PL153995B1 - Method of pbtaining novel derivatives of 4h-benzo/4,5/ cyclohepta/1,2-b/thiophene - Google Patents

Description

PATENT DESCRIPTION

Additional patent to patent No. - Pending: 86 12 22 / P. 253162, /

Priority ____

153 995

Int. Cl.

C07D 333/80

Hm

OFFICE

PATENT

RP

Application announced: ββ 12 22

Patent description published: 1991 11 29

Inventor

The holder of the patent: Sandoz AG,

Basel / Switzerland /

METHOD OF MANUFACTURING NEW 4-H-BFNZO / 4.5 JCYKLOHEETT / -1.2-b ^ THIOPHENE DERIVATIVES

The subject of the invention is a process for the preparation of new 4H-benzo ("4,5 ycyclohepta), 1,2-b JZthiophene derivatives with pharmaceutical properties.

European patents O 035 903 and O 115 690 and in U.S. patent 4 376 124 describe certain oC5H-dibenzo (-ad) -cycloheptene-5 -ylidene / carboxylic acids with anti-inflammatory as well as having an immunotulatory effect. In Acta. Cryst. 37, 279-281 (1981) and Spanish Patent No. 497 898 describe (9,10-dihydro-4H-benzocycloheeta) -1,2-b (thiophen-4-ylidene] acetic acid as an intermediate in the synthesis of tetracyclic compounds showing the operation of the CNS / deliberate renal system. European Patent No. 0 138 763 describes certain cycloheppennS-ylidene / carboxylic dibenzoids having pharmaceutical properties, especially anti-inflammatory, antipyretic and anesthetic properties.

Y (yideene) relates to a process for the production of (2-halo-10-oxy44H-benzo (-4.5) cyclohepta) "1,2-b-7tooeene-2-yideene-ohmic acid or its physiotherapeutic hydrolyzing ester or salt.

The above compounds, esters and salts are new and have especially beneficial antipyretic as well as anti-inflammatory and anesthetic effects, described below. More specifically, the compounds show improved tolerability characteristics as compared to structurally similar compounds, e.g. as disclosed in the aforementioned European Patent No. O 138 765.

The invention relates in particular to a process for the preparation of compounds of formula I wherein R.sup.1 is hydrogen or C.sub.1-4alkyl and R.sup.1 is chlorine, or a physiologically hydrolysable and acceptable ester or salt thereof. The alkyl moieties of the compounds of formula I can be branched or straight chain. Preferably Rj is C1-4ylcloo, especially methyl.

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The term physiologically hydrolysable and acceptable ester means asters in which the carboxyl group is estryilated and which hydrolyze under physiological conditions to give a physiologically acceptable, e.g. non-toxic, alcohol in the desired donor. Such esters include, for example, esters with aliphatic alcohols having 1-4 carbon atoms.

The salts of the compounds having a value of 1 according to the invention include, in particular, the pharmaceutically acceptable salts thereof. Acceptable salts include, for example, alkali metal salts such as sodium and potassium salts, as well as alkaline earth metal salts such as calcium salts.

Compounds according to the invention in which the 10-okay group is a 10-hydroxy group, e.g. compounds of formula I in which R 1 is hydrogen, exist in keto and enolate forms, e.g. in the case of compounds of formula I as tautomers of formula I Formula 1, wherein Rg is as defined above.

It is to be understood that when tautomeric forms are present, the invention embraces both the keto and the enol forms, i.e. while the compounds produced by the process of the invention are conveniently shown only in tarred form, the invention is in no way limited by the nomeeccature or graphical representation used. . The above also applies to starting materials exhibiting kJto-θnll tautomerism.

The compounds of formula I prepared by the process of the invention exist in two cis and trans isomeric forms, i.e., as the Z and E isomers. The invention includes both the individual cis and trans isomers as well as mixtures thereof. In the description and the claims, the cis (Z) and trans (E) isomers are designated according to the conventionally referred to as CIP / Angaw. Chem. 94, 614 (1982) and Loc. cit.y. Thus, the cis isomer is the formula I isomer and the trans isomer is the formula 1. The cis (Z) isomers are generally preferred. In this connection, the predominant cis-form compounds are preferably produced by the process of the invention. More preferably they are in pure or substantially pure cis form.

The individual cis and trans isomers can be obtained by known procedures, e.g. by separating mixtures of the ci / trans isomers, e.g. as described below in Example II.

The process according to the invention for the preparation of the compounds defined above is based on the fact that (in the case of the production of the physiologically hydrolysable and acceptable ester of the acid (3-chloro-10-OKy-H-benzo), 5) (cyclohepta), of the formula Ia, where R. and Rg are as defined above, and R. is a C1-4alkyl group, is reacted with 2-chloro-10oxy-HH-benzo (4.5, 7cyclohaptr) -1.2 -b J-thiofea-4-oa, of formula II, where Rj and Rg are as defined above, with the corresponding oxycarbonylmethylenophosionate, of formula III, where Rg is as defined above, and R. and Rg are each C. ^ alkH or benzyl, b / in the case of acid formation £ 2-chj ^ or ^ o- ^ 1 ^ 0- ^ c ^ xy- ^ 4H-be ^^ <^^ 4.5 ./cy^^opta/* 1,2-b-tilphan-4-ylidinyl / acetic acid, of formula 1 as defined above, is hydrolyzed by its eater as defined above, c) in the case of the production of α-yhllro-10-hydroxy-4H-bJnzl acid ^ 4,5 ./cyk^hepta/ 1,2-b Jtiof en ^ -yaieem Jochwego or His ester C._4 alki ^ Neg o, that is the compound of Formula 1. zdJfinlowanego above, or an ester of formula Ia zdefiniowanθgo above, wherein in the above formulas 1 and la R is hydrogen, is subjected to acid £ _10/4 alkoxy Cj_ / -4H-benzo ^ 4 5 ./cycloh ^ ΐβ / ^- 1,2-b Jt iof Jn-4-ylidθnl ^ acetic or its C1-4 alkH ester, that is, a compound of chip 1, defined above or an ester of formula la zdJ, finalize pov ^^ that ^ J, but in which the formulas 1 or Ia, R. represents the group C1-4alkylooa, cleavage of eteι ^ ι ^ wJmu, d / transforms the acid into £ 2-chloro-10-oxy-4H-bβJao ^ 4.5, / cżklohepta / 1, 2-ythiophene-4 lidθno. / Acetic, formula 1, as defined above, in Its physiologically hydrolysing and permissible ester with a chip of a deionylate above, and then the obtained acid 2-yhloro-10-oxy-4H-bβenoa4 is isolated, 5. / Cyclohepta / ^- 1,2-bithiofin-4-acetic / acetic acid, of the formula (I), finalizes the carriage, in free or salt form.

Step a) can be carried out in a manner known per se, e.g. under the conditions of Homer or the like, e.g. by reacting a compound of formula II with a compound of formula III in the presence of a base such as

Like dry NaOH, with the simultaneous formation of the ylide of formula 3. The reaction is conveniently carried out in an extraneous solvent or diluent such as dimethylsulfoxide at a temperature of

153 995 ηρ · 50-120 ° C in inert atmosphere. As it should be noted, the oxycarbonyl portion of the starting oxycarbonylmethylene phosphate forms the ester portion of the end product. Suitable starting oxycarbonyl meneylenephosphonates are compounds in which the oxycarbonyl part is a physiologically hydrolyzable and acceptable ester moiety in the final product and in which the oxy part is non-hydroxy. Conveniently, the 10-oxy group on the starting material, e.g. for compounds having a number 2, the group R 20-, is other than hydroxy so as not to cause undesirable reactions at that position. Conveniently the 10-oxy group, e.g., R 5 O - in a compound of Formula 2, is C 1-4 alkoxy. When such starting materials are used, and when end products containing a 10-hydroxyl group are desired, they are obtained by applying step c /.

Process according to step b / may be carried out by any known method of hydrolysis of esters, eg. Alkaline hydrolysis, especially in the presence of hydroxide at temperatures meealu alkaUzznego of n ^p. 20 ° to re ^f Lux in the presence otioj ^ę tna ^g of ^L in a solvent ^b rozcle ^{S k} and displaceable manner, such as ethanol. The starting compound used in step b (the C1-4 alkyl ester can be prepared according to step a). Other Convenient Esters The starting compounds can be prepared analogously.

The process of step c / may be carried out using known methods for cleaving enol-ester groups, e.g. by treatment with a suitable organic or non-organic acid, e.g. a mineral acid such as ΗΗΟΟ, HCl, HBr or phosphoric acid, or with a strong organic acid such as As triflurodic acid, as well as alHetic and aromatic sulfonic acids. The reaction is conveniently carried out for example. In an inert organic solvent such as tetra ^h at a temperature of e.g. ydroforan. ² 0-70 ° C.

Converting resulting compounds of the formula 1 in a hydrolyzable and their iizJoUogicznle acceptable esters of step d / may be carried out by known eg. By reaction with a suitable diazoakkanem in an inert organic solvent, for example. StyUiwym ether at a temperature of about ⁰ to ^d -1 ^^ ° C. Gd ^y group W-Otay in related ^ę Relationship wyjśctowym is other than (lydtolts ^ eg. When the compounds of formula 1 wherein R is a C ₁ _4-alkiUiwe used EIE As compounds starting materials, esterification may be accompanied by cleavage of this group, so that when end products from this roe are desired the 10-oxy group, as a starting point, the yield may be lowered. Cleavage in the shell may, however, be limited by the choice of a suitable esterification method, e.g. via chloride. acidic As an intermediate.

The starting compounds of formula 2 used in step a / can, for example, be prepared by the reaction described in scheme 1.

The steps e (and f) can be carried out by known methods, e.g. by: a) reacting the compound of formula 4 with N-bromosuccininide, f) reacting with a C 1-4 alkanol, e.g. methanol, and then treating the obtained product with an alkali metal hydroxide, e.g. KOH , according to, for example, the procedure of Example I described below, steps ii / · The starting compounds of the number 4 are known, see, for example, Helv. Clim. Acta. 49, 214/1966 / or can be prepared analogously to known compounds.

When individual Z or E isomers of the compounds are desired, the isomer separation is conveniently carried out using the esters prepared in step a). The individual Z and E isomers of the esters can then be hydrolyzed e.g. according to step b /.

The compounds of formula (I) prepared by the process according to the invention and their physiologically hydrophobic and acceptable esters and pharmaceutically acceptable salts have pharmacological activity and are useful as pharmaceuticals.

In particular, these compounds show anti-inflammatory activity, e.g. as demonstrated by the A / Arthritis Test in rats. In this test, arthritis is induced according to the method of Pearson and Wood Arthr. Rheum ·. 2, 440 (1959). The active compounds are active in this test against the development of arthritis at doses of 5-30 mg / kg / day.

The associations also show an anti-inflammatory effect, which was demonstrated in the B / test of the fever blown UPS / E. coli / in rats. In this test, males rats / Sprague-Oawley / o weigh,

130-180 g are starved during the night. Body temperature is measured in the morning using a human probe connected to a ttletry πlometer. The animals are then injected subcutaneously with 1 ml / 150 g body weight of a heated suspension of dead E.coli (0D _g Q ₀ = 1.555 / in saline). Two hours later the temperature is taken and this value is taken as the starting temperature. Six hours after the treatment, the test animals receive an oral dose of the test compound in the form of a suspension in 0.5%.

153 995 tragacanth or only tragacanth / group of agricultural accounts /. After 2 hours, the temperature is dreamed up again. It is calculated to raise the temperature for each rat and expressed as a% average increase of ^g in relation ^D ru ^{g dust} control;) / ^K oło l, 5-2,0 ° C ^p ot normal ^^^^ J /. The EDgQ is determined by a resolution analysis as the dose at which the increase in rectal temperature is 50% relative to the control group. In this test, the compounds produced in accordance with the invention are active in doses of 15-60 mg / kg.

The compounds according to the invention also have an anesthetic effect on groans, for example, in the C / Arthritis Pain Test in rats. In this test, male OFA rats weighing 110-120 g are treated with 0.1 ml. Mycobacterium smagmatis suspension in paraffin oil / 0.6 mg Mycobbat. 0.1 ml of oil /, injected subcutaneously at the beginning of the tail. Hindpaw arthritis develops around day 12 after treatment, 30 minutes prior to test compound administration, a control measurement is performed by flexing the joint in the right or left hind foot using a Statham transducer for the voice of the rat. Rats that are not ^^ The tongue of the voice is rejected. The test substance is administered orally and causes the flexion operation after 1, 3 and 5 hours. The pressure at which voicing occurs is recorded, the value taken for each interval is the average value of three consecutive measurements. Animals with a voting threshold doubling for the control measurement are considered protected. The value of ΕΟ ^ θ at each time after Probit treatment is the dose at which 50% of the animals are protected. The compounds according to the invention are active in this test in doses of 3.2-100 mg / kg.

Due to their anti-inflammatory activity, the compounds according to the invention can be used in the treatment of inflammatory joints, e.g. for the treatment of arthritic and rheumatic diseases such as chronic involuteinitis, as well as other chronic inflammatory joints where anti-inflammatory treatment is indicated.

Due to the activity of the blood vessel, the compounds of the present invention can be used as a rolling or temperature-lowering control agent, e.g. in reducing fever associated with infectious diseases or in other cases where anti-angiitis therapy is prescribed.

Due to their analgesic effect, the compounds according to the invention can also be used as anesthetic agents, especially in the treatment of inflammatory pain.

In order to show how important the nature of the substituent in the ^ 2-position of the thiortic ring is, comparative studies of the compounds known from European Patent No. 138,765 and the compound of Example III were carried out in the rat arthritis test (AA test) and in the LPS test in rats . The tests shown in Table 1 show that the known compounds are almost inactive compared to the compound of Example 3 (the Z isomer).

T a b 1 and c a 1 Wynnets study comparators

Compound No. - - - - - 1 ED50 mg / kg p.o. - - - n 1 1 AA test, LPS test 1 - - -. 1 AND > 20 1 > 60 1 2 1 > 20 ' > 60 1 3 1 > 20, > 60 1 4 1 | ^- > 20 ' > 60 1 5 1 8 1 - W. - -. ... (·. 14 1

Compounds Nos. 1-4 are known compounds of formula I, wherein Rj is -CH6 and Rg respectively:

1. c / o / n / CH _3/2

2. -CHgOH

3. -COOH

4.- S i / CH-y / j

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Compound No. 5 is the compound of Example 3 (Z isomer), produced by the process of the invention. In addition, tests were carried out to demonstrate the superiority of the compound from Example 3 (Isomer Z) over N10-methoxy-4H-benzo (4.5) (cyclohepta) ^- 1,2-b Jthiophen-4-ylidene (acetic acid) known from European No 138 765 in the rat carrageenan paw edema test conducted as follows:

The test substance was orally administered as a suspension in saline / 0.5% tragant / 30 ml / kg / 1 hour before the injection of carrageenan. 0.1 ml of a 1% suspension of carrageenan in saline was injected sub-descending into the hind paw. A control record was taken immediately after the carrageenan injection (0 h value) and the 3 and 5 hour swellings were measured using an antiphoogometer according to Kempper and Ameen. 5 rats / Sprague-Dawley rats weighing 150-170 g / dose were used in each trial. ^ y <ni.ki obtained for animals marked with the test substance were expressed as a percentage of the results obtained for the control animals. EDgp is the dose causing 50% inhibition of carrageenan-induced edema after 3 hours.

Table 2

------------- - Ł Compound i 1 ^{Ε-50 m} 9 / ^k 9 p. °. carrageenan swelling * of paw ¹ discharged fever and LPS i ------, ------------ _r ---------------- ₇ from example III and 1 1 / zoomer Z / i 12, 14, known from EP-A-138765 ¹ 17 ¹ 20 ¹

¹ ______________- ------------ 1________________1

By the method according to the invention, the active substances can be administered by any known method, in particular by intravenous administration, in particular orally in the form of, for example, tablets or capsules. The compounds may also be administered parenterally, for example in the form of injectable solutions or suspensions.

The rates hatched for the above-mentioned uses depend on the mode of administration, the therapy desired to treat the particular condition, and the active compound employed. In general, the indicated daily dose is about 350 mg to about 1.0 g for anti-inflammatory and anti-inflammatory action and about 0.4 to about 2.0 g for anticoagulant treatment, conveniently administered once in divided doses 2-4 times daily or delayed. actions. Dosages suitable for oral administration contain from about 80 mg to about 1.0 g (anti-inflammatory and anesthetic effect) or from about 100 mg to about 2.0 g of active compound admixed with a solid or compound pharmaceutical diluent or carrier.

In connection with the uses described above, it should be emphasized that the compounds according to the invention surprisingly show a reduced side effect, in particular ulceration, compared to other non-steroidal anti-inflammatory agents. Oak already mentioned, the active compounds also show a better tolerability compared to the compounds described in European Patent No. 0 138 765. Thus, summarizing the compounds prepared according to the invention:

and / are used as active ingredients in pharmaceutical preparations, e.g. used as anti-inflammatory, antipyretic or anesthetic agents, and / are used to treat inflammation or to control or lower the temperature, or to relieve pain when such treatment is required, the treatment being by administering an anti-inflammatory, antipyretic or anesthetic effective amount of the active compounds according to the invention, and iii) ingredients of a pharmaceutical formulation in association with a pharmaceutically acceptable diluent or carrier.

The following examples illustrate the process of the invention.

Example I.

1 / Wn '' ^ o ^Γ ^ ^{^} ^ ^r ^ ^: it ethyl ester of 2-chloro-10-methoxy-4H-belzo / * 4.5. / Cyclohepta/ ^- 1,2-b J thiophene-f- ylddeno J / acetic.

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The 4.7 of phosphonoacetic acid triethyl ester is dropwise mixed with a suspension of 0.65 g of sodium hydride / 8 (% in white oil / in 25 ml of dimethyloloxide and the mixture is stirred for 15 minutes at room temperature). A solution of 3.2 g of 2 is then added. chloro-10-meeokuy4H-benzo / 4,5 J cyclohepta ^ / ^- 1,2-b Jt iofen-4-one in 120 ml of di ^ methyl ^ ohom ^ s ^ I ^ du and the mixture rea ^k c ^y jn ^ę stirred for ⁵ hours at 80 ° C and then poured into 1.7 ^{1 d} H ^ O. .n ^M Leszan ^{and E} in the water extracted with ethyl acetate, the organic layer was washed three times with water and once with brine and dried over ^ NagSO The desired ester is obtained in the form of a mixture of (Z, E) isomers after evaporation of the solvent The individual isomers are successively described in Example 11 below.

(ii) The starting compounds used in the above process are obtained as follows:

iia (2-chltro-9,10-dibtomo-9,10-dihydro-4H-binzo) ^- 4.5. / Cyclohepta / 2. 1,2-b) (thiophan-4-one.

125 g of 2-chloro-O-4H-binzo, 4,5Jfcyclohepta 1,2-b Jthiophen-4-one, 179 g of Nbromine suUcc ^ ti ^ midium and 1 g of dibenzoyl peroxide in 1.7 lCl ^ are heated in reflux for 1.5 hours, stirred for 2 hours in an ice bath and filtered. The filtrate is evaporated, the residue is mixed with 1.5 1 of hexane and filtered to give the desired compound, mp 13O-135 ° C.

iib / 2-chloro-10mmethoxy-4H-banzo / ~ 4,5_7cyclohepta / 1,2-bJthiophene-4-one.

50.8 g of the product from step iia / are suspended in 1 liter of CHgOH and refluxed for 13 hours. Then 21 g of KOH are added and the mixture is stirred for 7 hours while refluxing. After cooling, the precipitate that formed was filtered off, washed with CHgOH, HgO, and dried to give the desired compound, mp 190-194 ° C. .

Example 11. Resolution of the (Z / and / E) isomers of the β 2-chloro-10-methoxy-4H-bθnro (~ 4.5 J) / cyclohepta / 1,2-b Jliofen-4-ylidene / acetic acid ester .

The mixture of isomers obtained according to Example 1 is separated chrommtographically using silica gel 60 (Merck, 0.040-0.063 mm) and a mixture of hexane: toluene / 1: 2 / as eluent.

Rf values of isomeric products / Merck DC plates, silica gel 60 F ₂ g ₄ , coating thickness 0.25 mm, with hexane: toluane mixture / 1: 21 as eluent /:

(Z) isomer? 0.24 isomer (E?) 0.15

Example III. Ε 2-chloro-10-mitokuy-4H-bθnzo / * 4.5 Jtcyckoheit / '1,2-b Jt iofen-4-ylidene-acetic acid. 1 g of the product from example 1, the mixture of / Z / and / E / J isomers or from example 2, the individual / Z / or / E / J isomers are dissolved in 140 ml of ethanol, combined with 70 ml of 2N NaOH and heated for 3 hours while boiling under reflux. The resulting solution was evaporated to 1/3 volume and poured into 250 ml of ice water. The aqueous layer was adjusted to pH 1 by adding 4H HCl, the precipitated oead was filtered off, washed with water and dried to give the desired compound.

Oane NMR / ~ / 360 MHz / in CDClg} for individual isomers / Z / and / E /: isomer / Z / Η-Cg, s, <a 6.93

H-Cg, s. Ó> 6.16 O-CO-CH-s, d = 5.89 mp 193-1 ⁹ 6 ° C / with decomposition / isomer / E / H-Cg, s, cT = 6 , 98 Η-Cg, s, 6.23 ςΓ O-CO-CH = s, d = 5.92, and the melting point of ^9-3 and ⁹⁶ ° C / with decomposition / / CT ppm, s' singlet /.

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Claims (4)

Patent claims 1. A process for preparing a 4H-benzo / 4,5 / -cyclohept / ^- 1,2-b / t thiophene formula 1, wherein is hydrogen or a C ^ _ alki.Oową _4, and R represents a chlorine atom or a a physiologically hydrolyzable and acceptable ester or salt, characterized by reacting a compound of Formula 2, wherein Rj and Rg are as defined above, with a compound of Formula 3, wherein Rg is C1-4alkyl, R4 and Rg are each C1-4 4 alkyl or benzyl, whereupon the ester of formula Ia is formed, in which R Rg and Rg are as defined above, optionally subjected to hydroysis, or optionally compounds of the formulas 1 or Ia, in which Rg and Rg are as defined, and R5 is an alkyl group, are subjected to ether cleavage, or optionally a compound of formula I , in which R1 and Rg are as defined above, is converted to an ester of formula Ia, in which R1 'R2 Rg ^is as defined above, and the obtained compound of formula I as defined above is isolated in free or in form salt. 2. A method according to Shoot, characterized in that when preparing a compound of formula 1, wherein is mejγloo and Rg is as defined in claim 1 or a salt thereof, the ester of formula Ia, as defined in claim 1, is hydrolyzed, wherein R1 is mseyl, Rg is as defined above and Rg is C1-4alkyl, and the resulting compound of Formula I is isolated in free or salt form. * Process according to Claim 2, characterized in that in the preparation of a compound of formula 1 as defined in claim 2 or a salt thereof, in the predominantly, preferably pure or essentially pure, cis isomeric form, the ester of this compound with of formula Ia, as defined in claim 2 ', wherein said ester is predominantly in pure or substantially pure cis isomeric form. The method according to claim 2, characterized in that the cis isomeric form is isolated from the compound of formula 1 or a salt thereof obtained initially in the form of a cis / taans isomeric mixture. 153 995 COOH PATTERN 1 r ₂ II CH AND SCHEME 1 Department of Publishing of the UP RP. Circulation 100 copies Price: PLN 3,000