GB2023599A

GB2023599A - Furopyridone derivatives

Info

Publication number: GB2023599A
Application number: GB7921911A
Authority: GB
Original assignee: Parcor SARL
Current assignee: Parcor SARL
Priority date: 1978-06-22
Filing date: 1979-06-22
Publication date: 1980-01-03
Also published as: IT7949482A0; FR2429219B1; BE877157A; JPS552698A; JPS6345394B2; GB2023599B; EP0006772A1; FR2429219A1; IE791036L; DE2961213D1; CH638214A5; IE48418B1; EP0006772B1; LU81237A1; DK259379A; IT1117227B

Description

1 a GB 2 023 599 A 1

SPECIFICATION Therapeutic composition containing thienopyridone or furopyridone derivatives

This invention relates to a therapeutic_ composition comprising, as active ingredient, thieno-and furopyridone derivatives.

Thus, this invention relates to a therapeutic composition having in particular blood-platelet 5 aggregating inhibiting and anti-inflammatory activities, comprising, as active ingredient, an efficient amount of a thienopyridone or furopyridone derivative having the following general formulae:

0 R IC M (1) Ar R -U, C 0 in which X is an oxygen or sulfur atom; R represents a hydrogen or halogen atom or a C,-4 alkyl group, and Ar represents an aryl orheteroaryl group optionally substituted with at least a halogen atom ora 10 lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group.

Illustrative aryl groups are phenyl and naphthyl groups optionally substituted as indicated above, and an illustrative heteroaryl group is pyridyl group optionally substituted with the above defined groupp, Of all the compounds represented by the general formula (1) or (11), only the compound of formula15 (11) in which R=H, X=S, and Ar=C,H5 is a known compound. It has already been mentioned in the literature (D. E. AMES Et 1. RIBEIRO, J. C. S. Perkin 1, 1975, 1390), but it has never been studied from a therapeutic standpoint and the process for its preparation is relatively complex.

Thus, this invention relates also to thieno- or furopyricline dervatives having the following general formulae:

0 R -f: Ar (1) Ar R -0 C 0 in which X is an oxygen or sulfur atom, R represents a hydrogen or halogen atom or a C,-4 alky, group and Ar represents an aryl or heteroaryl group optionally substituted with at least one halogen atom or lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group, provided that R=H, X=S and Ar=phenyl are not simultaneously present.

This invention relates also to a process for the preparation of derivatives of the formula (1) or (11), comprising heating in an inert solvent and at a temperature between 1 501C and the boiling point of the solvent selected, a compound having the following formula (111) or (IV):

CON 3 Ar (111) Ar 00 cc R -U^3 OV) in which X, R and Ar have the above-defined meanings.

The solvent inert with respect to the reagents and the reaction products is diphenyImethane or diphenyl ether, for example. This reaction by heat treatment, involves the rearrangement of the azides of the formula (111) or (R) to the isocyanates of the formula (V) or (V1) which undergo thermal cyclization to the derivatives (1) and (11), according to the following reaction scheme:

3 5 (111) Ar - A&L-> (V) kX P. -U, "" -A> (11) 3 5 (V1) The starting compounds of the formulae (111) and (IV) are prepared from the corresponding acids to the formulae (VII) and (Vill) which are first converted to the acid chlorides of the formulae (XI) and (XII), the latter being, in turn, conventionally converted to the azidei, for example by reaction with. sodium azide in aqueous solution, according to the following reaction scheme:

GB 2 023 599 A 2 cow Ar --I%.

(V11) R - r "3 (111) U",^m Y= a: OX) y = 0M0CP.': (X0 Ar m ov) R -F l(Y R-Ul -,L---> 1.xl-11 COY (V111) Y - cl: (X) y - OMDC,11.s: (XII) The following acids of the formula (Vill, in which: X=S, R=H, Ar=C6H,,; X=S, R=H, Ar=4-Cl-C,H4; X=S, R=H, Ar--4-CH3_C6"4; X=S, R=H, Ar_-4-NOi'-C,H4 and X=O, R=H, Ar--C6H., are described in the literature=S. FISICHELLA, G. SCARLATA & D. SCHIOTTO, Ann. Chim. 5 (Italia), 1973, 63,55; S. FISICHELLA, G. MINERI, G. SCARLATA & D. SCIOTTO, !bid. 1973,63,779.

The other acids of the formula (Vil) and (VIII) which are used in the method according to this invention are new and were prepared according to the process described in the above-mentioned references, according to the following reaction scheme:

invention.

CW it AC2P' EY + Ac0. Ey CHO - Ar-CHi-COCH > Will R --- li AV'Cfcom:30' (Vill) 10 X The following non-limiting Examples illustrate the process for the preparation of derivatives of this EXAMPLE 1 6-Phenyi-thieno(3,2-c)pyrid-4-one (Derivative No. 1) 15, a) Preparation of azide (111) To a solution of a-phenyl-A-(2-thienyl) acrylic acid (50 g; 0.217 mole) of triethylamine (31 ml.0.22 mole) and chloroform (350 ml) cooled to -51C are added dropwise 21 ml (-0.22 mole) ethyl chloroformate. After stirring the mixture for -T1 hour at -51C, a solution of sodium azide (17 g; 0.26 mole) in 60 ml water is added dropwise thereto. On completion of the addition, the resulting material is stirred at OC for 1 hour, after which water is added thereto and it is then decqnted. The organic phase 20 is washed with water and then dried over sodium sulfate and filtered.

b) Preparation of derivative (/) The filtrate obtained in step a) is added dropwise to 200 mi diphenyl methane previously heated at 160"C, the chloroform distilling off gradually. When the addition is complete, the material is stirred for a further 15 minutes at the same temperature, after which it is cooled, diisopropyl ether is added thereto, 25 and the material is then filtered and washed with the same ether and dried in vacuo, to give 31-55 g (Yield: 63.5%) beige crystals (M.p. =230'C) which may be recrystallized from methanoldimethylformamide.

EXAM P LE 2 6-p.Fluorophenyl-thieno(3,2-c)pyrid-4-one (Derivative No. 2) This compound is prepared according to the procedure of Example 1, from a(4-fluoro-phenyi)-P (2-thienyi)acrylic acid (M.p.=1 91 OC): beige crystals, M.p.=2620C (methanol-dimethyiformamide).

Yield: 44.5%.

EXAMPLE 3

6-o.Chlorophenyi-thieno(3,2-c)pyrid-4-one (Derivative No. 3) This compound is prepared according to the procedure of Example 1, from ct-(2-chloro-phenyi)-P (2-thienyi)acrylic acid (M.p.=1 970C): beige crystals, M.p.=2321C; yield: 27%.

EXAMPLE 4 6-p.Chlorophenyi-thieno(3,2-c)pyrid-4-one (Derivative No. 4) Prepared according to the procedure of Example 1, from a-(4-chlorophenyl)-,8-(2-thienyi)acrylic 40 acid (M.p.=224'C): pale green crystals; M.p.: 260IC; Yield: 60%.

EXAMPLE 5

6-p.Toiyi-thieno(3,2-c)pyrid-4-one (Derivative No. 5) Prepared according to the procedure of Example 1, frorn a-(p-Tolyti)-P-(2- thienyi)-acrylic acid (M.p.=209OC): Yellow crystals, M.p. 26WC (methanol-dime-thylformamide), Yield: 51%.

k 3 GB 2 023 599 A 3 EXAMPLE 6

6-p.Methoxyphenyi-thieno(3,2-c)pyrid-4-one (Derivative No. 6) Prepared according to the procedure of Example 1, from a-(4-methoxy- phenyi)--(2thienyl)acrylic acid (M.p.=2030C): greenish crystals, M.p.=251 C (dimethylformamide); Yield: 64%.

EXAMPLE 7

6-(3,4-Dimethoxy-phenyi)-thieno(3,2-c)pyrid-4-one (Derivative No. 7) Prepared according to the procedure of Example 1, from ct-(3,4-dimethoxyphenyi)-P-(2- thienyi)acrylic acid (M.p.=220OC): yellow crystals, M.p.=2200C (methanol- dimethylformamide); Yield:

60.5%.

1 EXAMPLE8 6-(3,4,5-Trimethoxy-phenyi)-thieno(3,2-c)pyrid-4-one (Derivative No. 8) Prepared according to the procedure of Example 1, from a-(3,4,5- trimethoxy-phenyi)-A-(2thienyl)acrylic acid (M.p.=217IC): yellow crystals, M.p.=2400C (methanol-dimethylformamide); Yield: 62%.

EXAMPLE 9 6-o.Nitrophenyl-thieno(3,2-c)pyrid-4-one (Derivative No. 9) Prepared according to the procedure of Example 1, from a-(2-nitro-phenyi)P-(2-thienyi)acrylic acid (M.p.=21 1 'C): yellow crystals, M.p.=236 "C (methanol-dimethylformamide); Yield: 20%.

EXAMPLE 10 20 6-p.Nitrophenyi-thieno(3,2-c)pyrid-4-one (Derivative No. 10) Prepared according to the procedure of Example 1, from a-(4-nitro-phenyl)- P-(2-thienyi)acrylic acid (M.p.=2360C): yellow crystals, M.p.>2601IC; Yield: 51 %.

EXAMPLE 11

6-m.Trifluoromethylphenyi-thieno(3,2-c)pyffd-4-one (Derivative No. 11) Prepared according to the procedure of Example 1, from a-(3trifluoromethyi-phenyi)-P-(2- 25 thienyl)acrylic acid (M.p.=2320C)., white crystals, M.p.=245 C (methanol- dimethylformamide); Yield:

58%.

EXAMPLE 12

2-Chloro-6-phenyl-thieno(3,2-c)pyrid-4-one (Derivative No. 12) Prepared according to the procedure of Example 1, from a-phenyl-p-(5chloro-2-thienyl)acrylic 30 acid (M.p. 21151Q. Orange crystals, M.p. >260C (dimethylformamide), Yield: 64%.

EXAMPLE 13

2-Methyi-6-phenyi-thieno(3,2-c)pyrid-4-one (Derivative No. 13) Prepared according to the procedure of Example 1, from a-phenyi-p-(5methyi-2-thienyi) acrylic acid (M.p.=207OC): beige crystals; M.p. >2600C (dimethylformamide); Yield: 54%.

EXAMPLE 14 6-(3-Pyridyi)-thieno(3,2-c)pyrid-4-one (Derivative No. 14) Prepared according to the procedure of Example 1, from a-(3-pyridyi)-P-(2thienyi)acrylic acid (M.p.=21 OOC): Yellow crystals, M.p. >2600C (dimethylformamide); Yield: 41 %.

EXAMPLE 15

5-Phenyi-thieno(3,2-c)pyrid-7-one (Derivative No. 15) Prepared according to the procedure of Example 1, from a-phenyi-p-(3- thienyi)acrylic acid (M.p.=1 751C): pinkish crystals, M.p.=2030C (methanol-dimethyiformamide); Yield: 50%.

EXAMPLE 16

5-o.Chlorophenyi-thieno(3,2-c)pyrid-7-one (Derivative No. 16) Prepared according to the procedure of Example 1, from a-(2-chlorophenyi)P-(3-thienyi)acrylic acid (M.p.=1 960C): beige crystals, M.p.=2290C; Yield: 39%.

EXAMPLE 17 6-Phenyi-furo(3,2-c)pyrid-4-one (Derivative No. 17) Prepared according to the procedure of Example 1, from a-phenyl-p-(2- furyl)acrylic acid 50 - (M.p.=1 461C): Beige crystals, M.p.=2 1 OOC; Yield: 65%.

4 GB 2 023 599 A 4 EXAMPLE 18

6-a-Naphthyi-furo(3,2-c)pyr-id-4-one Prepared according to the procedure of Example 1, from a-(1 -naphthyl)-P- (2-furyi)acrylic acid (M.p.=219'C): Beige crystals, M.p.=230IC; Yield: 39.5%.

The results of toxicological and pharmacological investigations reported below demonstrate the 5 useful activities of the derivatives of this invention, particularly their blood-platelet aggregation inhibiting and anti-inf lammatory activities.

1. TOXICOLOGICAL INVESTIGATION The compounds according to this invention benefit from an excellent tolerance and a low toxicity.

Thus, the LD.J24 hrs/kg body weight in animals, as determined in mice by the technique according to 10 Miller & Tainter, by the oral route, is in excess of 400 mg for all derivatives.

In addiflon, the tests relating to acute, chronic, sub-chronic and delayed toxicity effected in various animal species failed to evidence any local or systemic reaction, any perturbation in the regularly effected biological control tests, or any anomaly in the microscopic and macroscopic examinations in the animals sacrificed and autopsied at the end of the experiments.

11. PHARMACOLOGICAL INVESTIGATION 1 1 Blood-platelet aggregation inhibiting activity Blood is taken from the jugular vein in Wistar rats. From this citrated blood, and after centrifugation, is reconstituted a plasma containing 600. 000 20.000 blood-platelets per MM3, which will be used in all aggregation determinations.

a) Determination ofA.D.P. -induced blood-platelet aggregation 0.4 mi plasma are placed in a siliconized tube provided with a magnet bar, which is also siliconized. The tube is introduced into an aggregometer coupled with an apparatus designed to record the optical density variations. When light transmission has reached a s ' table value, 0.5 m] of a solution containing 10 pM A.D.P. (Adenosine-Di Phosphate) are introduced into the tube.

Blood-platelet aggregation then produces an increase of the light transmission, followed by a decrease subsequent to the deaggregation stage.

The maximal variation of the optical density thus determined characterizes the intensity of the aggregation.

b) Determination of collagen-inducedblood-platelet aggregation The A.D.P. solution is substituted with a collagen (bovine tendon extract) solution.

c) Results Different groups of 20 rats are used, each group being orally administered a test derivative at a dosage of 100 mg/kg body weight. The results obtained in both tests are given in following Table i which indicates the percent inhibition of blood-platelet aggregation obtained, with respect to the control 35 group, 3 hours after treatment with the compounds of this invention, in the A.D.P. and collagen tests.

z GB 2 023 599 A 5 TABLE 1

Percent inhibition Treatment A.D.P. Collagen Derivative No. 1 62.0 91.4 No. 2 60.5 91.7 No. 3 58.8 92.0 No. 4 61.2 90.5 No. 5 62.6 91.4 No. 6 62.2 91.7 No. 7 61.7 90.6 to No. 8 60.4 92.2 Is No. 9 59.1 90.8 09 No. 10 60.4 90.2 No. 11 60.1 90.7 No. 12 60.6 91.4 No. 13 61.5 90.6 No. 14 60.8 91.2 No. 15 62.5 90.8 No. 16 60.1 90.2 No. 17 59.8 90.4 Anti-inflammatory activity a) Method of the carrageenin-induced localized edema 0.1 ml of a 1% carrageenin solution is injected in the metatarsal flexor muscles of the right rear limb of rats at time 0. The animals of the treated group are additionally orally administered 100 mg/kg 5 of the test derivative, respectively one hour prior to, simultaneously with, and 1 and 2.5 hours after injection of the phlogogenic agent. The determinations effected with a ROCH micrometer at times 0, 1 hr, 2 hrs, 3 hrs and 5 hrs after carrageenin adminstration are a measure, as a function of time, of the percent anti-inflammatory activity by comparison with the reference group.

The results obtained are reported in following Table 11:

TABLE 11

GB 2 023 599 A 6 Derivative No. 1 hr 2 hrs 3 hrs 5 hrs 1 35 39 45 49 2 37 41 46 50 3 37 40 45 48 4 41 44 48 52 38 41 46 51 6 40 43 49 52 7 40 44 48 51 8 36 39 45 59 9 38 41 46 50 41 45 51 53 11 40 44 49 52 12 36 40 46 50 13 38 42 47 50 14 38 41 47 so 39 43 48 51 16 37 41 47 50 17 41 44 49 51 b) Method of the ovalbumin-induced systemic edema 1 ml ovalburnin and 0.5 ml of a 1 % Evans Blue solution are simultaneously injected in rats by the intraperitoneal route. On the other hand, the animals of the treated group are orally administered 100 mg/kg of the test derivative 1 hour prior to and simultaneously with the ovalburnin. The intensity of the 5 penomenon thus induced is rated according to a scale from 1 to 5, as a function of the progress of the inflammatory syndrome. The mean edematous intensity and the percent decrease of the edema reaction with respect to the control group. are thus determined as a ful3ction of time The percent anti-inflammatory activity obtained 2 hrs and 3 hrs after ovalbumin injection are set forth in following Table 111.

p k i 7 GB 2 023 599 A 7 TABLE Ill il percent anti-inflammatory activity Derivative No. 2 hrs 3 hrs 1 45 52 2 48 54 3 48 55 4 47 53 50 55 6 52 58 7 48 55 8 46 53 9 46 52 49 55 51 57 in 45 52 13 46 53 14 48 54 47 53 16 46 54 17 45 51 The results of the above investigations demonstrate the good tolerance and the useful bloodplatelet aggregation inhibiting and anti-inflammatory properties of the derivatives of the formulae (1) and (11) which make them highly useful in human and veterinary medicine.

The therapeutic composition of this invention may be formulated for oval administration as tablets, coated tablets, capsules, drops and syrups. It may also be formulated for rectal administration as suppositories and, for parenterai administration, as injectable solutions.

Each unit dose contains advantageously 0.040-0.750 g active ingredient. The daily dosage regimen may vary from 0.040 g to 1.50 g active ingredient, according to the age of the patient and the condition treated.

Non-limiting Examples of pharmaceutic formulations of the therapeutic composition of this invention are given below.

1. TABLETS

Derivative No. 1 0.125 g Excipient: lactose, polyvinylpyrrolidone, alginic acid, potato starch, magnesium stearate 2. COATED TABLETS Derivative No. 4 0. 100 g Exciplent: Eudragit S, talc, magnesium stearate, gum arabic, white sugar for pharmaceuticals, white wax, carnauba wax.

3. CAPSULES Derivative No. 6 0.150 g Exciplent: magnesium stearate, talc, lactose.

8 GB 2 023 599 A a 4. INJECTABLE AMPOULES Derivative No. 12 0. 100 g Excipient: isotonic solvent, sufficient to make 3 mi.

SUPPOSITORIES Derivative No. 15 0. 150 g Excipient: Semi-synthetic triglycerides The toxicological and pharmacological investigations reported above demonstrate the low toxicity of the derivatives of this invention together with their outstanding blood-platelet aggregation inhibiting and anti-inflammatory activities.

Thus, the therapeutic composition of this invention may profitably be administered to humans, for 10 preventive or curative purposes, in the treatment of diseases which induce a pathological modification of blood-platelet aggregation, such as the thrombo-embolic diseases.

It may also be administered for its anti-inflammatory and anti-edematous properties in the treatment of all inflammatory reactions without thereby interfering with the evolution of the underlying pathological process. It is applicable in such cases as rheumatic polyarthrosis, arthrosis, coxarthrosis, 15 ankylosing spondylarthritis, gout, acute conditions of the locomotor system, in post-operative surgery and in odonto-stomatology.

Claims

1. Therapeutic composition having, in particular, blood-platelet aggregation inhibiting and anti- inflammatory activities comprising, as active ingredient, an efficient amount of a thienopyridone or 20 furopyridone derivative having the following general formulae:

0 R c At (1) Ar R -U, r 0 (11) in which X is an oxygen or sulfur atom, R represents a hydrogen or halogen atom or a C1-4 alkyl group, and Ar represents an aryl or heteroaryl group optionally substituted with at least a halogen atom or a 25 lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group.

2. Therapeutic composition as claimed in claim 1, wherein the aryl group is a phenyl or naphthyl group and the heteroaryl group is the pyridyl group.

3. Therapeutic composition as claimed in claim 1 or 2, formulateed in a form suitable for oral, parenteral or rectal administration, the active ingredient being combined with a therapeutically 30 acceptable carrier.

4. Therapeutic composition as claimed in any one of the claims 1 to 3, in unit dosage form, each unit dose containing 0.040-0.750 g active ingredient.

5. Thleno- or furopyridone derivatives having the following general formulae:

0 R lc Ar (1) m it - 0 (11) 7 in which X is an oxygen or sulfur atom, R represents a hydrogen or halogen atom or a C,-4 alkyl group, 35 and Ar represents an aryl or heteroaryl group optionally substituted with at least a halogen atom or a lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group, provided R=H, X=S and Ar=phenyl are -not simultaneously present.

6. Derivatives as claimed in claim 5, wherein the aryl group is a phenyl or naphthyl group and the 40 heteroaryl group is the pyridyl group.

7. Process for the preparation of thienopyridone or furopyridone derivatives having the following general formulae:

0 --]c (1) m R - 0 (11) in which X is an oxygen or sulfur atom, R represents a hydrogen or halogen atom or a C1-4 alkyl group, 01 9 i GB 2 023 599 A 9 and Ar represents an aryl or heteroaryl group optionally substituted with at least a halogen atom or a lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group, comprising heating within an inert solvent and at a temperature between 150C and the boiling point of the solvent selected, a compound of the following formulae (111) or (IV):

- ?ON3 R (111) er in which X, R and Ar have the above-defined meanings.

R - 1 1 U1 L 3 (IVY

8. Process as claimed in claim 7, wherein the inert solvent is selected from diphenyimethane and diphenyl ether.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1j980. Published by the Patent Office, 25 Southampton Buildings, London. WC2A 'I AY, from which copies may be obtained.