Note: Descriptions are shown in the official language in which they were submitted.
2169187
Boehringer M~nnheim GmbH
3833/00/WO
Use of phenols and phenol derivatives a~ pharmaceutical
aqents with a fibrinogen-lowering action
The present invention concerns the new use of phenols
and phenol derivatives to produce pharmaceutical agents
with a fibrinogen-lowering action. The invention also
concerns new phenols and phenol derivatives, processes
for the production thereof and pharmaceutical agents
which contain these compounds.
The invention concerns the use of phenols and phenol
derivatives of the general formula I
R ~ ~ ~ X (I)
for the production of pharmaceutical agents with a
fibrinogen-lowering action,
in which
R denotes hydrogen or one to three substituents which
independently of each other are selected from the
series halogen, Cl-C4 alkyl, C1-C4 alkoxy, hydroxy,
cyano or trifluoromethyl,
216~1 87
B symbolizes saturated or unsaturated alkylene chain
with up to six C atoms which is unsubstituted or
optionally substituted by one or two methyl groups
in an arbitrary position wherein one of the
saturated C atoms can be replaced by an oxygen atom
or by one of the groups >NH, >C=O or >CH-OH and two
adjacent saturated C atoms can also be replaced by
a group -CONH- or -NHCO- and
X is in the meta or para position relative to B and
denotes the following groups:
- a hydroxy group, or a Cl-C4 alkyl urethane
group which is derived therefrom or a
substituted or unsubstituted phenyl urethane
group,
- a C1-C6 alkyloxy, omega-hydroxy-C2-C6 alkyloxy,
omega-halogen-C2-C6 alkyloxy or omega-cyano-
Cl-C6 alkyloxy group which is unbranched or
substituted in any position by one or two
methyl groups,
- a Cl-C4 alkyl urethane group derived from the
omega-hydroxy-C2-C6 alkyloxy group, a
substituted or unsubstituted phenyl urethane
group, phosphoric acid ester group, aliphatic
carboxylic acid ester group or an optionally
substituted benzoic acid ester group,
- an aminocarbonyl-Cl-C6 alkyloxy or a N-hydroxy-
aminocarbonyl-Cl-C6 alkyloxy group
2169187
- carboxymethoxy, 1-carboxy-ethoxy, l-carboxy-
propyloxy or 3-carboxy-propyloxy
- the residue -O-C(CH3)2-CH2-O-CO-(CH2)2-COOH
- a benzoyloxy residue which can be optionally
substituted
as well as enantiomers, diastereomérs, Z or E
isomers thereof and if desired physiologically
tolerated salts or esters thereof.
R denotes one to three substituents which, independently
of each other, are the same or different and are at any
position on the benzene ring relative to the substituent
B. In the definition of R halogen denotes fluorine,
chlorine, bromine and iodine, chlorine being preferred
in this case. Cl-C4 alkyl or C1-C4 alkoxy comprises a
straight-chained or branched alkyl residue with 1-4 C
atoms, methyl and isopropyl being preferred.
Unbranched alkylene chains with 2-6 C atoms are
preferred for B and one of the saturated C atoms can be
replaced by an oxygen atom or by one of the groups NH,
>CO or >CH-OH. Two adjacent saturated C atoms may be
together replaced by a group CONH- or -NHCO-. In the
case that a C atom is replaced by an oxygen atom, the
oxygen atom is preferably in the para position relative
to the phenoxy oxygen of group X. The same applies to
the preferred position of an individual carbonyl group
>C=O or of a secondary alcohol group >CH-OH. However, in
the case that >C=O or >CH-OH forms part of chain B made
of three carbon atoms, these groups are preferably in
the alpha position relative to one of the two benzene
- 4 - 2l69l ~7
rlngs .
There are preferences for the position of amino or
carbonyl amino groups. The groups -CO-CH=CH- and
CH=CHCO- are preferred among the compounds with an
unsaturated group B ("chalcones").
Cinnamic amides with the residues -CH=CH-CONH- and
-NHCO-CH=CH- are preferred as compounds that have a
carbonyl amino group in addition to a double bond as a
component of group B.
The substituent X is in the meta or para position
relative to the substituent B. C1-C6 alkyloxy for
substituent X denotes a straight-chained or branched
alkyloxy chain, preferably methoxy, ethoxy and n-
butyloxy. The following alkoxy groups àre particularly
preferred which are substituted at the terminal C atom
by a hydroxy, halogen or cyano group: a) omega-hydroxy-
C2-C6 alkyloxy, b) omega-halogen-C2-C6 alkyloxy and c)
omega-cyano-C1-C6 alkyloxy or/and carry one or two
methyl groups on the C atom that is adjacent to the
ether oxygen. Omega-hydroxy-C2-C6 alkyloxy preferably
denotes 2-hydroxy-ethoxy, 4-hydroxy-butoxy, 3-hydroxy-2-
propoxy or 3-hydroxy-2-methyl-2-propoxy. Omega-halogen-
C2-C6 alkyloxy preferably denotes omega-chloro-C2-C6
alkyloxy and in this case in particular 2-chloro-ethoxy
and 4-chloro-butoxy. Omega-cyano-C1-C6 alkyloxy
preferably denotes cyano-methyloxy and 5-cyano-
pentyloxy.
If group X comprises a C1-C4 alkyl urethane group then
the alkyl group can be straight-chained or branched.
Methyl, ethyl and t-butyl urethane are preferred. The
2I 691 87
phenyl residue in phenyl urethane can be unsubstituted
as well as substituted by halogen, preferably chlorine
in the 3 or 4 position.
If the substituent X comprises a benzoic acid ester
residue, then the phenyl residue is optionally
substituted once or several times preferably with
halogen, methoxy or methyl. Acetic acid, propionic acid
or n- or iso-butyric acid come preferably into
consideration as aliphatic carboxylic acid residues. If
X denotes a benzoyloxy residue, this can be optionally
substituted in the meta or para position preferably by
halogen.
Particularly preferred residues R are 4-chloro or
3-chloro, 4-fluoro, 4-trifluoromethyl or 3-trifluoro-
methyl, 4-methyl, 4-methoxy, 4-cyano, 2,4-di-chloro and
2-methoxy-5-chloro.
Particularly preferred residues B are -CONHCH2CH2-,
-CH=CH-CO-, COCH=CH-, -NHCH2-, -CH2NH-, -CH2NHCH2-,
>CHOH, -NHCO-, -CONH-, NHCOCH2-, -CH2NHCO-, carbonyl,
unbranched C1-C6 alkylene or unbranched C2-C5 alkylene
carbonyl in particular ethylene carbonyl, trimethylene
carbonyl and pentamethylene carbonyl.
Preferred residues X are in the para position relative
to B and are hydroxy, carboxy-methoxy, l-carboxy-ethoxy,
1-carboxy-propyloxy, 3-carboxy-propyloxy, 2-hydroxy-
ethoxy, 3-hydroxy-propyl-2-oxy, 3-hydroxy-2-methyl-
propyl-2-oxy, propyl-2-oxy and the residue -O-C(CH3)2-
CH2-O-CO-(CH2)2-COOH.
Compounds of the general formula I are particularly
- 6 - 2169I~7
preferred in which R denotes 4-chloro, 4-trifluoro-
methyl or 4-cyano, B is >CHOH, -CONHCH2CH2-, tri-
methylene, trimethylene carbonyl or pentamethylene
carbonyl, X is in the para position relative to B and
represents 1-carboxy-ethoxy, propyl-2-oxy, 3-hydroxy-
propyl-2-oxy or the residue -O-C(CH3)2-CH2-O-CO-(CH2)2-
COOH.
Particularly preferred compounds of the general formula
I are those in which R denotes 4-chloro, X is in the
para position relative to B and denotes 1-carboxy-ethoxy
and B represents trimethylene, trimethylene carbonyl or
pentamethylene carbonyl.
The present invention also concerns new phenols and
phenol derivatives which are encompassèd by formula I.
Compounds covered by formula I are already described in
the literature
in which
a) B denotes the group -CONHCH2CH2-, R is a chlorine
atom in the para position, X is a hydroxy group
carboxymethoxy, 1-carboxy-propyloxy or the
p-chlorobenzoyloxy residue in the para position
b) R is hydrogen and X is a hydroxy group in the para
position while B denotes the group CONHCH2CH2-
c) R is a chlorine atom in the para position, Bdenotes a trimethylene group and X represents a
hydroxy group in the para position
.,., 2169187
d) X is a 1-carboxyethoxy residue in the para position
and R is a chlorine atom in the para position while
B denotes a methylene, carbonyl or aminomethylene
group
e) X denotes a 3-hydroxy-propyl-2-oxy residue in the
para position, R is a chlorine atom in the para
position and B denotes the group >CHOH.
Thus the compound in which R = H, B = -CONHCH2CH2- and
X = 4-OH is mentioned by Aso and Murakoshi in the
Symposia on Enzyme Chem. 8, 64-65 (1953) (Jap.) in
connection with phosphomonoesterase inhibition. Other
publications describe their use as a starting material
or as a reaction component. They are also described as a
precursor for the production of lipid-lowering
substances for example in DE-OS 2149070 as is the
compound in which R = Cl, B = -CONHCH2CH2- and X = 4-OH.
The compound in which R = 4-Cl, B = -CONHCH2CH2- and
X = 4-OCH2-COOH is also a subject matter of DE-OS
2149070. It belongs to a series of substances which
lower serum lipids as well as the cholesterol level
which are for example effective against atherosclerosis.
The compound in which R = H, B = -(CH2)3- and X = 4-OH
serves as a starting material for the synthesis of
lipid-lowering compounds of the "fibrate" type (Kyushin
Pharm., Ltd., J.Med. Chem. 31, 1205-9 (1988)). It proved
to be an inhibitor of fungal growth (Bultman et al., CA
89:85632), an antimicrobial agent (Jurd et al., US
3915889, CA 84:39706; Jurd et al., US 3867548, CA
83:23435; Jurd et al., US 3775541, CA 81:22227d; King et
al., Antimicrob. Agents Chemother. 1, 263-7 (1972); Jurd
2169187
- 8 -
et al., J. Pharm. Sci. 60, 1753-5 (1971); as a substance
that inhibits algal growth (Chan and Jurd, Experientia
29, 1196-7 )(1973)) and a sporostatic agent (Lewis and
Jurd, Spores 5, 384-9 (1972)).
It was now found that compounds of formula I are highly
effective substances which reduce the fibrinogen
concentration in blood which is above all of importance
for the treatment of cardiovascular diseases such as
peripheral arterial occlusive disease, coronary heart
disease and disturbances of the cerebral circulation.
It is clear from the evaluation of epidemiological
studies that an increased plasma level of fibrinogen in
humans is linked with a considerably increased risk of
contracting coronary heart disease. High fibrinogen
levels contribute in various ways to the formation of
atheromas: by increasing plasma viscosity, as a co-
factor in platelet aggregation, by influencing the
amount of fibrin that is deposited when coagulation is
initiated. Fibrinogen that accumulates in the arterial
wall is claimed to promote the proliferation of smooth
muscle cells (Naito et al., Atherosclerosis 83 (1990),
9) and to accelerate the deposition of LDL and other
lipids (Smith, Eur. Heart J. 11 (1990), 72). The most
important rheological factors of the microcirculation
are the fibrinogen-dependent parameters plasma viscosity
and erythrocyte aggregation. High concentrations of
fibrinogen (and other protein fractions) lead to an
enormous increase in plasma viscosity and erythrocyte
aggregation. A therapeutic lowering of the plasma
fibrinogen level results in a consideràble improvement
of the blood flow properties and thus an increase in the
microcirculation with an improved oxygen release.
-- 2169187
- 9 -
The compounds of formula I have a pronounced fibrinogen-
lowering action which is superior to that of bezafibrate
that is described as being able to lower fibrinogen
(Cook et al., TIPS Reviews 11 (1990), 450).
The mechanism of action of the compounds according to
the invention should not be confused with that of
"fibrinogen antagonists". The latter are substances
which are capable of preventing the binding of
fibrinogen to a GP IIb-IIIa receptor located on blood
platelets whereas the compounds of the general formula I
reduce the concentration of fibrinogen in blood.
The production of the compounds of the general formula I
used according to the invention is known.
Thus for example the phenols of the general formula Ia
encompassed by the general formula I of the present
invention
~ CON~C~C ~ (Ia)
are produced by reacting an amine of the general formula
II
.
H~N ~ (CHz)~ ~ (II)
` ~ , 2l69l$7
-- 10 --
in the presence of acid-binding agents with a carboxylic
acid of the general formula III
~ COO~ (III)
Q
or with a reactive derivative thereof. R in the formulae
(I) and (III) has the aforementioned meaning. Acid
halides are suitable as the reactive derivatives and in
particular acid chlorides and acid imidazolides. Alkali
hydroxides (reaction under Schotten-Baumann conditions)
or organic bases such as pyridine (see e.g. DE-AS 2 14g
070) or triethylamine come into consideration as acid-
binding agents.
These phenols are in turn also precursors for phenoxy-
alkylcarboxylic acids and esters of the general formula
I in which B = -CONHCH2CH2- and X = carboxymethoxy or 1-
carboxyl-ethoxy. Such phenoxyalkylcarboxylic acids are
produced for example according to DE-AS 2 149 070 by
reacting the phenols (Ia) with alpha halogenacetic acid
esters or alpha halogenpropionic acid esters in inert
solvents such as 2-butanone and in the presence of acid
acceptors such as pulverized potassium carbonate. The
ethyl esters of bromocarboxylic acids or chloro-
carboxylic acids are preferably used as halogen-
carboxylic acid esters. The oxycarboxylic acid esters
that are formed are subsequently saponified by heating
with alcoholic alkaline lye to form the carboxylic
acids.
21 691 87
Compounds of the general formulae Ibl or Ib2
,~C 1-1 = C I I--C--~ ( Ibl )
~ C--C~ - C ~--~ ( I b2 )
in which R and X have the above-mentioned meaning are
obtained by condensation of an acetophenone of the
general formula IVa or IVb
~ 1~ 3 (IVa) ~ C ~ C1~3 (IVb)
with a benzaldehyde of the general formula Va or Vb.
= O X ~ C(~- ~ (Vb)
~la)
2169I87
- 12 -
The condensation is preferabIy carried oùt in an
aqueous-alkaline environment e.g. in the presence of
aqueous sodium hydroxide solution. In some cases the
condensation can also preferably proceed in the presence
of a mineral acid such as aqueous-alcoholic hydrochloric
acid.
The chalcones Ibl and Ib2 are preferably reduced to the
trimethylene compounds Id according to the invention in
two steps: Firstly the chalcones are reduced to the
dihydrochalcones of the general formula Ic1 or Ic2
~3C4ZCIILC~ ~ C~lz~~X
(Icl) (IC2)
which is achieved by catalytic hydrogenation of the
former e.g. in the presence of noble metals or in the
presence of homogeneous catalysts of the triphenyl-
phosphine/rhodium salt type at room temperature and
normal pressure in a solvent such as e.g. THF.
Subsequent reduction of the dihydrochaLcones under the
conditions of the WOLFF-KISHNER reduction i.e. by
heating with hydrazine hydrate in strong alkali yields
the trimethylene compounds of the general formula Id
'~)3 ~ '
~ (Id)
in which R and X have the meaning stated above.
2I69187
- 13 -
Compounds of the general formula Ie
~ ~,~OC~2CH7CI1
in which R and B have the meaning statèd above are
produced by reacting a phenol of the general formula If
, ~ e~ o(~
with 1,3-dioxolan-2-one (ethylene carbonate) while
heating. The reaction is carried out in a solvent in the
presence of K2C03. Further reaction of compounds of the
general formula Ie with alkyl or phenyl isocyanates
leads to alkyl or phenyl urethanes of the general
formula Ig
~ c~ZOco ~ (Pl~)
(Ig)
R
in which R and B have the meaning stated above, Alk
represents a C1-C4 alkyl residue and Phe denotes
unsubstituted or substituted phenyl.
- 14 - 2169187
The further reaction of compounds of the general formula
If with alkyl or phenyl isocyanates under the usual
conditions also leads to alkyl or phenyl urethanes of
the general formula Ih
,~_ ~ OCo ~ (P~C )
(Ih)
in which R, B, Alk and Phe have the meaning stated
above.
Compounds of the general formula Ii
~c~ cO_~ oc~ e, COOH
in which R has the meaning stated above, n = 1-6 and R
denotes hydrogen or methyl are produced by Friedel-
Crafts acylation of a phenoxycarboxylic acid ester of
the general formula VII
<~S OC~Q,Coo~,2
~ (VII),
in which R1 has the meaning stated above and R2 denotes
C1-C4 alkyl, with a carboxylic acid of the general
formula VIII
2I 691 87
- 15 -
~ (C~z)~- CO 0~ (VIII),
in which R has the meaning stated above and n denotes
the numbers 1 - 6, in the presence of polyphosphoric
acid as the F.-C. catalyst. The ester obtained in this
process is subsequently saponified.
Compounds of the general formula Ik
,~C~z~ Ch2~4~ (Ikl l
in which R and X have the meaning stated above, are
produced by allowing a benzylamine of the general
formula IX
~C~HL
~ (IX)
to react with a benzaldehyde of the general formula X
~=Cl~x (X)
216918`7
- 16 -
for example in ethanol to form the Schi`ff base and
hydrogenating the latter, without isolating it, at
normal pressure in the presence of for example platinum
dioxide to form compound Ik.
If desired the synthesized compounds of the general
formula I can, if they are acidic or basic, be converted
into physiologically tolerated salts and in the case of
carboxylic acids it is possible to convert them into
esters using physiologically acceptable alcohols.
Pharmacologically acceptable inorganic or organic bases
such as e.g. sodium hydroxide, potassium hydroxide,
calcium hydroxide, methylglucamine, morpholine or
ethanolamine are suitable for forming salts from
carboxylic acids of the general formula I. Acids such as
hydrochloric acid, sulphuric acid, acetic acid, citric
acid, maleic acid, fumaric acid and tartaric acid are
suitable for forming salts from bases of the general
formula I.
If the compounds of the general formula I contain a
carboxyl group, esters of these carboxylic acids which
come into consideration are those formed with lower
monovalent alcohols (such as e.g. methanol or ethanol)
or with multivalent alcohols (such as e.g. glycerol).
However, those alcohols which also carry other
functional groups such as e.g. ethanolamine are also
included.
The pure enantiomers can be produced from the racemates
of the compounds of the general formula I that are
obtained by racemate resolution (by salt formation with
- 17 - 21 691 8 7
optically active bases). Pure enantiomers can also be
obtained by using optically active starting materials in
the synthesis.
In order to produce pharmaceutical agents, the
substances of the general formula I are admixed with
suitable pharmaceutical carrier substances, aromatics,
flavourings and dyes and are for example formed into
tablets or coated tablets or are suspended or dissolved
in water or oil, for example in olive oil, with addition
of appropriate auxiliary substances. `-
The substances of the general formula I and saltsthereof can be administered enterally or parenterally in
a liquid or solid form. Water is preferably used as the
injection medium which contains common additives used in
injection solutions such as stabilizers, solubilizers or
buffers. Such additives are for example tartrate and
citrate buffer, complexing agents (such as ethylene
diamine tetraacetic acid and non-toxic salts thereof)
and high-molecular polymers such as liquid polyethyl
oxide to regulate viscosity. Solid carriers are for
example starch, lactose, mannitol, methylcellulose,
talcum, highly-dispersed silicic acids, high-molecular
fatty acids (such as stearic acid) animal and vegetable
fats and solid high-molecular polymers (such as
polyethylene glycols). Preparations that are suitable
for oral administration can if desired contain
flavourings and sweeteners.
The dose can depend on various factors such as form of
administration, species or age or individual state of
health. The compounds of formula I are usually
administered in amounts of 1.5 to 15 mg, preferably 5 -
` -- 2169187
- 18 -
10 mg per day and per kg body weight. It is preferred to
divide the daily dose into two applications, two tablets
with a content of active substance of 85 to 200 mg each
being administered at each application. The tablets can
also be retarded by which means only one tablet with 100
- 1000 mg active substance has to be administered per
day.
Apart from the compounds mentioned in the examples and
those formed by combining all substituents mentioned in
the claims, within the sense of the present invention
the following compounds of formula I are preferred which
can be present as pure enantiomers, as mixtures of
enantiomers/racemates, as E or Z-isomers or mixtures
thereof as well as if desired salts or/and esters:
Compound R B X Melt.p.~c
H CoNHcH2cH2 . 4-OH 164-165
2 4-CI CONHCH2CH2 4-OH 174-175
3 4-CI CONHCH2CH2 4-OCO-C6H4-CI(P) 196-197
4 4-CI CONHCH2CH2 4-OCH2-COOH 199
4-CI CONHCH2CH2 4-OCH(Et)-COOH 166-167
6 4-CI (CH2)3 4-OH 33
7 4-CI CH2 4-OCH(Me)-COOH 119-121
8 4-CI CO 4-OCH(Me)-COOH 144-146
9 4-CI CH(OH) 4-OCH(Me)-CH20H OEL
10 4-CI NHCH2 4-OCH(Me)-COOH n.n.
11. 4-CI CONHCH2CH2 4-OCONHEt 194-196
12. 4-CI CONHCH2CH2 4-OCONHtBu 175
13. 4-CI CONHCH2CH2 4-OCONH-C6H5 195-196
14. 4-CI CONHCH2CH2 4-OCH2-CONHOH 162
2169187
-- 19 --
Compound R B X Melt . P ~C
15. 4-CI CONHCH2CH2 4-OCH(Me)-COOH 185-186
16. 4-CI CONHCH2CH2 4-OC(Me)2-CH2OH 140
17. 4-CI CONHCH2CH2 4-OC(Me)2-CH2OPo(oH)2 157
18. 4-CI CONHCH2CH2 4-OCONHMe 197-198
19. 4-CI CONHCH2CH2 3-OCH2CH2-OH 83-84
20. 4-CI CONHCH2CH2 4-OCH2CH2-OH 159-160
21. 4-CI CONHCH2CH2 4-OCH2CH2-OCONHMe 172-173
22. 4-CI CONHCH2CH2 4-OCH2CH2-OCONH-C6H4-Cl(P)
201
23. 4-CI CONHCH2CH2 4-oCH(Me)2 179
24. 4-CI CONHCH2CH2 4-OCH2-CN 118
25. 4-CI CONHCH2CH2 4-(CH2)3-coH 187-189
26. H (CH2)3 4-OH 51-52
27. H (CH2)3 4-OCONHEt 68-69
28. 4-CI (CH2)3 4-OCONHEt 114
29. H (CH2)3 4-OCH(Me)-COOH 66-67
30. 4-CH3 (CH2)3 4-OCH(Me)-COOH - 97-98
31. 4-CF3 (CH2)3 4-OCH(Me)-COOH 42-44
32. 4-OCH3 (CH2)3 4-OCH(Me)-COOH 82-83
33. 4-CI CH=CH-CO 4-OCH(Me)-COOH 195
34. 4-OCH3 CH=CH-CO 4-OCH(Me)-COOH 163-166
35. 4-Me CH=CH-CO 4-OCH(Me)-COOH 174-177
36. 4-CF3 CH=CH-CO 4-OCH(Me)-COOH 204-207
37. 4-CI CO-CH=CH 4-OCH(Me)-COOH 188-189
38. 4-CI (CH2)2-co 4-OCH(Me)-COOH 129-130
39. 4-OCH3 (CH2)2-cO 4-OCH(Me)-COOH 100-102
40. 4-CH3 (CH2)2-co 4-OCH(Me)-COOH 143-144
41. 4-CF3 (CH2)2-co 4-OCH(Me)-COOH 152-155
42. 4-CI (CH2)3-Co 4-OCH(Me)-COOH 113-114
43. 4-CI NHCO 4-OCH(Me)-COOH 231-232
44. 4-CI NHCOCH2 4-OCH(Me)-COOH 177
45. 4-CI CONH 4-OCH(Me)-COOH 213-214
46. 4-CI CH2NH 4-OCH(Me)-CH20H xHCI 138-141
47. 4-CI CH2NHCO 4-OCH(Me)-COOH 187-188
48. H (CH2)3 3-OCH2-COOH 78-79
2169187
-- 20 --
Com~l.,.d R B X ~elt . p . oc
49. 4-CI (CH2)3 3-OCH2-COOH
50. H (CH2)3 4-OCH2-COOH 94-95
51. 4-CI (CH2)3 4-OCH2-COOH 12-113
52. 4-F (CH2)3 4-OCH(Me)-COOH
53. 3-CI (CH2)3 4-OCH(Me)-COOH
54. 2.4-di-CI (CH2)3 4-OCH(Me)-COOH
55. 3-CF3 (CH2)3 4-OCH(Me)-COOH
56. 2-OCH3-5-CI -"- 4-OCH(Me)-COOH
57. 4-CN CH=CH-CO 4-OCH(Me)-COOH
58. 4-F CH=CH-CO 4-OCH(Me)-COOH
59 4-CN (CH2)2-co 4-OCH(Me)-COOH
60. 4-F (CH2)2-co - 4-OCH(Me)-COOH
61. 4-CI (CH2)4 4-OCH(Me)-COOH
62. 4-CI (CH2)6 4-OCH(Me)-COOH
63. 4-CI NH 4-OCH(Me)-COOH
64. H NHCO 4-OCH(Me)-COOH
65. H NHCH2 4-OCH(Me)-COOH
66. 4-CI NHCH2CH2 4-OCH2-COOH
67. 4-CI NHCH2CH2 4-OCH(Me)-COOH
68. 4-CI CONHCH2CH2 4-OC(Me)2CH20-C0-NHMe 139-141
69. 4-CI " 4-0C(Me)2CH20-C0-CH2-CH2-C00H
134-135
70. 4-CI CH=CH-C0 3-OH 124-125
71. 4-CI (CH2)2-C0 3-OCH2-COOH 117-119
72. H CH2-NH-CH2 4-OCH2-COOH xHCI 222-224
73. 3-CI " 4-OCH2-COOH xHCI 232-234
74. 4-CI " 4-OCH2-COOH xHCI 244-245
75. H 4-OCH2CH2OH xHCI 172-174
76. 4-CI " 4-OCH2CH2OH xHCI 215-218
77. H (CH2)3 4-OCH2-COOH 94-95
78. 4-CI (CH2)3 4-OCH2-COOH 112-113
79. H (CH2)3 3-OCH2-COOH 78-79
,, 2169I87
- 21 -
Experimental procedures for the preparation of new
compounds are described in the following as examples.
Ex~mples of embodiments:
Example 1:
2- r 4~ r 3-(4-cyanophenyl)propyl~phenoxy]ropionic acid
a) 4'-Hydroxy-4-carboxy-chalcone
15.0 g (0.1 mol) 4-carboxybenzaldehyde is added to
a solution of 150 ml water, 14.0 g (0.35 mol)
sodium hydroxide and 13.6 g (0.1 mol) 4-hydroxy-
acetophenone under nitrogen and it is allowed to
react for 36 hours. Water is then added, it is
extracted twice with ethyl acetate and the aqueous
phase is adjusted to pH 7 with dilute HCl. The
precipitated product is suction filtered and washed
with water. After drying and recrystallizing from
ethanol one obtains 22.0 g (82 % of theory) product
with a melting point of 283-284C.
b) 4-[3-(4-Hydroxyphenyl)propyl]benzoic acid
22.0 g (81 mol) of the chalcone is hydrogenated for
two hours at 20C and 40 mbar in a mixture of
800 ml THF, 3.5 ml 70 % HCl04 and 5 g 10 %
palladium carbon. After separating the catalyst, it
is evaporated. Yield 20.5 g (98 % of theory),
melting point 129-131C (toluene).
2I69187
- 22 -
c) 4-[3-[4-Acetoxyphenyl)propyl]benzoic acid
20 g (78 mmol) of the hydroxy compound from b) is
stirred for one hour at 0C with 40 ml (246 mmol)
acetic hydride and 1.0 g dimethylaminopyridine.
20 ml ethanol is then added at 0C, it is stirred
for 5 min and 600 ml water is added. It is
extracted with ether, the ether phase is dried
(Na2SO4) and evaporated. The residue is
recrystallized from 66 % ethanol. Yield 12.0 g
(51 % of theory), melting point 134-136C.
d) 4-[3-(4-Acetoxyphenyl)propyl]benzamide
A mixture of 12.0 g (40 mmol) of the benzoic acid
synthesized according to c), 20 ml (0.27 mmol)
thionyl chloride and three drops of DMF are stirred
for two hours at 60C. It is then evaporated to
dryness, the residue is dissolved in methylene
chloride and gassed with ammonia at 0C until
amidation is completed. It is evaporated and washed
with cold methylene chloride. Yield 11.4 g (95.3 %
of theory), melting point 104-106C (ethanol).
e) 4-[3-(4-Hydroxyphenyl)propyl]benzamide
A mixture composed of 11.4 g (38 mmol) of the
acetoxy compound obtained according to d), 45 ml 2N
NaOH (90 mmol) and 90 ml ethanol is stirred for
20 min at 50C, the ethanol is then removed by
distillation and it is diluted with water. The
phenol is precipitated by acidifying with 2N HCl.
It is suction filtered, washed with water and
dried. Yield 9.1 g (93 % of theory), melting point
" 2l69l87
174-175C (ethanol).
f) 2-[4-[3-[4-Aminocarbonylphenyl)propyl]phenoxy]-
propionic acid methyl ester
A mixture of 7.0 g (27.5 mmol) of the phenol
obtained according to e), 100 ml butanone and 9.5 g
(69 mmol) anhydrous, pulverized K2CO3 is stirred
for 15 minutes at 80C, then a spatula tip full of
potassium iodide and several mg of the crown ether
crown (18,6) as well as 5.0 g (30 mmol) 2-bromo-
propionic acid methyl ester are added successively
and it is stirred for 16 hours at 80C. It is then
suction filtered while warm, the filtrate is
concentrated by evaporation and the residue is
crystallized using isohexane. It is suction
filtered and dried. Yield 9.2 g (98.3 % of theory),
melting point 102-103C (ethyl acetate).
g) 2-[4-t3-(4-Cyanophenyl)propyl]phenoxy]propionic
acid methyl ester
9.0 g (2.9 mmol) of the carbonamide obtained
according to f) is dissolved at 140C in 90 ml
toluene, 7.0 g (5.6 mmol) phosphorus pentoxide is
added and it is stirred for a further 10 min at
140C. After cooling the toluene is removed by
decanting, the undissolved material is treated
twice with hot ethyl acetate and the ethyl acetate
extracts are combined with the toluene phase. The
organic solvent is evaporated and 7.2 g (85 % of
theory) product remain in the form of a colourless
oil; practically analytically pure.
- 24 - 21 6~ 1 8 7
h) Title compound
A mixture of 7.0 g (20 mmol) of the ester
synthesized according to g), 20 ml 2N NaOH and 40
ml ethanol is stirred for one hour at 50C, the
ethanol is then removed by distillation. The
residue is diluted with water, the aqueous phase is
shaken twice with ether in order to remove neutral
substances and subsequently it is acidified with
dilute HCl. The acidic solution is extracted three
times with ether. The ether is dried (Na2SO4),
evaporated and the residual crude product is
chromatographed by means of a short silica gel
No. 60 column using methylene chloride + 1 % acetic
acid as the mobile solvent. Yield 5.0 g (74.6 % of
theory) colourless oil.
Exam~le 2:
[4-~3-~4-Chlorophenyl)propyllphenol
a) 4'-Hydroxy-4-chloro-chalcone
13.6 g (0.1 mol) 4-hydroxy-acetophenone is
dissolved in a solution composed of 10.0 g NaOH and
100 ml water, 14.1 g (0.1 mol) 4-chlorobenzaldehyde
is added and it is stirred for 48 hours at room
temperature under nitrogen. Afterwards it is
diluted with water, acidified with dilute HCl and
the precipitated precipitate is suction filtered.
After washing with water and drying (in a vacuum
over KOH). The yield was 23.8 g (92 % of theory),
melting point 187C (methanol).
- 25 - 21 691 87
b) Title compound
A mixture composed of 22.0 g (85 mmol) 4'-hydroxy-
4-chloro-chalcone, 500 ml methanol, 10 ml
concentrated HCl and 5 g 10 % palladium carbon is
gassed with hydrogen at room temperature and normal
pressure in a shaking apparatus until uptake is
completed. The catalyst is then removed by suction
filtration, it is evaporated in a vacuum and the
residue is dissolved in ether. The ether phase is
washed neutral by shaking with saturated NaHC03
solution, it is then dried with Na2S04 and
evaporated. It is subsequently purified on a RP-18
medium pressure chromatography column using
methanol:water = 8:2 vol. as the mobile solvent.
Yield 14.2 g (68 % of theory).
Ex~mple 3:
2-~4-~3-(4-Chlorophenyl)proPyl]Phenoxy~propionic acid
methyl ester
a) 2-[4-[3-(4-Chlorophenyl)propyl]phenoxy]propionic
acid methyl ester
It is prepared from 4-[3-(4-chlorophenyl)propyl]-
phenol (see above) and 2-bromo-propionic acid
methyl ester analogously to example lf). The
product was used in a non-purified form (oil, yield
nearly 100 ~) in the saponification described in
b).
2169187
- 26 -
b) Title compound
A mixture composed of 6.3 g (18.9 mmol) of the
ester prepared according to a), 60 ml methanol and
30 ml 2N NaOH is stirred for 4 hours at 50C, the
methanol is then evaporated in a vacuum and the
acid is precipitated by means of dilute HCl. It is
suction filtered, washed with water and dried over
KOH in a vacuum. Yield 5.3 g (88 % of theory),
melting point 81-82C (heptane).
Exampl~ 4
2-[4-~2-(Benzoylamino)ethyl]phenoxy]ethanol
A suspension of 60 ml absolute toluene, 8.0 g (33 mmol)
4-[2-(benzoylamino)ethyl]phenol and 4.7 g pulverized,
dry K2CO3 is stirred for 15 minutes at 120C, 5.8 g
(66 mmol) ethylene carbonate is then added and it is
kept for a further two hours at 120C. It is diluted
with acetone, suction filtered in a hot state, the
filtrate is evaporated in a vacuum and the residue is
crystallized from ethanol. Yield 4.6 g (49 % of theory),
melting point 135-136C.
~x~mpl~ 4~:
2-t3-[2-(Benzoylamino)ethyl]-phenoxy]ethanol is prepared
from 3-[2-(benzoylamino)-ethyl]phenol and ethylene
carbonate In an analogous manner.
Yield 61 % of theory, colourless oil.
- 27 - 21 691 8 7
Ex~mpl~ 5:
2-~4-r6-(4-Chlorophenyl)-1-oxo-hexyl~phenoxy]propionic
acid
a) - ethyl ester
A mixture of 8.1 g (35.7 mmol) 6-(4-chlorophenyl)-
hexanoic acid, 6.9 g (35.7 mmol) 2--phenoxypropionic
acid ethyl ester and 50 g polyphosphoric acid is
kept for 10 min at 80C while stirring and it is
subsequently stirred into ice water. It is
extracted with ether, the ether phase is dried with
Na2SO4 and subsequently it is evaporated. The
residue is dissolved in methylene chloride. It is
filtered on a short silica gel column and
evaporated. Yield 10.2 g (71 % of theory),
colourless oil.
b) Title compound
The ester is saponified analogously to example lh)
and it is finally recrystallized from a mixture of
cyclohexane and toluene. Yield 87 % of theory,
melting point 74-76C.
2169187
- 28 -
Example 6:
Ph~rm~cologic~l tost
Method: Turpentine-induced hypofibrinogenaemia of the
rat
The intramascular administration of 0.05 ml turpentine
triggers a dramatic increase in plasma fibrinogen in the
rat. This is presumably an acute phase reaction as a
result of which fibrinogen increases as an acute phase
protein.
500 ~1 blood is taken from the tail vein of 250-300 g
Sprague-Dawley rats (breeder: IFFA-CREDO, France) and
the basal plasma fibrinogen concentration in this is
determined by means of the CLAUSS method using a two
channel coagulometer (Biomatik 2000 coagulometer,
Sarstedt Co.). Afterwards the animals receive orally
50 mg/kg of the test substance (stAn~Ard dose) in 1 %
tylose solution. Two hours after administration of the
test substance 0.05 ml turpentine is injected
intramascularly into one of the hind limbs. A further
two hours after the turpentine administration, the test
substance is again administered orally as well as after
24 and 48 hours. 24 and 72 hours after the turpentine
administration, 500 ~1 blood is taken from the tail vein
of the animals and fibrinogen is determined. The
measured fibrinogen values are determined, related to
the fibrinogen values of a concurrent control group
which received tylose that was free of substance and are
stated as a percentage inhibition.
2~ C~
- 29 -
Results:
This method was used to test the following substances
for their effectiveness as fibrinogen-lowering agents.
In each case the values of the measurement 24 hours
after turpentine administration are stated.
Turpentine-indu¢ed hyperfibrinogenaemia
Com~Gund of the rat ~% inhibition after 24 h)
Ex~mple using 50 mg/~g substance
1 17
3 21
22
23 19
31 17
42 22
Reference
compound:
Bezafibrate 13
