CS257299B2 - Production method of derivatives of bicyclo (4.2.%) octanes - Google Patents

Description

The invention relates to a process for the preparation of compounds of formulas 1, 2 and 3 wherein:

/ 2 /

/ 3 / n is 2 or 3,

R 6 is CH 3 OH,

R ₂ denotes hydrogen or methyl and

R ₃ represents a straight or branched alkyl having 5 to 10 carbon atoms, a group

or - (CH ₂ ) _n -phenyl wherein a is 0.1 or 2, b is 3-7, m is 0.1 or 2, and

R is a group

Q- _{x x where χ} j _e - _NHCC h ₃ or il

-NHC-CgHi ..

Compounds of formulas 7, 8 and 9 of formulas 1, 2 and 3 are prepared by deprotecting the compounds of general formulas.

/ 9 /

The term alkyl includes straight and branched hydrocarbon chains containing the specified number of carbon atoms. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl-neopentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl.

Cycloalkyl means a saturated monocyclic hydrocarbon radical having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Phenyl includes all possible isomeric phenyl radicals.

Alternatively, "or, if appropriate, means that the circumstances described may or may not occur, and thus the use of this term includes both of these eventualities.

The term treatment as used herein means treating diseases of mammals, particularly humans, and includes:

(i) prevention of disease in subjects who may have at their disposal but not yet diagnosed:

ii) inhibiting the disease, i.e., arresting its development; or iii) eliminating the disease, ie, regression of the disease.

Number system for bicycles [4.2. The octane skeleton in the scheme below is used to name the intermediates and products of the invention.

The absolute stereochemistry of carbons 1, 2, 3, and 6 and 3 'of the side chain attached to carbon atom 2 are specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon is specified by either R or S. If the compound is a racemic mixture, the stereochemistry of each chiral carbon is specified by either R * or S ^K , referring to the individual enantiomer in the racemate. In this way the relative stereochemistry is unambiguous and the racemic modification is denoted by an asterisk x. The olefin stereochemistry is designated according to the IUPACE-Z system. The classical nomenclature is used to name compounds having a triple bond such as alkynyl; two challenges coming from the same atom represent - vliden. Examples of names are given below in a preferred embodiment.

A preferred subclass of compounds of the invention includes compounds of formulas 1, 2 and 3, wherein n is 2. Another preferred subclass includes compounds of the invention wherein R 1 is linear or branched alkyl having 5 to 10, preferably 5 or 7,

Methods for preparing starting compounds and intermediates for preparing compounds of formulas 1, 2 and 3 are described in U.S. Pat. No. 257,285.

The Pt protecting group can be removed from the starting compounds of formulas 7, 8, or 9 as described in J. Amer. Chem. Soc., 94, 619 (1972) by treatment with a dilute aqueous acid such as a mineral acid, preferably sulfuric acid in acetonitrile, or with hydrogen fluoride or tetrabutylammonium fluoride in tetrahydrofuran at a temperature between 0 ° C to 40 ° C for 1 to 24 hours. The E and Z isomers prepared by the two procedures described above can be separated by chromatography.

The compounds of the invention are useful in the treatment of cardiovascular diseases; in particular, they function as vasodilators and inhibit the accumulation of cholesterol on the vascular walls and in the plasma. They are also potent inhibitors of platelet aggregation and deprive them of pro-coagulants and pro-atherosclerotic factors. Therefore, these compounds are useful in the treatment and prevention of cardiovascular diseases including atherosclerosis, thrombotic and vasopastic diseases. They can also be used as antihypertensives and cholesterol lowering agents.

The compounds of the invention exhibit a spectrum of activity similar to prostaoyclines. However, unlike prostacyclins whose therapeutic efficacy is diminished by their extreme chemical instability, the compounds of the invention maintain high biological activity because they have significantly higher chemical stability and a combination of the above properties is a prerequisite for prophylactic and / or therapeutic use especially in cardiovascular treatment. dysfunctions and diseases. Many of these compounds have selective antithrombotic effects and achieve this therapeutic effect without substantially affecting blood pressure.

Administration of the active compounds in the pharmaceutical compositions described below can be accomplished by any of the routes known for cardiovascular affecting agents. Such procedures include oral, parenteral, topical and other systemic administration.

According to the intended method, the formulations may be in the form of a solid, semi-solid or liquid dosage form, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions and the like, preferably in unitary dosage form suitable for single-dose accurate dosing. The formulations may comprise conventional pharmaceutical carriers or exipients, and the active compound of formula 1, 2 or 3, and / or a pharmaceutically acceptable salt thereof, and may further comprise other drugs, pharmaceutical agents, carriers, excipients, etc.

The present invention also provides a method of treating cardiovascular disease in a mammal which comprises administering an effective amount of the compounds of formulas 1, 2 or 3, or pharmaceutical compositions containing the compounds as active ingredients.

Pharmaceutical compositions suitable for the treatment of cardiovascular diseases are described below. These compositions contain an effective amount of the compounds of Formulas 1, 2 and 3 in an acceptable, non-toxic carrier.

The amount of active compound to be administered will of course depend on the subject being treated, the degree of the disease, the mode of administration, and the attending physician's opinion. However, the effective dose is in the range of 0.001 to 15 mg / kd / day, preferably up to 3 mg / kg / day. For a human with an average weight of 70 kg, this amount is 0.07 to 1000 mg per day, preferably 0.7 to 210 mg per day.

The novel compounds prepared according to the invention may be formulated with suitable pharmaceutical excipients known in the art for the production of effective cardiovascular preparations. In general, the effective amount of the active ingredient is about 0.001% by weight. % to about 10 wt. based on the total weight of the preparation to be prepared. The balance comprises suitable additives in an amount of from about 90% by weight. % to about 99.999 wt.

For solid preparations, conventional non-toxic solid carriers include, for example, pharmaceutically acceptable mannitol, lactose, starch, magnesium stearate, saccharin sodium, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. The active compounds mentioned above can be formulated as suppositories using, for example, polyalkylene glycols, e.g. polypropylene glycol as carrier. Liquid pharmaceutical preparations can be prepared, for example, by dissolving, dispersing, etc., the active compound as defined above and the selected pharmaceutical ingredients in a carrier such as water, saline, aqueous dextrosis, glycerol, ethanol and the like to form a solution or suspension. If desired, the pharmaceutical compositions may also contain small amounts of non-toxic additives such as wetting or emulsifying agents, pH adjusting agents and the like, for example, sodium acetate, sorbizan monolaurate, sodium triethanolamine acetate, triethanolamine acetate, and the like.

Methods for preparing these dosage forms are known or will be apparent to those skilled in the art; see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easto, Pennsylvania,

The 15th edition, 1975. The compositions or compositions to be administered will in each case contain the active compound (s) in an effective amount to alleviate the disease symptoms of the subject being treated.

Parenteral administration is generally by injection, either subcutaneously, intramuscularly or intravenously. Injectables may be in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solutions or suspensions in liquids suitable for injection, or as emulsions. Suitable additives are, for example, water, saline, dextroza, glycerol, ethanol and the like. If desired, the pharmaceutical compositions to be administered may contain a small amount of nontoxic suitable additives such as wetting or emulsifying agents, pH adjusting agents and the like such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.

More recently, parenteral administration involves implantation of a slow release or sustained release system such that a constant dose level is maintained. See, eg, US Patent No. 3,710,795.

For administration, the suppositories include conventional binders and carriers such as polyalkylene glycols or triglycerides. Suppositories may be prepared from mixtures containing the active ingredient in the range of 0.5 to 10%, preferably 1 to 2%.

The following examples serve to illustrate the invention and to illustrate it. They are by no means intended to be limiting.

Example 1

A. Preparation of methyl- (Z) -3'S, 1S, 2S, 3R, 6S / -4- [2- (3'-tert-Butyldimethylsilyloxy-3'-cyclohexylprop-1'-ynyl) -3-tert-butyldimethylsilyloxybicyclo [ 4.2.Octo-7-ylidene butyrate and related compounds.

A mixture of 0.52 g methyl- (Z) 3'-S, 1S, 2S, 3R, 6S / -4- [2- (3'-hydroxy-2'-cyclohexylprop-1'-ynyl) 3-hydroxybicyclo [4.2] o] oct-7-ylidene] butyrate, 0.55 g t-butyldimethylsilyl chloride, 0.18 g 4-dimethylaminopyridine, 2 ml triethylamine and 10 ml dichloromethane were stirred at 23 ° C for 24 hours.

After dilution with 20 ml of dichloromethane, the mixture is washed with 10 ml of water, three times with 20 ml of 1N hydrochloric acid and 10 ml of saturated sodium bicarbonate solution. After drying over sodium sulfate, 0.78 g of the title compound is obtained.

In the same way, but using other suitable esters, the following compounds are obtained:

methyl- (Z) - (3'-S, 1S, 2S, 3R, 6S) -5- [2- (3'-tert-butyldimethylsilyloxy-3'-cyclohexylprop-1'-ynyl) 3-tert-butyldimethylsilyloxybicyclo β .2. ooct-7-ylidene] pentanoate;

methyl- (Z) - (3S ^x , 1S ^X , 2S ^X , 3R *, 6S *) - 4- [2- (3'-tert-butyldimethylsilyloxy-3'-cycloprop-1'-ynyl) 3-tert. butyldimethylsilyloxybicyclo [4.2.0] oct-7-ylidene] -butyrate;

methyl- (E) - (3'S, 1S, 2S, 3R, 6S) -4- (η 2 - / 3'-tert-butyldimethylsilyloxy-3'-cyclohexylprop-1'-ynyl) -3-tert-butyldimethylsilyloxybicyclo [2.2.1] ooct-7-ylidene] butyrate;

methyl (E) - (3'S ^x , 1S ^Jt , 2S ^x , 3R ^X , 6S ^x) -4-|[2-/3'- tert -butyldimethylsilyloxy-3'-cyclohexylprop- 1'-vinyl/-3-terc. butyldimethylsilyloxybicyclo. 2. oocok-7-ylidene butyrate;

methyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -4- [2- (3'-tert-butyldimethylsilyloxy-3'-cyclopentylprop-1'-ynyl) -3-tert-butyldimethylsilyloxybicyclo] -2.2 .oJokt-7-ylidene methyl butyrate and / ZP / ^x 3'S, ^{lS! <,} 2S ^{5 <,} 3R ^*, 6S ^ste /-4-Q2"/3'-terc.butyldimetylsilyloxy-2'-cyklopentylprop-1 ' -inyl / -3-tert-butyldimethylsilyloxybicyclo [4.2]. o-oct-7-ylidene butyrate.

B. Preparation of /Z/-/3'-S,ls,2S,3R,6S/-4-j[2-/3'- tert.butyldimethylsilyloxy-3'-cyclohexylprop-l'-inyl/-3-terc Butyldimethylsilyloxybicyclo [4.2.0] oct-7-ylidene] -1-butanol and related compounds.

To a stirred mixture of 0.1 g lithium aluminum hydride in 15 ml diethyl ether was added dropwise a solution of 0.78 g methyl- (Z) - (3'S, 1S, 2S, 3R, 6S) -4-? 2- / 3'-tert. butyldimethylsilyloxy-3'-cyclohexylprop-1'-ynyl / -3-tert-butyldimethylsilyloxybicyclo [4.2]. o] oct-7-ylidene butyrate in 5 ml diethyl ether. The mixture was heated to reflux for 2 hours. After cooling the reaction mixture, 0.1 ml of water, 0.1 ml of 15% sodium hydroxide and 0.3 ml of water are gradually added dropwise. The resulting precipitate was filtered off. Evaporation of the filtrate gave 0.7 g of the title compound.

In the same manner, but using other suitable starting compounds prepared as described in paragraph A above, the following compounds were prepared:

(Z) - / 3'S, 1S, 2S, 3R, 6S / 5- (2'-3'-tert-butyldimethylsilyloxy-2'-cyclohexylprop-1'-vinyl) -3- tert -butyldimethylsilyloxybicyclo £ 4. 2.0] oct-7-yl] -1-pentanol;

/ Z / 3S ^X , 1S ^X , 2S ^X , 3R ^X , 6S ^{x /} -4-£2- / 3'- tert-Butyldimethylsilyloxy-3'-cyclopropyl- 1'-vinyl O] oct-7-ylidene-1-butanol;

/E/-/3'-S, 1S, 2S, 3R, 6S/-4-£2-/3'- tert.butyldimethylsilyloxy-3'-cyclohexylprop-1'-inyl-3- tert -butyldimethylsilyloxybicyclo 4.2.0 oct-7-ylidene-1-butanol;

(E) - (3'S-, 1S ^x , 2S ^x , 3R ^x , 6R ^x ) -4- 2- (3'-tert-butyldimethylsilylocy-3'-cyclohexylprop-1'-ynyl) -3-tert-butyldimethylsilyloxybicyclo- 4.2.0] oct-7-ylidene] -1-butanol;

/Z/-/3'-S,lS,2S,3R,6S/-4-£2-/3'- tert-butyldimethylsilyloxy-3'- cyclopentylprop-l'-inyl/-3- tert -butyldimethylsilyloxybicyclo- 4.2 . o] oct-7-ylidene] -1-butanol and (Z) - (3'S ^x , 1S ^x , 2S ^X , 3R ^X , 6S ^X) -4- $$$ 2- '3-tert-butyldimethylsilyloxy-3'- cyclopentylprop-1'-ynyl] -3-tert-butyldimethylsilyloxybicyclo [4.2.0] oct-7-ylidene] -1-butanol.

C. Preparation of /Z/- / 3'S, 1S, 2S, 3R, 6S / 4-, 2- / 3'-hydroxy-3'-cyclohexylprop- 1'-vinyl/-3-hydroxybicyclo[4.2.Ó]okt -7-ynylene-1-butanol and related compounds.

To a solution of 0.15 g of (Z / -) - 3S, 1S, 2S, 3R, 6S/-4-£2-/3- tert -butaldimethylsilyloxy-3'-cyclohexylprop- 1'-vinyl/-3- tert -butyldimethylsilyloxybicyclo [E, 4.2-oct-7-ylidene] -1-butanol in 3 ml of tetrahydrofuran was added 5 ml of 1M tetrabutylammonium fluoride in tetrahydrofuran. After 12 hours at 23 ° C, the solution is diluted with 20 ml of water and the product is extracted into diethyl ether. Evaporation of the solvent and purification of the product by flash chromatography on silica gel with ethyl acetate / hexane (1: 1) gave 0.8 g of the title compound.

In the same manner, but using the other compounds described in paragraph B of this example, the following compounds were prepared:

(Z) - / 3'S, 1S, 2S, 3R, 6S / 5-, 2- (3'-hydroxy-3'-cyclohexylprop-1'-vinyl) - 3-hydroxybicyclo-4.2.0 oct-7-ylidene-1 -pentanol;

/ Z / - / 3S ^X , 1S ^X , 2S ^X , 3R ^X , 6S ^{x /} -4-£2-/3'- Hydroxy-3'-cycloprop-1'-inyl/-3-hydroxybicycloi4.2.0 1-Oct-7-ylidene-1-butanol;

/E/-/3S,1S,2S,3R,6S/-4-£2-/3'- Hydroxy-3'-oyklohexylprop- 1'-inyl/-3-hydroxybicyclo- 4.2.2] -oct-7 -ylidene] -1-butanol;

(E) - (3-s, 1S ^X , 2S ^X , 3R ^X , 6S ^X ) -4- [2- (3'-hydroxy-3'-cyclohexylprop-1'-ynyl) -3-hydroxybicyclo] 4.2. O] oct-7-ylidene-1-butanol;

/Z/-/3š,lS,2S,3R,6S/-4-[2-/3'-hydroxy-3'-cyclopentylprop-1'-inyl/-3-hydroxybicyclo£4.2.0]okt-7- ylidene] -l-butanol A'- '/ Z / - / ^x 3'S, ^{lS> e, 5R} 2S, 3R ^!! 6S ^K / -4- [2- (3'-hydroxy-3'-cyclopentylprop-1'-ynyl) 3-hydroxybicyclo [4. 2. o] Oct-7-ylidene] -1-butanol.

Claims (1)

the subject of the invention A process for producing bicyclo [4.2.0] octane derivatives of formulas 1, 2 or 3 wherein 7 ¹ (CH) _n HO (1) / (3) n has a value of 2 or 3, denotes a group C 1 OH, R ₂ is hydrogen or methyl and R ₃ is straight or branched alkyl having 5 to 10 carbon atoms, a group of the formula "(C1-4) or - (CH3) -phenyl, wherein 2 m ^J a is 0.1 or 2, b is 3 to 7 m is 0, 1 or 2 and R is a radical of formula X, where 9 9 X is -NHCCH3 or -NHC-C8H, wherein the group is a compound of formula 7, 8 or 9. by removing the protective ⁿ 2/8 / (9) / 7) to form compounds of formulas 1, 2 or 3.