GB2050363A - Esters of 2-(6-methoxy-2- naphthyl)-1-propanol, method of preparation and pharmaceutical compositions thereof - Google Patents
Esters of 2-(6-methoxy-2- naphthyl)-1-propanol, method of preparation and pharmaceutical compositions thereof Download PDFInfo
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- GB2050363A GB2050363A GB8014797A GB8014797A GB2050363A GB 2050363 A GB2050363 A GB 2050363A GB 8014797 A GB8014797 A GB 8014797A GB 8014797 A GB8014797 A GB 8014797A GB 2050363 A GB2050363 A GB 2050363A
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- methoxy
- ena
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- naproxen
- naphthyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
Abstract
Esters of 2-(6-methoxy-2-naphthy])-1-propanol of formula (I> <IMAGE> in which R is an alkyl radical of 1 to 20 carbon atoms are described. The compounds exhibit antiinflammatory, antirheumatic, analgesic and antipyretic activity.
Description
SPECIFICATION
Esters of 2-(6-methoxy-2-naphthyl)-1 -propanol This invention relates to esters of a carboxylic acid and a 2-substituted propanol and specifically, propanol substituted by a 6-methoxy-2-naphthyl group of formula (I)
in which R is the alkyl residue of carboxylic acid containing between 1 and 20 carbon atoms.
It has been found that compounds offormula (I) exhibit very outstanding properties, specifically antiinflammatory, antirheumatic, analgesic and antipyretic properties comparable to the properties of a known substance, specifically Naproxen, which is the more active enantiomer of the 2-(6-methoxy-2natphthyl) propionic acid. Yet compared with Naproxen the compounds according to the presente invention are less toxic, exhibit an activity which is substantially more pronounced and cause much less noticeable gastric injury.
The object of the present invention is to provide compounds of formula (I). Another object of the present invention is to provide pharmaceutical compositions having antiinflammatory, anti rheumatic, analgesic and antipyretic activity which contain, as the active substance, at least one of the compounds of formula (I):
Another object of the present invention, is to provide a process for the preparation of the compounds of formula (I) according to which 2-(6-methoxy-2-natphyl)-1-propanol (II) is reacted with a carboxylic acid of formula R-COOH in which R is as defined hereabove, in the presence of an acid catalyst.According to one embodiment of the invention, the preparation may be carried out from the same substituted alcohol with one active derivative of the same carboxylic acid according to the reaction scheme shown hereinbelow:
In the above reaction scheme, X is OH or an activating group, for instance a halogen atom or an alcoxycarboniloxy residue, for instance the group C2H5O-CO-O-.
The process according to the present invention is illustrated by the example hereinbelow.
EXAMPLE 1 2-(6-Methoxy-2-naphthyl)-propyl acetate
a) 2-(6-Methoxy-2-naphthyl- 1-propanolJ In a three-neck flask provided with a mechanical stirrer, a condenser and a funnel, there are placed 300 ml of THF, 53.5 g of 2-(6-Methoxy-2-napthyl) propionaldehyde and 25 ml of water containing 2.5 g of NaOH.
Under stirring, 2 g of NaBH4 is slowly added keeping the temperature at 40"C. The mixture is stirred for one hour at room temperature and then there is added slowly under stirring and cooling, acetic acid for the purpose of destroying the excess of NaBH4. The greater part of the solvent is evaporated under vacuo, then water is added and the material is extracted three times with ether using a 100 ml portion each time. The ether extract is combined, evaporated under vacuo and the oily residue is crystallized from a mixture 50:50 of petroleum ether and ethyl ether.
The yield is 49.9 g (93.3%); M.P. 82-84"C.
b) 2-(6-Methoxy-2-naphthyl)propyl acetate In a three-neck flask provided with mechanical stirrer, condenser and a funnel, there are introduced 500 ml of ethyl ether, 58.9 g (0.725 mole) of pyridine and slowly under agitation 58.8 g (0.725 mole) of acetyl chloride.
The solution is cooled to 0 C and then there is introduced slowly through the funnel, 108 g (0.5 mole) of 2-(6-methoxy-2-naphthyl)propyl alcohol, dissolved in 200 ml of ethyl ether. The temperature rises up to about 40"C. Stirring is continued for a period of four hours at room temperature and then the solution is poured into 250 ml of water. The mixture is stirred and the organic phase is separated, washed with 0.1 N HCI solution. The organic phase so washed, is dried over anhydrous sodium sulfate. The solvent is evaporated under vacuo and the oily residue is distilled. The pure ester distills at 175 -178 C at a pressure of 0.01 mm Hg.
The yield is 102 g (75%).
According to the same procedure described hereinabove, the following substances are prepared:
- 2-(6-methoxy-2-naphthyl)propyl propionate;
Boiling Point-178-183 C at a pressure of 0.01 mm Hg.
- 2-(6-methoxy-2-naphthyl )propyl hexanoate
Boiling Point-188-190 C at a pressure of 0.01 mm Hg.
EXAMPLE 2
Preparation of 2-66-methoxy-2-naphthylJpropyl enanthate
In a three-neck flask provided with stirrer, condenser, and a funnel there are introduced 500 ml of ethyl ether, 58.9 g (0.725 mole) of pyridine and slowly under stirring 107.4 g (0.725 mole) of enanthyl chloride. The solution is cooled to 0 C. Through the funnel, there are introduced 108 g (0.5 mole) of 2-(6-methoxy-2naphthyl)propyl alcohol dissolved in 200 ml of ethyl ether. The temperature rises to 40 C. Stirring is continued for four hours at room temperature and then the solution is poured into 250 ml of water. The mixture is stirred, the organic phase is separated, washed with 0.1 N HCI solution. The organic phase so washed is dried over anhydrous sodium sulfate. The solvent is distilled under vacuo and the oily residue is distilled.The pure ester boils at 191-193"C at 0.01 mm Hg. The yield is 125.3 g (73,2%).
Ultraviolet light spectrum: a solution of the substance in ethanol (25 mcg/ml) exhibits two maxima:
(1) at260 + 1 - 270 + 1 and (2) at316+1-331l1.
The substance is insoluble in water, soluble in chloroform, ethanol, acetone, hexane and in addition, in oils.
Application of the same procedure described hereinabove gives other esters of 2-(6-methoxy-2naphthyl)propanol as indicated in Table 1 hereinbelow, which also reports the physical properties and analytical values.
TABLE 1
R b.p. C/mm Hg ANALYSIS
Calcd. Found Calcd. Found
CH3 175-78/0.01 74.42 - 74.10 6.98 - 6.96
C2H5 178-83/0.01 75.00 - 74.84 7.35 - 7.31
C4H9 183-87/0.01 76.00 - 75.80 8.00 - 7.95 C5H11 188-89/0.01 76.43 - 76.20 8.28 - 8.31
C6H13 191-93/0.01 76.82 - 76.80 8.54 - 8.50
C7H15 193-95/0.01 77.19 - 77.00 8.77 - 8.80 C8H17 194-98/0.01 77.53 - 77.40 8.98 - 8.95 C9H19 198-200/0.01 77.84 - 77.81 9.19 - 9.10
C10H21 181-83/0.005 78.12 - 78.10 9.37 - 9.31 C11H23 185-87/0.005 78.39 - 78.43 9.55 - 9.56
C12H25 188-89/0.005 78.64 - 78.60 9.70 - 9.76
C14H29 191-93/0.005 79.00 - 79.00 10.00 - 10.20
C15H31 192-94/0.005 79.29 - 79.16 10.13 - 10.00
C16H33 195-97/0.005 79.50 - 79.61 10.26 - 10.15
C17H35 199-200/0.005 79.66 - 79.58 10.37 - 10.41
C18H37 201-202/0.005 79.84 - 79.77 10.48 - 10.44
The pharmaceutical properties of the compounds according to the present invention, together with toxicological data are reported by way of example with the compound 2-(6-methoxy-2-naphthyl)propyl enanthate referred to hereinafter with the symbol ENA.
Antiinflammatory activity
This activity has been evaluated by comparison with Naproxen in equimolar dose. There are utilized male rats of average weight, about 150 g. Two tests, that is one acute and one sub-acute, have been carried out.
a) acute test: plantar edema caused by carragenin according to C.A. Winter et al. Proc. Soc. Exp. Biol.
Med., 111,544(1962).
The two substances under test are administered through the oral route in an equimolar dose: ENA = 60 mg/kg, Naproxen = 40 mg/kg, in 1% carboxymethylcellulose (CMC) at 20 ml/kg immediately after the appearance of the edema as a result of the subplantar injection of carragenin in the amount of 1% in the dose of 0.05 ml/paw. The results of this test are reported in Table 2.
b) sub-acute test: plantar edema caused by nystatin according to E. Arrigoni-Martelli et al, Pharmacolo gy, 5,215 (1971). The two substances are administered through the oral route in an equimolar dose for two successive days as follows:
The first day, ENA = 30 mg/kg, Naproxen = 20 mg/kg in 1% CMC in the amount of 10 ml/kg.
The second day, ENA = 60 mg/kg, Naproxen = 40 mg/kg in 1% CMC in the amount of 20 mg/kg.
Edema has been caused the night preceding the first treatment by the subplantar injection of nystatin in the amount of 300,000 U/ml in the amount of 0.1 ml/paw. The results of this test are reported in Table 3.
TABLE 2
Antiinflammatory activity - acute test
Each value is the average of 10 paws.
Treatment % Inhibition of Edema after:
2 hours 4 hours 6 hours 8 hours
ENA 62 49 61 85
Naproxen 60 31 30 36
Statistical equal ENA more ENA more ENA more
Comparison activity active active active
P N.S. P < 0.025 P < 0.01 P < 0.05
As the data hereinabove show, ENA is as active as Naproxen in the second hour, but becomes more active in the subsequent hours, and after 8 hours still exhibits a very considerable activity.
TABLE 3 Antiinflammatory activity - sub-acute test
Each value is the average of 10 paws.
DAY No.1
Treatment % Inhibition of Edema after:
1hour 2hours 4hours 8hours
ENA 12 8 10 11
Naproxen 5 4 4 5
Comparison ENA more equal ENA more ENA more
active activity active active P < 0.001 P N.S. P < 0.01 P < 0.01 DAY No. 2
Treatment % Inhibition of Edema after: 1 hour 2 hours 4 hours 8 hours
ENA 6 12 12 17
Naproxen 5 8 7 11
Statistical equal equal equal ENA more
Comparison activity activity activity active
P N.S. P N.S. P N.S. P < 0.005 As it is clearly shown by the data, ENA exhibits a therapeutic activity towards a stable previously induced edema which is not only comparable to that of Naproxen, but particularly for very prolonged periods of time is greater and is statistically very significant.
Analgesic activity
The analgesic activity has been determined by comparison with Naproxen in an equimolar dose. Two tests are carried out: one in female mice-of about 25 g average weight and one in male rats of about 100 g average weight.
a) test in the female mouse: contorsions due to phenylquinone according to L.C. Hendershot et al, J.
Pharm. Exp. Ther., 125,237 (1959).
The two compounds are administered through the oral route in essentially equimolar doses with respect to each other: ENA 30 mg/kg, naproxen 20 mg/kg in 1% CMC in the dose of 20 ml/kg. The contorsions are induced at different intervals after the administration of the compounds by endoperitoneal injection of 0.02% phenyquinone in 5% alcohol in the dose of 10 ml/kg.
The results of this test are reported in Table 4.
b) test in the male rat: this test is carried out by applying pressure on an inflamed paw according to L.O,
Randall et al, Arch. Int. Pharmacodyn., 111,409 (1957).
The two compounds are administered through the oral route in doses which are equimolar with respect to each other: ENA 60 mg/kg, naproxen 40 mg/kg in 1% CMC in the dose of 20 ml/kg immediately after the inducement of the inflammation: sub-planar injection of 10% yeast in the amount of 0.1 ml/paw.
The results of this test are reported in Table 5.
TABLE 4
Analgesic activity - test in the mouse
Each figure is the average of eight mice.
Treatment % Inhibition of contorsions after:
1 hour 2hours 4hours 6hours
ENA 27 57 44 46
Naproxen 14 68 30 13
Statistical equal equal equal ENA more
Comparison activity activity activity active
P N.S. P N.S. P N.S. P < 0.01
As the data hereinabove show, ENA exhibits an activity comparable to that of Naproxen in the first few hours, but the activity is maintained still high in the sixth hour while with Naproxen, the activity is substantially reduced.
TABLE 5
Analgesic activity - test in the rat
Each figure is the average of 10 paws.
Treatment % Inhibition of pain after:
1 hour 2 hours 3 hours 4 hours 5 hours
ENA 240 400 . 152 131 100
Naproxen 47 79 67 64 64
Statistical ENA more ENA more equal equal equal
Comparison active active activity activity activity
P < 0.001 P < 0.001 P N.S. P N.S. P N.S.
As the data shows, in this test ENA exhibits greater analgesic activity than Naproxen in a significant manner in the first few hours. After the first few hours, greater activity is apparent, but not statistically significant.
Antip yretic activity This activity has been determined by comparison with Naproxen in equimolar doses. Two animal species have been utilized. Male rats of weight about 250 g and female rabbits of about 2.6 kg of weight.
a) the test in the rat: pyrexia caused by yeast according to U.M. Teotino et al, J. Med. Chem., 6, 248 (1963).
The two compounds are administered through the oral route in doses which are equimolar with respect to each other: ENA 60 mg/kg, Naproxen 40 mg/kg in 1% CMC, in the dose of 10 ml/kg. The fever has been induced the previous night by subcutaneous injection of a 20% yeast suspension in the dose of 10 ml/kg. The results are reported in Table 6.
b) the test in the rabbit: pyrexia caused by yeast.
The two compounds are administered in the oral route by equimolar doses: ENA 60 mg/kg, Naproxen 40 mg/kg in 1% CMC in the dose of 10 ml/kg immediately after the first inducement of fever by means of 20% yeast suspension, which is centrifuged, filtered and the filtrate injected endovenously in the dose of 1 ml/kg.
This treatment to cause fever has been repeated twice at intervals of one hour and 30 minutes. The results are reported in Table 7.
TABLE 6
Antipyretic activity - test in the rat
Each data is the average of 5 animals.
Treatment Reduction of fever in "C after:
1hour 2 hours 4 hours 8 hours
ENA 0.80 1.22 1.32 1.00
Naproxen 0.76 1.24 1.32 0.94
Statistical equal equal equal equal
Comparison activity activity activity activity
P N.S P N.S. P N.S. P N.S.
In this test, the activity of the two substances is about parallel and both of them retain high activity in the eighth hour.
TABLE 7
Antipyretic activity - test in the rabbit
Each data is the average of 4 animals.
Treatment Reduction of fever in "C after:
2 hours 4 hours 6 hours 8 hours
ENA 0.59 0.58 0.48 0.51
Naproxen 1.04 0.61 0.28 0.25
Statistical ENA less equal ' ENA more ENA more
Comparison active activity active active
P < 0.05 P N.S. P < 0.05 P < 0.05
In this test, the antipyretic activity of ENA is at first lower than that of Naproxen, and then it is equal, and then in the sixth and eighth hours remains constant while the activity of Naproxen becomes inferior in a statistically significant manner.
Acute toxicity
The acute toxicity of ENA has been determined on two species of animals: mice of both sexes of average weight about 20 g and rats of both sexes of average weight about 200 g.
Four routes of administration have been used: oral, endoperitoneal, endovenous and subcutaneous. In each instance, the animals were deprived of food the night before the test. There are utilized ten animals, that is five males and five female per each dose of treatment. The values of DL 50, expressed in ml/kg, are calculated according to the method of probits on the basis of the mortality found within a period of eight days of the treatment.
The results are reported in Table 8. They show the comparison of DL 50 of ENA with the DL 50 of
Naproxen, which comparison is partly based upon literature data and partly upon original experimental work.
TABLE 8
Acute toxicity - DL 50 in mglkg
Species Route DL 50 Equivalent DL 50 Ratio
ENA to Naproxen Naproxen Naproxen/ENA
Mouse oral 4200 2800 1234* 0.44
i.p. 5000 3333 550 0.17
i.v. 1000 667 435* 0.65
s.c. > 9000 > 6000 1100 < 0.18
Rat oral 3200 2133 543* 0.25
i.p. 3330 2222 575* 0.26
i.v. 1000 667 400 0.60
s.c. > 3000 > 2000 1000 < 0.50 (*) A.P. Roszkowski et al, J. Pharm. Exp. Ther., 179, 114(1971).
As shown in the ratios in the last column of the above table, ENA is much less toxic, about 1/2 to 1/5 as
compared to Naproxen, keeping also in mind the different molecular weight.
Toxicity in the fetus
This type of toxicity has been investigated in two animals species, rats and rabbits.
a) the test in the rat: ten female rats have been treated in the first 20 days of gestation through the oral
route with ENA in the dose of 20 ml/kg/day, equal to 13.2 mg/kg of Naproxen. Afterwards, the animals have
been sacrificed in order to remove the fetuses and to observe the uterus. The properties which have been
observed are: the growth of the mother, the number of live fetuses, the number of dead fetuses, average
weight of the litter, number of reabsorptions and malformations.
Results: no toxic symptons on the gestation and on the fetuses has been observed.
b) the test in the rabbit: five female rabbits have been treated in the first 24 days of gestation through the
oral route with ENA in the dose of 20 mg/kg/day, equal to13.2 mg/kg of Naproxen. Afterwards the animals
have been sacrificed in order to remove the fetuses and to observe the uterus. The properties which have
been observed have been: the growth of the mother, the number of live fetuses, the number of dead fetuses,
the average weight of the litter, the number of reabsorptions and malformations.
Results: no toxic symptons have been observed either on the gestation or on the fetuses.
Sub-acute toxicity through the rectal route
Six rabbits, that is three male and three female rabbits of average weight about 2 kg have been treated.
The daily treatment for a period of ten days consisted of suppositories containing 300 mg of active material
which was introduced deep down in the rectal orifice while the orifice was kept closed for a period of 30
minutes with cocher clamps. This treatment has not shown significant variation of the general state of
health, the body weight, hematic crasis, lever function, glycemia, azotemia, glycosuria, proteinuria,
ematuria.
Sub-acute toxicity through the oral route (ulcerogenesis) The comparison has been carried out by using an amount of ENA which is equimolar to that dose of
Naproxen which is known to be ulcerogenic. Male rats of 150 g about average weight, have been used, being
kept partially fasting (only at night) in a total number of five. The daily treatment has been carried out by
introducing into the esophagus: ENA in the amount of 150 mg/kg/day, Naproxen 100 mg/kg/day in 1% CMC
in the dose of 5 mg/kg. A few hours after the fifth administration, one animal died between the treatments
with Naproxen and it was decided to sacrifice all the animals to observe them. The results of the
observations made during the five-day period and of the death are reported schematically in Table 9.
TABLE 9
Ulcerogenic gastro-enteric effect in rats
ENA Naproxen
Observations prior to death Animals Animals n - /O n -% Significant paleness 0 0 2 40
Weight reduction 15% beginning
onOday 0 0 3 60
Lack of growth between the 4th and
5th day 0 0 4 80
Blood in the fetus 0 0 2 40
Diarrhea 0 0 2 40
Death (due to peritonitis) 0 0 1 20
Observations after death
Lack offeeding 0 0 2 40 Anemicdigestivetube 0 0 5 100
Gastro-intestinal ulcer 0 0 1 20
As it appears from the data hereinabove, the daily dose of Naproxen which has been used is very toxic up to the point of being lethal through the gastro-enteric route, while the equimolar dose of ENA gives no symptoms of intolerability nor symptoms of gastro-entero injury even after five days.
EXAMPLE 3
Capsules of soft gelatin : every capsule contains: 2-(6-methoxy-2-naphthyl)propyl enanthate 350 mg
EXAMPLE 4
Suppositories: each suppository contains: 2-(6-methoxy-2-naphthyl)propyl enanthate 300 mg
Miglyol 50 mg
Witepsol E 85 460 mg
Witepsol W 35 to 2.2 9 EXAMPLE 5
Suppositories:each suppository contains: 2-(6-methoxy-2-naphthyl)propyl enanthate 600 mg
Miglyol 10 mg
Witepsol E 85 370 mg
Witepsol W 35 to 2.3 9 EXAMPLE 6 5% Cream: 100 g of cream contain: 2-(6-methoxy-2-naphthyl)propyl enanth ate 5g Cetylstearyl alcohol 5 g
Isopropyl myristate 7g Oil of vaseline 5g Spermacetes 7g Stearic acid 2g
Polysorbitan monolaurate 60 0.5g Carboxyvinyl polymer with triethanolamine lg Benzoic acid 2 g
Distilled water 100 g
EXAMPLE 7
Phthials of300 mg: each 2 ml phthial contains: 2-(6-methoxy-2-naphthyl)propyl enanthate 300 mg
Lidocain base 10 mg
Benzyl Alcohol 50 mg
Ethyl oleate (or olive oil Fu) to 3 ml.
This composition of the present invention may be used to relieve a living subject from inflammation, pain, fever in the dose of 300-1200 mg/day.
Claims (5)
1. An ester of 2-(6-methoxy-2-naphthyl)propanol of formula (I)
wherein R is an alkyl radical of 1 to 20 carbon atoms.
2. A compound according to claim 1 which is 2-(6-methoxy-2-naphthyl)propyl enanthate.
3. A pharmaceutical composition having antiinflammatory, antirheumatic, analgesic, and antipyretic activity which comprises as the active ingredient at least one compound according to claim 1.
4. A pharmaceutical composition according to claim 3 wherein the active compound is 2-(6-methoxy-2naphthyl)propyl enanthate.
5. The process for the preparation of an ester of 2-(6-methoxy-2-naphthyl)propanol of formula (I) which consists of reacting 2-(6-methoxy-2-naphthyl)propanol of formula (II) with a compound of formula (III) according to the equation hereinbelow:
wherein R is an alkyl radical between 1 and 20 carbon atoms, X is OH or halogen or an alcoxy-carbonyloxy radical and isolating said compound of formula (I) from the reaction mixture.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT22738/79A IT1114245B (en) | 1979-05-17 | 1979-05-17 | 2- (6-METHOXY-2-NAFTYL) PROPYL ESTERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Publications (2)
Publication Number | Publication Date |
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GB2050363A true GB2050363A (en) | 1981-01-07 |
GB2050363B GB2050363B (en) | 1983-04-27 |
Family
ID=11199868
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Application Number | Title | Priority Date | Filing Date |
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GB8014797A Expired GB2050363B (en) | 1979-05-17 | 1980-05-02 | Esters of 2-(6-methoxy-2-naphthyl)-1propanol method of preparation and pharmaceutical compositions thereof |
Country Status (19)
Country | Link |
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JP (1) | JPS5625131A (en) |
AT (1) | AT366359B (en) |
AU (1) | AU516763B2 (en) |
BE (1) | BE883330A (en) |
CH (1) | CH642257A5 (en) |
DE (1) | DE3016616C2 (en) |
DK (1) | DK208880A (en) |
ES (1) | ES491555A0 (en) |
FR (1) | FR2456724A1 (en) |
GB (1) | GB2050363B (en) |
IE (1) | IE49479B1 (en) |
IT (1) | IT1114245B (en) |
LU (1) | LU82448A1 (en) |
MX (1) | MX6220E (en) |
NL (1) | NL8002737A (en) |
NO (1) | NO801195L (en) |
PT (1) | PT71198A (en) |
SE (1) | SE8003496L (en) |
ZA (1) | ZA802666B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2204869A (en) * | 1987-05-18 | 1988-11-23 | Procter & Gamble | Novel anti-inflammatory esters, pharmaceutical compositions and methods for reducing inflammation |
US4912248A (en) * | 1987-05-18 | 1990-03-27 | The Procter & Gamble Company | Novel anti-inflammatory agents, pharmaceutical compositions and methods for reducing inflammation |
-
1979
- 1979-05-17 IT IT22738/79A patent/IT1114245B/en active
-
1980
- 1980-04-24 NO NO801195A patent/NO801195L/en unknown
- 1980-04-30 DE DE3016616A patent/DE3016616C2/en not_active Expired
- 1980-05-02 ZA ZA00802666A patent/ZA802666B/en unknown
- 1980-05-02 GB GB8014797A patent/GB2050363B/en not_active Expired
- 1980-05-02 CH CH343580A patent/CH642257A5/en not_active IP Right Cessation
- 1980-05-05 AU AU58081/80A patent/AU516763B2/en not_active Ceased
- 1980-05-05 AT AT0237680A patent/AT366359B/en not_active IP Right Cessation
- 1980-05-07 PT PT71198A patent/PT71198A/en unknown
- 1980-05-09 SE SE8003496A patent/SE8003496L/en not_active Application Discontinuation
- 1980-05-12 NL NL8002737A patent/NL8002737A/en not_active Application Discontinuation
- 1980-05-13 IE IE978/80A patent/IE49479B1/en unknown
- 1980-05-13 DK DK208880A patent/DK208880A/en unknown
- 1980-05-14 LU LU82448A patent/LU82448A1/en unknown
- 1980-05-14 FR FR8010948A patent/FR2456724A1/en active Granted
- 1980-05-16 JP JP6586680A patent/JPS5625131A/en active Pending
- 1980-05-16 ES ES491555A patent/ES491555A0/en active Granted
- 1980-05-16 MX MX808822U patent/MX6220E/en unknown
- 1980-05-16 BE BE2/58567A patent/BE883330A/en not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2204869A (en) * | 1987-05-18 | 1988-11-23 | Procter & Gamble | Novel anti-inflammatory esters, pharmaceutical compositions and methods for reducing inflammation |
US4912248A (en) * | 1987-05-18 | 1990-03-27 | The Procter & Gamble Company | Novel anti-inflammatory agents, pharmaceutical compositions and methods for reducing inflammation |
Also Published As
Publication number | Publication date |
---|---|
IE800978L (en) | 1980-11-17 |
ES8104179A1 (en) | 1981-04-01 |
BE883330A (en) | 1980-09-15 |
ZA802666B (en) | 1981-05-27 |
AU5808180A (en) | 1980-11-20 |
IT7922738A0 (en) | 1979-05-17 |
NO801195L (en) | 1980-11-18 |
CH642257A5 (en) | 1984-04-13 |
MX6220E (en) | 1984-12-21 |
NL8002737A (en) | 1980-11-19 |
PT71198A (en) | 1980-06-01 |
ES491555A0 (en) | 1981-04-01 |
FR2456724A1 (en) | 1980-12-12 |
AT366359B (en) | 1982-04-13 |
DE3016616C2 (en) | 1982-09-16 |
DK208880A (en) | 1980-11-18 |
DE3016616A1 (en) | 1980-11-20 |
GB2050363B (en) | 1983-04-27 |
JPS5625131A (en) | 1981-03-10 |
SE8003496L (en) | 1980-11-18 |
AU516763B2 (en) | 1981-06-18 |
IT1114245B (en) | 1986-01-27 |
ATA237680A (en) | 1981-08-15 |
IE49479B1 (en) | 1985-10-16 |
FR2456724B1 (en) | 1984-04-20 |
LU82448A1 (en) | 1980-07-31 |
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