KR830001214B1 - Process for preparing benzocyclo heptapyrans - Google Patents

Abstract

Title compds. I(R1 = H, C1-4 alkanoyl; R2 = C5-10 alkyl, C5-10 alkenyl; R3 = H, CH3; Z = C2 alkylene chain), useful as hypertension treating medicine, were prepd. by dehydrating corresponding compds. I(R1 = H). Thus, (±)-6a,11a-trans-1-hydroxy-3-(1,3-dimethyheptyl)-6,6-dimethyl-9-oxo-10-ethoxy-carbony-6,6a,7,8,9,10,11,11a-octahydrobenzo≮b≉ cyclohepta≮d≉ pyran was prepd. from a mixt. of (±)-6a,10a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro dibenzo ≮b,d,≉ pyran-9-one, triethyloxonium tetrafluoroborate and ethyldiazoacetate.

Description

Method for preparing benzocyclo heptapyran

The present invention relates to a method for preparing octahydro and hexahydrobenzo [b] cyclo-hepta [d] pyranes of the general formula (I), which are therapeutic agents for hypertension.

R ¹ in the general formula is hydrogen or alkoxy having 1 to 4 carbon atoms; R ² is alkyl having 5 to 10 carbons or alkenyl having 5 to 10 carbons; R ³ is hydrogen or methyl; Z is a substituted or unsubstituted, saturated or unsaturated alkylene chain having 2 carbon atoms, which is a group selected from the following group,

R ⁴ is hydrogen or alkoxycarbonyl having 1 to 4 carbon atoms; R ⁵ is alkyl having 1 to 4 carbon atoms.

The very potent biological action of compounds with structures similar to the active ingredients of cannabis sativa L. has generated much research and interest over the past few years. Numerous chemical modifications have been made to find a cannabinoid family of compounds that have clinically useful and very potent effects, and U.S. Pat. Published with respect to benzo [b, d] pyrans, novel methods for preparing such compounds are summarized in the following document.

[Archer et al. J. Org. Chem., 42, 2277 (1977).

Much research has been done in the field of synthetic chemistry on the modification of substitution patterns of pharmacologically active dibenzo [b, d] pyrans, but there are almost duss on structural modification of the basic tricyclic nucleus of such compounds. It is not. Synthesis of B-ring homocannabinoid derivatives (eg, dibenzo [b.d] oxepin) has recently been reported in the following references. Mastsumoto et al., J. Med. chem., 20, 25 (1977); Freedman, U.S. Patent No. 3,859,306].

Likewise, benzopyran forms with 5- or 6-membered C-rings are described in US Pat. Nos. 2,972,880, 4,051,152, 4,007,207 and 4,025,630.

An object of the present invention is a 6,6,7-tree which is structurally similar to dibenzo [dd] pyran, but at the same time has a strong pharmacological effect without causing the fatal side effects observed in conventional marijuana-positive compounds. To provide a cyclic compound.

The compound of general formula (I) according to the present invention is prepared as follows.

Hexahydrodibenzo [b.d] pyran-9-one of formula (II)

(Wherein R ² and R ³ are as defined above).

In the presence of boron trifluoride or trialkyloxonium tetrafluoroborate salts and reacted with alkyl esters of 1 to 4 carbon atoms of diazoacetic acid, where Z is a partial formula (III) or (IV), wherein R ⁴ Alkoxy carbonyl); Reacting the obtained compound with an acid under hydrolysis conditions to prepare a compound of formula (I) wherein Z is partial formula (III) or (IV), wherein R ⁴ is hydrogen; Reacting the obtained compound with alkylmagnesium bromide having 1 to 4 carbon atoms to prepare a compound of formula (I) wherein Z is a partial formula (V) or (VI); The obtained compound is reacted with a dehydrating agent to prepare a compound of formula (I) of the present invention, wherein Z is a partial formula (i), (iv), (iii) or (X).

Preferred compounds are compounds of formula (I) wherein R ¹ is hydrogen and R ³ is methyl.

이고 R⁵가 메틸인 일반식(Ｉ)화합물이다.Another preferred compound is that Z is

And R ⁵ is methyl.

In a particularly preferred case of the benzocycloheptapyran according to the invention R ¹ is hydrogen, R ² is alkyl, R ³ is methyl and Z is

And R ⁵ is methyl (I).

The present invention also includes a pharmaceutical composition consisting of at least one of benzocyclo heptapi of the general formula as an active ingredient and a suitable diluent or carrier. These compositions are useful for treating anxiety, pain, depression, glaucoma and hypertension.

R¹은 수소이고, R²는 알킬이며, R³는 메틸이고, Z는 다음중에서 선택되고

R⁵는 메틸인 일반식(Ｉ)화합물과 약학적 담체로 이루어진다.Preferred compositions according to the invention,

R ¹ is hydrogen, R ² is alkyl, R ³ is methyl, Z is selected from

R ⁵ consists of a compound of formula (I) which is methyl and a pharmaceutical carrier.

The invention also includes a method of treating hypertension by administering an amount of benzocyclo-heptapyran of general formula (I) sufficient to lower blood pressure in a patient suffering from hypertension and in need of treatment or suspected of initial hypertension. do.

,R²가 알킬이고, R³가 메틸이고, Z는 다음 중에서 선택되고

,R⁵는 메틸인 일반식(Ｉ)화합물을 그의 혈압강하 유효량 투여하는 것이다.Preferred therapy according to the invention is that R ¹ is hydrogen,

, R ² is alkyl, R ³ is methyl, Z is selected from

, R ⁵ is a compound of formula (I), wherein methyl is an antihypertensive effective amount.

In General Formula (I), R ¹ is hydrogen or alkanoyl having 1 to 4 carbon atoms. The term "alkanoyl having 1 to 4 carbon atoms" refers to acyl residues of carboxylic acids having 1 to 4 carbon atoms, examples being formyl, acetyl, propynyl, n-butyryl and isobutyryl.

In the general formula, R ² is defined as an alkyl group having 5 to 10 carbon atoms or an alkenyl group having 5 to 10 carbon atoms. Such terms represent the meanings given throughout the chemical literature in dibenzopyrans. Examples of the "alkyl of 5 to 10 carbon atoms" group include n-pentyl, n-hexyl, n-heptyl, 1,1-dimethylheptyl, 1,2-dimethylheptyl, 1-ethyloctyl, 1,1-dimethyloctyl, Linear and branched alkyl groups such as 1,2,3-trimethylheptyl, 1-propylhexyl, isooctyl, n-decyl and the like. Likewise "alkenyl having 5 to 10 carbon atoms is a straight and branched chain alkenyl known in the art (e.g. 2-pentenyl, 3-hexenyl, 5-heptenyl, 1,1-dimethyl-2-heptenyl, 1 , 2-dimethyl-1-heptenyl, 2,3-dimethyl-2-heptenyl, 1-ethyl-2-octenyl, 2-ethyl-1-heptenyl, 2-mesenyl, 1-nonenyl, 1 -Methyl-1-nonenyl) and related alkenyl groups.

In the above definition of Z, R ⁴ means hydrogen or an alkoxycarbonyl group having 1 to 4 carbon atoms, and examples of the alkoxycarbonyl group having 1 to 4 carbon atoms include methoxycarbonyl, ethoxycarbonyl and isopropoxy carbonyl. And tert-butoxycarbonyl. R ⁵ means an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl n-propyl, iso-butyl, and the like.

Compounds according to the invention are named herein with respect to the general formula having the following numbering system.

In the above general formula, Z is as defined above, and the two ring carbon atoms defined by Z are numbered 9 and 10 in order as shown in the partial formula defining Z. Those skilled in the art will note that because the junctions of the rings defined as 6a, 11a are completely saturated, there may be several optical isomers oriented asymmetrically at these centers.

When naming such optical isomers, the following regulations apply.

Hydrogen atoms attached at the 6a-position are oriented in the opposite direction to hydrogen atoms attached at the 11a-position relative to the molecular plane, said molecules having a "trans" stereochemical configuration, in particular 6a, 11a-trans racemic Defined as a sieve.

It should also be noted that two optical isomers with trans coordination are possible. For example, the absolute stereochemical coordination of 6a-hydrogen atoms can be pointed downward relative to the ring plane, in which case it is referred to as 6a S-hydrogen atom.

Likewise, the 11a-hydrogen atom may be above the plane and in this case is called the 11aS-hydrogen atom.

Conversely, if the 6a-hydrogen atom is above the ring plane, it is referred to as a 6aR hydrogen atom, and if the 11a-hydrogen atom is oriented downward in the plane, it is referred to as an 11aR hydrogen atom. The two 6a, 11a-trans isomers form dl racemates or (±) isomer pairs. Likewise, both 6a and 11a hydrogen atoms may be oriented in the same direction with respect to the molecular plane, in which case these compounds are referred to as "cis" racemates, in particular as "6a, 11a-cis" racemates.

When both 6a-hydrogen and 11a-hydrogen atoms are oriented upward relative to the molecular plane, more precisely referred to as 6aR, 11aS-cis isomers, whereas when both hydrogen atoms are oriented down the plane, the 6aS, 11aR-cis isomers And these two cis isomers together form a dl racemate or (±) pair.

The absolute stereochemical configuration of the 6a and 11a positions of the benzocycleheptapyran according to the invention will not be mentioned in the following description. It is to be understood that the expression "cis" includes not only the individual mirror images of the 6a and 11a positions, but also the dl or (±) -mixture of such enantiomeric isomers in the compound having the general formula. Likewise, the term "trans" also includes separate discrete 6aS, 11aS isomers and their 6aR, 11aR enantiomers and racemates that are (±) -mixtures of these trans isomers. The specific stereochemical coordination at the 6a and 11a positions of the compounds of the present invention is determined by the stereochemical coordination of the starting materials from which these compounds are derived, since the stereochemical properties of the starting materials are maintained throughout the synthesis process.

Furthermore, since the optically active isomer alone may have little or no pharmacological activity, it is preferable to use racemates that are (±) mixtures of these isomers rather than to prepare and use each of the optically active isomers. The (±) -6a, 11a-trans isomer generally exhibits slightly higher biological activity than the corresponding (±) -6a, 11a-cis isomer. Therefore, it is preferable to prepare and use the (±) -trans-benzo [b] cyclohepta [d] pyran of the present invention. Such compounds are preferred as active ingredients in the compositions and processes of the present invention.

In the nomenclature of the compounds according to the invention, the stereochemical properties of the molecules are first indicated by (±) -trans, (±) -cis and the like. All compounds are named benzo [b] cyclohepta [d] -pyrans and the various substituents are named in the order in which they are located in the ring.

The benzo [b] cyclohepta [d] pyrans according to the invention are derived from hexahydrodibenzo [b, d] pyran-9-ones of general formula (II). These starting materials can be readily prepared according to the various synthetic methods described in the chemical literature and can be prepared with (±) -6a, 10a-cis and (±) -6a, 10a-trans-hexahydrodibenzo [b, d] pyrans. -9-ones can be prepared by the methods described in US Pat. Nos. 3,953,603 and 3,507,885. Optically active cis and trans pyranone derivatives can be prepared according to the methods described in the following references: Archer et al., J. Org. Chem. 42, 2277 (1977).

(여기서, R⁴는탄소수 1 내지 4의 알콕시카보닐이다)인 일반식(Ｉ)의 호합물인 β-케토에스테르의 혼합물이 얻어진다. 이 반응은 대표적으로는 탄소수 1 내지 4의 알킬디아조아세테이트, 촉매(트리알킬옥소늄테트라플루오보레이트 또는 삼불화붕소) 및 헥사하이로디벤조[b,d] 피란-9-온을 디클로로메탄, 클로로포름, 디클로프로판등의 할로겐화탄화수소, 디에틸에테르, 테트라하이드로푸란등의 에테르, 벤젠, 디클로로벤젠, 톨루엔등의 방향족 물질같은 적합한 불할성 용매중에서 혼합하므로써 이루어진다. 이 반응혼합물을 약 -10°내지 20℃에서 약 10분 내지 3시간동안 교반한다. 반응물질은 편리하게는 대략 동몰량으로 사용하나, 생성되는 벤조사이클로헵타피란의 수율에 큰 영향을 비치지 않는 범위에서는 어느것을 과량 사용해도 무방하다. 바람직하게는 알킬 디아조-아세테이트를 약 2 내지 3 몰과량의 디벤조피란온 및 트리알킬 옥소늄 테트라플루오로보레이트의 혼합물(1 : 3몰비)과 반응시킨다. 반응혼합물을 묽은 수산화나트륨 또는 묽은 탄산수소나트륨 같은 수성염기로 세척하면 생성물이 쉽게 분리된다. 유기층을 분리하고 감압하에서 용매를 증발시켜 제거하면, 9 및 10-위치의 기하이성체 혼합물이 반응생성물로써 얻어진다.The compounds according to the invention are prepared as follows: 1-hydroxy-3-alkyl (or 3-alkenyl) -6a, 7,8,9,10,10a-hexahydro-6H-dibenzo [b, d] The pyran-9-one is reacted with an alkyl ester having 1 to 4 carbon atoms of diazoacetic acid in the presence of trialkyloxoniumtetra fluoroborate or boron trifluoride. This diazoacetic acid ester reacts with the 9-keto group of dibenzopyranone, resulting in nitrogen evolution and at the same time the ring expands, where R ¹ is hydrogen, R ² is alkyl or alkenyl, and R ³ is hydrogen or methyl And Z is

The mixture of (beta) -ketoester which is a compound of general formula (I) whose R <^4> is a C1-C4 alkoxycarbonyl is obtained here. This reaction typically comprises alkyldiazoacetates having 1 to 4 carbon atoms, a catalyst (trialkyloxoniumtetrafluoroborate or boron trifluoride) and hexahydrodibenzo [b, d] pyran-9-one in dichloromethane, chloroform And ethers such as halogenated hydrocarbons such as diclopropane, diethyl ether and tetrahydrofuran, and mixing in a suitable insoluble solvent such as aromatics such as benzene, dichlorobenzene and toluene. The reaction mixture is stirred at about −10 ° to 20 ° C. for about 10 minutes to 3 hours. The reactants are conveniently used in approximately equimolar amounts, but any of them may be used in excess insofar as it does not significantly affect the yield of benzocycloheptapyran produced. Preferably the alkyl diazo-acetate is reacted with a mixture of about 2 to 3 molar excess of dibenzopyranone and trialkyl oxonium tetrafluoroborate (1: 3 molar ratio). The product is easily separated by washing the reaction mixture with an aqueous base such as dilute sodium hydroxide or dilute sodium bicarbonate. When the organic layer is separated and the solvent is removed by evaporation under reduced pressure, a mixture of geometric isomers at the 9 and 10-positions is obtained as reaction product.

In particular, these reactions give a mixture of 9-oxo-10-alkoxycarbonyl and 9-alkoxycarbonyl-10-oxo-octahydrobenzo [b] cyclohepta [d] pyran. These are separated into their respective components by conventional purification methods such as liquid-chromatography, fractional crystallization and high pressure liquid chromatography.

The 9-oxo-10-alkoxycarbonyl and 9-alkoxycarbonyl-10-oxo-octahydrobenzo [b] cyclohepta [d] pyrans thus prepared are not only useful as pharmacological agents, but preferably the present invention. It is used as an intermediate in the synthesis of the compound according to. Hydrolysis of these compounds, for example, results in corresponding β-keto acids, which are readily decarboxylated at elevated temperatures. Hydrolysis of the alkoxycarbonyl derivatives usually follows the method. That is, it is made to react with bases, such as acid, such as hydrochloric acid, and sodium hydroxide.

인 상기 일반식(Ｉ)로 나타내진다.Typically, 9-oxo-10alkoxycarbonyl or 9-alkoxycarbonyl-10-oxo-octahydrobenzo [b] cyclohepta [d] pyran is converted into organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, sulfuric acid, hydrochloric acid, It is dissolved in an acid containing an inorganic acid such as nitric acid or a mixture of these acids, and it is heated to about 50 to 200 ° C. for about 1 to 3 hours. The hydrolysis is most often done with an acid which acts as a solvent, but in a given case it is also possible to use an aqueous water-miscible solvent such as water or lower alkanes, if convenient. The alkoxycarbonyl moiety is converted to a hydroxy carbonyl moiety, whereby under the above reaction conditions, carbon dioxide is soon established to yield the corresponding 9-oxo or 10-oxo-octahydrobenzo [b] -cyclohepta [d] pyran. Lose. These compounds have R ¹ being hydrogen, R ² being alkyl or alkenyl, R ³ being hydrogen or methyl, Z being

It is represented by the said general formula (I) which is.

The 9-oxo or 10-oxo derivatives thus formed can be isolated simply by extracting the acidic or basic reaction mixture with a suitable water immiscible organic solvent (eg diethyl ether, dichloromethane, benzene, etc.). Removal of the organic solvent yields the corresponding 9-oxo or 10-oxo-octahydrobenzo [b] cyclohepta [d] pyran, which can be further purified by standard methods such as crystallization or chromatography if desired.

The 9-oxo and 10-oxo derivatives thus formed not only exhibit useful pharmacological activity but are also useful as synthetic intermediates, and when reacted with alkyl Grinad reagents having 1 to 4 carbon atoms, the corresponding 9-alkyl-9-hydroxy and 10-alkyl-10-hydroxy-octahydrobenzo [b] cyclohepta- [d] pyran is obtained.

As noted above, the reaction of 9-oxo and 10-oxo-octahydrobenzo cycloheptapyrans with alkylgrignard reagents having 1 to 4 carbon atoms results in the corresponding 9-alkyl-9-hydroxy or 10- according to the present invention. An alkyl-10 hydroxy-octahydrobenzo [b] cyclohepta [d] pyran is obtained.

These compounds are those in which R ¹ is hydroxy and Z is

R <^5> is represented by general formula (I) which is C1-C4 alkyl. Commonly used Grignard reagents include methylmagnesium bromide, ethyl magnesium bromide and isobutyl magnesium bromide. This reaction is carried out according to standard Grignard reaction conditions. For example, 6a, 11a-cis-1-hydroxy-3-n-octyl-9-6,6a, 7,8,9,10,11,11,11a-octahydrobenzo [b] cyclohepta [ d] 9-oxo derivatives such as pyran can be reacted with an excess of Grignard reagent (eg, 2 molar excess of n-propyl magnesium bromide). The reaction is usually carried out in an inert solvent such as tetrahydrofuran or diethyl ether, generally at a temperature of about 0 ° to 50 ° C., and the reaction is usually completed after about 10 to 20 hours. After the reaction mixture is washed with aqueous acid, the organic layer is separated and the solvent is evaporated to recover the product simply. Examples of this reaction product are 6a, 11a-cis-1-hydroxy-3-n-octyl-9-hydroxy-9-n-propyl-6,6a, 7,8,9,10,11, 11a-octahydrobenzo [b] -cyclohepta [d] pyran. It should be noted that these products are isomeric mixtures related to the 9-position. In some cases the 9-hydroxy group is oriented below the plane of the ring (ie α) and the 9-alkyl group is oriented above the plane of the ring (ie β), while in other cases the 9-hydroxy group is oriented above the plane, This is because the 9-alkyl group may be oriented down the plane. These mixtures can be separated by chromatography, if desired, or as intermediate mixtures for pharmacological use and for the synthesis of other compounds according to the invention.

Dehydration of the 9-alkyl-9-hydroxy and 10-alkyl-10-hydroxy octahydrobenzo cycloheptapyrans of the present invention affords the corresponding 9-alkyl 10-alkyl hexahydro benzocycloheptapyranes of the present invention. You can do this compound where Z is the next group,

R ⁵ is represented by General Formula (I) as described above.

Dehydration of 9-alkyl-9-hydroxy or 10-alkyl-10-hydroxy derivatives can be carried out by reaction with an acid such as sulfuric acid, methanesulfonic acid, P-toluenesulfonic acid or trifluoroacetic acid. Since water is formed, it is generally performed under anhydrous conditions. The present reaction is preferably carried out in a solvent which forms an azeotrope with water because water can be removed from the reaction mixture by distillation of the azeotrope. Representative suitable solvents are benzene, toluene and carbon tetrachloride and the like. The reaction is typically carried out in benzene in a flask equipped with a Dean Stark trap to remove water. Other methods of removing the water produced as part of the reaction can also be used, including the use of molecular sieves. The dehydration reaction is generally carried out at about 40 to 110 ° C. (boiling point of the azeotrope), and the reaction is almost complete in about 1 to 10 hours.

For example, the mixture is washed with an aqueous base to remove excess acid from the reaction mixture, the organic layer is separated and the solvent is evaporated to yield the product 9-alkyl or 10-alkyl-hexahydrobenzo [b] cyclohepta [d. Piran is easily separated. If necessary, it may be further purified by a conventional method such as chromatography.

It should be noted that all of the above-mentioned synthesis reactions are made for compounds having a 1-hydroxy group, i.e., a compound of formula (I) wherein R ¹ is hydrogen. Any 1-hydroxy compound mentioned herein can be converted to a 1-alkanoyloxy derivative wherein R ¹ is an alkanoyl having 1 to 4 carbon atoms by reacting with an acylating agent. For example, 10- such as 1-hydroxy-3-isodecyl-10-oxo-6,6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran, etc. The oxo-derivatives can be reacted with approximately equimolar amounts of acylating agents such as alkanoic acid halides or anhydrides having 1 to 4 carbon atoms to obtain the corresponding 1-alkanoyloxy-10oxo derivatives. Reduction of these derivatives as described above gives the corresponding 1-alkanoyloxy-10-hydroxy octahydrobenzo cycloheptapyran according to the invention. These 1-alkanoyloxy compounds are useful as pharmacological agents and may be converted to 1-hydroxy derivatives simply by hydrolysis with acids or bases, if necessary.

Next, typical compounds of benzocycloheptapyran and the like according to the present invention are exemplified. However, it is not limited to these.

(±) -6a, 11a-trans-1-hydroxy-3-n-hexyl-9-oxo-10-ethoxycarbonyl-6,6a, 7,8,9,10,11a-octahydrobenzo [ b] cyclohepta [d] -pyran;

(±) -6a, 11a-cis-1-hydroxy-3- (1,2,3-trimethyl-hexyl) -6,6-dimethyl-9-methoxycarbonyl-10-oxo-6,6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] -pyran;

(-)-6a, 11a-trans-1-hydroxy-3- (1-methyl-2-heptenyl) -2-isobutoxycarbonyl-10-oxo-6,6a, 7,8,9,10 , 11,11a-octahydrobenzo [b] cyclohepta [d] -pyran;

(±) -6a, 11a-trans-1-acetoxy-3- (1,2-dimethyl-octyl) -6,6-dimethyl-9-oxo-6,6a, 7,8,9,10,11 , 11a-octa-hydrobenzo [b] cyclohepta [d] -pyran;

(±) -6a, 11a-cis-1-formyloxy-3- (2-hexenyl) -10-oxo-6,6a, 7,8,9,10,11,11a-octahydrobenzo [b ] Cyclohepta [d] -pyran;

(±) -6a, 11a-cis-1-hydroxy-3-n-octyl-6,6-dimethyl-9-ethyl-9-hydroxy-6,6a, 7,8,9,10,11a- Octahydrobenzo [b] cyclohepta [d] -pyran;

(±) -6a, 11a-trans-1-isobutyoxy-3-n-heptyl-10α-hydroxy-10β-methyl-6,6a, 7,8,9,10,11,11a-octahydro- Benzo [b] cyclohepta [d] pyran;

(±) -6a, 11a-cis-hydroxy-3 (1,1-dimethyl-heptyl) -9-ethyl-6,6a, 7,10,11,11a-hexahydrobenzo [b] -cyclohepta [ d] -pyran;

(-)-6a, 11a-trans-1-hydroxy-3- (1,2-dimethyl-1-hexenyl) -6,6-dimethyl-9-n-propyl-6,6a, 7,8, 11,11a-hexahydrobenzo [b] cyclohepta [d] cyclohepta [d] -pyran;

(-)-6a, 11a-trans-1-acetoxy-3- (1-ethyl-2-methylhexyl) -6,6-dimethyl-10-isopropyl-6,6a, 7,8,11,11a -Hexahydrobenzo [b] cyclohepta [d] -pyran;

(±) -6a, 11a-cis-1-propionoxy-3-n-pentyl-6,6,10-trimethyl-6,6a, 7,8,9,11a-hexahydrobenzo [b] -cyclohepta [d] pyran;

(±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethyl-octyl) -6,6-dimethyl-9-ethyl-6,6a, 7,8,11,11a-hexa Hydro-benzo [b] cyclohepta [d] -pyran.

Octahydro and hexahydrobenzo [b] cyclohepta [d] pyrans according to the present invention are both novel compounds with useful pharmacological activity and are often useful for treating diseases occurring in the human body. The invention also relates to a pharmaceutical composition consisting of at least one compound according to the invention and one or more pharmaceutically toxic diluents, carriers or excipients. If desired, one or more pharmacologically active other drugs may be added to the composition containing the compound of the present invention.

The compositions according to the invention can be administered to mammals, in particular humans, for the purpose of treating or suppressing anxiety, depression, glaucoma, pain. Particularly preferred compositions of the present invention are compositions useful for the treatment of hypertension, which consist of an effective amount of the general formula (I) compound and a carrier. Particularly preferred compositions useful for the treatment of hypertension are those in which R ¹ is hydrogen, R ² is alkyl, R ³ is methyl and Z is

And R ⁵ is methyl and consists of a compound of the general formula (I) and a suitable carrier.

The compositions take the form suitable for the route of administration required in each particular case. According to the present invention, oral administration is preferable, and for this, the compound is used as a carrier and diluent such as textrose, lactose, mannitol, calcium silicate, potato starch, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, potassium benzoate and the like. , And related excipients.

The composition may be compressed or filled into gelatin capsules. Alternatively, the mixture may be dissolved in a liquid such as 10% aqueous solution of glucose, isotonic saline, sterile water, or the like and administered parenterally intravenously or by injection. These solutions can be lyophilized and stored in sterile ampoules, if necessary, for immediate intramuscular injection if sterile water is added and reconstituted.

Particularly preferred compositions for the treatment of human hypertension are (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,9-trimethyl-6,6a, 7,10, 11,11a-hexahydrobenzo [b] cyclohepta [d] pyran or (±) -6a, 11a, -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,9- About 100 mcg to 250 mcg of a compound such as trimethyl-6,6a, 7,8,11,11a-hexahydrobenzo [b] cyclohepta [d] pyran, or a mixture of these isomers and about 300 to 500 mg of a carrier such as sucrose or starch Is done. The composition is formulated into tablets and administered to hypertensive patients 1 to 4 tablets per day or as needed by the patient.

As already pointed out, the compounds according to the invention have several pharmacological uses. Most of these compounds show activity in standard trials for analgesic, anti-depressant and anti-anxiety activity.

Particularly preferred compounds are 9-alkyl and 10-alkyl-hexahydrobenzocycloheptapyrans, especially compounds wherein the 9-alkyl or 10-alkyl group is methyl. Although these compounds are preferred because of their biological properties, all other compounds of the present invention are also biologically useful. For example, (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-ethoxycarbonyl-10-oxo-6,6a When the, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran is analyzed by standard mouse activity test, the minimum effective dose (MED) is only 2.5 mg / kg when administered orally. .

Likewise, (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-oxo-6,6a, 7,8,9,10, In the case of 11,11a-octahydrobenzo [b] cyclohepta [d] pyran, the MED of oral administration was 5.0 mg / kg as a result of a septum lesion test in rats. As a result of testing the ability to lower blood pressure in rabbits, (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,10β-trimethyl-10α hydroxy- In the case of 6,6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran, the MED upon intravenous administration is 16 mcg / kg, whereas (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,2-trimethyl-6,6a, 7,10,11,11a-hexahydrobenzo [b] cyclohepta [d In the case of a mixture of pyran and 6,6a, 7,8,11,11a-hexahydro derivatives the MED was only 2 mcg / kg upon intravenous administration.

As can be readily seen above with regard to the biological effects, the compounds of the present invention are useful for treating hypertension, anxiety, depression, pain, glaucoma and related diseases. Thus these compounds can be used to treat animals and humans suffering from one or more of these diseases. The present invention also relates to a method for treating or preventing hypertension by administering an antihypertensive effective amount of a compound of the present invention having a blood pressure-enhancing action to a mammal suffering from hypertension and having to be treated or at risk of hypertension.

Particularly preferred methods for treating hypertension in accordance with the invention are those in which R ¹ is hydrogen, R ² is alkyl, R ³ is methyl, Z is selected from the group

R ⁵ is to administer the general formula (I) compound, which is methyl. Benzocyclo heptapyran derivatives according to the present invention having an antihypertensive effect can be administered by various routes including oral, intramuscular, subcutaneous and intravenous routes, and in the human body, the effective amount varies depending on the specific hypertension state to be treated. However, it generally ranges from about 0.1 to 10 mcg per kilogram of patient weight. A typical daily dose for treating hypertension is about 1 to 500 mcg for patients weighing about 50 to 75 kg and commonly used doses are about 50 mcg to 100 mcg.

The process for preparing benzocycloheptapyrans by the present invention is described in the following examples. However, the following examples merely illustrate the compounds included in the present invention and methods commonly used for their preparation, and do not limit the present invention thereto. In addition, unless otherwise indicated, the "theoretical value" of the mass spectrometry results in the examples are calculated based on the exact mass of the most abundant isotopes of carbon, hydrogen and oxygen, and the "measured value" is data measured by high-performance mass spectroscopy. .

Example 1

(±) -6a, 11a-trans-1-hydroxy-3- (1,3-dimethylheptyl) -6,6-dimethyl-9-oxo-10α-ethoxycarbonyl-6,6a, 7,8 , 9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran.

12.97 g of (±) -6a, 10a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6a, 7,8,9,10,10a-hexahydrodi A solution of benzo [b, d] pyran-9-one in 175 ml of dichloromethane is stirred under nitrogen atmosphere and cooled in an ice bath. To this was added 14 g of triethyloxonium tetrafluoroborate followed by 7.7 ml of ethyl diazoacetate. The reaction mixture is stirred at about 5 ° C. for 1 hour and diluted with 250 ml of 5% aqueous sodium hydrogen carbonate solution. The organic layer is separated and the water is extracted with fresh dichloromethane. The organic layers are combined, dried and evaporated under reduced pressure to remove 16.2 g of product as a red oil. The oil thus obtained is applied to a chromatography column packed with silica gel and eluted with 2% ethyl acetate in dichloromethane. The fractions identified by thin layer chromatography to contain the desired product are removed by evaporation of the solvent under reduced pressure. 5.36 g of the desired product is produced as a clear oil. The oil was crystallized from hexane and dichloromethane to give (±) -6a, 11a, trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-oxo-10α-ethoxy Carbonyl-6,6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran is obtained. Melting Point: 101-102 ° C

IR (CHCl ₃ ): 5.78 μ (C = 0 ester); 5.86μ (C = 0 ketone), H ¹ NMR (CDCl ₃ ): δ 7.82 (s, 1H); δ 4.34 (q. 2 H); 1.34 (t, 3 H);

Mass spectrometry m / e 458 (M ⁺ ); Elemental Analysis for C ₂₈ H ₄₂ O ₅

Theoretic: C 73.33 H 9.23

Found: C 73.10 H 9.44

Example 2

(±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-ethoxycarbonyl-10-oxo-6,6a, 7,8 , 9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran.

Chromatographic separation of the crude product obtained as described in Example 1 afforded a fraction containing the desired compound as a result of analysis by thin layer chromatography. Collect the appropriate fractions and remove the solvent by evaporation under reduced pressure to give 2.74 g of pale yellow oil of the desired product. This oil was crystallized from hexane to give (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-ethoxycarbonyl-10-oxo- 6,6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran is obtained.

Melting Point: 121 to 124 ° C

IR (CHCl ₃ ): 5.67 mu (C = 0 ester); 5.90 mu (C = 0 ketone), H ¹ NMR (CDCl ₃ ): δ 4.22 (q.2H); δ 1.26 (t, 3H)

Mass spectrometry m / e 458 (M ⁺ ); Elemental Analysis for C ₂₈ H ₄₂ O ₅

Theoretic: C 73.33 H 9.23 O 17.44

Found: C 73.07 H 9.05 O 17.34

Example 3

(±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-oxo-10β-ethoxycarbonyl-6,6a, 7,8 , 9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran.

1.0 g of (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-oxo-10a-ethoxycarbonyl-6,6a, A solution of 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran in 25 ml of pyridine is stored at 25 ° C. for 48 hours. The reaction mixture is diluted with water and 100 ml of ethyl acetate, and the aqueous mixture is washed twice with 200 ml of 1N hydrochloric acid each time, once with 100 ml of water and once with 50 ml of brine. After drying the remaining organic layer, the solvent was evaporated and removed under reduced pressure to yield 900 mg of product as yellow oil, which was crystallized from hexane to give (±) -6a, 11a-trans-1-hydroxy-3- (1). , 1-dimethylheptyl) -6,6-dimethyl-9-oxo10β-ethoxycarbonyl-6,6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] Piran is obtained. Melting Point: 96 ~ 98.5 ℃

IR (CHCl ₃ ): 5.78 μ (C = 0 ester); 5.86 mu (C = 0 ketone), H ¹ NMR (CDCl ₃ ): δ 4.95 (s. ¹ H); 1.23 (t, 3 H);

Mass spectrometry m / e 458 (M ⁺ ); Elemental Analysis for C ₂₈ H4 ₄₂ O ₉

Theoretic: C 73.33 H 9.23

Found: C 73.59 H 9.29

Example 4

(±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-oxo-6,6a, 7,8,9,10,11, 11a-octa-hydrobenzo [b] cyclohepta [d] pyran.

(±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-oxo-10α-ethoxycarbonyl-6,6a, 7,8 6.0 g of 9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran and the corresponding 10β-ethoxycarbonyl-derivative mixture are 800 ml of acetic acid containing 320 ml of concentrated hydrochloric acid and 100 ml of water. The solution dissolved in was stirred and heated to reflux for 2 hours. The reaction mixture is cooled to room temperature and diluted with 1 L of water. The aqueous reaction mixture is extracted three times with 200 ml of dichloromethane each time. The organic extracts are combined, washed with water, 5% aqueous sodium bicarbonate solution and brine in that order and dried. Removal of the solvent by evaporation under reduced pressure yields 4.8 g of green oil. This oil is applied on a chromatography column packed with silica gel and eluted with 3% ethyl acetate and benzene. Analysis by thin layer chromatography showed that fractions containing a single product were collected and evaporated to remove the solvent, yielding 2 g of clear oil.

The oil was crystallized from hexane to give (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-9-oxo-6,6a, 7, 8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran is obtained as white crystals.

Melting Point: 102.5 ~ 104.5 ℃

IR (CHCl ₃ ): 5.90 μ (C = 0); H ¹ NMR (CDCl ₃ ): δ 5.35 (s, 1H); δ 1.17 (s, 6H); δ 0.80 (t, 3H);

Mass spectrometry m / e 386 (M ⁺ ); Elemental Analysis for C ₂₅ H4 ₃₈ O ₃

Theoretic: C 77.68 H 9.91

Found: C 77.62 H 9.88

Example 5

(±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-10-oxo-6,6a, 7,8,9,10,11, 11a-octahydrobenzo [b] cyclohepta [d] pyran.

3.3 g of (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-2-ethoxycarbo according to the overall process described in Example 4 Neil-10-oxo-6,6a, 7,8,9,11,11a-octahydrobenzo [b] cyclohepta [d] pyran dissolved in acetic acid, water and concentrated hydrochloric acid was heated under reflux for 2 hours, and Stir.

The product was isolated, purified by chromatography and crystallized from methylcyclopropane and dichloromethane (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl- 10-oxo-6,6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran is obtained as white crystals.

Melting Point: 81.5-83.5 ℃

IR (CHCl ₃ ): 5.95 μ (C = 0); H ¹ NMR (CDCl ₃ ): δ5.92 (s, 1H); δ 1.17 (s, 6H); 0.82 (t, 3 H);

Mass spectrometry m / e 386 (M ⁺ ); Elemental Analysis for C ₂₅ H4 ₃₈ O ₃

Theoretic: C 77.68 H 9.91

Found: C 77.56 H 10.18

Example 6

(±) -6a, 11a-trans-1,10α-dihydroxy-3- (1,1-dimethylheptyl) -6,6,10β-trimethyl-6,6a, 7,8,9,10,11 , 11a-octahydrobenzo [b] cyclohepta [d] pyran.

10 ml of a 3-mol solution in which methyl magnesium bromide was dissolved in 10 ml of anhydrous diethyl ether was refluxed, and 1.051 g of (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) was added thereto. ) -6,6-dimethyl-10-oxo-6,6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran dissolved in 40 ml of anhydrous diethyl ether Add dropwise over 10 minutes. The mixture is heated to reflux for 18 hours with stirring and cooled to room temperature, and then diluted with 100 ml of 0.1 N hydrochloric acid solution which has been cooled to 0 ° C. in an ice bath. 1N hydrochloric acid was added dropwise to the reaction mixture to adjust the pH to 5, the organic layer was separated, and the aqueous layer was extracted with 50 ml of fresh diethyl ether.

The combined organic layers were washed twice with 100 ml of water each time, once with 50 ml of brine, dried and evaporated under reduced pressure to give 804 mg of white foamy material. This is applied to a chromatography column packed with silica gel and eluted with a concentration gradient from 2% to 3% using acetonitrile in dichloromethane. Fractions confirmed to contain a single component by thin layer chromatography were collected and the solvent was removed by evaporation under reduced pressure to yield 649 mg of white foam. It is crystallized from hexane to give (±) -6a, 11a-trans-1,10a-dihydroxy-3- (1,1-dimethylheptyl) -6,6,10β-trimethyl-6,6a, 7,8, 9,10,11a-octahydrobenzo [b] cyclohepta [d] pyran is obtained. Melting point 113-115 ° C

UV (CH ₃ OH) λ _max 208 (ε = 50187); H ¹ NMR (CDCl ₃ ); δ 1.20 (s, 6H); δ 0.83 (t, 3 H).

Mass spectrometry m / e 402 (M ⁺ ); Elemental Analysis for C ₂₆ H ₄₂ O ₃ .

Theoretic value: C, 77.56; H, 10.52

Found: C, 77.62; H, 10.33

Example 7

Rechromatography of the crude product obtained as described in Example 6 yields a fraction containing a single component different from the product of Example 6. The fractions were combined and the solvent removed to remove 56 mg of (±) dl-6a, 11a-trans-1,10β-dihydroxy-3- (1,1-dimethylheptyl) -6,6,10α-trimethyl-6, 6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran is obtained as a white solid.

H ¹ NMR (CDCl ₃ ); δ 4.95 (s, 1H); δ 1.19 (s, 6H); δ 0.83 (t, 3 H).

Mass spectrometry of C ₂₆ H ₄₂ O ₃

Calc .: 402.31338; Found: 402.31316

[Examples 8 to 9]

(±) -6a, 11, a-trans-1,9α-dihydroxy-3- (1,1-dimethylheptyl) -6,6,9β-trimethyl-6,6a, 7,8,9,10 , 11,11a-octahydrobenzo [b] cyclohepta [d] pyran and (±) -6a, 11a-trans-1,9β-dihydroxy-3- (1,1-dimethylheptyl) -6, 6,9α-trimethyl-6,6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran.

9.7 ml of a 3-mol solution in which methylmagnesium bromide was dissolved in 20 ml of diethyl ether was refluxed, and 957 mg of (±) -6a, 11a-trans-1-hydroxy-3- (1) was added to 40 ml of diethyl ether. , 1-dimethylheptyl) -6,6-dimethyl-9-oxo-6,6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran Apply over minutes. The reaction mixture is heated to reflux for 12 hours with stirring. It is cooled to room temperature and poured into 50 ml of ice water. 1N hydrochloric acid was added to the cooled aqueous reaction mixture to adjust the pH of the solution to 7, the organic layer was separated, and the aqueous layer was extracted with 50 ml of fresh diethyl ether. The organic layers are combined, washed once with 50 ml of brine once with 100 ml of water and dried. Evaporation of the solvent under reduced pressure yields 943 mg of a clear oil. Crystallization from acetonitrile and dichloromethane gave (±) -6a, 11a-trans-1,9α-dihydroxy-3- (1,1-dimethylheptyl) -6,6,9β-trimethyl-6,6a, A white crystal of 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta [d] pyran is obtained. Melting Point: 155.5 ~ 157 ℃

UV (CH ₃ OH) λ _max 209 (ε = 44012); H ¹ NMR (CDCl ₃ ); δ 4.91 (s, 1H); δ 1.17 (s, 6H); δ 0.82 (t, 3 H).

Mass spectrometry m / e 402 (M ⁺ ); Elemental Analysis for C ₂₆ H ₄₂ O ₃

Theoretic value: C, 77.56; H, 10.52

Found: C, 77.29; H, 10.28

The solvent is evaporated under reduced pressure, the crystallized filtrate is concentrated to dryness, the residue is applied to a chromatography column filled with silica gel and 5% methane in dichloromethane is eluted into the solution. Collect thin fractions containing single components by thin layer chromatography and evaporate to remove 50 mg of (±) -6a, 11a-trans-1,9β-dihydroxy-3- (1,1-dimethylheptyl)- 6,6,9α-trimethyl-6,6a, 7,8,9,10,11,11a-octahydrobenzo [b] cyclohepta (d] pyran is obtained as a white solid.

UV (CH ₃ OH) λ _max 209 (ε = 44012); H ¹ NMR (CDCl ₃ ); δ 6.04 (s, 1 H); δ 1.18 (s, 6H); δ 0.84 (t, 3 H).

Mass spectrometry for C ₂₆ H ₄₂ O ₃

Theoretic value: 402.31338; Found: 402.31316.

Example 10

(±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,9-trimethyl-6,6a, 7,8,11,11a-hexahydrobenzo [ b) cyclohepta [d] pyran and (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,9-trimethyl-6,6a, 7,11 , 11a-hexahydroxybenzo [b] cyclohepta [d] pyran.

(±) -6a, 11a-trans-1,9α-dihydroxy-3- (1,1-dimethylheptyl) -6,6,9β-trimethyl-6,6a, 7,8,9,10,11 100 mg of a mixture (50:50) of 11a-octahydrobenzo [b] cyclohepta [d] pyran and the corresponding 9β-hydroxy-9α-methyl compound was added to 100 ml of benzene containing 100 mg of p-toluenesulfonic acid. The dissolved solution is stirred and then heated to reflux in a flask equipped with a Dean Stark trap to remove water. The reaction mixture was heated to reflux for one hour, cooled to room temperature and washed twice with 50 ml of water and once with 25 ml of 5% aqueous sodium hydrogen carbonate solution. The organic layer is separated, dried and evaporated to remove the solvent under reduced pressure to give the crude product as a brown oil. This oil is applied to a chromatographic column filled with fluorosilic acid and eluted with a 2% diethyl ether solution in petroleum ether to purify it. Thin layer chromatography results in the collection of fractions containing the main component and removal of the solvent (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,9-trimethyl- 6,6a, 7,8,11,11a-hexahydro [b] cyclohepta [d] pyran and the corresponding 6,6a, 7,10,11,11a-hexahydrobenzo [b] cyclohepta [d] A mixture of pyrans is obtained.

H ¹ NMR (CDCl ₃ ); δ 4.9 (s, 1H); Mass spectrometry for δ 1.7 (s, 3H); C ₂₆ H ₄₀ O ₂ .

Theoretical Value: 384.30281 Found: 384.30181

Example 11

(±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,10-trimethyl-6,6a, 7,8,11,11a-hexahydrobenzo [ b] cyclohepta [d] pyran and (±) -6a, 110-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,10-trimethyl-6,6a7,8,9 , 11a-hexahydrobenzo [b] cyclohepta (b] pyran.

(±) -6a, 11a-trans-1,10α-dihydroxy-3- (1,1-dimethylheptyl) -6,6,10β-trimethyl-6,6a7, according to the overall process of Example 10. 75 ml of a mixture of 500 mg of a mixture of 8,9,10,11,11a-octahydrobenzo [b] -cyclohepta [p] pyran and the corresponding 10β-hydroxy-10α-methyl compound and 50 mg of p-toloenesulfonic acid were obtained in 75 ml. React in benzene. The reaction mixture is completed in a conventional manner and the crude product is purified by chromatography on fluorosil (eluent: 2% diethyl ether solution in petroleum ether). Collect the appropriate fractions and concentrate to dryness (±) -6a, 11a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,10-trimethyl-6,6,7,8, A mixture of 11,11a-hexahydrobenzo [b] cyclohepta [d] pyran and a corresponding 6,6a, 7,8,9,10,11a-hexahydrobenzo [b] cyclohepta [d] pyran is obtained. .

H ¹ NMR (CDCl ₃ ); δ 4.9 (s, 1H); δ 2.4 (s, 3H); Mass spectrometry for C ₂₆ H ₄₀ O ₂ .

Theoretical Value: 384.30281 Found: 384.30234

Example 12

Compositions suitable for treating hypertension according to the present invention have the following composition:

(±) -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,9-trimethyl-6,6a, 7,10,11,11a-50 mcg hexahydrobenzo [b] cyclo Hepta [d] pyran.

(±) -trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,9-trimethyl-6,6a7,8,11,11a-hex 50 mcg Sahydrobenzo [b] cyclohepta [d] pyran.

Polyoxyethylene sorbitan monooleate 50mcg

250 mg starch powder

The ingredients must be thoroughly mixed and can be filled into empty gelatin capsules. In the human body, such capsules may be administered orally 1 to 4 times a day to treat hypertension.

Claims (1)

A method for preparing hexahydrobenzo [b] cyclohepta [d] pyran of formula (I), wherein the compound of formula (Ia) is reacted with a dehydrating agent.

R ¹ is hydrogen or alkanoyl having 1 to 4 carbon atoms, R ² is alkyl having 5 to 10 carbon atoms or alkenyl having 5 to 10 carbon atoms, R ³ is hydrogen or methyl, and Z is a group selected from

Z in general formula (Ia) is

Wherein R ⁵ is alkyl having 1 to 4 carbon atoms.