IE44660B1 - 2-(4-(3'-thenoyl)-phenyl)-propionic acid and base addition salts thereof - Google Patents
2-(4-(3'-thenoyl)-phenyl)-propionic acid and base addition salts thereofInfo
- Publication number
- IE44660B1 IE44660B1 IE616/77A IE61677A IE44660B1 IE 44660 B1 IE44660 B1 IE 44660B1 IE 616/77 A IE616/77 A IE 616/77A IE 61677 A IE61677 A IE 61677A IE 44660 B1 IE44660 B1 IE 44660B1
- Authority
- IE
- Ireland
- Prior art keywords
- thenoyl
- composition
- phenyl
- compound
- propionic acid
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- 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]
Abstract
The present invention concerns a process of preparation of a novel substituted propionic acid. This compound, which is the 2-¢4-(3-thenoyl)-phenoyl!-propionic acid, is obtained by the intermediary of the ethyl 2-methyl-2-¢4-(3-thenoyl)-phenyl! malonate and fluorophenylthenyl methanone. This compound is of particular interest as an analgesic anti-inflammatory agent and anti-aggregating agent for blood platelets.
Description
This invention relates to propionic acid derivatives and is concerned with a substituted propionic acid having pharmacological properties, a process for preparing the same and pharmaceutical compositions containing said compound as an essential active ingredient.
The substituted propionic acid of the invention is the compound 2-[4-(3'-thenoyl)-phenyl] -propionic acid, which has the structural formula:
(1)
The compound of formula I has an asymmetric carbon atom and can be separated, by techniques known per se , into the optically active isomers.
Salts formed by the compound of formula I with 15 inorganic or organic bases, particularly the salts which are pharmaceutically acceptable, are included within the scope of the present invention. Such salts can be obtained in any conventional manner.
The compound of formula I can be obtained by 20 alkaline hydrolysis of the compound diethyl 2-methyl-2-1 4 6 6 Ο |_4-(3'-thenoyl)-phenyl] -malonate, which has the structural formula:
C00CoHc 2 5
CH.
COOC2H5 (II) followed by decarboxylation.
The intermediate represented by formula
II, which itself is believed to be a novel compound, may be obtained by reacting a fluorophenyl thienyl ketone of the structural formula:
II c
(III)
IO
IO with diethyl 2-methyl-malonate in a dipolar aprotic solvent e.g. hexamethyl phosphorotriamide, and in the presence of a strong base, e.g. sodium hydride.
The fluorophenyl thienyl ketone of formula III, which is also believed to be a novel compound, may be prepared by condensing 3-thenoyl chloride with fluorobenzene under Friedel-Crafts reaction conditions.
The compound of formula I has been found to have pronounced activity as an analgesic, anti-inflammatory and blood platelet anti-aggregating agent.
4666
- 4 The analgesic activity of the compound of formula I has been proved by a test using acetic acid on mice (Siegmund method, modified by Koster, Anderson and Debeer). The active dose AD5Q (mg/kg) is equal to 9 for the compound of the invention, whereas aspirin (acetylsalicylic acid) in this test has an Αϋ^θ of 130, Pyramidon (phenyl dimethyl amino dimethylpyrazolone) has an Αϋ^θ of 32 and Pethidine (ethyl l-methyl-4-phenyl-4-piperidine-carboxylate hydrochloride) has an ADj-θ Of 17. The word Pyramidon is a
Trade Mark.
The anti-inflammatory activity, which was determined, among other methods, by the oedema test using oarrageenin in rats (Winter et al., Proc. Soc. Exp.Biol. Med. 1972,
III, 544-547) has proved to be excellent. The active dose AD3θ (mg/kg) of the compound of the invention is
, while that of phenyl butazone (l,2-diphenyl-3,5-dioxo4-n-butyl-pyrazolidine) is 50 and that of Pyramidon is
82.
In connection with the inhibition of erythema due to ultra-violet ih the guinea pig (C.V.Winder, J.Wax, V.BUrr et al., Arch. Int. Pharm. (1958), 116-261), the compound of the invention proved to be thirty times more active than aspirin. At 5 mg/kg. the protection of the animal was complete and was of the same order as that pro25 vided by Indomethacine [l-(4-chlorobenzoyl)-S-methoxy-2methyl-indole-3-acetic acid'l or Ketoprofene [2-(3’-benzoylphenyl) -propionic acid].
2- [4-(3'-Thenoyl)-phenylJ -propionic acid has the property of inhibiting, both in vitro and in vivo, the aggregation of the plasma platelets of a rabbit, which aggregation is induced by 5-adenosine diphosphate (A D P) and collagen. The method whioh was used for proving this pharmacological property is based on that described by Born (Journal of Physiology -1962) and determined with the assistance of a Mustard aggregometer. The result is expressed by a coefficient resulting from the ratio; the smallest active concentration (in micromoles) of the standard over the weakest active concentration of the product. (The term active concentration is used as meaning that amount which provides an inhibition of the aggregation equal to or higher than 50%).
Compound & θ
Aspirin
Phenergan (10-(2-dimethylaminopropyl)phenothiazine) 1
2- [4- (31 -thenoyl) phenyl] -propionic acid 4
Collagen
The word Phenergan is a Trade Mark.
The compound of the Invention or its pharmaceutically acceptable base addition salts will normally be administered in the form of a pharmaceutical composition comprising as an essential active ingredient a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutical diluent or excipient therefor.
Advantageously for clinical use, the composition will be made up in a dosage unit form appropriate to the desired mode of administration. Thus for oral administration the composition may be in the form of a tablet, pill, or capsule, or a syrup or suspension to be taken in discrete amounts, whilst for parenteral administration the composition may be in the form of an injectable solution packaged in a container such as an ampoule. For rectal administration, the composition may be in the form of a suppository. Alternatively the composition may be in a form intending for topical administration, for example, an ointment. If desired, the oral dosage unit forms may be made gastroresistant by being lacquered with a cellulose derivative.
Sufficient of the pharmaceutical composition of the invention may be administered to give a daily dosage of the active compound of between 20 and 1000 mg.
The following Examples illustrate the preparation of the compound of the invention and of pharmaceutical compositions containing it.
EXAMPLE 1
Preparation of 2- ^4-(31-thenoyl)-phenyl] -propionic acid
Stage I [4-fluorophenyl] [3-thienyl] ketone (formula 1X1)
To a solution of 42.5 g (0.29 mole) of 3-thiophenecarbonyl chloride in 315 ml.of fluorobenzene are added in small fractions, and while stirring and cooling on an ice bath, 57 g (0.42 mole) of anhydrous aluminium chloride. The reaction is slightly exothermic and the temperature rises to 10°C. The mixture is then brought over 45 minutes to 60°C and then refluxed for 15 minutes. Cooling takes place and the resulting mixture is poured onto iced water, followed by extraction with chloroform. The organic phase obtained is washed with a 5% solution of sodium bicarbonate and dried over Ma^SO^. After evaporation of the solvent and distillation under vacuum, 18.3 g of product are obtained
2θ (yield: 30%), Βρθ 125-13O°C; Mp: 74°C (hexane).
Stage II
Diethyl 2-metlj^^j2-laD}j^’-thenoyl)-phenyl] -malonate
To a sodium hydride suspension (4 g. of 50% suspension 25 (0.083 mole))in 83 ml of freshly distilled hexamethyl phosphorotriamide, are added dropwise, at room temperature,
14.4 g (0.083 mole) of diethyl 2-methyl-malonate. The reaction is slightly exothermic. 17.1 g (0.083 mole) of [4-fluorophenyl] [3-thiepyl] ketone are then added in small fractions. The temperature is then maintained for 10 hours at 100°C. Dilution is then carried out with 300 ml of benzene, followed by washing with H^O and drying over NagSO^. After evaporation of the solvent and vacuum distillation, a yellow oil is obtained.
4 6 6 0
Stage III
2- [4-(31-thenoyl)-phenyl J -propionic acid (formula I)
12.1 g (3.3 x 10 2 mole) of diethyl 2-methyl-2[4-(3'-thenoyl)-phenyll-malonate and 80 ml of a 5% aqueous sodium hydroxide solution are refluxed for 6 hours. After cooling and washing the solution with benzene, the aqueous phase is acidified with ^NHCl. The oil which forms is extracted with chloroform. After drying over Ν32δ0^ and evaporation of the solvent, 9 g of a thick oil are obtained, and this is recrystallised to obtain 3.4 g of a white solid, which is the required product.
EXAMPLE 2.
A compressed tablet was produced in accordance with known pharmaceutical techniques from the following:
active ingredient 150 mg (Compound X) lactose 100 mg wheat starch 139 mg gelatine 5 mg talcum 5 mg magnesium stearate 1 mg
400 mg
The tablet was coated with a gastro-soluble film based on cellulose polymers, such as hydropropyl methyl cellulose or ethyl cellulose.
EXAMPLE 3.
A capsule was prepared from the following:
active ingredient 50 mg (Compound I) lactose 60 mg wheat starch 68 mg magnesium stearate mg
180 mg
EXAMPLE 4.
An ointment was prepared from the following:
active ingredient (Compound I) 5 g Emulgade F 25 g Eutanol G 13 g Propylene glycol 10 g 10 purified water 47 g
Emulgade F is a mixture of cetyl-stearyl alcohols, sodium cetyl-stearyl sulphate and ethoxylated fatty acids of vegetable origin, whilst Eutanol G is 2-octyl-dodecanol.
EXAMPLE 5.
A lyophilisable injectable solution was prepared using the sodium salt of the compound of formula I (in an amount equivalent to 50 mg of compound I) dissolved in 5 ml. of water.
EXAMPLE 6.
Suppositories were made from a mixture such that each suppository contained 400 mg of the active compound (formula I) and sufficient of a semi-synthetic glyceride to give a total weight of 2 g.
Claims (13)
1. The compound 2- [4-(3'-thenoyl)-phenyl] -propionic acid having the formula; II ca— cooh CH.
2. Pharmaceutically acceptable base addition salts of the compound claimed in Claim 1.
3. A pharmaceutical composition comprising the compound claimed in Claim 1, or a pharmaceutically acceptable base addition salt thereof, and a pharmaceutical diluent or excipient therefor.
4. A composition as claimed in Claim 3 in a dosage unit form.
5. A composition as claimed in Claim 4, wherein the dosage unit is in a form intended for oral administration.
6. A composition as claimed in Claim 4, wherein the dosage unit is in a form intended for rectal administration.
7. A composition as claimed in Claim 4, wherein the dosage unit is a packaged injectable solution intended for parenteral administration.
8. A composition as claimed in Claim 3 wherein the composition is in a form intended for topical administration. 4 4 6 6 0 - 10
9. Ά pharmaceutical composition substantially as described in any one of the foregoing Examples 2 to δ.
10. A process for preparing 2- 4-(3'-thenoyl)-phenyl propionic acid, which comprises subjecting diethyl 2-methyl5 2- [4-(3'-thenoyl)-phenyl] -malonate to alkaline hydrolysis followed by decarboxylation.
11. Process according to Claim 10, wherein the diethyl 2-methyl-2-C4-(3'-thenoyl)-phenylj -malonate is prepared by reacting(4-fluorophenyl)(3-thienyl)ketone with diethyl 2 10 -methyl-malonate in a dipolar aprotic solvent and in the presence of a strong base.
12. Process according to Claim 11, wherein the (4-fluorophenyl) (3-thienyl)ketone is prepared by condensing 3-thenoyl chloride with fluorobenzene under Eriedel-Crafts reaction 15 conditions.
13. Process for preparing 2-[4-(3'-thenoyl)-phenyl] propionic acid, substantially as described in the foregoing
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7608470A FR2345148A1 (en) | 1976-03-24 | 1976-03-24 | NEW SUBSTITUTE PROPIONIC ACID, PREPARATION AND APPLICATION |
Publications (2)
Publication Number | Publication Date |
---|---|
IE44660L IE44660L (en) | 1977-09-24 |
IE44660B1 true IE44660B1 (en) | 1982-02-10 |
Family
ID=9170850
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE616/77A IE44660B1 (en) | 1976-03-24 | 1977-03-23 | 2-(4-(3'-thenoyl)-phenyl)-propionic acid and base addition salts thereof |
Country Status (26)
Country | Link |
---|---|
JP (1) | JPS52139057A (en) |
AR (1) | AR212262A1 (en) |
AT (1) | AT358026B (en) |
AU (1) | AU2351877A (en) |
BE (1) | BE852463A (en) |
CA (1) | CA1102343A (en) |
CH (1) | CH597220A5 (en) |
CS (1) | CS199667B2 (en) |
DD (1) | DD128778A5 (en) |
DE (1) | DE2711585A1 (en) |
DK (1) | DK128077A (en) |
ES (1) | ES457112A1 (en) |
FR (1) | FR2345148A1 (en) |
GB (1) | GB1517688A (en) |
HU (1) | HU176990B (en) |
IE (1) | IE44660B1 (en) |
IL (1) | IL51720A0 (en) |
IT (1) | IT1115272B (en) |
MX (1) | MX4565E (en) |
NL (1) | NL7703215A (en) |
NO (1) | NO771033L (en) |
OA (1) | OA06109A (en) |
SE (1) | SE7703317L (en) |
SU (1) | SU657748A3 (en) |
YU (1) | YU65377A (en) |
ZA (1) | ZA771724B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2030131B (en) * | 1978-09-12 | 1982-12-22 | Taiyo Pharma Ind | Process for producing 2-(4-(2-thienyl-carbonyl) phenyl) propionic acid |
EP0046337A3 (en) * | 1980-08-20 | 1982-09-15 | Imperial Chemical Industries Plc | Triazole compounds, a process for preparing them, their use as plant and pharmaceutical fungicides and as plant growth regulators and compositions containing them |
GB2181728B (en) * | 1985-10-21 | 1990-01-24 | Indian Drugs & Pharma | 4-(3-thienyl)phenylalkanoic acids and derivatives and process for their preparation |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1007643A (en) * | 1972-10-24 | 1977-03-29 | Janssen Pharmaceutica Naamloze Vennootschap | Aroyl-substituted phenylacetic acid derivatives |
-
1976
- 1976-03-24 FR FR7608470A patent/FR2345148A1/en active Granted
-
1977
- 1977-03-11 YU YU00653/77A patent/YU65377A/en unknown
- 1977-03-15 AT AT176577A patent/AT358026B/en not_active IP Right Cessation
- 1977-03-15 BE BE175792A patent/BE852463A/en not_active IP Right Cessation
- 1977-03-17 DE DE19772711585 patent/DE2711585A1/en not_active Withdrawn
- 1977-03-18 CS CS771807A patent/CS199667B2/en unknown
- 1977-03-21 IT IT7721461A patent/IT1115272B/en active
- 1977-03-21 CA CA274,355A patent/CA1102343A/en not_active Expired
- 1977-03-22 ZA ZA00771724A patent/ZA771724B/en unknown
- 1977-03-22 CH CH359977A patent/CH597220A5/xx not_active IP Right Cessation
- 1977-03-22 IL IL51720A patent/IL51720A0/en unknown
- 1977-03-23 MX MX775559U patent/MX4565E/en unknown
- 1977-03-23 NO NO771033A patent/NO771033L/en unknown
- 1977-03-23 SU SU772462808A patent/SU657748A3/en active
- 1977-03-23 ES ES457112A patent/ES457112A1/en not_active Expired
- 1977-03-23 IE IE616/77A patent/IE44660B1/en unknown
- 1977-03-23 HU HU77LI310A patent/HU176990B/en unknown
- 1977-03-23 AU AU23518/77A patent/AU2351877A/en not_active Expired
- 1977-03-23 SE SE7703317A patent/SE7703317L/en unknown
- 1977-03-23 DK DK128077A patent/DK128077A/en not_active Application Discontinuation
- 1977-03-23 GB GB12327/77A patent/GB1517688A/en not_active Expired
- 1977-03-24 NL NL7703215A patent/NL7703215A/en not_active Application Discontinuation
- 1977-03-24 AR AR266969A patent/AR212262A1/en active
- 1977-03-24 JP JP3164377A patent/JPS52139057A/en active Pending
- 1977-03-24 DD DD7700198055A patent/DD128778A5/en unknown
- 1977-03-28 OA OA56120A patent/OA06109A/en unknown
Also Published As
Publication number | Publication date |
---|---|
CH597220A5 (en) | 1978-03-31 |
ZA771724B (en) | 1978-02-22 |
NL7703215A (en) | 1977-09-27 |
FR2345148B1 (en) | 1978-10-20 |
AT358026B (en) | 1980-08-11 |
DD128778A5 (en) | 1977-12-07 |
DK128077A (en) | 1977-09-25 |
SE7703317L (en) | 1977-09-25 |
MX4565E (en) | 1982-06-17 |
AU2351877A (en) | 1978-09-28 |
CA1102343A (en) | 1981-06-02 |
IE44660L (en) | 1977-09-24 |
OA06109A (en) | 1981-06-30 |
YU65377A (en) | 1983-01-21 |
AR212262A1 (en) | 1978-06-15 |
JPS52139057A (en) | 1977-11-19 |
NO771033L (en) | 1977-09-27 |
ATA176577A (en) | 1980-01-15 |
BE852463A (en) | 1977-09-15 |
GB1517688A (en) | 1978-07-12 |
CS199667B2 (en) | 1980-07-31 |
DE2711585A1 (en) | 1977-09-29 |
SU657748A3 (en) | 1979-04-15 |
IL51720A0 (en) | 1977-05-31 |
ES457112A1 (en) | 1978-03-01 |
FR2345148A1 (en) | 1977-10-21 |
IT1115272B (en) | 1986-02-03 |
HU176990B (en) | 1981-06-28 |
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