:~ with water and then extracted with ether and the ; 25 organic phase is washed wi~h water and then dried over magnesium sulfate and evaporated to dryness to give a residue, which crystallizes from isopropyl ether to give 5.5 g o~ 2-[6-n-butyl-2-methyl-5-t4-nitrobenzyl)-pyrimidin-4-yl]meroaptoethanol melting at 65C.
~0 ~:~ Exàmple 35: 2-16-n-Propyl-2-methyl-5-(~-nitr~enzyl)- .
pyri~idin-4-yl]mercaptoethanol For~ula (XII): R1 = n-propyl, R2 = methyl, X = S, R3 = CH2CH20H, `,~: .
.~,.,.,.. , ....... ~ :
.
- 63 - 20 4 ~)327 V = NO2 Prepared by the procedure of Example 34.
Crystals melting at 110C.
Example 36: ~thyl [6-n-butyl-2-methyl-5-(4-nitro-benzyl)pyrimidin-4-yl]mercaptoa~etate Pormula (XII): R~ = n-butyl, R2 = methyl, X = S, ~ = CH2C02Et, V =
N0~
Prepared by the procedure of Example 22.
Oil used as such for the next step.
Example 37: 6-n-Butyl-2-methyl-4-amino-5-(4-nitro-benzyl)pyrimidine Formula (XII): R1 = n-butyl, R2 = methyl, XR3 = NH2, V = N02 25.4 g of 6-n-butyl-2-methyl-4-chloro-5-(4-nitrobenzyl)pyrimidine, prepared in Example 20, are heated in 400 ml of ammoniacal methanol at 170C for 12 : 25 hours in an autoclave. After cooling, the solution is evaporated under vacuum and the residue obtained is ; taken up with water and then extracted with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated under vacuum. ~he res~due obtained crystallizes from ether to give 15.4 g of 6-n-butyl-2-methyl-4-amino-5-(4-nitrobenzyl)pyrimidine in the form or crystals melting at 135C.
`~ 35 . . .
.
, - 64 - 20~1327 Ex,ample 38: 6-n-Propyl-2-methyl-4-amino-5-(4-nitro-benzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, 05 XR3 = NH2, V = N02 Prepared by the procedure of Example 37.
Crystals melting at 152~C.
ExamDle 3~: N-[6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]morpholine Formula (XII): Rl = n-butyl, R2 = methyl, V = N02, XR3 = ~ O
8 g of 6-n-butyl-2-methyl-4-chloro-5-(4-nitro-benzyl)pyrimidine, prepared in Example 20, are dis-solved in 100 ml of xylene. 10 ml of morpholine are added and the,mixture is refluxed for 16 hours. After cooling, the xylene is evaporated off under vacuum and the residue is taken up with ether and washed with a dilute solution of sodium hydroxide and then with water. The ether phase is dried over magnesium sulfate and evaporated under vacuum to give a residue, which crystallizes from isopropyl ether to give 5 ~ of N-C6-n-butyl-2-methyl-5-(4-nitrobenzyl)pyrimidin-4-yl~-morpholine in the form of crystals melting at 124C.
Exam~le 40: N-l6-n-Propyl-~-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]~orpholine Formula (XII): Rl = n-propyl, R2 = methyl, V = NOz, , . . .
- 65 - 20~327 XR3 = N~O
05 Prepared by the procedure of Example 39.
Crystals melting at 125C.
Example 41: N-~6-n-Propyl-2-methyl-5-(4-nitrobenzyl)-pyri~idin-4-yl]thiomorpholine Formula (XII): R1 = n-propyl, R2 = methyl, V = NO2, XR3 = N~ S
Prepared by the procedure of Example 39.
Crystals melting at 133C.
Exam~le 42: 4-t6-n-Propyl-2-methyl-5-(4-nitrobenZyl)-pyrimidin-4-yl]-1-(2-methoxyphenyl)pipera-zine Formula (XII): Rl = n-propyl, R2 = methyl, : 25 V = N02, XR3 =
Cl-bO
Prepared by the procedure of Example 39.
Crystals melting at 110C.
:~:
... , . ,, ~
' . . .~
.
- 66 - 20453~7 E~am~le 43: 6-n-Propyl-2-methyl-5-(4-nitrobenzyl)-4-mercaptopyri~i~ine Formula (XII): R~ = n-propyl, R2 = methyl, 05 XR3 = SH, V = N02 24 g of 6-n-propyl-2-methyl-5-(4-nitrobenzyl)-4-chloropyrimidine, prepared in Example 19, and 5.5 g of thiourea are refluxed for 6 hours in 75 ml of ace-tone in the presence of 0.05 ml of concentrated hydro-chloric acid. The crystals obtained are filtered off, washed with acetone and then taken up in a mixture com-posed of 150 ml of ethanol, 150 ml of water and 25 g of sodium hydroxide pellets. The mixture is refluxed for 5 hours, the solvents are then evaporated off under vacuum, the residue is taken up with water and then acidified with concentrated hydrochloric acid and the crystals obtained are fi tered off and washed with water to give 12 g of 6-n-propyl-2-methyl-5-(4-nitro-benzyl)-4-mercaptopyrimidine melting at 212 C.
Exam~le 44: 6-n-Propyl-2-methyl-4-methylthio-5-(4-nitrobenzyl)pyrimidine Fornula (XII): Rl = n-propyl, R~ = methyl, XR3 = SCH3, V = N0, 4 g of 6-n-propyl-2-methyl-4-mercapto-5-~4-nitrobenzyl)pyrimidine, prepared in Example 43, are dissolved in 75 ml of ethanol. 0.6 g of sodium hydrox-ide dissolved in 10 ml of water is added and the mixture is stirred at room temperature for a few mlnutes. 1.5 ml o~ methyl iodide are then added to the reaction medium and tha solution is stirred for 2 hours ;~ 35 at room temperature and then for 2 hours under reflux.
., .. "~,., . , . . - :
- ' ' . , ., . . ~ .
, - 67 - 20~ ~327 After evaporation of the solvents under vacuum, the rlesidue is taken up with water and then extracted with ether; the ether phase is dried over magnesium sulfate and then evaporated to dryness to give 3.7 g of 6-05 n-propyl-2-methyl-4-methylthio-5-(4-nitrobenzyl)pyrimi-dine in the form of an oil, which is used as such for the next step.
~xample 45: 2-t6-n-Propyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yl]mercaptoethanol Formula (XII): Rl = n-propyl, R2 = methyl, R3 = CH2CH2OH, X = S, V =
Prepared by the procedure of Example 12.
Oil used as such for the next step.
Example 46: N-[6-n-Propyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yl]morpholine Pormula (XII): R, = n-propyl, R2 = methyl, V = NH2, XR3 = N O
Prepared by the procedure of Example 12.
Oil used as such for the next step.
Exam~le 47: N-[6-n-Propyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yl;thio~orpholine Formula (XII): R1 = n-propyl, R2 = methyl, - 68 - 20 ~ e~2~
V = NH2, XR3 = N S
05 Prepared by the procedure of Example 12.
Oil used as such for the next step.
Example 48: 4-[6-n-Propyl-2-methyl-s-(4-aminobenzyl)-pyrimidin-4-yl]-l-(2-methoxyphenyl)pipera lo zine Formula (XII): R1 = n-propyl, R2 = methyl, V = NH2, XR3 = N N~
\ \=:/
Prepared by the procedure of Example 12.
Oil used as such for the next step.
Exam~le 49: B~hyl ~6-n-butyl-2-methyl-5-[4-amino-benzyl)pyrimidin-4-yl]mer~aptoacetate Formula (XII): R, = n-butyl, R2 = methyl, V = NH2, R3 = CH~CO~Et, X - S
Prepared by the procedure o~ Example 12.
Oil used as such for the next step.
Exam~le:50: 2-16-n-Butyl-2-methyl-5-(4-aminoben~yl)-pyrimidin-4-yl]mercaptoethanol Formula (XII): R1 - n-butyl, R2 = methyl, ~,~
, . ~
~ .
69 20~ ~327 V = NHz, R3 = CH2CH20H, X = ~
Prepared by the procedure of Bxample 12.
05 Oil used as such for the next step.
Example 51: 6-n-Propyl-2-methyl-4-thiomethyl-5-(4-aminobenzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, V = NH2, XR3 = SCH3 Prepared by the procedure of Example 12.
Oil used as such for the next step.
Example 52: 6-n-Butyl-2-methyl-4-amino-5-(4-amino-kenzyl)pyrimidine Formula ~XII): Rl = n-butyl, R2 = methyl, V = NH2, XR3 = NH2 Prepared by the procedure of Example 12.
Oil used as such for the next step.
Xxample S3: 6-n-Propyl-2-methyl-4-amino-5-(4-amino-benzyl)pyrimidine Formula (XII): R~ = n-propyl, R, = methyl, V = NHz, XR3 = NH2 Prepared by the procedure of Example 12.
Oil used as such for the next step.
.:
~ 70 - 20~327 E~ L~-~: 2-[(6-n-Propyl-2-methyl-4-hydroxyethyl-mercaptopyrimidin-5-yl)methylphenyl-4-yl]-aminocarbonylbenzenesulfonic acid 05 Formula (I): R~ = n-propyl, R2 = methyl, R3 = CH2CH20H, X = S, N~OO~
R~
HO3S~
Prepared by the procedure of Example 13.
Crystals melting at 226-8C.
15 Example 55: 2-[(6-n-Butyl-2-methyl-4-hydroxyethyl~er-captop~rimidin-5-yl)methylphenyl-4-yl]-a~inocarbonylbenzenesulfonic acid Formula (I): Rl = n-butyl, R2 = methyl, R3 = CH2CH20H, X = S, N~OO~, R4 =
~03 Prepared by the procedure of Example 13.
Crystals melting at 198-9C.
~x~m~le 56: 2-~[6-n-propyl-2-methyl-4-(morpholin-l-yl) pyrimidin-s-yl]methylphenyl-4-yl]amino-carbonyl~enzenesulfonic acid Formula (I): Rl - n-propyl, R2 = methyl, .
20~ :~?32 7 XR3 = ~ 0, R4 =
Prepared by the procedure of Example 13.
Crystals melting at 213-6C.
Example 57: 2-[~6-n-Butyl-2-methyl-4-aminopyri~idin-5-yl)methylphenyl-4-yl]aminocarbonylbenzene-sulfonic acid Formula tI~: Rl = n-butyl, R2 = methyl, XR3 = NH2, R~
HO3S~
Prepared by the procedure of Example 13.
Crystals melting at 239-240Co lç_g~: 2-[~6-n-propyl-2-methyl-4-t(2-methoxy-phenyl)piperazin-4-yl)pyrimidin-5-yll-: ~ethy}phenyl-~-yl]aoinocarbonylbenzenesul-fonic acid ,:
Formula (I): Rl ~ n-propyl, R~ ~ methyl, XR3 = ~N~, ~; OCH3 R, =
.
-` ' ' -;, . .
. . ' .
- 72 - 20~327 Prepared by the procedure of Example 13.
Crystals melting at 215-7C.
Exam~le S~: 2-[[6-n-Propyl-2-methyl-4-methylthiopyrimi-05 din-5-yl]methylphenyl-4-yl]aminocarbonyl-benzenesulfonic acid Formula (I): Rl = n-propyl, R2 = methyl, N~OO
XR3 = SC~3, R, =
Prepared by the pr~cedure of Example 13.
Crystals melting at 254-7C.
ExamDle 60: 2-t[6-n-Propyl-2-methyl-4-(thiomorpholin-4-yl)pyrimidin-5-yl]methylphenyl-4-yl]amino-carbonylbenzenesulfonic acid Formula (I): Rl = n-propyl, R2 = methyl, x~ = N/ \S . R~
Prepared by the procedure of Example 13.
Cry tal~ melting at 207-210C.
Exam~le 61: 2-tt6-n-Butyl-2-methyl-4-(ethoxycarbonyl-~ethylthio)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rl = n-butyl, Rl = methyl, 20~327 X = S, R3 = CH2CO~Et, N~CO~
R~
05 HO3$~
Prepared by the procedure of Example 13.
Crystals melting at 262-3C.
Exam~le 62: 2-[t6-n-Propyl-2-methyl-4-(ethoxycarkonyl-methylthio)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonyl-3-methylkenzenesulfonic acid Formula (I): R1 = n-propyl, R2 = methyl, X = S, R3 = CH2CO2Et, R, =
Prepared by the procedure of Example 13 from 3-methylsulfobenzoic anhydride.
Crystals meltin~ at 224-227C.
:
Preparation of 3-methylsulfobenzoic anhydride A) ~thyl 6-methyLanthranilate 16.2 g of 6-methylanthranilic acid are dis-solved in 150 ml of tetrahydrofuran. 17.5 g of N,N-carbonyldiimidazole are added and the mixture is stirred for one hour at room temperature and then for 6 hours under reflux. The mixture is concentrated under ~' .
- . - s '~ :
, .
- 74 ~ 20 4~327 vacuum, 200 ml of ethanol are added and the mixture is refluxed for 6 hours. After evaporation of the solvent ~mder vacuum, the residue is taken up with isopropyl ether, the crystals are filtered off and the filtrate 05 is treated with charcoal and then evaporated to give 9.5 g of ethyl 6-methylanthranilate in the form of an oil, which is used as such for the next step.
B) 3-Methyl-~-etho~ycarbonylbenzenesulfonyl chloride 10.4 g of ethyl 6-methylanthranilate are added at -5C to 40 ml of concentrated hydrochloric acid. A
solution of 4.4 g of sodium nitrite in 10 ml of water is added dropwise at -5C and the mixture i5 stirred for 30 minutes at this temperature.
In a separate procedure, 8 g of sulfur dioxide are dissolved in 50 ml of acetic acid, and 1.~ g of copper(IIl chloride are added. The solution obtained is added dropwise to the reaction mixture, still at -5C. After having been stirred for one hour at 20 C
and then for one hour at 4n C, thè mixture is pou~ed on to ice and extracted with ether. The organic phase is dried over magnesium sulfate to give 6.7 g of 3-methyl-2-ethoxycarbonylbenzenesulfonyl chloride in the form of an oil, which is used as such for the next step.
C) 3-Methylsulfobenzoic anh~lde 6.7 g of 3-methyl-2-ethoxycarbonylbenzene-sulfonyl chloride are re~luxed for 3 hours in 60 ml of dlstilled water and 5 ml o~ concentrated hydrochloric acid. The solution obtained is filtered on active charcoal and then evaporated to dryness. The residue obtained is refluxed for 3 hours in 50 ml of acetic anhydride. The solution is evaporated to dryness under vacuum and the residue obtained crystallizes from an ether/pentane mixture. The crystals obtained are 20~327 fi.ltered off and dried to give 3.2 g of 3-methyl-sulfobenzoic anhydride in the form of crystals melting at 130C.
05 Example 63: 6-n-Butyl-2-isopropyl-4-hydroxy-5-(4-nitrobenzyl)pyrimidine Formula (XI): Rl = n-butyl, R~ = isopropyl, T = OH, V = NO2 1~
2.8 g of sodium are dissolved in 150 ml of ethanol and the solution is cooled to 5C. 15.1 g of isobutyramidine hydrochloride are added and the mixture is stirred for fifteen minutes. 25 g of ethyl 2-(4-nitrobenzyl)-3-oxoheptanoate, prepared in Example 4, are added and the mixture is stirred for 3 hours at room temperature and then poured into water and acidi-fied with concentrated hydrochloric acid. The crystals obtained are filtered off and washed with water and then with isopropyl ether and acetone to give 16.1 g of 6-n-butyl-2-isopropyl-4-hydroxy-5-(4-nitrobenzyl)pyri-midine in the form of crystals melting at 143 C.
Examle 64: 6-n-Butyl-2-phenyl-4-hydroxy-5-(4-nitro-b~nzyl)pyrimidine Formula (XI): R~ - n-butyl, R, = phenyl, T - OH, V = NO~
Prepared by the procedure of Example 63 from benzamidinQ hydrochloride.
Crystals melting at 2~0C.
.
- 76 - 20~327 Exam~le 65: 6-n-Butyl-2-isopropyl-4-chloro-5-(4-nitrobenzyl)pyrimidine Formula (XII): Rl = n-butyl, R2 = iso-05 propyl, XR3 = Cl, V = N02 Prepared by the precedure of Example 19.
Oil used as such for the next step.
Ex~me~ 6: 6-n-Butyl-2-phenyl-4-chloro-5-(4-nitro-benzyl)pyrimidine Formula (XII): Rl = n-butyl, R2 = phenyl, XR3 = Cl, ~ = N02 Prepared by the procedure of Example 19.
Crystals melting at 85C.
Exam~le 67: ~thyl ~6-n-butyl-2-phenyl-5-(4-nitro-benzyl)pyrimidin-4-yl]mercaptoace~ate Formula (XII): Rl = n-butyl, R2 = phenyl, X = S, R3 = CH2C02Et, V =
: Prepared by the procedure of Example 22.
Cry6tals melting at 102C.
~x~m~l~ 68: Ethyl [6-n-butyl-2-isopropyl-5-~4-nitro-benzyl)pyrimidin-4-yllmercaptoacetate For~ula (XII): R~ = n-butyl, R2 = iso-propyl, X = S, R3 =
CHaco2Et ~ V = N02 , 204~327 Prepared by the procedure of Example 22.
Oil used as such for the next step.
Example 69: 2-~6-n-Butyl-2-phenyl-5-(4-nitrobenzyl)-05 pyrimidin-4-yl]mercaptoethanol Formula (XII): Rl = n-butyl, R2 = phenyl, X = S, ~3 = CH2CH20H ~ V =
Prepared by the procedure of Example 3~.
Crystals melting at 98C.
Example 70: 2-[6-n-Butyl-2-isopropyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]mercaptoethanol Forcula (XII): Rl = n-butyl, R2 = iso-propyl, X = S, R3 =
CH2CH20H, V = N2 Prepared by the procedure of Example 34.
Oil used as such ~or the next step.
The following were prepared by the procedure of Example 12:
~X~19L~1: Ethyl ~6-n-butyl-2-phenyl-5-(4-amino-bensyl)pyrimidin-4-yl~mercaptoacetate For~ula (XII): Rl = n-butyl, R2 = phenyl, X = S, R3 = CH2CO2Et, V =
Oil used as such for the next step.
..... . , , .
- ~ ' . ' ' . ' - ~
,. - . -. ~
. . .
- 78 - 20~327 E~mple 7~: Ethyl [6-n-butyl-2-i~opropyl-5-(4-amino-benzyl)pyrimidin-4-yl]mercaptoacetate Formula ~XII): R~ = n-butyl, R2 = iso-05 propyl, X = S, ~ =
CH2CO2Et, V = NH2 Oil used as such for the next step.
Example 73: 2-[6-n-Butyl-2-phenyl-5-(4-aminobenzyl)-pyrimidin-4-yl]mercaptoethanol For~ula (XII): Rl = n-butyl, R2 ~ phenyl, X = S, R3 = CH2CH2OH, V =
Crystals melting at 103C.
Examle 74: 2-t6-n-Butyl-2-isopropyl-5-(4-aminobenzyl3-pyrimidin-4-yl]mercaptoethanol : Formula (XII): Rl = n-butyl, R2 = iso-: propyl, X = S, R3 =
CH2CH20H, V = NH2 ; : Oil used as such for the next step.
The ~ollowing compounds were prepared by the procedure o~ Example 13:
m~le 75: 2-t~6-n-Butyl-2-phenyl-4-~ethoxycarbonyl-methylthio)pyrimidin-5-yl~methylphenyl-4-yl]a~inocarbonylbenzenesulfonic acid ,~ .
~: 35 Formula ~ Rl = n-butyl, R2 = phenyl, .: .....
, - ., : -.
204~327 X = S, R3 = CH2CO2Et, N ICO ~
R4 = I 11 HO3S~/
Crystals melting at 241-242C. .
~xample ~Ç: 2-[[6-n-Butyl-2-isopropyl-4-(ethoxycarbo-nylmethylthio)pyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid For~ula (I): Rl = n-butyl, R2 = isopropyl, X = S, R3 = CH2CO2Et, N~OO~, R =
Crystals melting at 227-229~C.
~ xample 77: 2-t[6-n-Butyl-2-phenyl-4-~hydroxyethyl-: ~ 25 thio)pyrimidin-5-yl]methylphenyl-4-yl]-: aminocarbonylb~nzenesulfonic acid For~ula (I): Ra ' n-butyl, R, - phenyl, X = S, R3 - CH~CH~OH, CO~
R~
Crystals melting at 220-221C.
.
. .
: . . . .
- ~ . ; - . .
,' ': ' ' . ,' ~ , - : - ~, - . : , ~ .
, - 80 - 20~327 Ex~m~le 78: 2-[[6-n-Butyl-2-isopropyl-4-(hydroxy-ethylthio)pyrimidin-5~yl]methylphenyl-4-yl]a~inocarbonylbenzenesulfonic acid 05 Formula (I): Rl = n-butyl, R2 = isopropyl, X = S, R3 = CH2CH20H, N~CO~, R4 = l ll o HO3S
Crystals melting at 240-241C.
Exam~ 79: 1-Methoxy-4-oxoheptan-2-one Formula (IV): R~ = n-propyl, s = 1, U = O, Rl4 = CH3 A solution of 127.5 ml of methyl methoxyacetate and 214.5 ml of pentan-2-one in 100 ml of toluene is added dropwise to 33.5 g of finely divided sodium in 600 ml of hot toluene, the temperature being kept at between 60C and 70C. When the addition is complete, the mixture is heated for 2 hours at 55-60C, 30 ml of methanol are then added dropwise, the mixture obtained is taken up with water and washed with ether and the : aqueous phase is acidified with concentrated hydro-chloric acid and then extracted with ether. The orga-nic phase is dried over magnesium sulfate and evapora-ted under vaauum. The oily residue is distilled under reduced pressure to give 103.8 g of 1-methoxy-4-oxo-heptan-2-one boiling at 100-110C.
.:
.... . . . .
. ' : '.
- 81 - 20~327 ~am~le 80: 3-(4-Aceta~idobenzylidene)-l-methoxy-4-oxoheptan-2-one Formula (IV'): R1 = n-propyl, s = 1, U =
05 O, R14 = methyl, V = NHCOCH3 63.2 g of 1-methoxy-4-oxoheptan-2-one and 65.2 g of 4-acetamidobenzaldehyde are dissolved in 480 ml of toluene in the presence of 20 ml of acetic acid and 4 ml of piperidine. The mixture is refluxed for 5 hours and 10.5 ml of water are removed via a Dean-Stark apparatus. The crystals obtained after cooling are filtered off and washed with water, methylene chloride and isopropanol and then recrystallized from 200 ml of methanol to give 43 g of 3-(4-acetamidobenzylidene)-1-methoxy-4-oxoheptan-2-one in the form of crystals melting at 160~C.
Example 81: 6-n-Propyl-2-phenyl-4-methoxymethyl-5-(4-acetamidobenzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = phenyl, XR3 = CH20CH" V = NHCOCH3 42 g of 3-(4-acetamidobenzylidene)-1-methoxy-4-oxoheptan-2-onej prepared in Example 80, are dissolved in 1250 ml of acetic acid. 128.7 g of dry ammonium acetate are added and the mixture is heated at 60-70 C
for 10 minutes. 30 ml of benzaldehyde are added at 60C and the mixture is stirred for 2 hours at this temperature. 500 ml o~ benzene are added and the mix-ture is then refluxed, 9.5 ml o~ water being removed via a Dean-Stark apparatus. The solvents are concen-trated under vacuum and the residue is taken up with water and extracted with ethyl acetate. The organic ~::
.
,., .. ,,.. ~........... ~
- 82 - 20~'?3 2 7 phase is washed with water, dried over magnesium sul-fate and evaporated under vacuum. The residue obtained is chromatographed on silica gel in the eluent chloro-form 95/acetone 5 to giv~ 3.5 g of 6-n-propyl-4-meth-05 oxymethyl-2-phenyl-5-(4-acetamidobenzyl)pyrimidine in the form of crystals melting at 135C.
Example 82: 6-n-Propyl-2-phenyl-4-methoxymethyl-5-(4-aminobenzyl)pyrimidine Formula (XII): R1 = n-propyl, R2 = phenyl, XR3 = CH2OCH3, V = NH2 1.8 g of 6-n-propyl-2-phenyl-4-methoxymethyl-5-(4-acetamidobenzyl)pyrimidine, prepared in Example 81, are dissolved in a mixture composed of 25 ml of ethanol and 25 ml of water. 2 g of sodium hydroxide pellets are added and the mixture is refluxed for 15 hours and then taken up with water and extracted with ether. The organic phase is dried and then evaporated under vacuum. The residue obtained is chromatographed on silica gel with ether as the eluent to give 1.2 g of 6-n-propyl-2-phenyl-4-methoxymethyl-5-(4-aminobenzyl)-pyrimidine in the form of crystals melting at 115 C.
25~ample ~3: 2-[[6-n-Propyl-4-methoxymethyl-2-phenyl-pyrimidin-5-yl]methylphenyl-4-yl]amino-carbonylbenzenesulfonic acid Formula (I): Rl = n-propyl, R~ = phenyl, XR3 = CH~OCH3, NHCO~
H
.. :
- 83 - 2 0 ~ r~ 3 2 7 Prepared by the procedure of Example 13.
Crystals melting at 186-187C.
Example 84: 2-[(6-n-Propyl-2-methyl-2-aminopyrimidin-05 5-yl)methylphenyl-4-yl]aminocarbonyl-benzenesulfonic acid Formula (I): Rl = n-propyl, R2 = methyl, XR3 = NH2, R
Prepared by the procedure of Example 13.
Crystals melting at 310-312C.
~xample ~5: N-[6-n-Butyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yll.morpholine Formula (XII): Rl = n-butyl, R2 = methyl A
V = NH2, XR3 = N~O
Prepared by the procedure of Example 12.
Oil used as such for the next step.
~Y~m~ 2-l(6-n-Butyl-2-methyl-4-(morpholin-1-yl)-pyrimidin-5-yl)methylphenyl-4-yl]amino-carbonylbenzenesulfonic acid Formula (I): Rl z n-butyl, R2 = methyl, ~
~' '.
,.. ,. , . - ~
~.
- 84 - 2 0~ ~3 2 7 R4 = I
Prepared by the procedure of Example 13.
Crystals melting at 213 6C.
~xample 87: 6-n-Propyl-2-methyl-4-hydroxy-5-[2'-(tetra-zol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): Rl = n-propyl, R2 = methyl, XR3 = OH, R4 N~
`N_N
Prepared by the procedure of Example 31 from 6-n-propyl-2-methyl-4-hydroxy-5-(2'-cyanobiphenyl-4-yl)-methylpyrimidine, prepared in Example 10.
; Crystals melting at 204-6C.
Exam~ 88: 6-n-Propyl-2-methyl-4-(2-hydroxyethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XII~: Rl = n-propyl, R2 = methyl, X = O, R3 = CH,CH2OH, : 30 ~
~ 35 8 g of 6-n-propyl-2-methyl-4-hydroxy-5-(2'-.,~,.. .
- 85 - 20~327 cyanobiphenyl-4-yl)methylpyrimidine, prepared in Exam-ple 10, are dissolved in 80 ml of acetonitrile in the presence of 4 g of potassium carbonate, and 3 ml of 2-bromoethanol are added. The mixture is brought to the 05 reflux temperature and hea~ed for 8 hours; the solvents are concentrated under vacuum and the residue is taken up with water and then extracted with methylene chlo-ride. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give an oily residue, which is chromatographed on silica gel.
Elution with an 80/20 methylene chloride/acetone mix-ture gives 2.1 g of pure 6-n-propyl-2-methyl-4-(2-hydroxyethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimi-dine in the form of crystals melting at 103 c.
If elution is continued with a 60/40 methylene chloride/acetone mixture, 2.8 g of 6-n-propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-3-(2-hydroxyethyl)-3,4-dihydro-4-oxopyrimidine are recovered in the form of an oil, which is used as such for the next step.
Example 89: 6-n-Propyl-2-methyl-4-(2-hydroxyethyl)oxy-5-12'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidine Formula (I): R, = n-propyl, R2 = methyl, X = O, R3 = CH2cH20H, ~, R, =
o N
N
H
3.8 g of 6-n-propyl-2-methyl-4-(2-hydroxy-ethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, prepared in Example 88, are dissolved in 80 ml of toluene. 2.7 g of trimethyltin nitride are added and '' ';.
2 0 4 r~ 3 2 7 the mixture is refluxed for 35 hours, cooled and extracted with a dilute solution of potassium hydro-xide, which is washed with ethyl acetate. The aqueous phase is then acidified by having sulfur dioxide 05 bubbled through it, and is extracted with chloroform.
After drying and evaporation of the solvent, the residue obtained is chromatographed on silica gel in an 85/15 chloroform/ethanol eluent to give 2 g of 6-n-propyl-2-methyl-4-(2-hydroxyethyl)oxy-5-[2'-ttetrazol-5-yl~biphenyl-4-yl]methylpyrimidine in the form of cry~tals melting at 154-155C.
Example 90: 6-n-Propyl-2-methyl-3-(2-hydroxyethyl)-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxopyrimidine hydrochloride Formula (I'): R = n-propyl, R2 = methyl, R' 3 = CH,CH~OH, N
~I_N
Prepared by the procedure of Example 89 from 6-n-propyl-2-methyl-3-(2-hydroxyethyl)-5-(2'-cyanobi-phenyl-4-yl)methyl-3,4-dihydro-4-oxopyrimidine, pre-pared in Example 88. The hydrochloride i8 obta1ned by bubbling hydrochloric acid into a tetrahydrofuran solu-tion o~ the compound in the form o~ the base.
Crystals melting at 240-1C.
. . ' ~ ' , .
.
20~327 Example 21: 6-n-Propyl-2-methyl-4-(prop-2-yl)oxy-S-(2'-cyano~iphenyl-4-yl)methylpyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, XR3 = ~ , V =
Prepared by the procedure of Example 30.
Oil used as such for the next step.
Example ~2: 6-n-Propyl-2-methyl-4-(prop-2-yl)oxy-5-t2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyri-midine Formula (I): Rl = n-propyl, R2 = methyl, ~1 XR3 = ~ , R~ = ~ ;~, ~ _N
Prepared by the procedure of Example 89.
Crys~als melting at 190-1C.
Example 93: N-t6-n-Propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methylpyri~idin-4-yl]thiomorpholine Formula (XII): R1 = n-propyl, R~ = methyl, XR, = ~ S , V =
' ,. . , ~ .
.
20~327 Prepared by the procedure of Example 39.
Crystals melting at 153-4C.
~Kample 94: N-[6~n-Propyl-2-~ethyl-5-[2'-(tetrazQl-5-05 yl)biphenyl-4-yl]methylpyrimidin-4-yl]-thiomorpholine hydrochloride Formula (I)O Rl = n-propyl, R2 = methyl, XR3 = ~ S , R4 =
N ~ N
Prepared by the procedure of Example 89. The hydrochloride is obtained by dissolving the compound in the form of the base in an acetone/ether mixture and bubbling hydrochloric acid.
Crystals melting at 240-241C.
~x~m~le 95: 6-n-Propyl-2-methyl-4-mercapto-5-(2'-cyanobiphenyl-4-yl)methylpyri~idine Formula (XII): Rl = n-propyl, R~ = methyl, XR3 = SH, V =
N~
Prepared by the procedure o~ Example 43.
Crystals melting at 202-3C.
.
,. ~ . . .
' ' ~ ' .
-.
: - , . ~ :
. .
- 89 - 20~327 ~cample 96: 6-n-Propyl-2-methyl-4-mercapto-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyri midine O 5 FGrmU1a ( I ): R~ = n-propyl, R2 = methyl, ~, XR3 = SH, R4 = l ll ,N~/
N_N
Prepared by the procedure of Example 89.
Crystals melting at 247-248C.
Example ~: 6-n-Propyl-2-methyl-4-methylthio-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XII): R1 = n-propyl, R2 = methyl, XR3 = SCH3, V =
Prepared by the procedure of Example 44.
Crystals melting at 134C.
:~ Exam~le ~: 6-n-Propyl-2-methyl-4-methylthio-5-t2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyri-~idine Formula (I): Rl - n-propyl, R, = methyl, ~; 35 . ~, ..
' - go - 20~327 XR3 = SCH3, R~ = N~
N~N - H
Prepared by the procedure of Example 89.
Crystals melting at 173-174~C.
Exam~le 99: 6-n-Propyl-2-methyl-4-(2~hydroxyethyl)-mercapto-5-(2'-cyanobiphenyl-4-yl)methyl-pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, ~ = S, R3 = CH2CH20H, V= ~3 Prepared by the procedure of Example 34.
Crystals melting at 97-C.
Exam~Ie 100: 6-n-Propyl-2-methyl-4-(2-acetoxyethyl)-~:~ mercapto-5-(2'-cyanobiphenyl-4-yl)methyl-~:~;: 25 pyrimidine ~ ;
Formula (XII)~: Rl = n-propyl, Rl = methyl, X = S, R, = CH2CH20COCH"
V ~ ~
~ 6.7 g of 6-n-propyl-2-methyl-4-(2-hydroxy-~:
.. - . .
, 91 - 2Q4-~327 ethyl)mercapto-5-(2'-cyanobiphenyl-4-yl)methylpyrimi-dine, prepared in Example 99, are refluxed in 35 ml of acetic anhydride for 3 hours. The acetic anhydride is evaporated off under vacuum, the residue is taken up 05 with ether and the ether solution is filtered on animal charcoal and then evaporated under vacuum to give 5.9 g of 6-n-propyl-2-methyl-4-(2-acetoxyethyl)mercapto-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine in the form of an oil, which is used as such for the next step.
Example 101: 6-n-Propyl-2-methyl-4-(2-hydroxyethyl)-mercapto-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): R, = n-propyl, R2 = methyl, X = S, R3 = CH2CH20H, R4 =
N~
N' 5.9 g of 6-n-propyl-2-methyl-4-(2-acetoxy-ethyl)mercapto-5-(2'-cyanobiphenyl-4-yl)methylpyrimi-dine, prepared in Example 100, are dissolved in 100 ml of toluene, and 3.7 g of trimethyltin nitride are added. The mixture is refluxed for 12 hours, cooled, taken up with ether and extracted with a dilute solu-tion of potassium hydroxide~ The aqueous phase i~acidified by having sulfur dioxide bubbled through it, and i8 then extracted with chloroform. The chloroform phase is dried over magnesium sulfate and evaporated under vacuum; the residue obtained is chromatographed on silica gel with an 85/15 chloroform/methanol eluent - 92 - 20~`~327 to give 2.5 g of a residue composed of a mixture of the expected alcohol and the acetylated derivative. This mixture is taken up in a dilute solution of potassium hydroxide and left to stand overnight at room tempera-05 ture. The aqueous solution is washed with ether andthen acidified by having sulfur dioxide bubbled through it, and the crystals obtained are filtered off and washed with ether to give 2.3 g of 6-n-propyl-2-methyl-4-(2-hydroxyethyl)mercapto-5-[2'-~tetrazol-5-yl)bi-phenyl-4-yl]methylpyrimidine in the form of crystals melting at 186-189~C.
~Y9~5LsLiQ2: Ethyl 2-(2'-cysnobiphenyl-4-yl)methyl-3-oxoheptanoate 5 Formula (VI): Rl = n-butyl, R3 = ethyl, V= I 11 NC~
Prepared by the procedure of Example 6.
Oil used as such for the next step.
Exampl~ 103: 6-n-Butyl-2-methyl-4-hydroxy-5-(2'-cyano-biphenyl-4-yl)methylpyrimidine Formula (XI): R~ = n-butyl, R, = methyl, ~, ~ = O~, V =
N~
Prepared by the procedure of Example 7.
Crystals meltin~ at 173C.
- 93 - 204~327 ~xample lQ~: 6-n-Butyl-2-methyl-4-chloro-5-(2'-cyano-biphenyl-4-yl)methylpyrimidine Formula (XII): Rl = n-butyl, R2 = methyl, 05 ,~
XR3 = Cl, V =
Prepared by the procedure of Example 19.
Crystals melting at 75C.
Example 105: 6-n-Butyl-2-~ethyl-4-methoxy-5-(2'-cyano-biphenyl-4-yl)methylpyrimidine Formula (XII): R1 - n-butyl, R2 = methyl, XR3 = OCH3, V =
Prepared by the procedure of EXample 30.
Oil used as such for the next step.
Exam~le 106: 6-n-Butyl-2-methyl-4-methoxy-5-[2~-(tetra zol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): Rl - n-butyl, R~ ~ methyl, XR3 - OCH3, R~ ' N
N~
94 _ 204.~327 Prepared by the procedure of Example 89.
Crystals melting at 148-149C.
Example 107: 6-n-Butyl-2-methyl-4-hydroxy-5-[2'-(tetra-05 zol-5-yl)biphenyl-4-yl]methylpyri~idine For~ula (I): R~ = n-butyl, R2 = methyl, XR, = ON, R. = N
Prepared by the procedure of Example 31.
Crystals melting at 248-249C.
Example 108: 6-n-Propyl-2-methyl-4-(2-methoxyethyl)-oxy-5-(2'-cyanobiphenyl-4-yl)methylpyri-midine Formula (XII): Rl = n-propyl, R2 = methyl, X = O, R3 = CH2CH2O
V = ~ 3 Prepared by the procedure oP Example 30 from 2-methoxyethanol.
Oil used as such for the next step.
.~
, , .
_ 95 - 20~-~327 Exa~le 10~: 6-n-Propyl-2-methyl-4-(2-methoxyethyl)oxy-5-~2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidine 05 Formula (I): Rl = n-propyl, R2 = methyl, X - 0, R3 = CH2CH2~CH3, ~, ,N~
o N N
Prepared by the procedure of Example 89.
Crystals melting at 169-170C.
Exa~m~le 110: 6-n-Propyl-2-methyl-4-(2-dimethylamino-ethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methyl-pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, : X = 0, R3 ~
V=
NC~
: 6 g of 6-n-propyl-2-methyl-5-(2~-cyanobiphenyl-4-yl)methyl-4-chloropyrimidine, prepared in Example ~1, ~: are added to a solution obtained by adding 1 g of 60~
sodium hydride to 75 ml of THF containing 2.7 g of 2-.
- 96 - 20~327 dimethylaminoethanol. The mixture is stirred for 4 hours under reflux, the solvent is then concentrated under vacuum and the residue is taken up with water and extracted with ether. The organic phase is washed with 05 water and then dried over magnesium sulfate to give 5.1 g of 6-n-propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-(2-dimethylaminoethyl)oxypyrimidine in the form of an oil, which is used as such for the next step.
E~aLlÇL~ 6-n-Propyl-2-methyl-4-(2-dimethylamino-ethyl)oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): Rl = n-propyl, R2 = methyl, X = O, R3 = CH2CH2 N~
R4 =
~`N_N
H
Prepared by the procedure of Example 89.
Crystals melting at 175-176C.
~89~l9~1lZ: 6-n-Propyl-2-methyl-4-~2-morpholinoethyl)-amino-5-(2'-cyanobiphenyl-4-yl)methylpyri-midine Formula (XII): Rl = n-propyl, R2 = methyl, ` .
-_ 97 - 20~327 X = NH, R3 = CH2CH2 N~O, 05 v= I 11 Prepared by the procedure of Example 39 from N-(2-aminoethyl)morpholine.
Oil used as such for the next step.
Example 113: 6-n-Propyl-2-methyl-4-(2-morpholinoethyl)-amino-S-[2'-(tetrazol-5-yl)biphenyl-4-yl~-methylpyrimidine For~ula (I): R, = n-propyl, R2 = methyl, X = NH, R3 = CH2CH2 N~O, R =
~`N_N
~ Prepared by the procedure of ~xample 89.
:- Crystals melting at 270-2 C.
Example 114: 6-n-Propyl-2-~ethyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-(2-hydroxyethyl)aminopyri-midine :~
:~: For-Nla (XII): R, = n-propyl, R2 = methyl, X = NH, R3 = CH2CH2OH, ~: : 35 ~ .
: .
', . . . . .
.. ~ . . .
.
,- ~ , .
. ' ' .
- 98 - 204.~327 ,~, V=
~/
Prepared by the procedure of Example 39 from ethanolamine.
Crystals melting at 135~C.
~m~le 115: 6-n-Propyl-2-methyl-5-[2'-(tetrazol-5-yl)-biphenyl-4-yl]methyl-4-(2-hydroxyethyl)-aminopyrimidine FQrmula (I): R~ = n-propyl, R2 = methyl, X = NH, R~ = CH2CH20H, R4 = _ ~` NH
Prepared by the procedure of Example 89.
Crystals melting at 149-150C.
E~9~RlgL~Lk: 6-n-propy}-2-methyl-4-(2-~ethylthioethyl)-oxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimi-dine :
Formula (XII~: R~ = n-propyl, Rl ~ methyl, X - 0, R3 = CH,CH2SCH3, :
::
.,,, . . ~ - .
. ~ . ~ ....
, ~ ~ . . .
- - ' ~
: , 2~4~327 Prepared by the procedure of Example llo from 2-methylthioethanol.
Oil used as such for the next step.
05 Exam~le lL7: 6-n-Propyl-2-methyl-4-(2-methylthioethyl)-oxy-5-t2'-(tetrazol-5-ylIbiphenyl-4-yl]-~ethylpyrimidine Formula (I): R1 = n-propyl, R2 = methyl, X = 0, R3 = CH~CH2SCH3, R4 = N~
N -Prepared by the procedure of Example 89.
Crystals melting at 121-122C.
Example 118: 6-n-Butyl-2-methyl-4-(2-methoxyethyl)-oxy-5-(2'-cyanobiphenyl-4-yl)methylpyri-midine Formula (XII): Rl = n-butyl, R2 = methyl, X = 0, R~ = CH2CH20CH3, V= 1 1.1 N~
Prepared by the procedure o~ Example 30.
Oil used as such for the next step.
- ' :
lOO- 20~.~327 Example 119: 6-n-Butyl-2-methyl-4-(2-methoxyethyl)oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidine 05 Formula (I): Rl = n-butyl, R2 = methyl, X = 0, R3 = CH2CH20CH3, R4 =
N
lo ~ N
N~H
Prepared by the procedure of Example 89.
Crystals melting at 128-129C.
~xample 120: 6-n-Butyl-2-methyl-4-(2-dimethylamino-ethyl)oxy-5-(2'-cyanobiphenyl-4-yl)methyl-pyri~idine Formula (XII): Rl = n-butyl, R2 = methyl, X = 0, R3 = CH2CH2 ~C
V = ~
NC
Prepared by the procedure of Example 110.
Oil used as suah ~or the next step.
:
' ' ' `: ' ' - :~ ' .. ~ `.
' :
.
2oL~327 Exam~le 121: 6-n-Butyl-2-methyl-4-(2-dimethylamino-ethyl)oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine 05 For~ula (I): R, = n-butyl, R2 = methyl, X = O, R3 = CH2CH2 ~CH
R4 =
~ _N
N H
Prepared by the procedure of Example 89.
Crystals melting at 166-167C.
Example 122: Ethyl 3-oxooctanoate For~ula (II): Rl = n-pentyl, R,3 = ethyl Prepared by the procedure of Example 1.
25Oil of b.p.,5 = 110-115 C.
Exam~le 123: Ethyl 2-(2'-cyanobiphenyl-4-yl)methyl-3-oxooctanoate ~
Foruula (VI): R, = n-pentyl, V = ~ J .
CN
R,3 = ethyl Prepared by the procedure of Example 3.
.
, - 102 - 204~327 Oil used as such for the next step.
xample 124: 6-n-Pentyl-2-methyl-4-hydroxy-5-(2'-cyanobiphenyl-4-yl)methylpyr~midine Formula (XI): Rl = n-pentyl, R2 = methyl, T = OH, V =
Prepared by the procedure of Example 7.
Crystals melting at 162C.
Exam~le 125: 6-n-Pentyl-2-methyl-4-hydroxy-5-[2'-(tet-razol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): R1 = n-pentyll R2 = methyl, XR3 = OH, R4 = N~
N'~N--N
H
Prepared by the procedure of Example 31.
Crystals melting at 195-196C.
mpLe 126: 6-n-Penty}-2,3-dimethyl-5-(2'-cyanobi-phenyl-4-yl)methyl-3,4-dihydro-4-oxopyri-midine Formula (XII'): Rl = n-pentyl, R2 =
methyl, R'3 = methyl, - 103 - 20~327 ,~
V = -W
05 7 g of 6-n-pentyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-hydroxypyrimidine, prepared in Example 124, are dissolved in 70 ml of dimethylformamide.
After the addition of 0.8 g of 60% sodium hydride, the mixture is stirred for 30 minutes at room temperature.
2 ml of methyl iodide are added and the solution is heated for 2 hours at 80C. The solvent is evaporated off under vacuum and the residue is taken up with water and extracted with ether. The ether phase is dried over magnesium sulfate and evaporated under vacuum and the residue is chromatographed on silica gel in a 90/lO
chloroform/acetone eluent to give 5.8 g of 6-n-pentyl-2,3-dimethyl-5-(2'-cyanobiphenyl-4-yl)methyl-3,4-di-hydro-4-oxopyrimidine in the form of an oil, which is used as such for the next step.
ExamDl e 127: 6-n-Pentyl-2,3-dimethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-pyrimidine hydrochloride Formula (I'): Rl = n-pentyl, R2 = methyl, R'3 = methyl, R~ = N~
N--H
Prepared by the procedure of Example 90.
Crystals melting at 215~217C.
,. ~, ., . . ~
- 104 - 2 ~ ~ ~ 3 2 7 Example ~8: 6-n-pentyl-2-methyl-4-chloro-s-(2~-cyan biphenyl-4-yl)methylpyrimidine Formula (XII): Rl = n-pentyl, R2 = methyl, XR3 = Cl, V =
~/
loPrepared by the procedure of Example 19.
Oil used as such for the next step.
~x~m~le 129: Ethyl 2-t6-n-pentyl-2-methyl-5-(2'-cyano-biphenyl-4-yl)methylpyrimidin-4-yl]oxy-15acetate Formula (XII); Rl = n-pentyl, R, = methyl, X = 0, R3 = CH2C02Et, ~ .
20V = l 11 ~ .
3 g of ethyl 2-hydroxyacetate are dissolved in 2550 ml of anhydrous tetrahydrofuran. 1.1 g of 60%
sodium hydride are added and the mixture is stirred for 30 minutes at 50-60C. 5.4 q of 6-n-pentyl-2-methyl-4-chloro-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, pre-pared in Example 128, are added and the mixture i8 re~luxed ~or 8 hours. ~he solvent is evaporsted o~
under vacuum and the residue is taken up with water and extracted with ethyl acetate. The organic phase i9 dried over magnesium sulfate and concentrated under vacuum to give an oil, which crystallizes from iso-35propyl ether to give 3.4 g of ethyl 2-[6-n-pentyl-2-, ..... .
2 0 4 -~ 3 2 7 methyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-4-yl]-oxyacetate in the form of crystals melting at 68C.
Example 130: ~thyl 2-[6-n-pentyl-2-methyl-5-t2'-05 (tetrazol-5-yl~biphenyl-4-yl]methylpyri-midin-4-yl]oxyacetate Formula (I): Rl = n-pentyl, R2 = methyl, X = O, R3 = CH2CO2Et, R4 =
N
N--Prepared by the procedure of Example 89.
Crystals melting at }46-148C.
~mDle 131: Ethyl 2-[6-n~propyl-2-methyl-5-t2'-cyano-biphenyl-4-yl)methylpyrimidin-4-yl]oxy-acetate For~ula (XII): R1 = n-propyl, R2 = methyl, X = O, R3 = cH2co2Et~
V= 1 11 ~/
Prepared by the procedure of Example 129.
Oil used as such for the next step.
.... ~ . :
~' , - 106 - 2Q~327 Example 132: Ethyl 2-t6-n-propyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyri-midin-4-yl]oxyacetate 05 Formula ( I ): Rl = n-propyl, R2 = methyl, X = o, R3 = CHzCO2Et, R =
~ ~,N
~ H
Prepared by the procedure of Example 89.
Crystals melting at 149-150C.
Example 133: 6-n-Propyl-2-mercapto-4-hydroxy-5-(4-nitrobenzyl)pyrimidine Formula (XI): Rl = n-propyl, R, = SH, T =
OH, V = NO2 5.7 g of sodium are dissolved in 150 ml of methanol, and 19 g of thiourea are added. The mixture is stirred for 5 minutes at room temperature and 55 g of ethyl 3-oxohexanoate, prepared in Example 1, are ~;: added. After refluxing for 8 hours, the solvent is concentrated to half its volume under vacuum and the : resldue is taken up with water and neutralized by the addition o~ dilute hydrochloric acid. The mixture i9 le~t to stand overnight at room temperature and the ¢rystals formed are filtered off, washed with ether and ethanol and dried to give 29 g of 6-n-propyl-2-mer-: capto-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of crystals melting at 240C.
.
204~327 E~ample 134: 6-n-Propyl-2-methylthio-4-hydroxy-5-(4-nitrobenzyl)pyrimidine Formula (XI): R, = n-propyl, R2 = SCH3, 05 T = OH, V = N02 26 g of 6-n-propyl-2-mercapto-4-hydroxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 133, and 8.3 g of potassium hydroxide are dissolved in 200 ml of methanol. The mixture is stirred ~or lo minutes at room temperature and 5.3 ml of methyl iodide are added.
The mixture is then refluxed for 2 hours. The solvent is evaporated of~ under vacuum and the residue is taken up with water. After acidification with a dilute solu-tion of hydrochloric acid, the aqueous phase is extrac-ted with chloroform. The organic phase is dried over magnesium sulfate and then evaporated under vacuum and the residue crystallizes from a chloroform/methanol mixture to give 13.4 g of 6-n-propyl-2-methylthio-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of crystals melting at 223C.
Example 1~5: 6-n-Propyl-2-methylthio-4-chloro-5-(4-nitrobenzyl)pyrimidine For~ula (XII): Rl = n-propyl, R2 = SCH3, XR3 = Cl, V = NO2 Prepared by the procedure of Example 19.
Crystals melting at 108C.
Example 136: 2-t6-n-propyl-2-methylthio-5-(4-nitr benzyl)pyrimidin-4-yl]mercaptoethanol Formul~ (XII): R~ = n-propyl, R2 = SCH3, l ~
- -' -' ~
20~i327 X = S, R3 = CH2CH20H, V =
Prepared by the procedure of Example 34.
05 Crystals melting at 97C.
Example 137: 2-[6-n-Propyl-2-methylthio-5-(4-ami-lo-benzyl)pyrimidin-4-yllmercaptoethanol Formula (XII): R~ = n-propyl, R2 = SCH3, X = S, R3 = CH2CH20H, V =
Prepared by the procedure of Example 12.
Oil used as such for the next step.
Example 1~: 2-[t6-n-Propyl-2-methylthio-4-(2-hydroxy-ethyl)~ercaptopyrimidin-5-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid For~ula (I): R~ = n-propyl, R2 = SCH3, X = S, R3 = CH2CH20H, R, =
HO3S~
Prepared by the procedure of Example 13.
Crystals melting at 198-201aC.
:~ 35 .
' ' ' ~'' ,, :
- , lOg- 20~327 ExamPle 139: 3-t6-n-Propyl-2-methyl-5-(2'-cyanobi-phenyl-4-yl)methylpyrimidin-4-yl]mercapto-propanol 05 Formula (XII): R = n-propyl, R2 = methyl, X = S, R3 = CH2CHzCH2OH, V= 1~ 1~
NC~ ~
5 g of 6-n-propyl-2-methyl-4-mercapto-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine, prepared in Exam-ple 95, are dissolved in 50 ml of ethanol. 0.4 g of sodium discolved in 10 ml of ethanol is added and the mixture is stirred for 10 minutes at room temperature.
2.5 g of 3-bromopropanol are added and the reaction mixture is refluxed for 6 hours. ~he solvent is then evaporated off under vacuum and the residue is taken up with water and extracted with ether. The ether phase is dried over magnesium sulfate and evaporated under vacuum to give 5 g of 3-[6-n-propyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-4-yl]mercaptopropa-nol in the form of an oil, which is used as such for the next step~
Example 140: 6-n-Propyl-2-~ethyl-4-(3-acetoxypropyl)-mercapto-S-(2'-cyanobiphenyl-4-yl)methyl-pyrimidine Forcula (XII): Rl = n-propyl, Rz = methyl, X = S, R3 = CH2CH2CH2OCOCH3, ~ V= ~0 ~ 3 NC
;:
.
: .
. . . ..
- llO - 2 0 ~ ~ 3 2 7 Prepared by the procedure of Example 100.
Oil used as such for the next step.
~Kample 141: 6-n-Propyl-2-methyl-4-(3-acetoxypropyl)-05 mercapto-5-t2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine Formula (I): Rl = n-propyl, R2 = methyl, X = S, R3 = CH2CH2CH20COCH3, R4 =
N~
Prepared by the procedure of Example 89.
Oil used as such for the next step.
Example 142: 3-t6-n-Propyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]-mercaptopropanol For~ula (I): R~ = n-propyl, R2 = methyl, X - S, R3 = CH2CH~CH20H, R4 =
3 g of 6-n-propyl-2-methyl-4-(3-acetoxypropyl)-~: mercapto-5-~2~-(tetrazol-5-yl)biphenyl-4-yl]methyl W ri-: midine, prepared in Example 141, are dissolved in 30 ml of ethanol in the presence of 1 g of sodium hydroxide pellets. The mixture i~ heated for one hour at 50 C.
:
2~327 The alcohol is evaporated off under vacuum, the residue is taken up with warm water, the solution is acidified by having sulfur dioxide bubbled through it, and is extracted with chloroform, the organic phase is concen-05 trated under vacuum and the residue obtained crystalli-æes from acetone to give 2.2 g of 3-[6-n-propyl-2-methyl-5-~2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimi-din-4-yl]mercaptopropanol in the form of crystals melting at 157-158C.
Example 143: 6-n-Propyl-4-hydroxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XI): Rl = n-propyl, R2 = H, T = OH, V = l ll 13 g of ethyl 2~(2'-cyanobiphenyl-4-yl)methyl-3-oxohexanoate, prepared in Example 6, are dissolved in 100 ml of diglyme. 8 g of formamidine acetate are added and the mixture is heated for 8 hours at 200 C
and then taken up with water and extracted with ethyl acetate. The organic phase is washed several times with a dilute solution of sodium hydroxide and the aqueous extracts are neutralized with hydrochloric acid to give 2.6 g of 6-n-propyl-4-hydroxy-5-(2'-cyanobi-phenyl-4-yl)methylpyrimidine in the form o~ crystals melting at 152C.
Exa~k~ 144: 6-n-Propyl-4-chloro-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine For~ula IXII): Rl = n-propyl, R2 ~ H, - 112 - 20~327 XR3 = Cl, V =
05 Prepared by the procedure of Example 19.
Crystals melting at 58C.
Example 145: 6-n-Propyl-4-methoxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine Formula (XII): Rl = n-propyl, R2 = H, XR3 = OCH" V =
Prepared by the procedure of Example 30.
Crystals melting at 110C.
Example 146: 6-n-Propyl-4-methoxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl~methylpyrimidine Formula (I): Rl - n-propyl, Ra = H
X = O, R3 = CH3, N~
N`N'N
H
:~ Prepared by the procedure of Example 89.
Crystals melting at 148-149C.
.. .. .
2 0 ~ 2 7 xam~le 147: 6-n-Propyl-2-amino-4-hydroxy-5-(4-ni~ro-benzyl)pyrimidine Formula (XI): Rl = n-propyl, R2 = NH2, T =
05 OH, V = NO2 18.8 g of guanidine hydrochloride are added to a solution of sodium ethylate obtained by adding 4.5 g of sodium to 150 ml of ethanol. The mixture is stirred for 5 minutes and 50 g of ethyl 3-oxo-2-(4-nitro-benzyl)hexanoate, prepared in Example 3, are added.
After 4 hours at room temperature and 4 hours under reflux, the mixture is taken up with water and the crystals are filtered off and washed with ether and acetone to give 22.1 g of 6-n-propyl-2-amino-4-hydroxy-5-(4-nitrobenzyl)pyrimidine in the form of crystals melting at 245-8C.
Example 148: 6-n-Propyl-2-amino-4-chloro-5-(4-nitro-benzyl)pyrimidine Formula (XII): R1 = n-propyl, R2 = NH2, XR3 = Cl, V = NO2 .
Prepared by the procedure of Example 19.
Crystals melting at 140C.
EY9~ 2: 2-~6-n-Propyl-2-amino-5-(4-nitrobenzyl)-pyrimidln-4-yl percaptoethanol Formula (XII): R = n-propyl, R2 = NH~, X = S, R3 = CH2CH2OH, V =
Prepared by the procedure of Example 34.
` '~
204~327 Crystals melting at 110C.
E~am~le 150: 2-t6-n-propyl-2-amino-5-(4-amino~enzyl) pyrimidin-4-yl]mercaptoethanol Formula (XII): Rl = n-propyl, R2 = NH2, X = S, R3 = CH2CH20H, V =
Prepared by the procedure of Example 12.
Crystals melting at 138C.
Exam~le 151: 2-[16-n-Propyl-2-amino-4-(2-hydroxyethyl)-mercaptopyrimidin-5-yl~methylphenyl-4-yl]-aminocarbonylbenzenesulfonic acid Formula (I): Rl = n-propyl, R2 = NH2, X =
S, R3 = CH2CH20H, R~ =
Prepared by the procedure of Example 13.
Crystals melting at 228-230C.
Examlple 152: N-2-[6-n-Butyl-2-meth~1-5-(2'-cyanobi-phenyl-4-yl)methylpyrimidin-4-yl]oxyethyl-phthalimide For~ula (XII): R~ = n-butyl, R2 = methyl, o X = 0, R3 = CH2CH2N ~ , ~
.. .-- 115 - 20~327 ~, V= ~
05 Prepared by the procedure of Example 110 from 2-phthalimidoethanol.
Crystals melting at 110C.
E~m~le 15~: N-2-[6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-1o yl)biphenyl-4-yl]methylpyri~idin-4-yl]oxy-ethylphthalimide For~ula (I): R~ = n-butyl, R2 - methyl, X = 0, R, = CH2CH2N ~ , R~ =
N'~/
Prepared by the procedure of Example 89.
Crystals melting at 200-201C.
15 1~: 6-n-Butyl-2-methyl-4-(Z-dimethylaoino-ethyl)mercapto-5-(2'-cyanobiphenyl-4-yl)-methylpyrimidine FormNla ~ Rl = n-butyl, R2 = methyl, :: CH3 X = ~, R3 =
.
.. - - ,.. . .
': - : -- 116 - 20~5327 ~, V= 1 11 ~/
05 Prepared by the procedure of Example 22 from N-2-mercaptoethyl-N,N-dimethylamine.
Oil used as such for the next step.
~am~le 155: 6-n-Butyl-2-methyl-4-(2-dimethylamino-ethyl)~ercapto-5-[2'-(tetrazol-5-yl)bi-phenyl-4-yl]~ethylpyrimidine Formula (I): R1 = n-butyl, R, = methyl, X = S, R3 = CH2CH2 ~ , R. =
; I H
Prepared by the procedure of ~xample 89.
Crystals melting at 187-188C.
~xample 1~: 6-n-~utyl-2-~eth~1-4-(2-methylthioethyl)-oxy-5-~2'-cyanobiphenyl-4-yl)methylpyrlmi-dine For~ula (XII): Rl = n-butyl, R, = m~thyl, X = O, R3 = CH2cH2scH
:~: V= l I
~ 35 . . .: ~ , ' 2 0 4 e~i 3 2 7 Prepared by the procedure of Example 110 from 2-methylthioethanol.
Oil used as such for the next step.
05 ~xam~le 157: 6-n-Butyl-2-methyl-4-(2-methylthioethyl)-oxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]-methylpyrimidine Formula (I): Rl = n-butyl, R2 = methyl, X = O ~ R3 = CH2CH
,N~
"N_N
Prepared by the procedure of Example 89.
Crystals melting at 121-122C.
~xam~le 1~: 2-[6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-4-yl]mercaptoethanol For~ula (XII): Rl = n-butyl, R2 = methyl, 2 5 X = S, R3 = CH2CH20H, V=
Prepared by the procedure of Example 22.
Oil used as such for tha next step.
'' , .
.
' - 118 - 20~ ~327 E~ample 159: 2-[6-n-Butyl-2-~ethyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-~-yl]mercaptoethyl acetate 05 Formula (XII): Rl = n-butyl, R2 = methyl, X = S, R3 = CH2CH20COCH3, ~ .
V= 1 11 NC~
Prepared by the procedure of Example 100.
oi l used as such for the next step.
Exam~le 160: 2-t6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]-mercaptoethyl acetate Formula (I): Rl - n-butyl, R2 = methyl, X = S, R, = CHzCH~OCOCH
: R" = ~ 3 ~ N
H
Prepared by the procedure Or Example 89.
Crystals melting at 112-114C~
~le 161: 2-l6-n-Butyl-2-~ethyl-5-~2~-(tetrazol-5 yl)biphenyl-4-yl pethylpyrimidin-4-yl]-~ercaptoethanol Forcula (I): R~ = n-butyl, R2 = methyl, . .
- ' : . . ... .
. . , -. . .
.
.. ' ~' . ' .
, . ~ , .
204~327 X = S, R3 = CH2CH20H, 05 ~ ~
3.7 g of 2-[6-n-butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]mercaptoethyl acetate, prepared in Example 160, are dissolved in 300 ml of ethanol and 100 ml of water in the presence of 1 g of sodium hydroxide pellets. The mixture is stirred for 48 hours at room t~mperature, the solvents are concentrated, 200 ml of water are added, the aqueous phase is washed with ethyl acetate and then with ether and acidified by having sulfur dioxide bubbled through it, and the crystals obtained are filtered off, washed with water and ether and chromato-graphed on silica gel with a 9/1 methylene chloride/
methanol eluent to give 1.7 g of 2-[6-n-butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl~mercaptoethanol in the form of crystals melting at 161-162C.
Exam~le 1~2: Ethyl 2-t6-n-butyl-2-~ethyl-5-(2'-cyano-biphenyl-4-yl)msthylpyri~idin-4-yl~oxy-acetate Formula tXII): Rl = n-butyl, R~ ~ methyl, X - 0, R3 8 CH2CO~Et ~
~ ~ v= ~1 ~ 35 .~ ~ ~ .. . . . . .
.
-. . , .. -.
- : .. . .
.
- . . ~: . .
- -20~5327 Prepared by the procedure of Example 129.
Oil used as such for the next step.
~xample 163: Ethyl 2-[6-n-butyl-2-methyl-5-[2'-(tetra-05 zol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]oxyacetate Formula ~ Rl = n-butyl, R2 = methyl, X = O, R3 = CH2CO2Et, Prepared by the procedure of Example 89.
Crystals melting at 133-135C.
Example 164: 4-l6-n-Propyl-2-methyl-5-(2'-cyanobi-phenyl-4-yl)methylp~ri~idin-4-yl~oxy-methyl-2,2-dimethyl-1,3-dioxolane Formula (XII): R1 = n-propyl, R2 = methyl, ~ CH2 X s o, R3 = ~ o ~<
. ~
V~
N~
Prepared by the procedure of Example 110.
Oil used as such for the next step.
: . ' ' ' .
- 121 - 204~327 ~ample 165: Sodium salt of 4-~6-n-propyl-2-methyl-5-[2'-(tetrazol-5-yllbiphenyl-4-yl]~ethyl-pyrimidin-4-yl]o~ymethyl-2,2-dimethyl-1,3-dioxolane Formula (I): Rl = n-propyl, R2 = methyl, CH2~
R~ =
~N--~1 Na Prepared by the procedure of Example 89, the sodium salt being obtained by treatment of the tetra-zole derivative with 0.9 equivalent of sodium hydroxide in alcoholic solution.
Crystals melting at 224-225~C.
Example ~66: Ethyl 2-t4-t3-cyanothien-2-yl)benzyl]-3-oxohexanoate Formula (VI): Rl = n-propyl, Rl3 = ethyl, ~S
V = ~ ~
NC
Prepared by the procedure of Example 3 from 4-(3-cyanothien-2-yl)benzyl bromide.
~;~ Oil used as such for the next step.
,~.,, . . :
:' -, ' 204~327 Preparation of 4-(3-cyanothien-2-yl)benzyl bromide A) 4'-Methyl-4-chlorobutyrophenone 53 ml of toluene and 70.5 g of 4-chlorobutyroyl 05 hloride are dissolved in 100 ml of methylene chloride and the solution is added at 10 D C to a suspension of 74 g of aluminum chloride in 200 ml of methylene chloride. The temperature is then allowed to rise for a quarter of an hour and the mixture is treated with iced water. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give 96.9 g of 4'-methyl-4-chlorobutyrophenone in the form of an oil, which is used as such for the next step.
B) ~-Chloro-~-(2-chloroethyl)-4'-methylcinnamaldehyde 130 ml of phosphorus oxychloride are added slowly, at 0 C, to 130 ml of dimethylformamide, and 117.5 g of 4'-methyl-4-chlorobutyrophenone, prepared in A), dissolved in 50 ml of dimethylformamide are then added dropwise. The mixture is subsequently stirred at room temperature for one hour and then at 50 C for 2 hours and at 70 C for 1 hour. The mixture is then poured on to ice and taken up with ether and the ether phase is washed with a saturated solution of sodium bicarbonate, dried over sodium sulfate and evaporated under vacuum to give 133.8 g of ~-chloro-~-(2-chloro-ethyl)-4'-methylcinnamaldehyde in the form of an oil, which is used as such for the next step.
C) 2-(4-Methylphenyl)-4,5-dihydrothiophene-3-carboxal-dehyde 15.9 g of ~-chloro-~-(2-chloroethyl)-4'-methyl-cinnamaldehyde, prepared in B), and 22 g of sodium sulfide (9H20) are added to 200 ml of THF. Water is added in a sufficient amount for the sodium sulfide to :
.
20~327 pass completely into solution, after which the mixture is refluxed for 3 hours, cooled and then taken up with ether. The organic phase is decanted, washed with water and then dried over magnesium sulfate and evapo-05 rated under vacuum to give 13.5 g of 2-(4-methyl-phenyl)-4,5-dihydrothiophene-3-carboxaldehyde in the form of an oil, which is used as such for the next step.
D) 2-(4-Methylphenyl)-3-cyano-4l5-dihydrothiophene 15 g of 2-(4-methylphenyl)-4,5-dihydrothio-phene-3-carboxaldehyde, prepared in C), and 6.5 g of hydroxylamine hydrochloride are mixed in 40 ml of ethanol and 10 ml of water. A solution of 4.7 g of sodium carbonate in 10 ml of water is added. The mix-ture is stirred at room temperature for half an hour and then extracted with ether. The ether phase is washed with water and then dried over sodium sulfate and evaporated under vacuum to give 15.2 g of a gummy yellow residue. This residue is added to 13 ml of acetic anhydride and the mixture warms up slightly, turns brown and becomes liquid. The mixture is sub-sequently refluxed for 1 hour and then poured on to ice, extracted with methylene chloride and washed with a saturated solution of sodium bicarbonate, the organic phase is then dried over magnesium sulfate and evapora-ted under vacuum and the residue obtained is chromato-graphed on silica gel in methylene chloride to give 10 g of 2-(4-methylphenyl)-3-cyano-4,5-dihydrothlophene in the ~orm of an oil, which is used a~ such ~or the next step.
E) 2-(4-Methylphenyl)-3-cyanothiophene 49.9 q of 2-(4-methylphenyl)-3-cyano-4,5-dihydrothiophene, prepared in D), are dissolved in 200 .j,.,. ,.. ,. . ~ . . .
~: - . ' ' ' '' ' ' ' ,' - 124 - 20~'327 ml of carbon tetrachloride, the mixture is heated to the reflux temperature and, after two hours, 11 g of bromine dissolved in 200 ml of carbon tetrachloride are added dropwise. Reflux is continued until the evolu-05 tion of hydrogen bromide has ceased, and the solvent isthen evaporated off under vacuum. The residue is taken up in 200 ml of anhydrous tetrahydrofuran, and 28 g of potassium tert-butylate are added. The mixture is refluxed for one hour and then cooled, water and sodium chloride are added and the resulting mixture is extrac-ted with ether. The organic phase is evaporated under vacuum to give 31.8 g of 2-(4-methylphenyl)-3-cyano-thiophene in the form of an oil, which is used as such for the next step.
F) 4-(3-Cyanothien-2-yl)benzyl bromide 24.5 g of 2-(4-methylphenyl)-3-cyanothiophene, prepared in E), are dissolved in 200 ml of carbon tetrachloride. 21.9 g of N-bromosuccinimide and 0.1 g of benzoyl peroxide are added. The mixture is refluxed for 24 hours. The crystals of succinimide are filtered off and the solvent is evaporated off under vacuum.
The residue is taken up in a mixture of hexane and ethyl acetate and the solution is kept for 24 hours in a refrigerator. The crystals formed are filtered off to give 14 g of 4-(3-cyanothien-2-yl)benzyl bromide in the form of crystals melting at 80C.
Example 167: 6-n-Propyl-2-methyl-4-hydroxy-5-[4-(3-cyanothien-2-yl)benzyl]pyrimidine Formula (XI): R~ = n-propyl, R2 = methyl, T = OH, V = ~ S
NC
- 125 - 204~327 Prepared by the procedure of Example 7.
Crystals melting at 180C.
Example 168: 6-n-propyl-2-methyl-4-chloro-s-[4-( 05 ~yanothien-2-yl)benzyl]pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, XR3 = Cl, V =
lo NC
Prepared by the procedure of Example 19.
Oil used as such f or the next step.
Example 169: 6-n-Propyl-2-methyl-4-methoxy-5-[4-l3-cyanothien-2-yl)benzyl]pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, XR3 = OCH3, V =
NC
Prepared by the procedure of Example 30.
Oil used as such for the next step.
Example 170: 6-n-Propyl-2-methyl-4-methoxy-5-~4-t3~
(tetrazol-S-yl)thien-2-yl]benzyl]pyrimi-dine Formula lI): R~ = n-propyl, R2 = methyl, : 35 ~:
,..... . .
20~327 XR3 = OCH3, R~
Prepared by the procedure of Example 89.
Crystals melting at 155C.
10Example 171: Ethyl 2-(2'-methoxycar~onylbiphenyl-4-yl)-methyl-3-oxoheptanoate For~ula (VI): R, = n-butyl, Rl3 = ethyl, --15V = ~ 3 MeO2C
Prepared by the procedure of Example 5.
20Oil used as such for the next step.
Example 172: 6-n-Butyl-2-methyl-4-hydroxy-5-(2'-methoxycarbonylbiphenyl-4-yl)methylpyrimi-dine : 25 : ~ Formula (XI): Rl - n-butyl, R2 = methyl, T - OH, V =
MeO2C
Prepared by the procedure of Example 7.
Crystals melting at ~09-210C.
' , - 127 - 20~327 Example 173: 6-n-Butyl-2-methyl-4-chloro-5-(2'-methoxy-carbonylbiphenyl-4-yl)methylpyrimidine Formula (XII): R1 = n-butyl, R, = methyl, XR3 = Cl, V = I ll MeO2C~~/
Prepared by the procedure of Example 19.
O11 used as such for the next step.
~xample 174: 6-n-Butyl-2-methyl-4-methoxy-5-(2'-methoxycarbonylbiphenyl-4-yl)methylpyrimi-dine Formula (XII): R1 = n-butyl, R2 = methyl, XR3 = OCH3, V =
M~2C
Prepared by the procedure of Example 30.
Oil used as such for the next step.
~: ~x~pl~ 175: 4'-[6-n-Butyl-2-methyl-4-methoxypyrîmidin-5-yl]methylbiphenyl-2-carboxylic acid Formula (I~: Rl = n-butyl, R, = methyl, XR3 = OCH3, V =
~2C
'~, 2.1 g of 6-n-butyl-2-methyl-4-methoxy-5-(2'-:
::
~,.,"..,~,,,, ~
- 128 - 20~.~327 methoxycarbonylbiphenyl-4-yl)methylpyrimidine, prepared in Example 174, and 0.35 g of sodium hydroxide pellets are dissolved in 15 ml of methanol and 10 ml of water.
I'he solution is heated at 60C for 10 hours, the sol-05 vents are evaporated off under vacuum, the residue istaken up with water and the aqueous phase is aci~ified with dilute hydrochloric acid. The crystals are fil-tered off, washed several times with water and dried to give 1.8 g of 4'-[6-n-butyl-2-methyl-4-methoxypyri-midin-5-yl]methylbiphenyl-2-carboxylic acid in the form of crystals melting at 168C.
Example 176: 6-n-Propyl-2-methyl-4-methoxy-5-(4-nitro-benzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, XR3 = OCH3, V = NO2 Prepared by the procedure of Example 30.
Oil used as such for the next step.
Example 177: 6-n-Propyl-2-methyl-4-methoxy-5-(4-amino-benzyl)pyrimidine Formula (XII): Rl = n-propyl, R2 = methyl, XR3 = OMe, V = NH~
5.3 g of 6-n-propyl-2-methyl-4-methoxy-5-(4-nitrobenzyl)pyrimidine, prepared in Example 176, are dissolved in 70 ml of diglyme. 1.15 g of lithium boro-hydride are added and the mixture is heated to the reflux temperature. 8 ml of methanol are added drop-wise over two hours and the mixture is subsequently refluxed for a further 2 hours and then taken up with water. The crystals are filtered off and dissolved in - 129 - 2~ ~ 32 7 isopropyl ether. The ether solution is dried over mag-nesium sulfate and evaporated under vacuum to give 3.8 g of 6-n-propyl-2-methyl-4-methoxy-5-(4-amino-benzyl)pyrimidine in the form of crystals melting at 05 179-181 C.
Exam~le 178: 2-[(6-n-Propyl-2-methyl-4-methoxypyrimi-din-5-yl)methylphenyl-4-yl]aminocar~onyl-benzenesulfonic acid Formula (I): R, = n-propyl, R2 = methyl, XR3 = OMe, R~ =
Prepared by the procedure of Example 13.
Crystals melting at 200-204C.
Exam~le 179: 6-n-Butyl-2-methyl-5-(~-nitrobenzyl)-4-(2-propionyloxyethyl)oxypyrimidine Formula (XII): R~ = n-butyl, Rz = methyl, X = O, R3 = CH2CH2OCOCH2CH3, v = NO2 Prepared by the procedure of Example 100 from 2-hydroxyethyl propionate, obtained by the catalytic hydrogenation of commercial 2-hydroxyethyl acrylate in the presence of Raney nickel.
Oil used as such for the next step.
, ' ~ ' -:
'~
.. ~ ' ~ .
.
- 130 - 2~ 3 2 7 Ex~ 180: 2-t6-n-Butyl-2-methyl-5-(4-nitrobenzyl)-pyrimidin-4-yl]oxyethanol Formula (XII): Rl = n-butyl, Rz = methyl, 05 X = O, R3 = CH2CH20H, V = NO2 Prepared by the procedure of Example 142.
Oil used as such for the next step.
E~b1~ 2-t6-n-Butyl-2-methyl-5-(4-aminobenzyl)-pyrimidin-4-yl]oxyethanol Formula (XII): Rl = n-butyl, R2 = methyl, X = O, R3 = CH2CH20H, V = NH2 Prepared by the procedure of Example 12.
Oil used as ~uch for the next step.
E~xample 182: 2-[[6-n-Butyl-2-~ethyl-4-(2-hydroxy2thyl)-oxypyrimidin-5-yl]methylphenyl-4-yl]a~ino-carbonylbenzenesul~onic acid ~: 25 Formula (I): Rl = n-butyl, Rl = methyl, ' X 5 O, R3 = CH2CH20H, ~:: R~ =
;~ HO3S
~: Prçpared by the procedure of Example 13.
:~:: Crystals melting at 238-9C.
~: 35 ::
.,.,, .......... . . : . .
- : . --. .:
.
. -' .
- 131 - 2 ~ ~32 Example 183: Ethyl t6-n-butyl-2-methyl-5-(2'-cyanobi-phenyl-4-yl)methyl-3~4-dihydro-4-oxo-pyrimidin-3-yl]acetate 05 Formula (XII'): R, = n-butyl, R2 = methyl, R' 3 = CH2C02Et, V = . ¦ ll NC~
Prepared by the procedure of Example 88.
Oil used as such for the next step.
~x~LDl9LL~: Ethyl [6-n-butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxopyrimidin-3-yl]acetate Formula (I'): R~ = n-butyl, Ra = methyl, R' 3 = CH2C02Et, R4 = N~
~` N
N--H
: Prepared by the procedure of Example 89.
Cryætals melting at 170-1C.
ExamDle 185: 6-n-Butyl-2,3-dimethyl-5-(2'-cyanobi-phenyl-4-yl)methyl-3,~-dlhydro-4-oxopyri-midine :~ Formula (XII'): R~ = n-butyl, R2 = methyl, ~ 35 .... ,, .. .: .
' , ' - ' . .
: -- 132 - 2Q~327 R~3 = methyl, v =
05 Prepared by the procedure of Example 126.
Oil used as such for the next step.
Example 186: 6-n-Butyl-2,3-dimethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-pyri~idine Formula (I'): R1 = n-butyl, R2 = methyl, R'3 = methyl, R~
N~/
~N'~
Prepared by the procedure of Example 127.
Example 187: 6-n-Butyl-2-methyl-3-(2-chlorobenzyl)-5-(2'-cyanobiphenyl-4-yl)methyl-3,4-dihydro-4-oxopyrimidine : 25 :
: Formula (XII'): R1 = n-butyl, R, = methyl, ~: Cl ::
3 CH2-~3 N
~ 35 :
... , ............. . : - :
' .
- 133 - 20~3 2 7 Prepared by the procedure of Example 88.
Oil used as such for the next step.
~xample 188: 6-n-Butyl-2-methyl-3-(2-chlorobenzyl)-5-05 [2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxopyrimidine Formula (I'): Rl = n-butyl, R2 = methyl, Prepared by the procedure of Example 89.
Ex~m~le 189: 6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-4-oxo-3,4-dihydro-3-(2-acetoxy-ethyl)pyrimidine Formula (XII'): R1 = n-butyl, R, = methyl, R' 3 = CH2CH20COCH3 ~
V =
NC/~
:
Prepared by the procedure of Example 88.
Crystals melting at 107C.
:: :
- 134 - 2~ 327 Ex~m~lç 190: 6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-yl)-biphenyl-4-yll~ethyl-3,4-dihydro-4-oxo-3-(2-acetoxyethyl)pyrimidine 05 Formula (I~): Rl = n-butyl, R~ = methyl, R' 3 = CH2CHzOCOCH3 ~
R4 = l ll N~
o ~N' H
Prepared by the procedure of Example 89.
Example 191: 3-t6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methylpyrimidin-4-yl]oxypropyl acetate Formula (XII): R~ = n-butyl, R2 ~ methyl, X = O, R3 = CH2CH2CH2OCOCH3, V= ~3 ; 25 : Prepared by the procedure of Example 88 ~elu-ent: 5/5 ethyl acetate/cyclohexane).
oi 1 used as such for the next step.
.. , :, , ~
.
, ,, , , .; . , 204~i32~1 E,xam~le 192: 6-n-Butyl-2-methyl-5-(2'-cyanobiphenyl-4-yl)methyl-3,4-dihydro-4-oxo-3-(3-acetoxy-propyl)pyrimidine 05 Formula (XII'): Rl = n-butyl, R2 = methyl, R' 3 = CH~CH2CH20COCH3 1 V= 1 11 N~/
Prepared by the procedure of Example 88 (elu-ent: 7/3 ethyl acetate/cyclohexane).
Crystals melting at 108C.
Example 193: 6-n-Butyl-2-methyl-5-t2'-(tetrazol-5-yl)-biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-3-(3-acetoxypropyl)pyrimidine For~ula (I'): Rl = n-butyl, R2 = methyl, R' 3 = CH2CH2CHzOCOCH3 ~
R4 =
~N
25 ~ N~ N
, : Prepared by the procedure of Example 89.
~ 35 :
",., . ,~, , .
, ' - 136 - 2Q~.~327 Exam~le 194: 3-[6-n-Butyl-2-methyl-5- r 2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidin-4-yl]-oxypropyl acetate 05 Formula (I): Rl = n-butyl, R2 = methyl, X = O, R3 = CH2CH2CH20COCH3, R4 = ~
r~
o N~N,N
Prepared by the procedure of Example 89.
Example 195: 3-[6-n-Butyl-2-methyl-5-[2'-(tetrazol-S-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-pyrimidin-3-yl]propanol Formula (I'): Rl = n-butyl, R2 = methyl, R'3 = CH2CH2CH20H, R. = ~
N ~ .
N~ ,N
~: 25 H
Prepared by the procedure of Example 142 Crystals melting at 181-2C.
Exam~le L~6: 2-t6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylp~rimidin-4-yl]-oxyethanol Formula (I): Rl = n-butyl, R2 = methyl, X = O, R3 = CH~CH20H, ... . . . . .
', ~ - ' ~ '''~
.
-20~ ~2 R4 =
N~ _N
Prepared by the procedure of Example 142.
Crystals melting at 173-4C.
Example 197: 2-[6-n-Butyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-3,4-dihydro-4-oxo-pyrimidin-3-yl]ethanol Formula (I'): Rl = n-butyl, R2 = methyl, R' 3 = CB2CH20H, R4 =
N
N~ ~N
N H
Prepared by the procedure of Example 142.
Crystals melting at lgS-6~C.
~DLlgL12~; 6-n-Propyl-2-mercapto-4-hydroxy-5-(2'-cyanobiphenyl-4-yl)methylpyrimidine For~ula ~XI): Rl = n-propyl, R, = 5H, T =
OH, V =
NC
;~ Prepared by the procedure of Example 133.
: 35 Crystals melting at l91~C.
:
- :', - '~ .;
' , :
- :
- 138 - 20~a327 The following products may be prepared by the procedures described above:
~ 6-n-Propyl-2,4-dihydroxy-5-[2'-(tetrazol-5-yl)bi-05 phenyl-4-yl]methylpyrimidine - 6-n-Butyl-2,4-dihydroxy-5-[2'-(tetrazol-5-yl)bi-phenyl-4-yl]methylpyrimidine - 6-n-Propyl-2,4-dichloro-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Butyl-2,4-dichloro-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Propyl-2-chloro-4-methoxy-5-(2'-carboxybiphenyl-4-yl)methylpyrimidine - 6-n-Butyl-2-chloro-4-methoxy-5-(2'-carboxybiphenyl-4-yl)methylpyrimidine - 6-n-Propyl-2-chloro-4-hydroxy-5-(2'-carboxybiphenyl-4-yl)methylpyrimidine - 6-n-Butyl-2-chloro-4-hydroxy-5-(2'-carboxybiphenyl-4-yl)methylpyrimidine - 6-n-Propyl-2,4-dimethoxy-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Butyl-2,4-dimethoxy-5-(2'-carboxybiphenyl-4~yl)-methylpyrimidine - 6-n-Propyl-2,4-dihydroxy-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Butyl-2,4-dihydroxy-5-(2'-carboxybiphenyl-4-yl)-methylpyrimidine - 6-n-Propyl-2,4-dimethoxy-5-E2'-(tetrazol-5-yl)bi-phenyl-4-yl]methylpyrimidine - 6-n-Butyl-2,4-dimethoxy-5-[2'-(tetrazol-5-yl)bi-phenyl-4-yl]methylpyrimidine - 6-n-Propyl-2-mercapto-4-hydroxy-5-E2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-mercapto-4-hydroxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine . ~ .. ..
~ ' .: ~
' ' ~ ' '~' . ' ~ ' . ' ,, :
.
, - 139 - 2~ ~ ~327 ~ 6-n-Propyl-2-methylthio-4-hydroxy-s-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methylthio-4-hydroxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine 05 - 6-n-Propyl-2-methylthio-4-methoxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methylthio-4-methoxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-2-methyl-3-phenyl-3,4-dihydro-4-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methyl-3-phenyl-3,4-dihydro-4-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-2 methyl-3-(2-chlorophenyl)-3,4-dihydro-4-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methyl-3-(2-chlorophenyl)-3,4-dihydro-4-oxo-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-2-methyl-4-methoxymethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methyl-4-methoxymethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-2-methyl-4-hydroxymethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methyl-4-hydroxymethyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-4-hydroxymethyl-5-[2'-(tetr~zol-5-yl)bi-phenyl-4-yl~methylpyrimidine - 6-n-Butyl-4-hydroxymethyl-5-[2'-(tetrazol-5-yl)bi-phenyl-4-ylImethylpyrimidine - 6-n-Propyl-4-methoxymethyl-5-~2'-(tetrazol-5-yl)bi-phenyl-4-yl]methylpyrimidine - 6-n-Butyl-4-methoxymethyl-5-[2'-(tetrazol-5-yl)bi-phenyl- 4-yl]methylpyrimidine - 6-n-Propyl-2-methyl-4-carboxy-5-[2'-(tetrazol-5-yl)-biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-2-methyl-4-carboxy-5-[2'-(tetrazol-5-yl)-' .
~0~27 biphenyl-4-yl]methylpyrimidine - 6-n-Propyl-4-carboxy-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine - 6-n-Butyl-4-carboxy-s-[2'-(tetrazol-5-yl)biphenyl-4-05 yl]methylpyrimidine- 6-n-Propyl-2-methyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine-4-carbaldehyde - 6-n-Butyl-2-methyl-5-~2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrimidine-4-carbaldehyde - 6-n-Propyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidine-4-carbaldehyde - 6-n-Butyl-5-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrimidine-4-carbaldehyde - .
. , ' - ' ' ': , -, :. : -. ~ , ' ,, ' ' ' , '; '' ' ,~
. . ,. , : .
20'~ 327 PHAR ~COLOGY
I. Principle 05 The affinity of the products of the Examples for angiotensin II receptors is evaluated by the tech-nique of displacing a radioligand specifically bound to rat adrenal angiotensin II receptors.
II. Procedure An aliquot of a rat adrenal gland homogenate incubates in the presence of a single concentration of [l2sI]-SIAII (Sar1,Tyr~,Ile~-angiotensin II), which is an angiotensin II receptor antagonist, and two concentra-tions of competing agents (10-5 M, I0-7 M) for 60 min at 25 C.
The reaction is completed by the addition of a buffer, followed by rapid filtration through glasspaper filters. The non-specific binding is determined in the presence of angiotensin II.
III. Expression of ~he resul~s The results are expressed, for the concentra-tions tested, as the percentage displacement of the radioligand specifically bound to the adrenal angio-tensin II receptors.
~:
.
, ' .:
- 142 - 2Q4-~327 IV. Results Product of % displacement of the labeled ligand lE-7M lE-5M
Example 13 64 96 Example 14 38 81 Example 16 31 65 10 Example 24 62 93 Example 27 20 76 Example 31 51 71 Example 32 67 94 15 Example 33 62 69 Example 54 65 84 Example 55 60 86 Example 56 59 86 ~0 Example 57 69 80 Example 58 53 78 Example 59 57 89 Example 61 63 96 25 Example 75 0 72 : Example 76 37 93 Example 77 4 63 30 Example 7~ 41 74 -,, . , ~ . , . , - ~ - ' .. . .
. .
, -. : : ~.-:
.
. ' ~ ': ' '- - , :
:: : ' -:
.
20~-~327 TOXICOLOGY
The products of the Examples described have an excellent tolerance after oral administration.
05Their 50% lethal dose in rats was found to be greater than 300 mg/kg.
CONCLUSION
10The products of the Examples described have a good affinity for angiotensin II receptors. In this respect, they may be used beneficially for the various patholoqical conditions in which angiotensin II is involved, in particular for the treatment of arterial hypertension and cardiac insufficiency, in dosages of 1 to 400 mg by oral administration and 0.01 to 50 mg by intravenous administration, in one or more dosage units per day.
~ ~ .
... .
.
Claims (20)
1. Pyrimidine derivatives of general formula (I) or (I'):
Formula (I) Formula (I') in which, in formula (I), R1 is a lower alkyl radical having 1 to 6 carbon atoms or a lower alkenyl radical having 2 to 6 carbon atoms;
R2 is the hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group OH, SH or NH2, a group OR5, SF5 or NHR5, R5 being a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or a group NHCOR6, R6 being defined in the same way as R5 except that it can also be an aromatic ring, a substituted or unsubstituted methanebiphenyl or a heterocycle; R2 can also be an aromatic ring or a heterocycle;
X can be a bond, an oxygen or sulfur atom, a radical NH or a halogen;
R3 will be absent when X is a halogen, or can be a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical or else a group -(CH2)n-CN, a group -(CH2)n-COOR7, a group -(CH2)n-OR7, a group a group -(CH2)n-O-COR, a group or a group -(CH2)n-SR7, n being an integer from 0 to 5 and R7 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms; R3 can also be a group -(CH2)p-CONR8R9 or -(CH2)p-NR8Rg, p being an integer from 0 to 5 and R8 and R9 independently being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or it being possible for R8 and R9 to form, together with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by a lower alkyl, an aromatic ring or a heterocycle; R3 can also be a group -(CH2)q-NH-(CH2)r-COOR10, -(CH2)q-NH-CO-NHR11 or -(CH2)q-NH-CS-NH-R11, q and r being integers from 0 to 5 and R10 and R11 independently being a lower alkyl radical having 1 to 6 carbon atoms, it also being possible for R11 to be an aromatic ring, a heterocycle or else a group -(CH2)n-COOR7, n and R7 being as defined above; R3 can also be the group SO3H, one of its esters or one of its amides; R3 can also be an amino acid group or one of its amides n, R6 and R7 being as defined above; finally, R3 can be a radical -(CH2)n-aromatic ring or -(CH2)n-heterocycle, n being as defined above; and R4 can be a nitro or amino group or a group -COOR12, R12 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a benzyl; R4 can also be the following radicals:
,, in which Rl2 is as defined above and Y and Z can inde-pendently be a hydrogen atom, a lower alkyl radical, a halogen atom, a lower alkoxy radical or a trifluoro-methyl radical;
and in formula (I'), R1, R2 and R4 are as defined in formula (I), R'3 is defined in the same way as R3 except that, unlike the latter, it may not be a group SO3H, one of its esters or one of its amides and that also, in the case of R'3, the number q may not be less than 2, the number p may not be equal to 0 and the number n may not be equal to 0, except in the case of a group -(CH2)n-COOR7, an aromatic ring or a heterocycle, it being possible for the afore-mentioned derivatives to take the form of addition salts, in particular pharmaceutically acceptable addition salts.
Formula (I) Formula (I') in which, in formula (I), R1 is a lower alkyl radical having 1 to 6 carbon atoms or a lower alkenyl radical having 2 to 6 carbon atoms;
R2 is the hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group OH, SH or NH2, a group OR5, SF5 or NHR5, R5 being a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or a group NHCOR6, R6 being defined in the same way as R5 except that it can also be an aromatic ring, a substituted or unsubstituted methanebiphenyl or a heterocycle; R2 can also be an aromatic ring or a heterocycle;
X can be a bond, an oxygen or sulfur atom, a radical NH or a halogen;
R3 will be absent when X is a halogen, or can be a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical or else a group -(CH2)n-CN, a group -(CH2)n-COOR7, a group -(CH2)n-OR7, a group a group -(CH2)n-O-COR, a group or a group -(CH2)n-SR7, n being an integer from 0 to 5 and R7 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms; R3 can also be a group -(CH2)p-CONR8R9 or -(CH2)p-NR8Rg, p being an integer from 0 to 5 and R8 and R9 independently being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or it being possible for R8 and R9 to form, together with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by a lower alkyl, an aromatic ring or a heterocycle; R3 can also be a group -(CH2)q-NH-(CH2)r-COOR10, -(CH2)q-NH-CO-NHR11 or -(CH2)q-NH-CS-NH-R11, q and r being integers from 0 to 5 and R10 and R11 independently being a lower alkyl radical having 1 to 6 carbon atoms, it also being possible for R11 to be an aromatic ring, a heterocycle or else a group -(CH2)n-COOR7, n and R7 being as defined above; R3 can also be the group SO3H, one of its esters or one of its amides; R3 can also be an amino acid group or one of its amides n, R6 and R7 being as defined above; finally, R3 can be a radical -(CH2)n-aromatic ring or -(CH2)n-heterocycle, n being as defined above; and R4 can be a nitro or amino group or a group -COOR12, R12 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a benzyl; R4 can also be the following radicals:
,, in which Rl2 is as defined above and Y and Z can inde-pendently be a hydrogen atom, a lower alkyl radical, a halogen atom, a lower alkoxy radical or a trifluoro-methyl radical;
and in formula (I'), R1, R2 and R4 are as defined in formula (I), R'3 is defined in the same way as R3 except that, unlike the latter, it may not be a group SO3H, one of its esters or one of its amides and that also, in the case of R'3, the number q may not be less than 2, the number p may not be equal to 0 and the number n may not be equal to 0, except in the case of a group -(CH2)n-COOR7, an aromatic ring or a heterocycle, it being possible for the afore-mentioned derivatives to take the form of addition salts, in particular pharmaceutically acceptable addition salts.
2. Derivatives according to claim 1 wherein, in general formulae (I) and (I'):
R1 is a lower alkyl radical having 1 to 6 carbon atoms, preferably n-propyl or n-butyl;
R2 is the hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, pre-ferably methyl or isopropyl, a group OH, SH or NH2, a group OR5 or SR5, R5 being a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl, or an aromatic ring;
X is a bond, an oxygen atom, a sulfur atom, a radical NH or a halogen;
R3 will be absent when X is a halogen, or can be a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl or isopropyl, a group -(CH2)n-COOR7, a group -(CH2)n-OR7, a group -(CH2)nO-COR7, a group -(CH2)n-SR7, a group n being an integer from 0 to 5, preferably from 0 to 3, and R7 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl or ethyl, a group -(CH2)p-CONR8R9 or -(CH2)p-NR8R, p being an integer from 0 to 5, preferably from 0 to 2, and R8 and R9, which are identical or different, being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl, or it being possible for R8 and R9 to form, together with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by an aromatic ring, or a radical -(CH2)n-aromatic ring, n being as defined above; and R4 is a group selected from the following radi-cals:
, , , R12 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms and Y and Z independently being a hydrogen atom, a lower alkyl radical or a halo-gen atom.
R1 is a lower alkyl radical having 1 to 6 carbon atoms, preferably n-propyl or n-butyl;
R2 is the hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, pre-ferably methyl or isopropyl, a group OH, SH or NH2, a group OR5 or SR5, R5 being a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl, or an aromatic ring;
X is a bond, an oxygen atom, a sulfur atom, a radical NH or a halogen;
R3 will be absent when X is a halogen, or can be a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl or isopropyl, a group -(CH2)n-COOR7, a group -(CH2)n-OR7, a group -(CH2)nO-COR7, a group -(CH2)n-SR7, a group n being an integer from 0 to 5, preferably from 0 to 3, and R7 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl or ethyl, a group -(CH2)p-CONR8R9 or -(CH2)p-NR8R, p being an integer from 0 to 5, preferably from 0 to 2, and R8 and R9, which are identical or different, being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl, or it being possible for R8 and R9 to form, together with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by an aromatic ring, or a radical -(CH2)n-aromatic ring, n being as defined above; and R4 is a group selected from the following radi-cals:
, , , R12 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms and Y and Z independently being a hydrogen atom, a lower alkyl radical or a halo-gen atom.
3. Pyrimidine derivatives of general formula (I'):
Formula (I') in which;
R1 is a lower alkyl radical having 1 to 6 carbon atoms or a lower alkenyl radical having 2 to 6 carbon atoms;
R2 is the hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms, a group OR5, SR5 or NHR5, R5 being a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or a group NHCOR6, R6 being defined in the same way as R5 except that it can also be an aromatic ring, a substituted or unsubstituted methanebiphenyl or a heterocycle; R2 can also be an aromatic ring or a heterocycle;
R'3 can be a lower alkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group -(CH2)n-CN, a group -(CH2)n-COOR7, a group -(CH2)n-OR7, a group a group -(CH2)n-O-COR7, a group or a group -(CH2)n-SR7, it being possible for n to be an integer from 0 to 5 and R7 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms; R'3 can also be a group -(CH2)p-CONR8R9 or -(CH2)p-NR8R9, p being an integer from 1 to 5 and R8 and R9 independently being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or it being possible for R8 and R9 to form, with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by a lower alkyl, an aromatic ring or a heterocycle: R'3 can also be a group -(CH2)q-NH-(CH2)r-COOR10, -(CH2)q-NHCONHR11 or -(CH2)q-NH-CSNHR11, q being an integer from 2 to 5, r being an integer from 0 to 5 and R10 and R11 indepen-dently being a lower alkyl radical having 1 to 6 carbon atoms, it also being possible for R11 to be an aromatic ring, a heterocycle or else a group -(CH2)n-COOR7, n and R7 being as defined above; R'3 can also be an amino acid or one of its amides n, R6 and R7 being as defined above; finally, R'3 can be a radical -(CH2)n-aromatic ring or -(CH2)n-heterocycle, n being as defined above; and R4 can be a nitro or amino group or a group -COOR12, R12 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a benzyl; R4 can also be the following radicals:
, , , , , , , , , , in which R12 is as defined above and Y and Z can inde-pendently be a hydrogen atom, a lower alkyl radical, a halogen atom, a lower alkoxy radical or a trifluoro-methyl radical, as well as their addition salts, in particular the pharmaceutically acceptable addition salts.
Formula (I') in which;
R1 is a lower alkyl radical having 1 to 6 carbon atoms or a lower alkenyl radical having 2 to 6 carbon atoms;
R2 is the hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms, a group OR5, SR5 or NHR5, R5 being a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or a group NHCOR6, R6 being defined in the same way as R5 except that it can also be an aromatic ring, a substituted or unsubstituted methanebiphenyl or a heterocycle; R2 can also be an aromatic ring or a heterocycle;
R'3 can be a lower alkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group -(CH2)n-CN, a group -(CH2)n-COOR7, a group -(CH2)n-OR7, a group a group -(CH2)n-O-COR7, a group or a group -(CH2)n-SR7, it being possible for n to be an integer from 0 to 5 and R7 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms; R'3 can also be a group -(CH2)p-CONR8R9 or -(CH2)p-NR8R9, p being an integer from 1 to 5 and R8 and R9 independently being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or it being possible for R8 and R9 to form, with the nitrogen atom to which they are attached, a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine, a phthalimide or a piperazine which can be substituted by a lower alkyl, an aromatic ring or a heterocycle: R'3 can also be a group -(CH2)q-NH-(CH2)r-COOR10, -(CH2)q-NHCONHR11 or -(CH2)q-NH-CSNHR11, q being an integer from 2 to 5, r being an integer from 0 to 5 and R10 and R11 indepen-dently being a lower alkyl radical having 1 to 6 carbon atoms, it also being possible for R11 to be an aromatic ring, a heterocycle or else a group -(CH2)n-COOR7, n and R7 being as defined above; R'3 can also be an amino acid or one of its amides n, R6 and R7 being as defined above; finally, R'3 can be a radical -(CH2)n-aromatic ring or -(CH2)n-heterocycle, n being as defined above; and R4 can be a nitro or amino group or a group -COOR12, R12 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a benzyl; R4 can also be the following radicals:
, , , , , , , , , , in which R12 is as defined above and Y and Z can inde-pendently be a hydrogen atom, a lower alkyl radical, a halogen atom, a lower alkoxy radical or a trifluoro-methyl radical, as well as their addition salts, in particular the pharmaceutically acceptable addition salts.
4. Pyrimidine derivatives according to claim 1 or 2 of general formula (I"):
in which R1, R2, X and R3 are as defined above, as well as their addition salts, in particular the pharmaceuti-cally acceptable addition salts.
in which R1, R2, X and R3 are as defined above, as well as their addition salts, in particular the pharmaceuti-cally acceptable addition salts.
5. Pyrimidine derivatives according to claim 1 or 2, of general formula (I'"):
in which R1, R2 and R4 are as defined above, as well as their addition salts, in particular the pharmaceuti-cally acceptable addition salts.
in which R1, R2 and R4 are as defined above, as well as their addition salts, in particular the pharmaceuti-cally acceptable addition salts.
6. Derivatives according to claims 1 to 5 wherein R1 is a group selected from n-propyl and n-butyl.
7. Derivatives according to claims 1 to 6 wherein R2 is selected from a methyl group or the hydrogen atom.
8. Derivatives according to claims 1 to 6 wherein R2 is a methylthio group.
9. Derivatives according to claims 1, 2, 3 or 6 to 8 wherein R3 is selected from an ethoxycarbonylmethyl group, a 2-hydroxyethyl group, a methyl group and the hydrogen atom.
10. Derivatives according to claims 1, 2, 3 and 6 to 8 wherein R'3 is selected from an ethoxycarbonylmethyl group, a 2-hydroxyethyl group and a methyl group.
11. Derivatives according to any one of claims 1, 2, 3 or 5 to 10 wherein R4 is selected from a 2-sulfoxy-benzoylamino group, a 2-carboxyphenyl group and a 2-(tetrazol-5-yl)phenyl group.
12. Derivatives according to any one of claims 1 or 5 to 9 or 11 which are selected from the derivatives of the formulae
13. Derivatives according to any one of claims 1, 2, 3 or 6 to 8 or 10 and 11 which are selected from the derivatives having the following structures:
14. Methods of preparing the compounds of formulae (I) and (I') according to any one of claims 1 to 13, where-in the pyrimidine ring is prepared by reacting a urea, a thiourea, an amidine or a guanidine with 1,3-keto-esters, 1,3-ketonitriles or 1,3-diketones of the formulae Formula (VI) Formula (VII) Formula (VIII) R1 being as defined above, R13 being a lower alkyl radical, preferably methyl or ethyl, s being an integer from 1 to 5, it being possible for U to be an oxygen or sulfur atom or a methylene, R14 being a hydrogen atom or a lower alkyl, preferably methyl or ethyl, and V
being a functional group making it possible, in the manner described, to obtain the groups R4 as defined above, in an alcohol, in the presence of a sodium or potassium alcoholate or of a base such as sodium hydroxide or potassium hydroxide, at a temperature which can range from room temperature to the reflux temperature of the solvent.
being a functional group making it possible, in the manner described, to obtain the groups R4 as defined above, in an alcohol, in the presence of a sodium or potassium alcoholate or of a base such as sodium hydroxide or potassium hydroxide, at a temperature which can range from room temperature to the reflux temperature of the solvent.
15. Methods of preparing the compounds of formula (I) or (I') in which R, is a group which comprise reacting an anhydride of the formula or of the formula with an amine derivative of the formula or in which R1, R2, R3 or R'3 and X are as defined above and Y and Z are a hydrogen atom, a lower alkyl radical, a halogen atom or an alkoxy radical.
16. Methods of preparing the compounds of formula (I) or (I') in which R4 is a group which comprise reacting a compound of the formula or in which R1, R2, X and R3 or R'3 are as defined above, with sodium nitride in dimethylformamide, in the presence of an ammonium salt such as ammonium chloride, at a temperature of between 100 and 150°C, or by heating in toluene with trimethyltin nitride, followed by treatment with gaseous hydrogen chloride.
17. A pharmaceutical composition which comprises a pharmaceutically effective amount of at least one compound of formula (I) or (I') as defined in any one of claims 1 to 13, or one of its pharmaceutically acceptable addition salts, which may or may not be incorporated in a pharmaceutically acceptable excipi-ent, vehicle or carrier.
18. A pharmaceutical composition with antagonistic activity towards angiotensin II receptors, which makes it possible to favorably treat cardiovascular diseases, in particular hypertension and cardiac insufficiency, said composition containing a pharmaceutically effec-tive amount of at least one compound of formula (I) or (I') as defined in any one of claims 1 to 13, or one of its pharmaceutically acceptable addition salts, which may or may not be incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.
19. A method of preparing a pharmaceutical composition, which comprises incorporating a pharmaceutically effec-tive amount of at least one compound of formula (I) or (I') as defined in any one of claims 1 to 13, or one of its pharmaceutically acceptable addition salts, into a pharmaceutically acceptable excipient, vehicle or carrier.
20. A method according to claim 19 wherein the pharma-ceutical composition is formulated as gelatin capsules or tablets containing from 1 to 400 mg of active ingredient, or as injectable preparations containing from 0.01 to 50 mg of active ingredient.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9008346 | 1990-07-02 | ||
| FR9008346A FR2663930B1 (en) | 1990-07-02 | 1990-07-02 | NOVEL PYRIMIDINE DERIVATIVES ANTAGONISTS OF ANGIOTENSIN II RECEPTORS; THEIR PREPARATION METHODS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR9014963 | 1990-11-29 | ||
| FR9014963A FR2669928B1 (en) | 1990-11-29 | 1990-11-29 | NOVEL PYRIMIDINE DERIVATIVES ANTIAGONISTS OF ANGIOTENSIN II RECEPTORS; THEIR PREPARATION METHODS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2045327A1 true CA2045327A1 (en) | 1992-01-03 |
Family
ID=26228124
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002045327A Abandoned CA2045327A1 (en) | 1990-07-02 | 1991-06-24 | Pyrimidine derivatives which are angiotensin ii receptor antagonists, their methods of preparation and pharmaceutical compositions in which they are present |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0465323A1 (en) |
| JP (1) | JPH04230370A (en) |
| KR (1) | KR920002555A (en) |
| AU (1) | AU7949191A (en) |
| CA (1) | CA2045327A1 (en) |
| IE (1) | IE912114A1 (en) |
| IL (1) | IL98674A0 (en) |
| NZ (1) | NZ238785A (en) |
| PT (1) | PT98171A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7205297B2 (en) | 2000-07-24 | 2007-04-17 | Krenitsky Pharmaceuticals, Inc. | Substituted 5-alkynyl pyrimidines having neurotrophic activity |
| US9434695B2 (en) | 2012-07-18 | 2016-09-06 | Sunshine Lake Pharma Co., Ltd | Nitrogenous heterocyclic derivatives and their application in drugs |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250548A (en) * | 1990-09-10 | 1993-10-05 | Abbott Laboratories | Angiotensin II receptor antagonists |
| FR2672892B1 (en) * | 1991-02-20 | 1994-01-14 | Synthelabo | DERIVATIVES OF 4-PYRIMIDINONES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| US5252574A (en) * | 1991-04-26 | 1993-10-12 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a substituted thiophene or furan |
| IT1250749B (en) * | 1991-08-02 | 1995-04-21 | Luso Farmaco Inst | HETEROCYCLIC COMPOUNDS ACTIVATED IN II ANTAGONIST |
| AU658426B2 (en) * | 1991-08-15 | 1995-04-13 | Zeneca Limited | Substituted heterocycles |
| AU653665B2 (en) * | 1992-01-17 | 1994-10-06 | Solahart Industries Pty Ltd | Solar hot water systems |
| ZA931062B (en) * | 1992-02-17 | 1993-08-17 | Ciba Geigy | Compositions for the treatment of glaucoma. |
| FR2688505B1 (en) * | 1992-03-16 | 1994-05-06 | Synthelabo | NEW PROCESS FOR THE PREPARATION OF 4-PYRIMIDINONES. |
| US5338740A (en) * | 1993-07-13 | 1994-08-16 | Pfizer Inc. | Angiotensin II receptor antagonists |
| IT1283620B1 (en) * | 1996-04-19 | 1998-04-22 | Luso Farmaco Inst | "PIRIMIDIN-4-ONI N-3 SUBSTITUTED FOR ACTIVITIES WITH THE ANTAGONIST" |
| US6440965B1 (en) | 1997-10-15 | 2002-08-27 | Krenitsky Pharmaceuticals, Inc. | Substituted pyrimidine derivatives, their preparation and their use in the treatment of neurodegenerative or neurological disorders of the central nervous system |
| US6583148B1 (en) | 1999-04-08 | 2003-06-24 | Krenitsky Pharmaceuticals, Inc. | Neurotrophic substituted pyrimidines |
| SE9903028D0 (en) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
| JP2005232081A (en) * | 2004-02-19 | 2005-09-02 | Bayer Cropscience Ag | Utilization of benzylpyrimidine derivative as agricultural and horticultural bactericide |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| CA2688161C (en) | 2007-06-04 | 2020-10-20 | Kunwar Shailubhai | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| ES2522968T3 (en) | 2008-06-04 | 2014-11-19 | Synergy Pharmaceuticals Inc. | Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| ES2624828T3 (en) | 2008-07-16 | 2017-07-17 | Synergy Pharmaceuticals Inc. | Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and others |
| EP2420501A4 (en) | 2009-04-17 | 2012-08-29 | Kowa Co | Novel compound having 3-heteroarylpyrimidin-4-(3h)-one structure and pharmaceutical preparation containing same |
| EP2484675B1 (en) * | 2009-09-29 | 2014-11-05 | Kowa Company, Ltd. | Novel phenylpyridine derivative and medicinal agent comprising same |
| WO2011105099A1 (en) * | 2010-02-25 | 2011-09-01 | 興和株式会社 | Compound containing a novel 4-alkoxypyridine formation and medicine containing same |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| US9486494B2 (en) | 2013-03-15 | 2016-11-08 | Synergy Pharmaceuticals, Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| JP6606491B2 (en) | 2013-06-05 | 2019-11-13 | シナジー ファーマシューティカルズ インコーポレイテッド | Ultra high purity agonist of guanylate cyclase C, method for producing and using the same |
| CN114292238B (en) * | 2022-01-07 | 2024-04-12 | 河北工业大学 | C6-alkylthio/amino substituted pyrimidine derivative and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2659694A1 (en) * | 1976-12-31 | 1978-07-13 | Bayer Ag | PROCESS FOR THE PREPARATION OF SUBSTITUTED CHLOROPYRIMIDINES |
-
1991
- 1991-06-19 IE IE211491A patent/IE912114A1/en unknown
- 1991-06-24 CA CA002045327A patent/CA2045327A1/en not_active Abandoned
- 1991-06-28 NZ NZ238785A patent/NZ238785A/en unknown
- 1991-06-28 EP EP91401773A patent/EP0465323A1/en not_active Withdrawn
- 1991-06-30 IL IL98674A patent/IL98674A0/en unknown
- 1991-07-01 PT PT98171A patent/PT98171A/en not_active Application Discontinuation
- 1991-07-01 AU AU79491/91A patent/AU7949191A/en not_active Abandoned
- 1991-07-02 JP JP3186965A patent/JPH04230370A/en active Pending
- 1991-07-02 KR KR1019910011214A patent/KR920002555A/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7205297B2 (en) | 2000-07-24 | 2007-04-17 | Krenitsky Pharmaceuticals, Inc. | Substituted 5-alkynyl pyrimidines having neurotrophic activity |
| US9434695B2 (en) | 2012-07-18 | 2016-09-06 | Sunshine Lake Pharma Co., Ltd | Nitrogenous heterocyclic derivatives and their application in drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0465323A1 (en) | 1992-01-08 |
| IE912114A1 (en) | 1992-01-15 |
| JPH04230370A (en) | 1992-08-19 |
| PT98171A (en) | 1993-08-31 |
| IL98674A0 (en) | 1992-07-15 |
| KR920002555A (en) | 1992-02-28 |
| NZ238785A (en) | 1993-10-26 |
| AU7949191A (en) | 1992-01-02 |
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