FI60396B - NOW THERAPEUTIC FORM OF THERAPEUTIC FORMATION OF THERAPEUTIC 4- (4-PIPERIDYLIDENE) -4H-BENZO (4,5) CYCLOHEPTA (1,2-B) THIOPHENE-10 (9H) -ONER - Google Patents

Description

«Ϋδ ^« Π rm Miv ANNOUNCEMENT ___, Λ ^ JÄT »^ (^ UTLAGGNI NGSSKRIFT 60396 ^ (45) issued 11 01 1932 ^ 1¾¾ 'Patent iceddelat v (51) Kv.lk.3 / lnt.CI.3 C 07 D 409/08 FINLAND — FINLAND (*> P »t * nuih» k «mui - P * t« narw6knin | 89/73 (22) Hak «ml * pllvi - Amaknlnssdtf 12.01.73 '' (23) Alkupllvt — Glltifh «T * dK | 12.01.73 (41) Tullut lulktoukal - Bllvlt offantllj 25.07.73

Patent and Registration Office .... . . ,,,,.

_. . . ,. ___. (44) Date of publication on the date of publication. -

Patent · oeh registerstyrelsen '' AmBlun utk ^ d och utl.skrift «n pubiicurad 30.09.81 (32) (33) (31) Pyydttty« iioikuu * —B «| Ird prlorltue 2U.01.72

Switzerland-Switzerland (CH) 985/72 (71) Sandoz A.G., Basel, Switzerland-Switzerland (CH) (72) Jean-Pierre Bourquin, Magden, Gvistav Schvarb, Allschwil,

Erwin Waldvogel, Aesch, Switzerland-Schweiz (CH) (7U) Oy Kolster Ab (5I +) A new method for the treatment of therapeutically valuable U- (U-piperidylidene) -Uh-benzo / 7 * J5 / cyclohepta / l »2-b / thiophene For the preparation of 10 (9H) -ones -Now for the preparation of therapeutically active substances U- (Up i pe ri dy 1 i den) -i + Hb en so, 5 / cy klohept a / 1,2 ~ b71 iof en —10 ( 9H) —one r

The invention relates to a new process for the preparation of therapeutically valuable 4- (4-piperidylidene) -4H-benzo / 4,57-cyclohepta [1,2-b] thiophene-10 (9H) -ones of the formula

E1 is a hydrogen atom or a 6-position chlorine or bromine atom or a 7-position chlorine atom or a methoxy group, and is an alkyl group having 1 to U carbon atoms, and for the preparation of their acid addition salts.

2 60396

According to the invention, compounds of formula I and their acid addition salts are obtained by administering 9,10-dichloro- or 9,10-dibromo-9,10-dihydro-4H-benzo / 4,57-cyclohepta / 1,2-b-thiophen-4-one. with the formula \ / \

R1 -4- I il I

wherein X is the same as above and X is a chlorine or bromine atom, react with an alcohol of formula

R3OH III

wherein R 1 is a lower alkyl group, the resulting 9-chloro or 9-bromo-9,10-dihydro-10-alkoxy-4H-benzo / 4,57-cyclohepta / 1,2-b-thiophen-4-one of formula —L tl h 1

1 [IJ Jl ____> IV

X / ^ γ wherein R 1, R 2 and X are as defined above by cleavage of a hydrogen halide of formula HX, wherein X is as defined above, 10-alkoxy-4H-benzo / 4,57-cyclohepta / 1,2-b] thiophene- To a 4-one of the formula

^ _T * B

R '—r I] In which R 1 and R 2 are as defined above, the compound of formula V obtained is reacted under Grignard reaction conditions with a Grignard compound of formula 6 0 3 9 6 3 / - \ R ..- N \ - MgHal 2 -. , wherein is as defined above and Hal is a chlorine, bromine or iodine atom to give 10-alkoxy-4- (4-piperidyl) -4H-benzo [4,5] cyclohepta / 1,2-b] thiophene-4- was whose formula is

Ri-l · I I___i | vii R 2 wherein R 1, R 2 and R 2 are as defined above, and the resulting compound of formula VII is converted by hydrolysis of the enol ether group and cleavage of the water to give a compound of formula I which is recovered as a base or acid addition salt.

The present invention relates to a chemically specific multi-step process for the preparation of 4-piperidylidene-4H-benzo / 3,57-cyclohepta / 1,2,2-thiophen-10 (9H) -ones, which compounds are described in Finnish Patent Publication No. 52,980. Finnish Patent Application No. 2386 / 72 relates to a process for the preparation of 4-piperidylidene-4H-benzo [5,5] cyclohepta [1,2-b] thiophen-10 (9H) -ones. The difference between the multi-step process of the present invention and the known processes mentioned above is that in the present process, 9,10-dihalo-9,10-dihydro-4H-benzo / 3,57-cyclohepta / 1,2-b] thiophene of formula II 4-one is initially cleaved by hydrogen halide, but is first reacted with an alkanol, and the compound of formula IV thus obtained is dehydrohalogenated. It is surprising that the alcoholysis takes place in high yield exclusively at the 10-position of the benzocycloheptathiophene ring. Reaction steps II -> IV -> V can be performed without isolating the compound of formula IV.

4 60396

Thus, the alcoholysis of a compound of formula II occurs selectively and virtually quantitatively at the 10-position of the tricycle, and not, as would be expected, at both the 9- and 10-positions, so no separation step is required to separate the valuable 10-compound from the 9-compound. This is surprising since J. Org. Chem. 15 (1950) 790-794 it is known that 2-thienyl chloride reacts more easily with an alcohol in the presence of a base than benzyl chloride. If both are treated, in equimolar amounts, with sodium amylate in the presence of amyl alcohol, 78% amyl-2-thienyl ether and 22% amylbenzyl ether are obtained.

According to Finnish patent publication 52,980, the alcoholysis is carried out after the addition of a piperidylidene group, whereby 9- and 10-enol ethers are formed, the hydrolysis of which results in a mixture of 9-keto and 10-keto derivatives which must be separated, e.g. by fractional crystallization with fumarates. The yield of such a separation is low (40% 9-ketone and 20% 10-ketone).

According to Finnish patent application 2386/72, hydrogen halide is cleaved from 9,10-dihalogen derivatives, and the formed unsaturated halides are reacted with an amine to a mixture of 9- and 10-amino derivatives in a ratio of 3: 2. In this case, too, the separation has to be carried out by fractional crystallization, and the yield is low: 30% of the 9-amino derivative and 10% of the 10-amino derivative. The Grignard reaction followed by aqueous cleavage and acid hydrolysis gives 9-ketones. The overall yield of this method is therefore also very low.

Thus, according to known methods, the compounds of the formula VI are reacted with the compounds of the formula R. ~ f ύ r "ϊ y vin in which Rj and X have the same meanings as above, the reaction products obtained are converted into the compounds of the formula

X

Rl___ ill IX

^ ----------

A

* 2 60396 5 in which R1 and X have the same meaning as above, the latter compounds are treated with potassium alcoholates, the enol ethers formed are hydrolysed, and the water is cleaved off.

A critical step in the known methods is the reaction of compounds of formula IX with alcoholates, which takes place indirectly via a triple bond to form predominantly 9-enol ether, but only small amounts of the desired 10-enol ether. No similar side reactions are observed when using compounds of formulas IV and V in the preparation of compounds of formula I.

In particular, the Grignard reaction of the compounds of the formula V with the compounds of the formula VI is excellent and gives fewer by-products than the corresponding reaction of the compounds of the formula VI with the compounds of the formula VIII.

The compounds of formulas IV and V are novel compounds.

The method according to the invention is described in more detail below.

To attach an ether group to a compound of formula II, it is reacted with compounds of formula III, conveniently by heating, preferably at reflux.

By adding silver nitrate, for example 1 mole of silver nitrate per 1 mole of the compound of formula II, the reaction can be accelerated, and the reaction then takes place at lower temperatures, for example at room temperature.

The reaction forms a compound of formula IV as a unitary reaction product: surprisingly, the ether group is practically quantitatively attached to the 10-position of the tricycle.

To convert compounds of formula IV to an enol ether of formula V, the hydrogen halide is cleaved under temporal conditions, e.g. by treating the compounds of formula IV with a solution of potassium hydroxide in an inert organic solvent such as methanol.

To carry out this process step in a practical manner, for example, a solution of a compound of formula V in a suitable organic solvent is added dropwise to a solution of a compound of formula VI in a suitable organic solvent and according to known methods and purified.

Conversion of compounds of formula VII to compounds of formula I, by hydrolysis of the enol ether group and cleavage of water, is also carried out according to known methods for the preparation of the corresponding compounds. Both reaction steps can be performed with aqueous acids.

When treating compounds of formula VII with strong acids, e.g. mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or strong organic acids such as trifluoroacetic acid, trichloroacetic acid, aliphatic or aromatic sulfonic acids, the desired final compounds are formed immediately.

The compounds of the formula I have histaminolytic properties, as shown by the results of a histamine toxicity test carried out in guinea pigs, and because of these properties they can be used in allergic diseases of various origins. The histaminolytic activity of these compounds is specific because no characteristic serotonin antagonistic and anticholinergic properties can be detected by the serotonin toxicity test and the acetylcholine toxicity test performed in guinea pigs.

Particularly interesting representatives of this class of compounds are 4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta / 1,2-thiophen-10 (9H) -one, 6-chloro and 7-chloro-4 (1-methyl-4-piperidylidene) -4H-benzo / 4,57 cyclohepta [1,2-b] thiophen-10 (9H) -one.

The compounds of formula I can also be used as starting materials in the preparation of other therapeutically active compounds.

The following examples illustrate the invention. Temperature values are in degrees Celsius.

Example 1 4- (1-Methyl-4-piperidylidene) -4H-benzo [3,57] cyclohepta [1,2-b] thiophen-10 (9H) -one a) 9-Bromo-9,10-dihydro- 10-Methoxy-4H-benzo [b, 57] cyclohepta [1,2-b] thiophen-4-one (Compound of Formula IV) 7 60396

A suspension of 20 g of 9,10-dibromo-9,10-dihydro-UH-benzo [N, 5-cyclohepta-

O

[λ, 2-b] thiophen-i + -one in 1 + 00 cm of methanol is boiled for 5 hours under reflux. 9-Bromo-9,10-dihydro-10-methoxy-1H-benzo [1,5] cyclohepta [1,2-b] thiophen-U-one is obtained (m.p. 103-106 °); yield 83% - According to microanalysis, the formula is C 2 H 2 BrO 8 S. Other analytical results: IUUCH ^ Cl ^): 16 U 0 C C = 0). % -NMR (CDCl 3): 3 »M 3) s» it, 85 (1) d (J = 5Hz), 5.5 (1) d (J = 5Hz), 7.1-7.6 (U) m; 7.75 (1) d (J = 5Hz), 8.0-8.2 (1) m.

b) 10-Methoxy-UH-benzo [5,5] cyclohepta [1,2-b] thiophen-U-one (compound of formula V)

To a solution of 17.5 g of 9-chromium-9,10-dihydro-10-methoxy-UH-benzo [Tt, 5] cycl

O

salmon / 1,2-b-thiophen-1 + -one In UOO cin methanol 9 g of potassium hydroxide are added and the solution is refluxed for 6 hours. Cool to 0-5 ° C, filter the precipitated crystals and recrystallize from methanol. In this way, pure 10-methoxy-1 + H-benzo [η 5,7] cyclohepta [1,2-b] thiophen-U-one is obtained, melting at 16-66 ° C; yield 95% · According to microanalysis, the formula is C 14 H 10 I 2 S 'Other-1: analMM "results: 1 H-NMR (CDCl 3): 3.7 (3) s; 6.2 (1) s; 7.0 -7.6 (m) m, 7.7 (1) d (J = 5Hz), 8.2-8.5 (1) m.

c) 10-Methoxy-N- (1-methyl-N-piperidyl) -1H-benzo [3,5] cyclohepta [1,2-b] thiophen-trans-ol (compound of formula VII) 3 3.07 g of iodine the activated magnesium portions are layered with 25 cm of anhydrous tetrahydrofuran and about 1/10 of a solution of 17.7 g of U-chloro-1-3 is added. ........

methylpiperidine base in 70 cm of anhydrous tetrahydrofuran. Addition of a few drops of 1,2-dibromoethane initiates the Grignard reaction. The remainder of the U-chloro-1-methylpiperidine solution is now added so rapidly that the reaction mixture boils without further heating. Finally, boil for another 1 hour at reflux. At 20 [deg.] C., 15.3 g of 10-methoxy-1H-benzo [η 5, 7-cyclohepta / 1,2-b] thiophen-1-one (for preparation, see Examples 2 and 3) are then added portionwise with slight cooling within HO minutes. After stirring at 20 ° for 1.5 hours, the reaction solution is poured into a mixture of 180 g of ice and 20 g of ammonium chloride. The free base is extracted with chloroform. The chloroform solution is concentrated and the residue is recrystallized from 270 cm of anhydrous ethanol. In this way, pure 10-methoxy-1- (1-methyl-1-piperidyl) -1H-benzo [1,7] cyclohepta [1,2-b] thiophen-1-ol base is obtained, melting at 19 DEG-196 DEG C.: in; yield 72%. According to microanalysis, the formula is C20H23NO2S * d) N- (1-methyl-N-piperidylidene) -UH-benzo [f], 5-cycloheptaZ1,2-T27thiophen-10 (9H) -one

A mixture of 3.1 g of methoxy-U- (1-methyl-U-piperidyl) -1H-benzo [1,7-cyclohepta [1,2-b] thiophene-H-ol base and 10 ml of 3-n hydrochloric acid is kept in a boiling water bath for 1 hour at 95-100 °. Finally, it is made alkaline by cooling at 20 ° with concentrated sodium hydroxide and the free base is extracted with chloroform.

8 60396

The chloroform solution is concentrated and the residue is recrystallized from ethanol / water 1: 1. In this way, a pure It-Cl-methyl-U-piperidylidene-1H-benzo [b] cyclohepta [2,2-t] thiophen-10 (9H) -one is obtained, melting at 152-153 °: in; yield 8%. According to the microanalysis, the formula is C H NOS. Other analytical results: IR (CH 2 Cl 2): 1655 (C = O); 1 H-NMR (CDCl 3): 1.9 ~ 2.9 (11) m; 3.75 (1) d (J = TH2); U, 2 (0 (J-7Hz), 7.0 (1) d (J = 2.5Hz); 7 »0-7» ^ (^) ni; 7 »5 (1) d (J = 2, 5Hz) Mass spectrum: M + = 309 ·

Example 2: 7-Chloro-t- (1-methyl-t-piperidylidene) -NH-benzo [5,7] cyclohepta [1,2-b] thiophen-10- (9H) -one a) 9-Bromo-7-chloro- 9,10-dihydro-10-methoxy-tH-benzoA, 57-cyclohepta / 1,2-b7-thiophen-U-one

A mixture of 10 g of 7-chloro-9,10-dibromo-9,10-dihydro-1H-benzo [1,5] cyclohepta [1,2-b] thiophen-t-one and 200 ml of methanol is boiled in 2b hours at reflux. The mixture is then filtered off with insoluble material and the methanol and filtrate are evaporated in vacuo. The evaporation precipitate is recrystallized from isopropanol to give the title compound, m.p. at 135-137 ° C »yield 85% · b) 7-chloro-10-methoxy-tH-benzo [5,5] cyclohepta [1,2-b] thiophen-t-one 10 g 9'-bromo-7-chloro-9,10- dihydro-10-methoxy-UH-benzo [5,5] cyclohepta [1,2-b] thiophen-t-one is refluxed with 5.2 g of 90- [potassium hydroxide] in U50 ml of methanol for 6 hours. The precipitated product is filtered at 20 ° C and recrystallized from tetrahydrofuran to give the title compound, m.p. is 216-218 ° C; yield 95% c) 7-Chloro-10-methoxy-t- (1-methyl-t-piperidyl) -NH-benzo [b] cyclohepta- [1,2-b] thiophene-t-ol

Proceed as in Example 1 c), but using 10-methoxy-UH-benzoA, 5,7-cyclohepta [1,2-b] thiophen-t-one instead of 7-chloro-10-methoxy-UH-benzo [5,7-cyclohepta] -1 2-b7tiofeeni-U-one. The title compound is obtained, m.p. is 223-227 ° C (decomposes); yield 80%.

d) 7-Chloro-N- (1-methyl-t-piperidylidene) -tH-benzo [5,5] cyclohepta [1,2-b] thiophen-10 (9H) -one

The procedure is analogous to Example 1 d), but replacing 10-methoxy-U- (1-methyl-t-piperidyl) -tH-benzo [5,5] cyclohepta [1,2-b] thiophene-U-ol 7-chloro-10-methoxy-1 + - (1-methyl-1 + -piperidyl) -1 + H-benzo [N] cyclohepta [1,2-b] thiophenyl] -1-ol to give the title compound which, after crystallization, melts at 150-151 ° C ; yield 92%.

Example 3 '· A) In analogy to Examples 1a or 2a, the following compounds of formula IV are obtained: - 9-bromo-6-chloro-9,10-dihydro-10-methoxy-1 + H-benzoA, 57-cyclohepta / 1 thiophene -oni, sp. 13 ^ -136 °; yield $ 80.99396-6,9-dibromo-9,10-dihydro-10-methoxy-1H-benzo [e, 5] cyclohepta [1,2-b] thiophenyl] ion; yield 85%, - 9-brine-9,10-dihydro-7,10-dimethoxy-1H-benzo [5,7-cyclohepta [1,2-b] thiophen-1-one; yield 90%, - 9-bromo-10-butoxy-9,10-dihydro-1H-benzo [%], 5-cyclohepta [1,2-b] thiophen-U-one, m.p. 90-91 °) and - 9-bromo-10-ethoxy-9,10-dihydro-1 + H-benzo [5,5] cyclohepta [1,2-b] thiophen-1 + -one; yield 80%.

B) In analogy to Examples 1 b) or 2 b), the following compounds of the formula IV are obtained from the compounds mentioned in A): - 6-chloro-10-methoxy-UH-benzo [ii, 57-cyclohepta [1,2-b] thiophen-ii-one , sp. 220-222 ° C; yield 90%, -6-bromo-10-methoxy-1H-benzoyl / cyclohepta / 1H-biophen-lt-one; yield 90%, -7,10-dimethoxy-1H-benzo [5,5] cyclohepta [1,2-b] thiophen-U-one; yield 90-10-butoxy-di-benzo [b], 5-cyclohepta [1,2-b] thiophen-U-one, m.p. 83 ~ 85 ° C; yield 90% and - 10-ethoxy-1H-benzo [a] cyclohepta [1,2-b] thiophen-4-one, m.p. 127 ~ 129 ° C; yield 90% C) In analogy to Examples 1 c) and 1 d), 6-chloro-U- (1-chloro-10-methoxy-UH-benzo [5,5] cyclohepta [1,2-b] thiophen-U-one) -methyl - (+ - piperidylidene) -HH-benzo [b] cyclohepta [1,2-b] thiophen-10 (9H) -one, mp 168-169 °; 90% yield (intermediate, 6-chloro-10 - methoxy-H- (1-methyl-1 + -piperidyl) -1 + H-benzo [1,5-cyclohepta [1,2-b] thiophen-1-ol, melting at 200-202 °), - 6- from bromo-10-methoxy-1H-benzo [f, 57] cyclo beta [1,2-b] thiophen-1 * -one 6-bromo-1- (1-methyl-1H-piperidylidene) -1 * H-benzo [beta], 5-cyclohepta-1,2-b7-thiophen-10 (9H) -one, mp 172-173 °, yield 90%, - 7,10-dimethoxy-1H-benzo [b, 5-cyclohepta-1,2-b] thiophene-1 -one 7-methoxy-H- (1-methyl-U-piperidylidene) -1H-benzocyclohepta-1,2-b7-thiophen-10 (9H) -one, mp 157-158 °, yield 90%, - 10-butoxy-1 + H-benzo [5 ', 5-cycloheptaZi, 2-b] thiophen-U-one from U- (1-methyl-U-piperidylidene) -1 + H-benzo [C, 57] cyclohepta [1,2-b] thiophene-10 (9H) -one, mp 152-153 °, 90% yield, and - 10-ethoxy-UH-benzo [5,7] cyclohept α, 1,2-b] thiophen-4-one from N- (1-ethyl-U-piperidylidene) -NH-benzo [5,5-cyclohepta [1,2-b] thiophen-10 (9H) -one, m.p. 113 ~ 115 ° C; yield 90%.

Example U:

In analogy to Examples 1 or 2, - 10-methoxy-1H-benzo [Ti, 57-cyclohepta [1,2-b] thiophen-1-one is obtained from 60396-4- (1-isopropyl-4-piperidylidene) -4H-benzo] 4,57-cyclohepta / 1,2-b / thiophen-10 (9H) -one, melting at 225-226 ° C of hydrogen fumarate (decomposes); yield 85% and - 10-ethoxy-4H-benzo / 4,57-cyclohepta-1,2-b] thiophen-4-one 4- (1-butyl-4-piperidylidene) -4H-benzo / 4,57-cyclohepta, 1,2 -b7thiophen-10 (9H) -one, m.p. 104-105 ° C; yield 90%.

Claims (1)

A new process for the preparation of therapeutically valuable 4- (4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene-10 (9H) -ones of the formula n E! - III vs * 2 wherein R 1 is a hydrogen atom or a chlorine or bromine atom in the 6-position or a chlorine atom or a methoxy group in the 7-position, and R 1 is an alkyl group having 1 to 4 carbon atoms, and for the preparation of their acid addition salts, characterized in that 9,10-dichloro - or 9,10-dibromo-9,10-dihydro-4H-benzo [4,57] cyclohepta [1,2-b] thiophen-4-one of the formula X ^ X s-! Wherein R 1 is as defined above and X is a chlorine or bromine atom, reacting with an alcohol of formula R 3 OH III wherein R 1 is a lower alkyl group is converted to the resulting 9-chloro or 9-bromo-9, 10-Dihydro-10-alkoxy-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-one of the formula X0Ro <> s \ I 1 '1 1 IV R1-h il II - o 12 60396 R 1, R 2 and X are as defined above, by halogenation of a hydrogen-hydrogen of formula HX, wherein X is as defined above for 10-alkoxy-4H-benzo / 4,5,7-cyclohepta [1,2-b] thiophen-4-one of formula wherein R 1 and R 1 are as defined above, the resulting compound of formula V is reacted under Grignard reaction conditions with a Grignard compound of formula R 8 -N 2 -MgHal wherein R 1 is as defined above and Hal is chlorine. , bromine or iodine atom to give 10-alkoxy-4- (4-piperidyl) 4H-benzo / 4,57-cyclohepta / 1,2-bthiophen-4-ol of the formula ° R s \ * 1-4 jj jl___l VII ^ OH S ^ r2 jos and R 1, R 2 and R 2 are as defined above, and the resulting compound of formula VII is converted by hydrolysis of the enol ether group and cleavage of the water to give the compound of formula I, which is recovered as a base or acid addition salt. 60396 13 For the preparation of therapeutically active 4- (4-piperidylidene) -4H-benzoZ, 4,57-cyclohepta / 1,2-b7thiophen-10 (9H) -one with the form In O / —'S / SN r'- 4- iii '-V. R2 color R ^ är en väteatom eller en i 6-position befintlig chloro- eller bromatom eller en i 7-position befintlig chloroatom or methoxy, ooh är en alkylgrupp med 1-4 kolatomer, ooh av deras syraadditionssalter, kännetecknat därav, att man omsätter en 9,10-dichloro- or 9,10-dibromo-9,10-dihydro-4H-benzo [4,57] cyclohepta [1,2-b] thiophen-4-one with formula χ X * -f! IO color Rj is an anhydrous betchel and X is chlorine or bromide, we are an alcohol with the form R3OH III color R is an alkyl group, which is preferably 9-chloro or 9-bromo-9.10-dihydro-10 -alkoxy-4H-benzo [3,5] cyclohepta [1,2-b] thiophen-4-one with formula X OR. R I I I IV 1— I I I