NZ206409A - Alkylbenzylidene derivatives and pharmaceutical compositions - Google Patents
Alkylbenzylidene derivatives and pharmaceutical compositionsInfo
- Publication number
- NZ206409A NZ206409A NZ206409A NZ20640983A NZ206409A NZ 206409 A NZ206409 A NZ 206409A NZ 206409 A NZ206409 A NZ 206409A NZ 20640983 A NZ20640983 A NZ 20640983A NZ 206409 A NZ206409 A NZ 206409A
- Authority
- NZ
- New Zealand
- Prior art keywords
- general formula
- radical
- benzylidene
- derivative
- benzylidene derivative
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/835—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups having unsaturation outside an aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, ***e
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Rheumatology (AREA)
- Anesthesiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number £06409
2 064 0 9
Priority Date(s): v!
Complete Specification Filed:
Class:
AS.//?.3 .'.//fu.lSs.P.T.T.
l1'V JUL 19861*
Publication Date:
, no c,
P.O. Journal, No: ....
HADJIS
i
'■SN0Vi985'
NEW ZEALAND
W iK
•■W/ J /LWJ,
THE PATENTS ACT 1953
PATENTS FORM NO. 5
COMPLETE SPECIFICATION
"NEW THERAPEUTICALLY USEFUL ALKYLBENZYLIDENE DERIVATIVES"
WE, SYNTHELABO, a French Body Corporate, of 58 rue de la Glaciere, 75013 Paris, France, hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:
- 1 - (followed by page la)
206 4 0
- i^ —
"NEW THERAPEUTICALLY USEFUL ALKYLBENZYLIDENE DERIVATIVES"
The present invention relates to new therapeutically useful alkylbenzylidene derivatives, to a process for their preparation and their application in therapy such as pharmaceutical compositions containing 5 them.
The alkylbenzylidene derivatives of the present invention are those compounds of the general formula:
wherein n represents an integer from 1 to 12 (preferably 10 1 to 4), R^ represents a straight-or branched-chain alkyl or alkenyl radical having 2 to 6 carbon atoms, R2 represents an amino radical (-NH0) a hydroxy radical (-OH) or a group -OM in which M represents an alkali metal, e.g.
sodium, or alkaline earth metal, e.g. calcium or magnesium, 15 and , X2 and X3 each represent, independently of one another, a hydrogen atom, a halogen atom, the methoxy radical or a straight-or branched-chain alkyl radical having
2 064
2
1 to 4 carbon atoms.
The preferred compounds of the invention are those of the general formula:
R
OH
1
:=N-(CH2)n-C0R2
(xi)
3
X
2
(wherein the various symbols are as hereinbefore defined), and more particularly those such compounds wherein X^ represents a chlorine atom or the methyl radical, X2 represents a chlorine atom or the methyl radical, and X3 represents a hydrogen atom. Amongst these the particularly 10 preferred compounds are those wherein n represents 3 and
R^ represents an ethyl, n-propyl, n-butyl or n-hexyl radical Of outstanding importance are A-[(5-chloro-2-hydroxy-3-n-propylphenyl)(4-chlorophenyl)methylene]-aminobutanoic acid and [(5-chloro-2-hydroxy—3-ethylphenyl)(4-15 chlorophenyl)methylene]-aininobutanoic acid, and their alkali metal and alkaline earth metal salts and their amides.
According to a feature of the present invention, the alkylbenzylidene derivatives of general formula I are prepared by the process which comprises reacting a
benzophenone of the general formula:
206409
(hi)
(wherein the various symbols are as hereinbefore defined) with a compound of the general formula:
H2N-taVn-C0R2
(IV)
(wherein n and R2 are as hereinbefore defined), optionally in the form of an acid addition salt such as the hydrochloride, at a temperature of 20° to 120°C in an organic solvent medium, such as methanol, ethanol or a methanol/toluene 10 mixture, in the presence of a base, for example an alkali metal alkoxide such as sodium methoxide or ethoxide.
The alkylbenzylidene derivatives of general formula I wherein R2 represents the amino radical can also be prepared by reacting a corresponding compound of general 15 formula I wherein R2 represents the hydroxy radical with carbonyldiimidazole and ammonia•
The compounds of general formula I wherein R2 represents a group -0M (M being as hereinbefore defined)
206 4 0 9
can be obtained from corresponding compounds wherein R2 represents the hydroxy radical by methods known per se, viz. methods heretofore used or described in the chemical literature for preparing alkali metal or alkaline earth 5 metal salts of carboxylic acids.
The benzophenone starting materials of general formula III are new and can be prepared, for example, according to the following reaction scheme:
C0C1
wherein the various symbols are as hereinbefore defined.
The Examples which follow illustrate the preparation of alkylbenzylidene derivatives of the present invention by the hereinbefore described process. The analyses and the IR and NMR spectra confirm the structures 15 of the compounds obtained.
206409
Example 1
4- [ (5-Chloro-2-hydroxy-3-n-propylphenyl )-(4-chlorophenyl)methylene ] -aminobutanamide. [x1=5-Cl,X2=4-C1,X3=H,n=3,R1=n-C3H7,R2=NH2^
1. (5-Chloro-2-hydroxy-3-n-propylphenyl)-
(4-chlorophenyl)-methanone.
17-15 ml (0.123 mol) of triethylamine are added to a stirred solution of 21 g (0.123 mol) of the phenol of the formula:
in 1.3 litres of methylene chloride and the mixture is heated to the reflux temperature. Heating is stopped and a solution of 21.54 g (0.123 mol) of the acid chloride of the formula:
in 100 ml of methylene chloride is introduced slowly into the solution so as to maintain the reflux. The mixture is then heated under reflux for 8 hours. The products are left in contact with one another overnight. 500 ml of cold
2 064
water are then added to the solution. The organic phase is decanted and washed once with 250 ml of a saturated solution of sodium bicarbonate and once with 250 ml of water.
The organic phase is dried over MgSO^ and filtered and the filtrate is evaporated to dryness. This gives an oil which crystallises on trituration in 120 ml of petroleum ether.
The crystals are filtered off, drained and redissolved in 300 ml of boiling petroleum ether. The solution is treated with 2 g of vegetable charcoal for 15 minutes, with stirring, the mixture is filtered hot and the filtrate is concentrated to a volume of about 150 ml. The resulting ester crystallises on cooling. It is filtered off, drained and dried in a desiccator.
Melting point = 49-50°C.
29.7 g (0.096 mol) of 4-chloro-2-propylphenyl 4-chlorobenzoate (obtained as described above) are heated to 100°C under a well-ventilated hood, with stirring, and 29.7 g (0.223 mol) of aluminium chloride are added in portions over a period of 10 minutes. The reaction medium is then heated in an oil bath to 160°C, still with stirring, and left for 15 minutes at this temperature before being allowed to cool to 50°C. It is then cooled with solid carbon dioxide for 1 hour and the solid obtained is crushed and finely ground in a mortar. The complex, in powder form, is
#»
2 064 0 9
{
then hydrolysed by pouring it gradually into a vigorously stirred mixture of 1 litre of water, 500 g of ice and 300 ml of concentrated hydrochloric acid. Extraction is carried out with a total of 3 litres of methylene chloride, 5 the organic layer is washed with 500 ml of water, decanted, dried over MgSO^ and filtered and the filtrate is concentrated to a volume of about one hundred ml. The crude product is then purified by passage through a column containing 700 g of silica, elution being carried out with 10 3 litres of methylene chloride. The fractions containing the product are dried over MgSO^ and filtered and the filtrate is evaporated to dryness. The oil obtained crystallises from 150 ml of petroleum ether. The crystals are filtered off on a frit, drained and dried in a desiccator. 15 Melting point = 55-56°C.
2. k-[(5-Chloro-2-hydroxy-3-n-propylphenyl) -
(4-chlorophenylmethylene] -aminobutanamide.
A mixture of 6.2 g (0.020 mol) of the previously obtained ketone, 3.05 g (0.022 mol) of 4-aminobutanamide 20 hydrochloride and 1.25 g (0.22 mol) of sodium methoxide in 600 ml of methanol is evaporated to dryness (bath at 100°C). 600 ml of ethanol are then introduced into the round-bottomed flask and the mixture is evaporated to dryness under the same conditions. A further 600 ml of ethanol are added and 25 evaporated off, under reduced pressure at the end of the evaporation. The residue is dissolved in 300 ml of methylene
2 06 4 n o
chloride and washed with 100 ml of water. The organic phase is decanted, dried over MgSO^ and filtered and the filtrate is evaporated to dryness under reduced pressure. The solid obtained is dissolved in 15 ml of hot ethyl 5 acetate. About 100 ml of diethyl ether are introduced into the solution (until a slight turbidity appears). The amide product (identified by name above) crystallises on cooling. The crystals are filtered off on a frit, washed with 20 ml of diethyl ether, drained and dried in a heated desiccator 10 at 60°C.
Melting point = 130-131°C.
Example 2
4-[(5-Chloro-2-hydroxy-3-ethylphenyl )-(4-chlorophenyl)methylene]-aminobutanoic acid and its sodium 15 salt.
[x1=5-Cl,X2=4-Cl(X3=H,n=3,R-L=C2H5 R2=OH and ONa]
1. (5-Chloro-2-hydroxy-3-ethylphenyl )-
(4-chlorophenyl)-methanone.
By following the same procedure as in Example 1.1. 20 but replacing the 4-chloro-2-n-propylphenol by A-chloro-2-ethylphenol, 4-chloro-2-ethylbenzyl 4-chlorobenzoate is obtained, which is reacted with aluminium chloride under the same conditions. The resulting benzophenone melts at 47-49°C.
2. 4-[(5-Chloro-2-hydroxy-3-ethylphenyl)-
(4-chlorophenyl)-methylene]-aminobutanoic acid and its sodium salt.
2 G r409
_2
9 g (3x10 mol) of the previously obtained
_2
benzophenone, 350 ml of methanol, 3.23 g (3*1x10 mol) of gabamide (viz. y-amino-butyric acid; abbreviated to GABA)
—2
and 1-72 g (3x10 mol) of sodium methoxide are 5 introduced into a 1 litre round-bottomed flask. The mixture is heated under reflux for 4 hours and a further 1-6 g (1.5x10 ^ mol) of GABA and 0.85 g (1.5x10 ^ mol) of sodium methoxide are added.
The mixture is heated under reflux for a further 10 4 hours and evaporated to dryness, the residue is taken up in 2.5 litres of water and the mixture is acidified to pH4 by adding citric acid- Extraction is carried out with 2 x 350 ml of methylene chloride, the organic phases are combined, washed with 400 ml of water, dried over Na2S0^ and 15 filtered and the filtrate is evaporated to dryness.
The residue is carried onto a frit with petroleum ether, drained and dried in a vacuum desiccator.
The acid product is recrystallised from diisopropyl ether.
Melting point = 131-132°C.
.7 ml of a 0.748N solution of sodium methoxide are added to a solution of 4.5 g of the acid in 100 ml of methanol. The methanol is evaporated off at 80°C, 100 ml of diethyl ether are then added and evaporated off and the sodium ^ 25 salt is carried onto a frit with diethyl ether, drained and dried in a vacuum desiccator.
Melting point of sodium salt> 250°C.
2 0 6 /?. ^ o
- 10 -Example 3
4-[(5-Chloro-2-hydroxy-3—tert.-butylphenyl)— (4-chlorophenyl )methylene]-aminobutanoic acid and its sodium salt.
[xi=5-Cl<X2=4-Cl<X3=H,n=3,R1=t-C^H9(R2=OH and ONa]
1. (5-Chloro-2-hydroxy-3-tert.-butylphenyl )-
(4-chlorophenyl)-methanone.
1.1. A solution of 56 g (0.32 mol) of p-chlorobenzoyl chloride in 200 ml of diethyl ether is added dropwise to a 10 solution of 57 g (0.309 mol) of 4-chloro-2-tert.-butylphenol, 32.3 g (0.32 mol) of triethylamine and 3.7 g (0.03 mol) of 4-dimethylaminopyridine in 800 ml of diethyl ether. After the mixture has been stirred for 6 hours at ambient temperature and left to stand overnight, 500 ml of water are 15 added. The organic phase is washed with a solution of sodium carbonate and then with water. After drying over MgSO^ and evaporation, a residue is obtained which is recrystallised from petroleum ether.
The resulting compound of the formula;
COO
melts at 103-104°C.
1.2. A solution of 4.5 g (0.0139 mol) of the previously obtained ester in 200 ml of pure benzene is introduced into
206409
- n -
a "Hanovia" photochemical reactor equipped with a 100 watt mercury lamp.
The solution is irradiated for 32 hours under a nitrogen atmosphere, with magnetic stirring. After the 5 benzene has been evaporated off, the residue is chromatographed on a column in order to isolate the product (Merck 40 silica gel; eluent: 9/1 petroleum ether/methylene chloride).
The pure fraction is distilled in a bulbed tube. 10 This gives (5-chloro-2-hydroxy-3-tert--butylphenyl)-(4-chlorophenyl)-methanone.
Melting point = 86.5-87°C. 2. 4-[(5-Chloro-2-hydroxy-3-tert--butylphenyl )-
(4-chlorophenyl)methylene]-aminobutanoic acid and its sodium 15 salt.
0.128 g (1.24 mmol) of 4-aminobutyric acid and 0.4 g (1.24 mmol) of (5-chloro-2-hydroxy-3-tert.-butylphenyl)-(4-chlorophenyl)-methanone are added to 25 ml of a solution of sodium ethoxide containing 1-3 mmol of sodium. 20 15 ml of alcohol are distilled fairly slowly, 10 ml of absolute ethanol are added and a further 15 ml of alcohol are then distilled. After evaporation to dryness, the residue is dissolved in 20 ml of water and the solution is acidified to pH4 with citric acid.
Extraction is carried out with methylene chloride and the extract is washed with water and dried over sodium
2 064 0 9
sulphate. After evaporation of the extract, the residue is recrystallised from heptane and then washed with pentane.
Melting point = 118-119°C and melting point =
125-126°C.
7.23 ml of an ethanolic solution of sodium ethoxide containing 0-332 mol/litre (ie. 2.4 mmol) are added to a solution of 1 g (2.45 mmol) of the obtained acid in 10 ml of absolute ethanol. After evaporation to dryness, the oil is dissolved in 10 ml of cold cyclohexane. The sodium salt 10 crystallises slowly. The salt is obtained after filtration, washing with pentane and drying in vacuo at 100°C for 8 hours-Melting point = 245°C (decomposition)-Table I which follows show pictorially the compounds of the invention which were prepared by way of Examples.
*
TABLE I
2 064-0 9
x
C ompound n
X1
X2
X3
Ri
R2
Melting poi nt ( C)
1
3
-CI •
4-C1
H
n-C3H^
NH2
130-131
2
3
-Cl
4-Cl
H
C2H5
NH2
128-130
3
3
-C1
4-Cl
H
C2H5
ONa
>250
4
3
-Cl
4-Cl
H
C2H5
OCa/2
245(d e c)
3
-Cl
4-Cl
H
C2E5
OMg/2
165-175
6
3
-Cl
4-Cl h
n-c3h?
ONa
207-209
7
2
-Cl
4-Cl h
c2e5
nh2
190-192
8
3
-Cl
4-Cl h
n~^6H13
OH
61.5-62
9
2
-Cl
4-Cl
H
n~C6H13
NH2
130.5-131
2
-Cl
4-Cl
H
n"C6E13
ONa
181-182
11
1
-Cl
4-Cl
H
n"C6H13
nh2
132-133
•12
3
-Cl
4-Cl
H
n~C6H13
nh2
92-92.5
13
2
-CH3
4-CH3
H
c2h5
nh2
167-168
14
1
-Cl
4-CE 3
H
n~C6H13
ONa
200-201
3
-Cl
4-CH3
H
n~C6H13
NH2
120.5-121
16
1
-Cl
4-Cl
H
n~C6H13
ONa
204-205
17
3
-Cl
4-Cl
H
n-c4h9
nh2
116-117
18
- •> Sm
-Cl
4-Cl
H
n-c3H7
nh2
153-155
- 14 -TABLE I (continuation)
2 064 0 9
Compound n
X1
X2
X3
R1
R2
Melting point (°C)
19
3
-CH3
4-CH-3
H
C2H5
NH2
110-111
3
-CH3
4-CH3
H
C2H5
ONa
215
21
2
-Cl
4-Cl
H
n-C3H7
ONa
> 250
22
2
-Cl
4-Cl
H
i-C.H9
ONa
244 (dec)
23
3
-Cl
4-Cl
H
i-c4h9
nh2
105-107
24
3
-Cl
4-CH3
H
n-C3E7
ONa
200-202
2
-Cl
4-CH3
H
n-C3H^
nh2
146-147
26
2
-Cl
4-CH3
H
n-C6H13
NH2
139-5-140
27
1
-Cl
4-Cl
H
n-C3K7
ONa
210-212
28
2
-CH3
4-CH3
H
C2H5
ONa
195
29
1
-Cl
4-Cl
H
n_C4H9
nh2
142-142-5
2
-Cl
4-Cl
H
n~C4H9
ONa
202-204
.
31
1
-Cl
4-Cl
H
n-C4H9
ONa
180-185
32
2
-Cl
4-Cl
H
n-C3H7
ONa
^ 250 (dec)
33
3
-Cl
4-CH3
H
n-C3H?
nh2
114-115
- 34
1
-Cl
4-CH3
H
n"C6H13
nh2
144.5-145
2
-Cl
4-CH3
H
n-CgHi3
ONa
196-197
36
4
-Cl
4-Cl
H
n_C6H9
nh2
145-146
37
3
-Cl
4-Cl
H
n-C4H9
OH
96.5-97.7
38
4
-Cl
4-Cl
H
n-C4K9
ONa
190-19 6
39
3
-Cl
4-Cl
H
•1"C4H9
ONa
138
TABLE I (continuation)
206409
Compound n
X1
X2
X3
R1
R2
Melting point (°C)
40
1
-Cl
4-Cl
H
n-C3H?
NH2
145-146
41
2
-Cl
4-Cl
H
i-C4H9
ne2
147-148
42
3
-Cl
4-CH3
e i"C4H9
ONa
>250
43
2
-Cl
4-Cl
H
n-C4E9
ne2
136.5-137-5
44
3
-Cl
4-CH3
H
i-C4H9
ONa
140-144
45
-Cl
4-CH3
e i-c4n9
ONa
>250
46
2
-Cl
4-CH3
H
i'c4h9
ne2
130 and 138
47
3
-Cl
4-CH3
H
i-c4H9
ne2
123-124
48
3
-Cl
4-CH3
B
n'C6H13
OH
69-70
49
3
-F
4-Cl
H
2;-CH=CH~
NK2
116 .1
50
3
-Cl
2-Br
H
:e2-ch=ch2
NH2
115.7-116.8
51
3
-Cl
4-CH3
H
n-C4H9
OH
119-120
52
1
-Cl
4-CH3
H
n-C4H9
nk2
142-143
53
1
-Cl
4-CH3
H
n-C4E9
ONa
201-203
54
2
-Cl
4-CH3
H
n-C4E9
ONa
211-213
- 55
3
-Cl
4-CH3
H
n-C4Hg nh2
113.5-114.5
56
1
-Cl
4-CjH,
h
C2E5
ONa
249-250
57
3
-Cl
4~C2Kt
H
C2H5
ONa
>225
i-c4k9
NH2
L35-5-136 .5
58
1
-Cl
4-CH3
H
and 155-5
59
2
-Cl
4~C2H!
e
C2H5
ONa
256-257
60
3
-Cl
4-C2h,
H
c2e5
nh2
162-163
TABLE I (continuation)
2 0 6409
Compound n
X1
X2
X3
ri
R2
Melting point (°C)
61
2
-Cl
4-CH,
H
nC4H9
NH2
143-144
62
3
-Cl
4-CH3
H
c2h5
ne2
143-145
63
2
-Cl
4-CH3
h
C2H5
ne2
171-173
64
2
-CH-,
a*
4-nC3H?
H
C2H5
ONa
212-213
65
1
-CH3
4-nC3H7
H
c2hs
ONa
177-178
66
3
-CH3
4-nC3H7
e
C2E5
ONa
170
67
1
-CH3
4-nC3H7
h c2h5
nh2
132-133
68
3
-CE3
4-nC3K7
h
C2E5
ne2
135-136
69
2
-CH3
4-nC3H7
h
C2S5
ne2
163-164
70
1
-Cl
4-C2H5
h
C2HS
ne2
139-140
71
2
-Cl
4-C2H5
h
C2B5
nh2
146-147
72
3
-Cl
4-Cl
H
iC3H7
ne2
166-167
73
3
-Cl
4-Cl h
t-C4H9
ne2
153-154
74
2
-Cl
4-Cl
H
C2HS
ONa
265-267
75
3
-Cl
4-Cl
H
t-C4H9
ONa
245 (dec)
76
3
-Cl
4-CH3
H
C2E5
ONa
238-240
77
2
-Cl
4-CH3
H
c2h5
ONa
258-260
78
3
-Cl
4-Cl
H
-ch-ch3
nch-ch.
ne2
135-136
79
3
-CH3
4-CH3
H
t-c4h9
nk2
126-127
80
3
-Cl
4-Cl
H
y
"ck<ch2ch.
OH
141-142
81
3
-Cl
4-iC3H?
e
C2H5
ne2
156-157
- 17 -TABLE I (continuation)
2 064 0
Compound n
X1
X2
X3
R1
R2
belting point <°C)
82
3
-CH3
4-CH3
h t-C4H9
ONa
271-273
83
3
-Cl
4-Cl b
i-c3b7
ONa
190 (dec)
84
3
-CH3
4-CH3
H
t-C4Hg
OH
153-154
85
2
-Cl
4-CH3
H
c2h5
OH
145-147
86
3
-Cl
4-CH3
H
•
C2E5
OH
114-116
87
3
-Cl
4-Cl
H
t-c4h9
OH
118-119
88
2
-Cl
4-Cl
H
C2H5
OH
148-150
89
3
-CH3
4-nC3H?
H
C2H5
OH
85-86
90
1
-CH3
4-nC3H7
H
C2H5
OH
152-153
91
2
-CE3
l-nC3H7
H
C2H5
OH
94-95
92
2
-Cl
J-C2H5
H
C2H5
OH
105-106
93
3
-Cl l"C2E5
H
C2H5
OH
83-84
94
1
-Cl l-C2H5
H
C2H5
OH
179-180
95
2
-Cl
4-CH3
H
n-C4H9
OH
118,5-113.5
96
1
-Cl
4-CH3
H
n~*C4H9
OH
158 (dec)
- 97
1
-Cl
4-CH3
H
i"c4h9
OH
163 (dec )
98
3
-Cl
4-CH3
h i-C4H9
OH
115-116
99
3
-Cl
4-CH3
H
i~C4H9
OH
126 and 136
100
3
-Cl
4-Cl
H
i-C4H9
OH
' 103-104
101
4
-Cl
4-Cl
H
h-c4h9
OH
123-123.5
102
2
-Cl
4-CE3
H
n"C6H13
OH
130-130.5
103
2
-Cl
4-Cl
H
n~C3H7
OH
130-131
104
1
-Cl
4-Cl
H
n~C4H9
OH
162-162.5
TABLE I (continuation)
2 064 09
Compound n
X1
X2
X3
Ri
R2
Melting point (°C)
105
2
-Cl
4-Cl
H
n-C4H9
OH
171-172
106
2
-CH3
4-CH3
H
C2H5
OH
132-133
107
1
-Cl
4-Cl
H
n-C^R^
OH
175-176
108
3
-Cl
4-CH3
H
n-C3H7
OB
107-108
109
2
-Cl
4-Cl
B
^C4H9
OH
160-163
110
2
-Cl
4-Cl
B
n-C3H7
OH
119-121
111
3
-CH3
4-CH3
B
C2H5
OH
115-116
112
1
-Cl
4-Cl '
B
n-C6H13
OH
156-157
113
1
-Cl
4-CH3
B
n~C6H13
OB
146-146 .5
114
2
-Cl
4-Cl
B
n"C6H13
OH
149.5-150
115
3
-Cl
4-Cl
H
n-C^Ej
OB
88 .5-91
116
3
-Cl
4-Cl
B
C2E5
OH
131-132
117
-Cl
4-Cl
H
n~C3H7
OH
114-115
118
4
-Cl
4-C1
H
n-C3H7
OH
128-129
119
4
-Cl
4-CH3
H
n~C3H7
OH
130-131
" 120
-Cl
4-CH3
H
n-C3H7
OH
101-102
121
-Cl
4-C2H5
H
C2H5
OH
114-114,5
122
4
-Cl
4"C2H5
H
C2H5
OK
107-108
123
4
-Cl
4-Cl
H
C2H5
OH
79
124
-Cl
4-Cl
H
C2H5
OH «
94-95
*
206409
Table II.
The starting benzophenones employed are shown in
TABLE II
Compound
X2
Ri
Characteristics
1
-Cl
4-Cl n-C^H-
Melting point = 55-56°C
2
-Cl
4-Cl
C2E5
Melting point = 47-49°C
3
-Cl
4-Cl n"C6H13
0ilft boiling point = 204 C (0.1 mm Hg)
4
-CH3
4-CE3
C2H5
Melting point = 38-39°C
-Cl
4-CE3
n~C6K13
Oil, boiling point = 192 C (0.1 ram Hg)
S
-Cl
4-Cl il-c.sg
OiI, boiling point = 168-170°C (0.03 mm Hg)
7
-Cl
4-Cl
Melting point = 65~66°C
8
-Cl
4-CH3
n-c3H7
Melting point = 63-64°C
9
-Cl
4-CS3
i-C4H9
Melting point = 71-72°C
-F
4-Cl ch2-ch«ce2
Melting point = 44.6°C
11
-Cl
2-Br ch2-ch«ch2
Oil
12
-Cl
4-ce3
n-C4Hg
Oil*, boiling point = 148-150°C (0.06 mm Hg)
13
-Cl i-r w 4 Cr.5
C2E5
Oil, n^ = 1.6060
14
-ch3
4-nC-E-
A 7
C2H5
Oil, = 1.5861
Z06409
TABLE II (continuation)
Compound
X1
X2
*1
Characteristi cs
-Cl
4-Cl i-C3H7
MeLting point = 54-55°C
16
17
-Cl 5-Cl
4-Cl 4-CH3
t-c4n9 c2h5
MeLting point = 86.5-
87 C «
MeLting point = 53-55 C
18
-Cl *
4-Cl
CIrra3
^CH«CH2
MeLting point - 45-47°C
19
-CE3 5-Cl
4-CH3
4-ic3n7
t-c4H9
C2as
MeLting point = 110-111°C
MeLting point = 42-43°C
The compounds of the invention were subjected to 10 pharmacological tests which showed their activity on the central nervous system.
The acute toxicity was determined on mice by intraperitoneal administration. The (50% lethal dose),
which causes the death of 50% of the animals, ranges from 15 250 to >1000 mg/kg animal body weight.
The antidepressive activity of the compounds was shown by the antagonism towards the head twitches caused in mice by L-5-hydroxytryptophan (L-5-HTP).
The mice (males CD1, Charles River France;
18-22 g body weight) receive increasing doses of the products to be studied, or the solvent, simultaneously with a 250 mg/kg dose of L-5-HTP, administered subcutaneously• Forty-five minutes after this injection of L-5-HTP, the
•»
2
0
21
number of head twitches for each mouse is counted for one minute.
percentage variation relative to the control batch are 5 calculated for each treatment.
dose or the dose which reduces the average number of head twitches by 50%) is determined by the graphical method of Miller and Tainter, Proc. Soc. Exp. Biol. Med. (1944), 57-261.
from 40 to 60 mg/kg animal body weight administered intraperitoneally.
The anticonvulsant activity of the compounds was shown by the antagonism towards the mortality caused by 15 bicuculline in mice.
Bicuculline is a relatively selective blocker of post-synaptic GABA-ergic receptors and its convulsant and lethal effects are antagonised by compounds which increase the level of GABA in the brain or which possess a GABA-20 mimetic activity.
The 50% active dose (AD^q) of the substances studied, that is to say the dose which protects 50% of the animals against the effect of bicuculline, was evaluated.
The AD^0 of the compounds of the invention varies 25 from 10 to 100 mg/kg animal body weight, administered intraperitoneally.
The average number of head twitches and the
Using the effect-dose curve, the AD5Q (50% active
The AD5Q of the compounds of the invention varies
2.0 & 4 09
The ulcer-inhibiting activity of the compounds was shown by the activity towards stress ulcers and ulcers induced by phenylbutazone.
The two tests, involving stress ulcers and ulcers 5 induced by phenylbutazone, were carried out on fasted female Wistar rats weighing 180-210 g, the compounds being administered orally in the form of a suspension in a 1% aqueous solution of Tween 80, immediately before the stress or 30 minutes after the oral administration of phenylbutazone. 10 In both cases, examination of the stomach was carried out 2 hours after the beginning of the ulcer-forming process.
The compounds have a significant action above 30 mg/kg animal body weight in the case of stress ulcers and above 100 mg/kg animal body weight in the case of ulcers 15 induced by phenylbutazone.
The gastric antisecretory activity of the compounds was shown on wake rats with a ligated pylorus.
Female Wistar rats weighing 200 to 220 g are fasted for 48 hours. The pylorus is ligated under ether 20 anaesthetic. The compounds are then administered intraperitoneally at doses of 1, 5, 25 and 50 mg/kg animal body weight, immediately after ligature of the pylorus. The animals are sacrificed 4 hours after ligature of the pylorus. The volume of the gastric secretion is measured and the free 25 acidity and total acidity are determined by titrimetry relative to a control determination. The compounds of the
2 064 0
invention reduce the volume of the gastric secretion by 45 to 55%, 50 to 65% and 70 to 85% respectively, the free acidity by 60 to 70%, 65 to 75% and 85 to 95% respectively, and the total acidity by 55 to 65%, 60 to 70% and 85 to 95% respectively.
The compounds of the invention are active as anti—depressants, anticonvulsants, ulcer inhibitors and gastric secretion inhibitors and also possess anxiolytic, analgesic and anti-inflammatory properties. They can be used in human and veterinary therapy for the treatment of various diseases of the central nervous system, for example for the treatment of depressions, psychoses and certain neurological diseases such as epilepsy, spasticity and dyskinesia, and for the treatment of various stress ulcers and gastric ulcers
The invention consequently includes all pharmaceutical compositions which contain, as active ingredient, an alkylbenzylidene derivative of general formula (I) in association with any excipient(s) suitable for their administration, in particular their oral administration (tablets, coated tablets, gelatin capsules, ordinary capsules cachets, or solutions or suspensions to be taken orally) or parenteral administration.
The daily dosage can range from 100 to 3000 mg.
206409
Claims (7)
1. A benzylidene derivative of the general wherein n represents an integer from 1 to 12, R^ represents 5 a straight- or branched-chain alkyl or alkenyl radical having 2 to 6 carbon atoms, R2 represents an amino radical, a hydroxy radical, or a group -OM in which M represents an alkali metal or alkaline earth metal, and X^, X2 and X3 each represent, independently of one another, a hydrogen 10 atom, a halogen atom, the methoxy radical or a straight- or branched-chain alkyl radical having 1 to 4 carbon atoms.
2. A benzylidene derivative according to claim 1 of the general formula: r - - 25 - 206409
OH
=N-(CH2)n-COR2 (ii) wherein the various symbols are as defined in claim 1. 3 • A benzylidene derivative according to claim 1 or 2 wherein n represents an integer from 1 to 4-5 4- A benzylidene derivative) according to claim 1, 2 or 3 wherein X^ represents a chlorine atom or the methyl radical, X2 represents a chlorine atom or the methyl radical, and represents a hydrogen atom.
5. A benzylidene derivative according to claim 4 10 wherein n represents 3 and represents an ethyl, n-propyl, n-butyl or n-hexyl radical.
6. An alkylbenzylidene derivative of the general formula depicted in claim 1 identified by reference to that general formula in TABLE I following Example 3. 15
7. 4-[(5-Chloro-2-hydroxy-3-n-propylphenyl)- (4-chlorophenyl)methylene]-aminobutanoic acid, its alkali metal and alkaline earth metal salts and its amide. i J 1 \\ sr ^' ' A\ 8* 4-[ (5-Chloro-2-hydroxy-3-ethylphenyl)-;.7WKf»8f,r;206409;- 26 -;(4-chlorophenyl )methylene]-aminobutanoic acid, its alkali metal and alkaline earth metal salts and its amide.;9. A process for the preparation of a benzylidene derivative of the general formula depicted in claim 1 which 5 comprises reacting a benzophenone of the general formula:;(III);(wherein the various symbols are as defined in claim 1) with a compound of the general formula:;H2N-(CH2'n-C0R2;(IV);10 (wherein n and R0 are as defined in claim 1) , optionally in the form of an acid addition salt, at a temperature of;7;from 20° to 120°C in an organic• solvent medium in the presence of a base.;10. A process for the preparation of a benzylidene ^ I5 derivative of the general formula depicted in claim 1;wherein R2 represents the amino radical which comprises;1; ';feting a corresponding compound of that general formula c n wherein R_ represents the hydroxy radical with;- 27 -;carbonyldiimidazole and ammonia.;11. A process for the preparation of a benzylidene derivative of the general formula depicted in claim 1 wherein R2 represents a group -0M (M being as defined in;5 claim 1) which comprises converting by a method known per se a corresponding compound of that general formula wherein R2 represents the hydroxy radical into an alkali metal or alkaline earth metal salt.;12. A process for the preparation of a benzylidene;10 derivative of the general formula depicted in claim 1;substantially as hereinbefore described with especial reference to Example 1, 2 or 3.;13. a benzylidene derivative of the general formula depicted in claim 1 when prepared by a process claimed in;15 claim 9, 10, 11 or 12.;14• A pharmaceutical composition which comprise, as active ingredient, a benzylidene derivative as claimed in any one of claims 1 to 8 in association with a pharmaceutically-acceptable excipient.;20 15. A benzylidene derivative of the general formula depicted in claim 1 for use as medicaments.;16. A benzylidene derivative of the general formula depicted in claim 1 for use as an antidepressant, an anticonvulsant, an inhibitor of ulcers and gastric secretion, and as an anxiolytic, analgesic and anti-inflammatory agent.;By Mrs/Their authorised Agent;"7mayi9s6 a. j. park & son;*r Per; Cc|\'
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8219981A FR2536746A1 (en) | 1982-11-29 | 1982-11-29 | ALKYL BENZYLIDENIC DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ206409A true NZ206409A (en) | 1986-07-11 |
Family
ID=9279618
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ206409A NZ206409A (en) | 1982-11-29 | 1983-11-28 | Alkylbenzylidene derivatives and pharmaceutical compositions |
Country Status (22)
Country | Link |
---|---|
JP (1) | JPS59116253A (en) |
AU (1) | AU2174583A (en) |
BE (1) | BE898323A (en) |
CA (1) | CA1204774A (en) |
CH (1) | CH656876A5 (en) |
DE (1) | DE3343000A1 (en) |
DK (1) | DK544283D0 (en) |
ES (1) | ES527584A0 (en) |
FI (1) | FI834339A (en) |
FR (1) | FR2536746A1 (en) |
GB (1) | GB2131024B (en) |
GR (1) | GR81258B (en) |
HU (1) | HU190636B (en) |
IL (1) | IL70334A0 (en) |
IT (1) | IT1167029B (en) |
LU (1) | LU85106A1 (en) |
NL (1) | NL8304070A (en) |
NO (1) | NO834361L (en) |
NZ (1) | NZ206409A (en) |
PT (1) | PT77752B (en) |
SE (1) | SE8305306L (en) |
ZA (1) | ZA838862B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2577923B1 (en) * | 1985-02-26 | 1988-09-09 | Synthelabo | CARBOXYLATED DIPHENYLAZOMETHINES, THEIR PREPARATION AND THEIR APPLICATION |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2319338A1 (en) * | 1975-08-01 | 1977-02-25 | Synthelabo | NEW A-PHENYL BENZYLIDENIC DERIVATIVES OF AMINO ACIDS, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM |
FR2516509B1 (en) * | 1981-11-18 | 1985-07-26 | Synthelabo | BENZYLIDENIC DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
AU520618B2 (en) * | 1978-02-27 | 1982-02-11 | Synthelabo | Benzylidene derivatives |
FR2422628A1 (en) * | 1978-04-14 | 1979-11-09 | Synthelabo | BENZYLIDENIC ESTERS AND THEIR APPLICATION IN THERAPEUTICS |
-
1982
- 1982-11-29 FR FR8219981A patent/FR2536746A1/en active Granted
-
1983
- 1983-09-29 SE SE8305306A patent/SE8305306L/en not_active Application Discontinuation
- 1983-11-28 LU LU85106A patent/LU85106A1/en unknown
- 1983-11-28 GB GB08331714A patent/GB2131024B/en not_active Expired
- 1983-11-28 HU HU834081A patent/HU190636B/en unknown
- 1983-11-28 DK DK5442/83A patent/DK544283D0/en not_active Application Discontinuation
- 1983-11-28 PT PT77752A patent/PT77752B/en unknown
- 1983-11-28 CH CH6353/83A patent/CH656876A5/en not_active IP Right Cessation
- 1983-11-28 FI FI834339A patent/FI834339A/en not_active Application Discontinuation
- 1983-11-28 JP JP58225327A patent/JPS59116253A/en active Pending
- 1983-11-28 AU AU21745/83A patent/AU2174583A/en not_active Abandoned
- 1983-11-28 GR GR73079A patent/GR81258B/el unknown
- 1983-11-28 IT IT23927/83A patent/IT1167029B/en active
- 1983-11-28 IL IL70334A patent/IL70334A0/en unknown
- 1983-11-28 ZA ZA838862A patent/ZA838862B/en unknown
- 1983-11-28 ES ES527584A patent/ES527584A0/en active Granted
- 1983-11-28 BE BE0/211944A patent/BE898323A/en not_active IP Right Cessation
- 1983-11-28 NZ NZ206409A patent/NZ206409A/en unknown
- 1983-11-28 DE DE19833343000 patent/DE3343000A1/en not_active Ceased
- 1983-11-28 NO NO834361A patent/NO834361L/en unknown
- 1983-11-28 CA CA000442044A patent/CA1204774A/en not_active Expired
- 1983-11-28 NL NL8304070A patent/NL8304070A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
GB8331714D0 (en) | 1984-01-04 |
HU190636B (en) | 1986-09-29 |
ES8406420A1 (en) | 1984-08-01 |
AU2174583A (en) | 1984-06-07 |
ZA838862B (en) | 1984-07-25 |
JPS59116253A (en) | 1984-07-05 |
IT8323927A0 (en) | 1983-11-28 |
NL8304070A (en) | 1984-06-18 |
FR2536746A1 (en) | 1984-06-01 |
ES527584A0 (en) | 1984-08-01 |
IT1167029B (en) | 1987-05-06 |
SE8305306L (en) | 1984-05-30 |
FI834339A (en) | 1984-05-30 |
SE8305306D0 (en) | 1983-09-29 |
IL70334A0 (en) | 1984-02-29 |
PT77752A (en) | 1983-12-01 |
PT77752B (en) | 1986-06-02 |
LU85106A1 (en) | 1985-07-17 |
FI834339A0 (en) | 1983-11-28 |
CA1204774A (en) | 1986-05-20 |
BE898323A (en) | 1984-05-28 |
DE3343000A1 (en) | 1984-05-30 |
DK544283D0 (en) | 1983-11-28 |
NO834361L (en) | 1984-05-30 |
CH656876A5 (en) | 1986-07-31 |
FR2536746B1 (en) | 1985-03-08 |
GB2131024A (en) | 1984-06-13 |
GR81258B (en) | 1984-12-11 |
GB2131024B (en) | 1986-02-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4152458A (en) | Acetohydroxamic acids | |
US4755524A (en) | Novel phenolic thioethers as inhibitors of 5-lipoxygenase | |
US4400394A (en) | Benzylidene derivatives | |
US4711903A (en) | Phenolic thioethers as inhibitors of 5-lipoxygenase | |
IE55872B1 (en) | Derivatives of omega-amino acids,the preparation and utilisation thereof,and the compositions containing these derivatives | |
US4267190A (en) | Antiinflammatory 4,5-diaryl-α,α-bis(polyfluoromethyl)-1H-pyrrole-2-methanethiols | |
IL91377A (en) | Butynylamine glycolate derivatives | |
IE47960B1 (en) | Tetrazole derivatives | |
CA1144551A (en) | Antiinflammatory 4,5-diaryl-a-(polyfluoroalkyl)-1h- pyrrole-2-methanamines | |
JPS638109B2 (en) | ||
IE45651B1 (en) | Aminoalkylpyrrolobenzoxazalkanes | |
JPH0222059B2 (en) | ||
EP0057881A2 (en) | An anti-inflammatory, analgesic, and antipyretic pharmaceutical composition, and method for producing it | |
NZ206409A (en) | Alkylbenzylidene derivatives and pharmaceutical compositions | |
US4588748A (en) | Therapeutically useful benzylidene derivatives | |
US4521619A (en) | Therapeutically useful sulphur-containing benzylidene derivatives | |
PL128998B1 (en) | Process for preparing novel 2-amino-3-benzoylphenylacetamides and their derivatives | |
FR2470770A1 (en) | NOVEL B-IMIDAZOLYLETHYL ETHERS OF QUINOLINE-2 OR 4-METHANOLS, PARTICULARLY USEFUL AS ANTIMICROBIALS, AND PROCESS FOR THE PREPARATION THEREOF | |
FR2514353A2 (en) | Antidepressant 4-benzyloxy-piperidine derivs. - prepd. by react-ng piperidine deriv. with benzyl deriv. | |
KR810000953B1 (en) | Method for the preparation of 2'-(carboxymethoxy)-chalcones | |
GB2063263A (en) | A 1-isopropyl-4-phenyl-2(1H)- quinazolinone Derivative | |
NO774285L (en) | ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE INDANDATIVE DERIVATIVES | |
IE43448B1 (en) | Substitued pheylacetic acids |