DE2536509A1 - BENZOCYCLOHEPTENE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

Benzocycloheptene derivatives, processes for their preparation and pharmaceuticals containing them

The invention relates to new and valuable benzocycloheptene derivatives the formula

in the R ^, an optionally substituted amino group, a lower alkyl radical substituted by a hydroxyl group or an optionally protected hydroxyl group, Rp is an optionally protected hydroxyl group, R ^ is hydrogen or an optionally substituted one Hydrocarbon radical and their salts. The compounds according to the invention have excellent pharmacological properties Effects, e.g., a potent bronchodilator effect, and are valuable for human therapy, e.g. for the treatment of asthma.

As medicines for the treatment of asthma, Isoproterenol and Metaproterenol are widely used, both of which have a stimulating effect on the ß-Re-

Telephone: (02 21) 23 45 41 - 4 Telex: 888 2307 dopa d - Telegram: Dompatent Cologne

60981271006

-Z-

2536503

have receptors of the adrenergic system. True, isoproterenol has a bronchodiatal effect, which is related to the ß "-receptors of the adrenergic system should, however, due to its strong cardiac stimulation, which is associated with the ß ^ -receptors of the adrenergic system supposed to be related to strong side effects.

This situation was a strong incentive for inten- sive ■ research by the applicant, the 'mation in the synthesis of new compounds (I) culminated who have a strong bronchodiiatatorische effect, yet only moderate or practically free from side effects, by stimulating of the ß ^ -receptors of the adrenergic system.

The invention accordingly relates to the compounds (I) and their salts, which are used as medicaments for treatment from asthma are valuable. The invention also relates to a process for the preparation of the new compounds (I) and its salts addressed.

In the formula (I), the optionally substituted amino group for which R ₁ stands can be an amino group, a monosubstituted or disubstituted amino group. As mono- or disubstituted amino groups, for example: methylamino, ethylamino, isopropylamino, benzylamino, dimethylamine, diethylamino, N-benzyl-N-methylamino, formylamino, acetylamino, propionylamino, N-methyl-N-formylamino, N-methyl-N -acetylamino, N-Methy1-N-trifluoroacetylamino, N-Benzoy1-N-methy1amino, N-Benzyloxycarbonyl-N-methylamino, methanesulfonylamino, ethanesulfonylamino, N-methy1-N-methanesulfonylamino, N-benzoxycarbonyl-N-methanesulfonyl, N-benzoxycarbonyl-N-methanesulfonylamino, methanesulfonyl-N-methanesulfonylamino, ! amino, propoxycarbonylamino, butoxycarbonylamino, carbamoylamino, methylcarbamoylamino and ethylcarbamoylamino. Of these, amino groups are advantageous, with lower alkyl radicals singly or twice substituted

609812/1006

ated amino groups (where the lower alkyl radical is advantageously a radical with up to 3 carbon atoms, e.g. methyl, ethyl, n-propyl and isopropyl) or monoacylamino groups (e.g. formylamino, acetylamino, methanesulfonylamino, methoxycarbonylamino, carbamoylamino and methylcarbamoyl- ¹ amino) , especially amino groups or with lower j

i alkyl radicals monosubstituted amino groups (advisable

Amino groups with a lower alkyl radical with up to

are substituted to 3 carbon atoms, e.g. methylamino, ethyl-; amino, n-propylamino and isopropylamino).

The lower alkyl radical substituted with hydroxyl groups, for which R ^ in the formula (I) stands, can be a straight-chain or branched alkyl radical with up to 6 carbon atoms, expediently with up to 3 carbon atoms, e.g. methyl, ethyl, n-propyl and isopropyl. Of these, methyl and ethyl radicals, in particular the methyl radical, are preferred. The above-mentioned lower alkyl radical can have one or more hydroxyl groups in any positions be substituted. A lower alkyl radical substituted by a hydroxyl group, e.g. hydroxymethyl, is expedient. 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyisopropyl and 2-hydroxyisopropyl. Of these, hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl, especially Hydroxymethy1.

When the hydroxyl group R ^. protected in formula (I) Any groups capable of protecting the hydroxyl group R ^ are suitable as protecting groups. as Examples of suitable protective groups may be mentioned: lower alkyl radicals with expediently up to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, tert-pentyl and n-hexyl), lower alkenyl radicals, the suitably contain up to 6 carbon atoms (e.g. vinyl and allyl), lower alkynyl radicals, which suitably contain up to

60 £ 812/1008

- 4 - 2538509

Contain 6 carbon atoms (e.g. ethynyl and propargyl), lower cycloalkyl radicals advantageously with a 3- to 7-membered Ring (e.g. cyclopentyl and cyclohexyl), substituted lower alkyl radicals (e.g. methoxymethyl and butoxymethyl), Aralkyl radicals (e.g. benzyl, α-methylbenzyl, 4-methylbenzyl, diphenylmethyl and trytyl), phenacyl (Phenacyl, p-bromophenacyl, etc.), of carboxylic acids, sulfonic acid, Acyl residues derived from carbonic acid or carbamic acids (e.g. formyl, acetyl, propionyl, butyryl, 2-methyi-2-butenoyl, monochloroacetyl, dichloroacetyl, Trifluoroacetyl, benzoyl, toluyl, mesitoyl, 4-chlorobenzoyl 3-benzoylpropanoyl, xanthene-9-carbonyl, benzenesulfonyl, Toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, Benzyloxycarbonyl, tert-butyloxycarbonyl, isobornyloxycarbonyl, Carbamoyl and trichloromethylimidoyl), silyl (e.g. trimethylsilyl), ester residues of inorganic acids (e.g. ester residues of nitrous acid, sulfuric acid, Boric acid, dibenzoylphosphoryl, p-nitrobenzylphosphoryl and p-bromobenzylphosphoryl), pyranyl, tetrahydropyranyl, tetrahydrofuranyl, thiopyranyl, 4-methoxytetrahydropyran-4-yl and 2-nitro-4-methoxyphenylthio.

If the hydroxyl group for the R "in the formula (I) is protected, the protecting group can be any of the protecting groups described above in connection with the hydroxyl group for which R ^ stands and which also can be protected, were named. The protective groups at R. and Rp can be bonded to one another and as those protecting hydroxyl groups.

Examples of such combined protective groups are: Lower alkylidene radicals (e.g. methylidene, ethylidene, Propylidene, isopropylidene, butylidene, pentylidene and hexylidene), substituted lower alkylidene radicals (e.g. 1-methoxyethylidene, 1-ethoxyethylidene, benzylidene (Phenylmethylidene), diphenylmethylidene, phenetylidene, 1-phenylethylidene, acetylisopropylidene, oxomethylidene,

609812/1006

Iminomethylidene and thioxomethylidene).

As an optionally substituted hydrocarbon residue, for which R- in the formula (I) is, for example: Straight-chain or branched lower alkyl radicals with advantageously up to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, 1-methylpropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 1,3-dimethylbutyl, 1,1-dimethylpropyl and 1-ethyl-1-methylpropyl), lower alkenyl radicals, advantageously those with up to 6 carbon atoms (e.g. vinyl, 2-propenyl, 2-butenyl, 1,3-dimethyl-2-butenyl, isopropenyl, 1,1-dimethyl-2-propenyl, Pentenyl, hexenyl and allyl), lower alkynyl radicals, advantageously those with up to 6 carbon atoms (e.g. Ethynyl, propargyl, 1-ethyl-1-methyl-2-propynyl and 1,1-dimethyl-2-propynyl), cycloalkyl radicals, are advantageous those with a 3- to 7-membered ring (e.g. cyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methyl- cyclobutyl, 2-methylcyclohexyl and cycloheptyl), cycloalkenyl radicals, preferably those with a 3- to 7-membered ring (e.g. 1-cyclopentenyl, 2-cyclopentenyl, 1-cyclobutenyl, 2-cyclobutenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl and 2-cycloheptenyl), aralkyl radicals (e.g. benzyl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, a-methylbenzyl, a-ethylbenzyl, a-Methy1phenäthyl, a-Ethylphenäthyl, α, ß-Dimethylphenäthyl, α, α-Dimethylphenäthyl and a-Ethyl-a-methylphenäthyl), Aralkenyl residues (e.g. styryl, 3-phenyl-2-propenyl, 3-phenyl-1-methyl-l-propenyl, a-Methylstyryl and a, ß_Dimethylstyryl), Aryl residues (e.g. phenyl, tolyl and naphthyl), Cycloalkylalkyl radicals whose cycloalkyl radical advantageously has a 3- to 7-membered ring (e.g. cyclohexylmethyl, 1-cyclohexylethyl, 3-cyclohexyl-1-methylpropyl and 4-methylcyclohexylmethyl) and cycloalkenyl-alkyl radicals, whose cycloalkenyl radical advantageously has a 3- to 7-glie-

609812/1006

third ring (e.g. 1-cyclohexenylmethyl). Particularly Of these, lower alkyl radicals with up to 4 carbon atoms (e.g. methyl, ethyl, isopropyl and tert, —butyl), cycloalkyl radicals with a 3- to 7-glie— drigen ring and aralkyl and cycloalkyl-alkyl radicals whose cyclic parts are replaced by 2 or 3 carbon atoms from -NH-in NHR-. are separated.

The lower alkyl radicals mentioned and the alkyl parts of the aralkyl and aralkyl groups mentioned are particularly preferred Cycloalkyl-alkyl radicals with the branching part in the α-position to the NH group.

Examples of suitable substituents on the hydrocarbon radicals mentioned above are hydroxyl groups, lower alkoxy radicals (e.g. methoxy, ethoxy, propoxy and butoxy) and halogen atoms (e.g. chlorine, bromine, iodine and Fluorine).

The compounds (I) can be prepared by various methods such as the following methods will:

Procedure 1

The compounds (I) and their salts can be prepared by reducing compounds of the formula

(II)

in which R ^ is an optionally substituted amino group, a lower alkyl radical substituted by hydroxyl groups, a group reducible to one of these groups or an optionally protected hydroxyl group, R _? an optionally protected hydroxyl group, A. a group of the formula -NHR., (in which R- has the abovementioned

609812/1006

has meaning) or a group reducible to -NHR., and X is a group of the formula> C = O or> CH-OH with the proviso that in cases in which A. is a group of the formula -NHR ₃ , X stands for> C = O.

Procedure 2

Of the compounds (I), the compounds in

4 where R _{3 is} a group of the formula R

is (in which R. is hydrogen or a lower alkyl radical and R [- is hydrogen or an optionally substituted hydrocarbon radical, including the case in which R. and R _1. together with the adjacent carbon atom form a ring group), ie compounds of the formula

HHCH \ (I ¹ )

in which R ^, Rp, R ₄ and R ^ have the meanings given above, and their salts by reduction of compounds of the formula

^R l

(III)

in which R ^ and R p are as defined above, Ap an amino group or a reducible to an amino group and X is a group of formula> C = O or> CH-OH, 9 ^e nwart in G of the formula ^e a Cärbonylverbindung

609812/1006

(IV)

in which R. and R ^ have the meanings given above, j getting produced.

Procedure 3

The compounds (I) and their salts can be prepared by hydrolysis of compounds of the formula

(ν) b κ ³

in which R _{1 is} an optionally substituted amino group, a lower alkyl radical substituted by hydroxyl groups, a group hydrolyzable to one of these groups or an optionally protected hydroxyl group and Rp and R ^ have the meanings given above.

Procedure 4

The compounds (I) and their salts can be prepared using compounds of the formula

_(VIJ

OZ-. ^X NE-, ¹ x 5

^Z 2

subjected to a reaction to remove the protective group or groups. In the formula (VI) are R>. an optionally substituted amino group, a lower alkyl radical substituted with hydroxyl groups, one convertible to these groups by a reaction to remove the protecting group or groups

1006

Group or an optionally substituted hydroxyl - j

group, R- and -OZ ₁ optionally substituted hydroxyl groups and Ζ «hydrogen or a protective group, while R, has the meaning given above with the proviso that at least one protective group is included in the formula.

If R. in the formulas (II) and (III) represents an optionally substituted amino group, a lower alkyl radical substituted by hydroxyl groups or an optionally substituted hydroxyl group, then the _{corresponding groups mentioned above for R 1} as examples are suitable . If R ^ is a group that can be reducible to an optionally substituted amino group, or a lower alkyl radical substituted by hydroxyl groups, the following groups come into consideration: The group that can be reducible to the optionally substituted amino group is, for example, a nitro group, nitroso, hydroxylamino, mono- or disubstituted hydroxylamino (N-substituted, O-substituted or Ν, Ο-disubstituted hydroxylatnino groups, where the substituents of N are, for example, the substituents of the substituted amino groups mentioned above in connection with R ^ and as substituents of O, for example, lower alkyl radicals, aralkyl radicals and Acyl radicals come into question), diazo, azido, phenylhydrazono, a group of the formula -N = B (where B is a divalent group which corresponds to the substituents of the substituted amino groups mentioned above for R ^). The group that can be reducible to the lower alkyl radical substituted by hydroxyl groups is, for example, an ether group / e.g. aralkyl ethers (e.g. benzyl ether and triethyl ether) _ 7 or an ester group, e.g. an ester group derived from carboxylic acids, carbamic acids or carbonic acid (e.g. acetyl ester, propionyl ester, trifluoroacetyl ester, monochloroacetyl ester)

609812/1006

ester, benzoyl ester, mesitoyl ester, 4-chlorobenzoyl ester, 3-benzoylpropanoyl ester, benzyloxycarbonyl ester, isobornyloxycarbonyl ester and carbamoyl ester) attached to the hydroxyl group or to those mentioned above for R., lower alkyl radicals substituted with hydroxyl groups are formed, alkoxycarbonyl (e.g. methoxycarbonyl and Ethoxycarbonyl), phenoxycarbonyl, benzyloxycarbonyl, acyl radicals derived from carboxylic acids (e.g. formyl, Acetyl and propionyl), lower alkyl groups, which advantageously contain up to 6 carbon atoms (e.g. methyl and ethyl) and with the aforementioned alkoxycarbonyl groups, phenoxycarbonyl groups, benzyloxycarbonyl groups or Acyl radicals derived from carboxylic acids are substituted.

If R. in the formula (V) represents an optionally substituted amino group, a lower alkyl radical substituted by hydroxyl groups and an optionally protected hydroxyl group, these are those for Ry. groups mentioned as examples in question. If R ₁ in this formula stands for a group which can be hydrolyzed to the optionally substituted amino group or to the lower alkyl radical substituted by hydroxyl groups, the following groups come into consideration: The group hydrolyzable to the optionally substituted amino group is, for example, an alkylidene amino group (e.g. Ethylideneamino), aralkylidenamino (e.g. benzylideneamino), a substituent which, together with the radical R ", forms a 2-substituted oxazoline ring / In this case the compound of the formula (V) can be represented by the following formula:

B,

I ι

609812/1006

where R_ has the meaning given above and Rg and R ₇ , which are identical or different, represent hydrogen, lower alkyl radicals with up to 6 carbon atoms, a cyclo | alkyl radical with a five-membered ring to seven-membered ring or aryl radicals / are. Examples of groups which can be hydrolyzed to the lower alkyl radicals substituted by hydroxyl groups are: The ether and ester groups which are formed on the hydroxyl groups of the lower alkyl radicals substituted by hydroxyl groups, which are mentioned above as examples of the groups which are reducible to the lower alkyl radicals R ^ substituted with hydroxyl groups, alkoxymethyl ethers (eg methoxymethyl and butoxymethyl), thioalkoxymethyl ethers (eg methylthiomethyl ether), pyranyl ethers or thiopyranyl ethers, which are attached to the hydroxyl group of those mentioned as examples of R., with hydroxyl groups substituted lower alkyl radicals are formed, and 'substituents which together with the radical Rp form an acetal or ketal ring (in this case the compound of the formula (V) has the general formula

in which R _{3 has} the meaning given above, R "and R _{q have} the same meanings as R ^ and R ₇ and B ^{f is} a lower straight-chain or branched alkylene radical with up to 6 carbon atoms or a straight-chain or branched lower alkylidene radical with up to to 6 carbon atoms).

In the formula (VI), the optionally substituted Amino groups, the lower alkyl radical substituted with hydroxyl groups and the optionally protected one

609812/1006

Hydroxyl group represented by R, can be, for example, the corresponding groups mentioned above for R-. Groups R ₁ which can be converted into an optionally substituted amino group or a lower alkyl radical substituted by hydroxyl groups by a reaction to remove the protective group are, for example, the groups mentioned above for R ₁ or R ₁ which form an optionally substituted Amino group or to a lower alkyl radical substituted by hydroxyl groups • are reducible or hydrolyzable.

In the formula (III), the group Α which can be reducible to an amino group can be any group which is represented by the reduction described below can be converted into an amino group, e.g. nitro, nitroso, Isonitroso (oximino), hydroxylamino, imino, diazo, azido and phenylhydrazone.

If in the formula (II) the _{group designated by A 1} is a -NHR-. is a reducible group, any groups can be used for this purpose, provided that they can be converted into -NHR- by the reduction described below. As examples of such groups for the case in which R- is a hydrocarbon radical, there may be mentioned: amino groups which are substituted with acyl radicals derived from carboxylic acids or carbonic acid (e.g. formylamino, acetylamino, propionylamino, isopropionylamino, butyrylamino, sec-butyrylamino, α, α-Dimethylpropionylamino, crotonylamino, cyclohexylcarbonylamino, 2-cyclohexen-1-ylcarbonylamino, cyclopentylcarbonylamino, benzoylamino and β-phenylpropionylamino), -N = R,., = NR ~, R-. R_

-N, -N

(wherein R- is as defined above) etc. When R- is hydrogen, -NHR ₃ can be any of the above as

6 0 ° ^Q / 10 0 6

Examples of groups mentioned can be.

In the formulas (I ¹ ) and (IV), the lower alkyl radical R ₄ , which advantageously contains up to 6 carbon atoms, can be straight-chain or branched, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec .-Butyl, be. The hydrocarbon radical R ₁ - can, for example, be one of the corresponding radicals mentioned above for R ~. It should be noted that R. and R ^ can form a ring group together with the neighboring C atom. Examples of these ring groups are: Cycloalkane, advantageously with a 3- to 7-membered ring (e.g. cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane) and cycloalkene, which advantageously contains a 3- to 7-membered ring (e.g. cyclopentene and cyclohexene). Of these, preference is given to cycloalkane with a 3- to 7-membered ring.

When in the formula (VI) -OZ ^ is a protected hydroxyl group is, for example, the protective groups mentioned above for R ^ come into consideration as protective groups.

The protecting group denoted by Zp in formula (VI) can be any group which is capable of protecting the amino group and can be removed by a reaction for removing protecting groups. Examples of such groups are acyl radicals and the aralkyl radicals mentioned above as protective groups for R ^. The protective group Z ₂ can be the amino group and / or hydroxyl group in the with the protective group in -OZ ,. and / or R-. Protect linked shapes. If Zp is linked with -OZ ^, the linking protective groups mentioned above in connection with R ^ and Rp come into consideration as linking protective groups.

For example, the groups of the following formulas are suitable as further linking protective groups:

609812/1006

(VI ') "LI / (VI "

J..> No .. ^ (VI ¹ '" ¹ )

Here R ^, Rp, R-> and -OZ ^ have the meanings given above, and Zl is a lower alkylidene radical with up to 6 carbon atoms (e.g. methylidene, ethylidene, propylidene, isopropylidene and butylidene), a substituted lower alkylidene radical ( for example benzylidene, phenylethylidene, 1-methoxyethylidene, 1-ethoxyethylidene, 1-phenylethylidene and acetylisopropylidene), fluorenylidene, phthaloyl or succinoyl. Z "represents hydrogen or a lower alkyl radical with up to 6 carbon atoms (e.g. methyl, ethyl, propyl, butyl, pentyl and hexyl), an aryl radical (e.g. phenyl), an aralkyl radical (e.g. benzyl and phenethyl), methylthio or methoxy , and these groups ZI ¹ can be substituted one or more times (for example with oxyl groups, lower alkoxy radicals with up to 6 carbon atoms and halogen atoms).

When the compounds of the formula (VI ¹ ) or (VI ") are subjected to a protective group deprotection reaction in Process 4, compounds of the formula (I) in which R _{3 is} hydrogen are usually obtained.

Methods 1 to 4 are described in detail below.

60981 Il 1006

The reduction in method 1 or 2 becomes ordinary
carried out according to a method that depends
of the respective starting material is suitably selected, for example, from one of the following customary processes:

1) Catalytic reduction with platinum, palladium, rhodium, Nickel or the like. as a catalyst.

2) Reduction with a metal hydride, e.g. lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, Sodium borohydride and sodium cyanoborohydride.

3) Meerwein-Ponndorf-Verley reduction with aluminum alkoxide, e.g. aluminum isopropoxide.

4) Reduction with metallic sodium, metallic magnesium or the like. with, for example, an alcohol.

5) Reduction using zinc dust with a base, e.g. *. a caustic alkali.

6) Reduction with the help of a metal, e.g. iron or
Zinc, with an acid like hydrochloric acid or acetic acid.

7) Electrolytic Reduction.

8) Reduction with the help of reducing enzymes.

Of these, methods (1) and (2) are preferred.
Of course, any methods other than the above-mentioned methods can be used as far as with
can be achieved-making ^- to them the objectives of F.

The suitable reaction temperature is different in
Depending on the starting materials and the reduction process used in each case, however, it is generally in the range from about -20 ° to 100 ° C. This reaction is usually carried out at normal pressure,
however, can optionally also under reduced or

609812/1006

increased pressure. The reduction is generally carried out in the presence of a suitable solvent carried out. Common solvents are suitable provided that they are the starting material more or less able to dissolve and not adversely affect the reaction, e.g. water, alcohols (e.g. methanol, ethanol and propanol), ethers (e.g. dimethyl ether, diethyl ether, methyl ethyl ether, tetrahydrofuran and dioxane), esters (e.g. ethyl acetate and butyl acetate), ketones (e.g. acetone and methyl ethyl ketone), aromatic hydrocarbons (e.g. benzene, toluene and Xylene), organic acids (e.g. acetic acid and propionic acid) and mixtures of two or more of these solvents.

In method 2, the reaction is carried out by reducing the compound (III) in the presence of the carbonyl compound (IV) carried out. Instead of the solvent, an excess of the carbonyl compound (IV) can be used in this reaction.

The reduction in process 1 or 2 can be carried out in stages. For example, when the starting material contains more than two reducible components, it is possible to ^{prepare the compound (I) or (I 1} ) by reducing these components stepwise. In process 1 or 2 according to the invention, the most varied of compounds which lead to the corresponding desired compounds (I) or (I ¹ ) are suitable as starting materials. Depending on the starting material and the desired compound, suitable reduction methods and conditions are thus selected from the above-mentioned methods and conditions.

The reaction in Method 3 is carried out by the compound (V) with water or a mixture of water with an organic solvent (e.g. methanol, Ethanol, acetone, tetrahydrofuran and dioxane)

609812/1006

is acting.

If necessary, a catalyst can be used for the hydrolysis. Suitable catalysts are
for example acids and bases. Examples of acids are inorganic acids (e.g. hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid) and organic acids (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulphonic acid and toluenesulphonic acid). Suitable bases are, for example, inorganic bases (for example sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate and
Sodium sulfite) and organic bases (e.g. triethylamine, pyridine, piperidine, N-methylaniline and triethanolamine).

When using an acid as a catalyst, this can
Acid adduct of the compound (V) can be isolated as an intermediate. This intermediate can in usual
Way to be further hydrolyzed. The intermediate product
can also be formed by the compound (V) with one of the above-mentioned catalysts or an electron acceptor, e.g. aluminum chloride, boron trifluoride, zinc chloride and iron (III) chloride in an organic solvent (e.g. benzene, diethyl ether, dioxane, chloroform and tetrahydrofuran) is implemented.

Although this hydrolysis proceeds satisfactorily at room temperature, the reaction can be used to regulate the reaction rate. even with a suitable one
Way increased or decreased temperature can be carried out. Generally at one temperature
in the range of about -40 ° to 150 ° C, preferably about
0 ° to 100 ⁰ C, worked. The response time is subject to
no particular restriction. In general is a
Range from about 5 minutes to 40 hours is appropriate,
with about 30 minutes to 15 hours being preferred.

609812/1006

The hydrolysis described above can optionally be carried out in stages.

The reaction in Method 4 is carried out by the compound (VI) is subjected to a deprotection reaction. Suitable for this purpose any reactions that can remove the protecting group. As examples of beneficial reactions of this type are the reduction, the oxidation and the solvolysis (e.g. hydrolysis and alcoholysis), The following reactions are specifically mentioned as examples:

1) Catalytic reduction with platinum, palladium, rhodium, Raney nickel or the like. as a catalyst.

2) Reduction with the help of metallic sodium, metallic potassium or the like. with liquid ammonia or an alcohol, e.g. ethanol or butanol.

3) Reduction with a metal hydride, e.g. lithium aluminum hydride, sodium aluminum hydride and sodium boron hydride.

4) reduction with a metal, e.g. Zinc or iron, in Presence of an acid such as an organic acid (e.g. formic acid and acetic acid) or an inorganic acid Acid (e.g. hydrochloric acid and sulfuric acid).

5) Hydrolysis with the help of an electron acceptor, e.g. an inorganic acid (e.g. hydrohalic acids (Hydrogen fluoride, hydrobromic acid, hydrobromic acid-acetic acid, hydrogen chloride and Hydrogen iodide), sulfuric acid, nitric acid, phosphoric acid, perchloric acid and boric acid), an organic Acid (e.g. trifluoroacetic acid, acetic acid, oxalic acid, p-toluenesulfonic acid and formic acid), an aqueous solution of said inorganic or organic acid, aluminum chloride, aluminum

609812/1006

bromide, zinc chloride, magnesium iodide, iron (III) chloride, Boron trichloride and boron tribromide.

6) hydrolysis with the help of an inorganic base, e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, Potassium carbonate, sodium hydrogen carbonate, aqueous ammonia and hydrazine hydrate, or an organic one Bases, e.g., pyridine hydrochloride, tetramethylammonium hydroxide, and collidine-lithium iodide.

7) reaction with an oxidizing agent, e.g. concentrated nitric acid, chromic anhydride, potassium permanganate, Ozone or benzoyl peroxide.

8) Reaction with thiourea, mercaptide or lead acetate.

9) Solvolysis with a solvent such as water, methanol and ethanol.

10) Physical treatment, e.g. electrolytic reduction, electrolytic oxidation and irradiation with UV light.

11) Enzymatic reaction, etc.

Of these, reactions (1), (3), (5) and (6) are preferred. The suitable reaction temperature is different depending on the particular reaction method used, but it is generally in Range between about -40 and 150 ° C, preferably between about 0 ° and 100 ° C. The reaction will generally carried out at normal pressure, but can optionally be carried out under reduced or increased pressure will.

The reaction in Process 4 can be carried out in stages will. For example, if the starting compound (VI) contains more than two protecting groups, the Compound (I) by gradually removing it

609812/1006

Protecting groups are obtained.

When the reduction is used as a reaction for removing the protecting group or groups, as protecting groups in R ^, Rp and / or -OZ ^ of the starting compound (VI) are from those for R ^, R _? and -OZ. The various protective groups mentioned lower alkyl radicals, lower alkenyl radicals, lower alkynyl radicals, aralkyl radicals, phenacyl radicals, acyl radicals and the like are advantageous. Of these, benzyl radicals and benzyloxycarbonyl radicals are preferred. When using solvolysis, of the protective groups in R., R.sup.1 and / or —OZ, lower alkyl radicals, lower alkenyl radicals, lower alkynyl radicals, substituted lower alkyl radicals, aralkyl radicals, acyl radicals, silyl radicals, ester radicals of inorganic acids, pyranyl, tetrahydropyranyl, tetrahydrofuranyl, or the like. advantageous. Of these, methyl, ethyl, benzyl, acetyl, benzyloxycarbonyl and trifluoroacetyl are preferred. Acyl residues or aralkyl residues, in particular acetyl residues, trifluoroacetyl residues, benzyloxycarbonyl residues and benzyl residues are preferred as protective group Zp.

If in process 1 or 2 in the starting compound (II), (III) and / or (IV) R 1, R ₂ , R ₃ and / or R _{5 are} the groups which can be reduced by reduction according to the invention these groups are also reduced, the corresponding compounds in which the abovementioned components have been reduced being obtained. For example, when R ^, or Rp in the starting compound is benzyloxy, desired compounds containing a hydroxyl group as a corresponding group can be obtained. When R ₃ in the starting compound is an alkenyl group, desired compounds containing an alkyl group can be obtained. If R_ or R ^ in the starting compound is phenyl or cycloalkenyl

1006

2536503

containing group, the desired compounds containing cycloalkyl as a corresponding group can be obtained. If R ^ in the starting compound (II) and / or (III) is one of the above-mentioned substituted amino groups, this group can also be reduced by reduction according to the invention, the desired compounds (I) or (I ¹ ) in which R is an amino group or another substituted amino group can be obtained. It should be noted that this case also falls within the scope of the invention.

If, in process 3, R _{1, R 2 and / or R 2 are} the hydrolyzable groups in the starting compound (V), these groups can also be hydrolyzed by the hydrolysis according to the invention, the desired compounds (I), the corresponding hydrolyzed Group included, can be obtained. For example, the desired compound (I) in which R2 is a hydroxyl group can be obtained from the starting compound (V) in which R1 is an acyloxy group.

When R. in the starting compound (V) is the above-mentioned substituted amino group, it can also be hydrolyzed by hydrolysis according to the invention, whereby the desired compound (I) in which R. is an amino group or other substituted amino group is obtained . As a specific example of this case, it can be mentioned that the desired compound (I) in which R _{1 is} a methylamino group, by this hydrolysis from the starting compound (V) in which R ^ is an N-methyl-N-tr
is, can be produced

in which R ^ is an N-methyl-N-trifluoroacetylamino group

Likewise, in cases where R3 is in the starting compound (VI) the reducible group is the desired compound (D which is the corresponding reduced group contains, by applying the reduction as a reaction at

609812 / $ 100

Method 4 can be obtained. If R ^ the solvolysier— bare group, the desired compound (I), which contains the corresponding solvolyzed group, can be obtained by applying the solvolysis reaction in Process 4. When R ^ in the starting compound (VI) is the above-mentioned substituted amino group, it can also be obtained by the reaction of method 4, yielding the desired compounds (I) in which R. is an amino group or other substituted amino group can be obtained.

As can be seen from the above descriptions, in processes 1, 2, 3 and / or 4, the symbols R ", R_ and R ^ contained in common in the starting compound and in the desired compound denote the groups falling under the same definitions, where in each case the groups denoted by Rp, R ^, and R ₁ - before and after the reactions are not always the same groups.

The desired compounds (I) according to the invention can be prepared from the respective reaction mixtures easily according to the usual separation and cleaning processes, e.g. by concentration, filtration, recrystallization and column chromatography isolate.

Due to the presence of a few asymmetric carbon atoms, the compounds (I) can be in several stereoisomeric forms, e.g., geometric isomers and optical isomers, so that they generally arise as mixtures of these isomers. If desired, certain geometric isomers can be used (e.g. trans-isomers and cis-isomers) according to suitable Methods can be prepared, e.g., 1) by stereospecific reaction, 2) reaction using an output connection that has the same configuration as the desired connection, and 3) Isolation of the desired isomer from a mixture

609812/1006

of isomers with the aid of processes derived from the above-mentioned separation and purification processes in are appropriately selected, e.g., by recrystallization and column chromatography.

The racemic mixtures can, if desired, after customary processes, e.g. by forming a salt with an optically active acid or base or by physical adsorption on a porous adsorbent resin. Of course they all fall these individual isomeric forms as well as their mixtures within the scope of the invention.

The desired compounds (I) according to the invention can also be obtained after using them in a conventional manner Way into salts, especially physiologically acceptable salts, e.g. acid addition salts, for example Salts of organic acids (e.g. in the hydrochloride, hydrobromide and sulfate) and salts with organic Acids (e.g. in maleates, fumarates, tartrates, toluenesulfonates, Naphthalene sulfonates and methanesulfonates) have been.

The products according to the invention prepared in the manner described, ie the compounds of the formula (I) and their salts, in particular the physiologically harmless salts, have pharmacological effects, for example the ability to stimulate the ß-receptors of the adrenergic system, analgesic effects, anti-inflammatory effect _; antihypertensive effect, etc. Particularly noteworthy is the stimulating effect on the ß-2 receptors of the adrenergic system, for example the bronchodilatoric effect. Because of these advantageous properties of the compounds (I) and their salts, they are valuable for the therapy and prophylaxis of diseases such as asthma, migraines, hypertension, etc. in warm-blooded animals, including humans.

609812/1008

The compounds (I) and their salts have very good stability.

For pharmaceutical use, the compounds according to the invention and their salts can be used in warm-blooded animals including humans as such or in admixture with one or more pharmaceutically acceptable ones Carriers orally or in other ways in drug forms such as powder, granules, tablets, capsules, Injectable solutions, inhalants, etc. administered will.

Pharmaceutical preparations which contain one or more compounds (I) or their salts can according to for the production of powders, granules, tablets, capsules, injection solutions, inhalants and the like by conventional methods. The choice of excipients depends on the route of administration, the solubility of the compounds (I) and their salts, etc. from.

The appropriate dosage will depend on the particular disease and symptoms, how it is administered, and other conditions. Advantageous doses in adult asthma therapy, in the range of about 1 to 1000 mg orally daily, about 0.01 up to 10 mg daily intravenously or about 0.1 to 100 mg / dose for topical application in drug forms such as nebulized Products (aerosol inhalations).

The following dosages are preferred for the therapy of asthma in adults:

1) For compounds (I) in which R ^ is an amino group or is a lower alkyl radical substituted by hydroxyl groups:

a) 1 to 100 mg daily for oral administration,

b) 0.01 to 1 mg daily for intravenous administration

609812/1006

chung,
c) 0.1 to 10 mg / dose when applied topically.

2) For compounds (I) in which R ^. one if necessary protected hydroxyl group is:

a) 10 to 1000 mg daily for oral administration,

b) 0.1 to 10 mg daily for intravenous administration,

c) 1 to 100 mg / dose when applied topically.

The compounds (I) according to the invention and their salts are also valuable as intermediates for the synthesis of a wide variety of medicaments. For example, the compounds (I) in which R ₁ and / or Rp are a protected hydroxyl group can easily be converted into the corresponding compounds (I) in which R .. and / or Rp are hydroxyl groups.

The starting compounds (II), (III), (V) and (VI) can be prepared, for example, by the following Formulas represented by the method are produced.

HQ i

HC Z

BzC k: BzO

CE ₂ OCH ^

CH ₂ OH 7

(C ₂ H) N

IiBr

CK7COOH

609812/1006

BzO

O'

COOH

BzO

- 26 ~

CHO

BzO-

NaHCO,

CrO-

COOCH,

BzO

(CH

0 '

(b)

HO

NO,

ENT

CH-, I 0

KpCO

NO,

CH-, O 5

Raney Ni

NH.

(CH-, C0) _o 0

(c)

NHCOCH ^

*1

PyHBr-, or Br ₂

HN <

R,

0 Br

NaNO,

NO

Z,

609812/1008

^l 2

O NO

1. H ₂ NOH.

2. TsC-e

ι. C ₂ H ₅ OK

2. Acid

NOTs

O NH.

-C = O

0 N = C reduction

OH NH ₂ E ₅

E,

NHCH <

OH N = C;

^E 5

HCOOC ₂ I.

CH _x ONa 0

NaNO

CHOH

0 NOH

609812/1008

Reduction ^E 2

O'NH.

reducing acylation

NHCOE

10

l.NBS 2.Base

Herein have R,

R.

2 '3'

named meanings.

4 '

R ₁ - and Z.

above

, d

, a-c

, has the same meaning as Bz is a benzyl radical; Py stands

₃ ,. ^ Corresponds to ^

for pyridine, Ts for tosyl, NBS for N-bromosuccinimide and DMSO for dimethyl sulfoxide.

The abovementioned starting compounds (II), (III), (V) and (VI) can be used for the process according to the invention in free form or as acid addition salts, for example as salts with inorganic acids (for example hydrochlorides, hydrobromides and sulfates) and used as salts with organic acids (e.g. maleates, fumarates, tartrates, toluenesulfonates, naphthalene sulfonates and methanesulfonates).

609812/1006

Of the abovementioned starting compounds, the compounds (II) are suitable, in particular the compound in which X stands for ^ C = O., also as an intermediate for the manufacture of various drugs other than compounds (I).

The invention is further illustrated by the following reference examples and examples.

Reference example 1

In 50 ml of a 4% solution of hydrogen chloride in 5 g of 1,2-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one are ether solved. While stirring, the solution becomes a solution of 10 g of isoamyl nitrite in 50 ml Diethyl ether was added dropwise. After 15 minutes, the crystals formed are filtered off, 3 g of 1,2-dimethoxy-6-oxoimino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one can be obtained in the form of colorless needles with a melting point of 162-163 ° C.

Elemental analysis for C-, -, H-, j-CLN Calculated C 62.64; H 6.07; N 5.62 Found C 62.58; H 6.07; N 5.48

Reference example 2

1 g of 1,2-dimethoxy-6-oxyimino-6,7, -S ^ -tetrahydro-SH-benzocyclohepten-S-one is added to 20 ml of methanol solved. After adding 0.5 g of 5% palladium carbon and 2 ml of 20% Ethanol hydrochloric acid undergoes a catalytic reduction in flowing hydrogen at normal temperature and normal pressure carried out. The catalyst is filtered off and the filtrate is evaporated to dryness. To the 20 ml of diethyl ether are added to the syrupy residue. The mixture is left in the refrigerator overnight ditched. The solid product formed is filtered off and from a 1: 1 mixture of methanol and

609812/1006

Recrystallized diethyl ether, 0.9 g of 6-amino-l, 2-dimethoxy-6, 7,8,9-tetrahydro-5H-benzocyclohepten-5-one hydrochloride in the form of colorless prisms with a melting point of 160 to 163 ° C (decomp.).

Elemental analysis for C-, ^ Η-, "O ^ N Calculated C 57.46; H 6.68; N 5.16 Found C 57.11; H 6.68; N 4.91

Reference example 3

In a mixture of 10 ml of methanol and 40 ml of acetone, 540 mg of 6-amino-1,2-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one hydrochloride are added solved. While the solution is stirred and cooled with ice, 600 mg of the adduct of lithium cyanoborohydride and dioxane are added

(LiBH ₅ CN «20 0)

added within 10 minutes. The mixture is stirred and cooled with ice for an additional 2 hours and then constricted. Water is added to the residue. The colorless oily precipitate formed in this way is treated with diethyl ether extracted. The extract is dehydrated over anhydrous magnesium sulfate and mixed with ethanol Acidified hydrochloric acid. The crystals formed in this way are filtered off, 400 mg of 6-isopropylamino-1,2- dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one hydrochloride can be obtained. By recrystallization from chloroform-diethyl ether, crystals become from the enamel point 172-174 ° C (dec.) obtained.

blernentaranai yse fu r C 16 ^H 2 H 3-H 'Ρ P N 4th .46 Calculated C. 61 , 24; H 7th 59; Ν, 4th .58 Found C. 61 .ii; 7th 20;

609812/1006

Reference examples 4 and 5

In the same manner as described in Reference Example 3, the products shown in Table 1 are obtained produced by reducing the corresponding starting materials.

Source material OCH,

Carbonyl compound

NH.

(Hydrochloride.)

product

OCH.

0 NHE.

3 (hydrochloride)

609812/1006

Table 1

ο co

O O

Reference at
game Carbonyl
link Reduction
middle product R-, in the forefront
existing general
my formula Crystal shape
(Solvent for
Recrystallization) , Melting point
(° c) 4th O ~ ^chq Sodium boron
hydride - ^CH 2 -O colorless prisms
(Methanol diethyl
ether) 202-209 5 CH ₃ COGH ₂ - ^ T ^ Lithium cyan
borohydride -CHCH ₂ - <r ^{:: =} ^ colorless prisms
(Methanol diethyl
ether) 213-217

I Ν)

¹ ul CT) cn O

Reference example 6

In 8 ml of 48% aqueous hydrobromic acid become 0.5 g of 6-amino-1,2-dimethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-hydrochloride solved. The solution is refluxed for 3 hours and then under reduced pressure Pressure evaporated to dryness. The residue is cooled with ice. The crystals formed in this way acetone is added, followed by filtration. Here, 0.3 g of 6-amino-1,2-dihydroxy-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-one hydrobromide obtained from melting point 140 to 143 ° C (decomp.).

Elemental analysis for C-, -.H-, _x O, N-HBr Calculated: C 45.85; H 4.55; N 4.86 Found: C 45.80; H 4.48; N 4.56

Reference Examples 7 to 9

In the manner described in Reference Example 6, the products listed in Table 2 are obtained by hydrolysis of the corresponding starting materials produced.

Starting material product

OH

OCH _x

(T NHR _x °

(HBr-SaIz)

609812/1006

Table 2

Reference at
game ^R 3 Crystal shape
(Solvent for
Recrystallization) Melting point '( ⁰ C)
(Decomp.) Etc. Remarks 7th CH-,
-CHx ' ⁵
CH ₂
. 7th colorless powder
shaped crystals
(Acetone diethyl
ether) no sharp
Melting point Source material in
Form of the hydrochloric
rids 8th -CH ₂ - ^ 3 colorless fluffy
Crystals
(Methanol diethyl
Mther) 139-143 Source material in
Form of the hydrochloric
rids 9 CH ^ '
- CH CH ₂ - £ 3 amorphous powder Infrared absorption
soektrum
(ca ~ NuJoI):
3350, 1670, 1600,
1300, 1200, 1020
820, 74-C, 700 - source material
in the form of free
base

Reference example 10 !

1 g of 1,2-dimethoxy-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-one is added to 3 ml of diethyl ether solved. 0.8 g of bromine are added to the solution with stirring. The mixture is stirred for an additional 30 minutes and then concentrated. To After adding water, the residue is extracted with ethyl acetate. The extract is dehydrated and then distilled. The residue is recrystallized from petroleum ether, 0.8 g of 6-bromo-1,2-dimethoxy-6, 7,8,9-j tetrahydro-SH-benzocyclohepten-S — one in the form of colorless Prisms with a melting point of 66-68 C can be obtained.

Elemental analysis for C -, -, H-,, -0-, Br

13 15 3

Calculated: C, 52.19; H 5.05 Found: C 52.35; H 4.59

Reference example 11

In 10 ml of acetonitrile, 0.5 g of 6-bromo-1,2-dimethoxy-6 , 7,8, -9-tetrahydro-5H-benzocyclohepten-5-one and 0.45 g N-benzyl-N-methylamine dissolved. The mixture is 3 hours heated on the reflux condenser, whereupon the solvent is distilled off. After adding diethyl ether to the The insoluble constituents are filtered off from the residue. The filtrate is washed with water, dried and distilled. The residue is purified by column chromatography Purified on silica gel (benzene-acetone = 30: 1) and treated with ethanolic hydrochloric acid, 0.1 g 6_ (N-Benzyl-N-methylamino) -1, 2-dimethoxy-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-one hydrochloride is obtained as a crystalline powder with a melting point of 170-180 ° C.

Elemental analysis for ^ 21 ^ 25 ^ 3 ^^ ' Calculated: C 6? .10; H. 6.97; N 3.73

Found: C, 66.87; H 7.04; N 3.66

609812/1006

Reference example 12

In 100 ml of anhydrous benzene, 5 g of 1,2-dimethoxy-6,7,8 ^ -tetrahydro-SH-benzocyclohepten-S-one solved. 15 g of aluminum chloride are added to the solution. The mixture is heated to the reflux condenser for 40 minutes and then poured into ice water and extracted with ethyl acetate. The extract is dehydrated and concentrated. To the arrears petroleum ether is given. The crystals formed in this way are recrystallized from 'ethyl acetate-petroleum ether, wherein 3.6 g of 1,2-dihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one obtained as colorless needles with a melting point of 178-182 ° C.

Elemental analysis for ^ 11 ^ 12 ^ 3 Calculated: C 68.73; H 6.29 Found: C 68.52j _H, 6 .31

Reference example 13

0.3 g of 1,2-dihydroxy-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-one, 2.5 g of potassium carbonate, 0.5 g of sodium iodide and 0.5 g of benzyl chloride were added. The mixture is refluxed for 7 hours, after which the acetone is distilled off. The residue will diluted with water and extracted with diethyl ether. The diethyl ether is then distilled off and the residue Purified by column chromatography on silica gel, 0.5 g of 1,2-dibenzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one as a colorless oil. This product is dissolved in 5 ml of 4% strength solution of hydrogen chloride dissolved in diethyl ether. A solution of 0.6 g of isoamyl nitrite in 5 ml of anhydrous diethyl ether is added with stirring added dropwise. The crystals formed in this way are filtered off and anhydrous with a small amount Diethyl ether rinsed. Here, 0.25 g of 1,2-dibenzyloxy-6-oxyimino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one obtained as colorless needles with a melting point of 178-179 ° C.

609812/1006

Elemental analysis for Cpc-HovO ^ N Calculated: C 74.79; H, 5.78; N 3.49 Found: . C 74.77; H 5.79; N 3.47 "

Reference example 14

3.55 g of 2-dibenzyloxy-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-one are dissolved in 70 ml of methanol. The solution ^; 1.2 g of sodium borohydride powder are added in small portions with stirring. The mixture is reacted for 15 minutes at room temperature and then under reduced ^; Pressure restricted. The residue is poured into ice water and extracted with chloroform. The chloroform extract is dehydrated and concentrated. The residue is recrystallized from diethyl ether-petroleum ether, 2.7 g of 1,2-dibenzyloxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycleptene being obtained as colorless, fluffy crystals with a melting point of 112-113 ° C .

Reference example 15

0.5 g of 1,2-dibenzyloxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene and 0.1 g of potassium hydrogen sulfate are added to 50 ml of benzene. The mixture is refluxed for 1 hour, the water being removed by azeotropic distillation. The R _e is action mixture was washed with water, dried and concentrated. Diethyl ether and petroleum ether are added to the residue and the mixture is then cooled, 0.4 g of 1,2-dibenzyloxy-8,9-dihydro-7H-benzocycloheptene being obtained in the form of crystals with a melting point of 157-160 ° C.

Reference example 16

0.4 g of 1,2-dibenzyloxy-8,9-dihydro-7H-benzocycloheptene are added to 10 ml of dimethyl sulfoxide solved. While cooling with ice and bubbling nitrogen through it, 0.3 g of N-bromosuccinimide is added and the mixture is left 30 minutes of reaction. The reaction mixture is poured into ice water, extracted with benzene, and the back

609812/1006

hepten in 200 ml of benzene is added 4.8 g of the adduct of triethylamine and sulfuric anhydride (C ^ H ^) ^ N.SOg and reflux the mixture for 1 hour. After adding 36 g of potassium carbonate, the mixture is boiled 30 minutes, 12 g of sodium methoxide are added and the mixture is refluxed for a further 7 hours. You pour that Reaction mixture in ice water, extracted with ethyl acetate, washes den'Extrakt with water, dried and the solvent is distilled off. The oily residue is allowed to cool, 5.65 g of 1,2-benzyloxy-5,6-tert-butylimino-6,7,8,9-tetrahydro-5H-benzocycloheptene being obtained obtained in the form of crystals with a melting point of 91-95 ° C.

stood with water, dries and constricts. A 1: 1 mixture of diethyl ether and petroleum is added to the residue ether, then filtered. This gives 210 mg of 1,2-dibenzyloxy-6-bromo-5-hydroxy-6,7,8,9-tetrahydro-SH-j benzocycloheptene with a melting point of 107-109 C.

Reference example 17

man

Heated in a sealed tube / 1.3 g of 1,2-dibenzyloxy-6-bromo-5-hydroxy-6, 7,8,9-tetrahydro-5H-benzocycloheptene and 25 g of tert-butylamine for 2 hours to 110- 120 ^° C., then the excess tert-butylamine is distilled off, the residue is diluted with water and extracted with chloroform. The extract is dehydrated and the solvent is distilled off. The residue is purified by column chromatography on silica gel (benzene-acetone = 9: 1) and petroleum ether is added to the oil obtained. The crystals formed on standing are isolated, 0.5 g of 1,2-dibenzyloxy-5-tert-butylamino-6-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene having a melting point of 98-100 C receives.

Reference example 18
To a solution of 5.85 g of 1,2-dibenzyloxy-5-tert.-

609812/1006

Elemental analysis for CpQH ₇₇ OpN Calculated: C 81.4-6; H, 7.78; N 5.28 Found: C 8. [.. 4-I; H, 8.11; N 2.94-

Reference example 19
150 mg of 6-amino-1,2-dihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one hydrobromide are added to 1.5 ml of pyridine. While cooling with ice, 300 mg of benzyloxy carbonyl chloride are added and the mixture is left to react for about 1 hour while stirring. The Pyri j is distilled

din from, diluted the residue with ice water, extracted with ethyl acetate, and dehydrated the extract the solvent is distilled off. The residue is purified by column chromatography on silica gel (benzene-acetone = 9: 1) and receives 105 mg of 6-benzyloxycarbonylamino-1,2-bis-benzyloxycarbonyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one as a colorless syrup.

Nuclear Magnetic Resonance Spectrum (CDC-S ,, 60 MHz): δ 5.08 (2H), 5.30 (4H), 7.38 (15H)

Reference example · 20

6 g of cis-S-amino-l ^ -benzyloxy-e, 7,8,9-tetrahydro-SH-benzocyclopenten-S-ol are added to a mixture of 200 ml of ethyl acetate and 100 ml of water and 12 grams of potassium carbonate. 6 g of ethyl chlorocarbonate are added dropwise to the mixture with stirring. One dries the organic Layer, concentrated under reduced pressure, the residue dissolved in 100 ml of acetone and chromic acid-sulfuric acid added with stirring until no more color change is observed. The excess chromic acid is decomposed with a small amount of methanol, then filtered, water is added to the filtrate and the mixture is extracted with chloroform. The extract is dried and concentrated under reduced pressure, 1,2-dibenzyloxy-6-ethoxycarbonylamino-6,7,8,9-tetrahydro-5H-benzocyclo-

60981 2/1006

hepten-5-one (melting point 120-122 ° C) is obtained. One solves the compound obtained in 50 ml of methanol, 3.7 g of sodium borohydride are added to the solution with stirring, are to Reaction mixture Excess water, extract the mixture with chloroform and dry the chloroform layer. It is concentrated under reduced pressure and 2.7 g of trans-l ^ -dibenzyloxy-G-ethoxycarbonylamino-6,7,8 ^ -tetrahydro-SH-benzocyclohepten-S-ol are obtained in the form of colorless crystals with a melting point of 171-174 ° C.

Elemental analysis for C ₀₀ EL _n Ot-N

do 5 ± 5

Calculated: C 72.86; H 6.77; N-3.04 Found: C 72.88; H, 6.68; N 2.88

Reference example 21

4.7 g of cis-6-amino-1,2-dibenzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol are left react with anhydrous acetic acid in 200 ml of methanol. After the reaction mixture has been concentrated under reduced pressure adding water to the residue, crystals being formed. In the manner described in Reference Example 20 if the crystals are oxidized with chromic acid, then reduced with sodium borohydride to form raw crystals which are recrystallized from chloroform. This gives 1.0 g of trans-6-acetylamino-1, 2-dibenzyloxy-6, 7,8,! J-tetrahydro-SH-cyclohepten-S-ol from melting point 219-223 ° C.

Elemental analysis for C ^ H ^ O ^ N - ^ EJd Calculated: C 73.61; H 6.86; N 3.18 Found: C 73.75; H 6.72; N 2.91 _

& 0981 2/1006

ι Reference example · 22 ι

To a mixture of 50 ml ethyl acetate and 100 ml ice \ water are added 1.17 g of cis-6-amino-l, 2-benzyloxy-6 _r 7,8,9-

tetrahydro-5H-benzocyclohepten-5-ol and then ι 0.325 g of ethyl chlorocarbonate in 25 ml of ethyl acetate dropwise, while cooling with ice and stirring. One separates the organic layer is dried, dried and concentrated under reduced pressure. It is added to the residue obtained 20 ml of diethyl ether, filtered the formed Crystals and the filtrate is concentrated, 0.55 g of cis-1,2-dibenzyloxy-6-ethoxycarbonyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol obtained in the form of colorless crystals with a melting point of 113-115 ° C.

Elemental analysis for 28 ^ 31 ^ 5 ^ Calculated: ^G * 72.86; H. 6.77; -N 3.04 Found: ° -. 72.89; H 6.64; N 3.02

Reference example 23

a) To a suspension of 16.6 g of 2-hydroxy-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-one 90 ml of concentrated hydrochloric acid and 3.7 g of paraformaldehyde are added to 90 ml of chloroform and stir the mixture vigorously for 20 hours at room temperature. The solution is filtered and washed the substance obtained with chloroform and water and dried, whereby 9.2 g of l-chloromethyl-2-hydroxy-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-one obtained in the form of colorless crystals with a melting point of 178-179 ° C (decomp.) will.

Nuclear Magnetic Resonance Spectrum. (DMSO-d ^) δ: 4.86 (2H, s), 6.86 (1Hd), 7.46 (lH, d) __

b) 13.7 g of 1-chloromethyl ^ -hydroxy-e ^ S ^ -tetrahydro-SH-benzocyclohepten-5-one are suspended in 200 ml of methanol. 10.5 ml of triethylamine are added to the suspension. The resulting mixture is refluxed for 3 hours

609812/1006

heated cooler. The solvent is evaporated under reduced pressure and the residue with benzene and Water shaken. The organic layer is washed with water, dried and under reduced; Evaporated pressure, leaving 12.5 g of 2-hydroxy-l-methoxy-; methyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one in j Form of colorless crystals with a melting point of 118-120 C; can be obtained.

c) 14.0 g of 2-hydroxy-1-methoxymethyl-6, 7,, 8,9-tetrahydro-5H-benzocyclohepten-5-one are dissolved in 180 ml of methanol. 5.7 g of anhydrous potassium carbonate, 11.6 g of potassium iodide and then 9.6 g of benzyl chloride were added. The mixture is taking 3 hours Stirring heated on the reflux condenser. The solvent is evaporated off under reduced pressure. Benzene and water are added to the residue. The organic layer is washed with water, dried and evaporated under reduced pressure, giving 21.3 g of crude 2-benzylioxy-1-methoxymethy1-6,7,8,9-tetrahydro-5H-benzocylohepj ten-5-one can be obtained as an orange oil.

Nuclear Magnetic Resonance Spectrum (CDC-C) 6: 1.63-2.02 (4H, m), 2.7l (2H, t), 3.05 (2H, t), 3. 4.68 (2H, s), 5.15 (2H, s), 6 ..89 (lH, d), 7.40 (5H, s), 7.68 _f

d) 13 ml of 47% hydrobromic acid are added to a solution of 20.6 g of the benzyloxy derivative obtained in section (c) in 75 ml of acetic acid. The mixture ... is left to react for 50 minutes at about 50 ^{° C. with stirring.} The reaction mixture is concentrated under reduced pressure and benzene is added to the residue. The organic layer is washed with water, dried and evaporated under reduced pressure. The residue is washed with a mixture of benzene and n-hexane, 13.2 g of 2-benzyloxy-1-bromomethyl-6, 7, 8, 9 | -

609812/1006

tetrahydro-SH-benzocyclohepten-5-one in the form of colorless Crystals with a melting point of 87-89 ° C can be obtained.

e) To a solution of 12.0 g of the according to section (d) i

produced bromine derivative in 120 ml of dimethyl sulfoxide I 24.0 g of sodium bicarbonate are added. The mixture obtained is heated to 100 ° C for 20 minutes while stirring, then poured into ice water and extracted with benzene. The extract is washed with water, dried and evaporated to dryness under reduced pressure, whereby 9.9 g of 2-benzyloxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-1-carbaldehyde were obtained in the form of colorless crystals with a melting point of 115-117 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl ^) Q : 10.70 (IH, s).

f) To a solution of 15.9 g of 2-benzyloxy-5-oxo-6,7,8,9-j tetrahydro-SH-benzocyclohepten-1-carbaldehyde in 400 ml of acetone, 30 ml of Jones reagent are added dropwise while the reaction temperature is kept below 30 ° C. The mixture is stirred for 3 hours at room temperature. After addition of 50 ml of methanol, the mixture is filtered and the filtrate evaporated under reduced pressure to _r T Ockene. Water and chloroform are added to the residue. The chloroform layer is extracted with aqueous sodium bicarbonate. The extract is acidified with 3N hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to dryness under reduced pressure, giving 11.9 g of crude 2-benzyloxy-5-oxo-6,7,8,9-tetrahydro-SH-benzocycloheptene-1-carboxylic acid in the form of a yellow powder with a melting point of 170-171 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl.,) Υ: 10.00 (IH).

60981 2/1 006

g) In 120 ml of acetone, 11.1 g of the according to section! (F) produced carboxylic acid derivative dissolved. To the solution 6.7 g of ground anhydrous potassium carbonate and 5.0 g of dimethyl sulfate are added. The mixture will Heated for 1 hour on the reflux condenser. The solution is evaporated under reduced pressure, the residue with! Benzene extracted and the extract washed successively with dilute ammonium hydroxide solution and water, dried and evaporated to dryness under reduced pressure, 10.3 g of methyl-2-benzyloxy-5-oxo-6,7, S ^ -tetrahydro-SH-benzocyclohepten-l-carboxylate in the form of pale yellow crystals with a melting point of 84-86 ° C.

Elemental analysis for ^ 20 ^ "? 0 ^ 4 Calculated: C 74.06; H 6.21 Found: C, 73.92; H 6.19

Nuclear Magnetic Resonance Spectrum (CDCIn) ν : 3.98 (3H, s).

Reference example 24

a) On the in. the Bezuqs examples 14 to 18 described

Methyl-2-benzyloxy-5,6-N-tert.-butylimino is also used 6,7,8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate as a pale yellow syrup from methyl 2-benzyloxy-5-oxo-6,7,8,9-tetrahydro-SH-benzocycloheptene-i-carboxylate obtain.

Nuclear Magnetic Resonance Spectrum (CDCi ₂ ,) 6: 1.O6 (9H s) 1.5O-3.2O (8H, m), 3.81 (3H, s), 5.52 (2H, s>, 6.74 (lH, d), 7.29 ( lH, d), 7.3K5H, s)

b) A mixture of 2.46 g of the prepared according to Section (a) tert-Butylimino derivative, 80 ml of dioxane, 2.5 ml of water and 0.78 g of acetic acid are refluxed for 2 hours

heated and reduced to dryness under reduced pressure!

steams. The residue is washed with benzene and an aqueous

609812/1006

2536503

shaken solution of 1.55 g sodium bicarbonate. The organic layer is separated, with water! washed, dried and evaporated to give 2.48 g of crude trans-methyl-5-acetoxy-2-benzyloxy-6-tert-buty1-amino-6 , 7,8,! ^ - tetrahydro-SH-benzocycloheptene-1-carboxylate in the form of a pale yellow syrup.

Nuclear Magnetic Resonance Spectrum (CDC ^) 6: 1.08 (9H, s), 1.23-2.00 (4H, m), 2.03 (3H, s), 2.28-3.38 (4-H, m), 3.86

(3H, s), 5.02 (2H, s), 5.69 (lH, d, J ₌ 7Hz), 6.69. (LH, d), - .7.26 (IH, d), 7 ^ 31 (5g, s) _ .

c) 1.94 g of sodium hydroxide are added to a solution of Z ₁ 4b g of the acetoxy derivative prepared in accordance with section (b) in 60 ml of ethanol

40 ml of water are added «The mixture is 16 hours at Room temperature stirred. After evaporating the solvent under reduced pressure, the reaction mixture is extracted with benzene. The extract comes with Washed water, dried and evaporated. By chromatography of the residue on silica gel 0.86 g of trans-Methy1-2-benzyloxy-6-tert-butylamino-5-hydiroxy-6, 7,8, S-tetrahydro-SH -benzocycloheptene-1-carboxylate obtained in the form of a pale yellow syrup.

Nuclear Magnetic Resonance Spectrum (CDC- £.,). 6: 1.03 (9H _r s) 1.25-3.4-2 (9H, m), 3.84 (3H, s), 4-.22 (lH, d, J-9Hz), - 5.04 (2H, s), 6.92 ( lH, d | J = 9Hz), 7.32 (-5H-, s), 7-.71 (lH, d, J-9Hz reference example 25

a) To a solution of 3.0 g of methyl 2-benzyloxy-5-oxo-6,7,8, S-tetrahydro-SH-benzocycloheptene-1-carboxylate in 30 ml of anhydrous tetrahydrofuran and 50 ml of anhydrous Diethyl ether are 3 ml jDsoamyl nitrite and, while is cooled with ice water, added 10.8 ml of 5% ethanolic hydrochloric acid. The reaction mixture is Stirred for 1.5 hours and under reduced pressure

609812/1006

Evaporated dry. The residue is washed with diethyl ether washed, leaving 2.87 g of methyl 2-benzyloxy-6-hydroxyimino-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate with a melting point of 158.5 to 159 ° C.

Elemental analysis for CgQH

Calculated: C 67.98; H 5.42; N 3.96 Found: C, 67.78; H 5.4-5; N 3.64

b) To a solution of 2.0 g of the hydroxyimino derivative prepared according to section (a) in 53 ml of acetic acid and 13 ml of acetic anhydride are added 2.4 g of Raney nickel. The mixture is left overnight at room temperature stirred under hydrogen at normal pressure. After filtration, the filtrate is evaporated under reduced pressure. The residue is stirred with 50 ml of ice-cold water and 10 drops of pyridine and then extracted with benzene. The extract is washed with water, dried and evaporated. By column chromatography the residue on silica gel (solvent for elution: Ethyl acetate-chloroform (1: 1)) 1.45 g of methyl 6-acetamido-2-benzyloxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo-cycloheptene-1-carboxylate obtained in the form of a pale yellow oil.

Elemental analysis for C ^ H ^ NOr- ■,

Calculated: C 69.28; H 6.08; N, 3.67- Found: G ₁ 69.12; H 6.35; N, 3.48 Nuclear Magnetic Resonance Spectrum (CDC ^) 6:

2.04 (3H, s), 3.92 (2H, s), 4.67-5.27 (IH, m), 5.18 (2H, s), - 6.47-6.90. (LH, m), 6.89 (lH, d), 7.35 (5H, s), 7.92 (lH, d)

609812/1008

c) To a solution of 3.10 g of methyl 6-acetamido-2-benzyloxy-5-OXO-6,7,8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate 1.45 g of sodium hydroxide are added to 60 ml of ethanol, while stirring and cooling with ice. The mixture is stirred for 2 hours and cooled during this. The excess reducing agent is by adding Acetic acid decomposes. By evaporating the solvent and adding water to the residue with subsequent Filtration gives 2.62 g of a white solid. By extracting the filtrate with ethyl acetate and subsequent evaporation gives 0.23 g of an oil. The two substances are united and out Recrystallized ethanol, leaving 1.50 g of trans-methyl-6-acetamido-2-benzyloxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate with a melting point of 138-139 ° C.

Nuclear Magnetic Resonance Spectrum (CDC-C) 5:

1.9O (3H, s), 3.85 (3H, s), 4.66 (lH, d, J = 7Hz), 5.05 (2H, s), 6.15 (lH, d, J = 7.5Hz), 6.74 (lH, d), 7.32 (6H).

By evaporation of the mother liquor and recrystallization of the residue from ethanol-diethyl ether, 0.88 g cis-methyl ~ 6-acetamido-2-benzyloxy-5-hydroxy-6,7,8,9-tetrahydro-SH-benzocycloheptene-1-carboxylate obtained from melting point 117-12O ° C.

Nuclear Magnetic Resonance Spectrum (CDC ^) δ:

1.79 (3H, s), 3.87 (3H, s), 4.95 (lH, s), 5.05 (2H, s), 5.63 (lH, d), 6.74 (lH, d), 7.30 (6H)

d) To a solution of 1.91 g of trans-methyl-6-acetamido-2-benzyloxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate 10 ml of 3N sodium hydroxide are added to 40 ml of ethanol. The mixture is 5 hours on Heated reflux condenser. After evaporation of the solvent, the residue is washed with ethyl acetate and water shaken out. An insoluble white precipitate is

609812/1006

filtered (390 mg). The filtrate is extracted with ethyl acetate. The extract is dried and evaporated, whereby 570 mg of a white powder are obtained. The two substances consist of methyl 6-amino-2-benzyloxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene carboxylate from melting point 167-17O ° C.

Nuclear Magnetic Resonance Spectrum (DMSO-cL) δ:

3.8O (3H, s), 4.37 (lH, d, J = SHz), 5.13 (2H, s), 6.97 (lH, d), 7.37 (5H, s), 7.56 (lH, d)

e) In the manner described in section (d) cis-methyl-6-acetamido-2-benzyloxy-5-hydroxy-6,7,8,9-tetrahydro-SH-benzocycloheptene-1-carboxylate (1.1 g) hydrolyzed with sodium hydroxide. The reaction product is converted to and off its fumarate in a conventional manner Recrystallized ethanol, leaving 200 mg of cis-methyl-6-amino-2-benzyloxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate fumarate with a melting point of 222 to 223 ° C (decomp.).

Nuclear Magnetic Resonance Spectrum (DMSO-dg) δ: 3.?8(3H,s), 4.84 (lH, s), 5.11 (2H ₁ S), 6.38 (lH, s), 6.89 (lH, d, J = 8.5Hz), 7.25 (lH, d, J = 8.5Hz), 7.

Reference example 26

a) To a solution of 8.6 g of 2-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one in 49 ml of concentrated sulfuric acid, a mixture of 4 ml of concentrated nitric acid and 8 ml of concentrated acid is added while stirring Sulfuric acid is added while the reaction temperature is kept below -7 ° C. After stirring for one hour the reaction mixture poured onto 250 g of ice and extracted with ethyl acetate. By evaporating the extract yellow crystals are formed which are washed with benzene, whereby 5.0 g of 2-hydroxy-l-nitro-6,7,8,9-

609812/1006

tetrahydro-SH-benzocyclohepten-S-one can be obtained. Nuclear Magnetic Resonance Spectrum (DMSO-cL-) 6:

1.6-2.9 (4H, m), 2.4--2.9 (4H ₅ Ia) ₁ 6.0 (IH, broad), 7.00

( ¹ H ₅ Ci), 7.62 (lH, d)

b) In the manner described in reference example 23-c, 2-hydroxy-1-nitro-6,7,8,9-tetrahydrQ-5H-benzo-

cyclohepten-5-one benzylated, with 2-benzyloxy-l-nitro-S ^^^ - tetrahydro-SH-benzocyclohepten-S-one in the form of pale yellow leaflets (from methanol) with a melting point of 105 to 107 ° C.

Nuclear Magnetic Resonance Spectrum (CDC ^) δ:

.18 (2H, s), 6.97 (lH, d), 7.32 (5H, s), 7.75 (lH, d)

Reference Example 27 ■ ■.

a) In the manner described in Reference Examples 14 to 18, 2-benzyloxy-1-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one is obtained in 2-benzyloxy-5,6-tert-butylimino-1-nitro-6,7,8,9-tetrahydro-5H-benzocycloheptene (from methanol) converted into yellow flakes with a melting point of 120-122 ° C.

Nuclear magnetic resonance spectrum (CDC ^) δ:

1.07 (9H, s), 5.12 (2H, s),; 6..85 (lH, d), 7.33 (6H, s and d)

received

b) A solution of 2.4 g of the according to section (a) / Imino-

derivative in 55 ml of dioxane _r 2.2 ml of water and 670 mg of acetic acid is refluxed for 12 hours. The reaction mixture is evaporated under reduced pressure and the brown oil obtained is dissolved in benzene, washed with aqueous sodium bicarbonate solution and concentrated. By recrystallization of the residue from methanol, 1.9 g of trans-2-benzyloxy-6-tert-butylamino-1-nitro-6,7,8, g-tetrahydro-SH-benzocyclo-

609812/1006

hepten-5-ol in the form of yellow rods with a melting point 155 to 157 ° C obtained.

Elemental analysis for ^ 00 ^ 28 ^ 2 ^ 4 Calculated: C 68.72; H 7.34; 1Γ 7.29 Found: C 68.68; H 7.13; »7.04 /

Nuclear Magnetic Resonance Spectrum (CDC ^ V) 6:

l.O5 (9H, s), 4.23 (lH, d, J = 8Hz), 5.10 (2H, s), 6.88 (lH, d), 7.2S (5H, s), '7.75 (lH, a)

Reference example

a) By reacting 8.0 g ^ -Benzyloxy-l-nitro-ö, 7,8,9-tetrahydro-SH-benzocyclohepten-S-one 7.2 g of 2-benzyloxy-6-hydroxyimino-1-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one are obtained in the manner described in reference example 25-a) obtained in the form of colorless flakes with a melting point of 218 ° C. (decomp.). Nuclear magnetic resonance spectrum (DKSO-d, :) δ:

5.33 (2H _f s), 7.37 (5H, s), 7.40 (lE, d), 7.9O (lH, d)

b) By reacting 11.6 g of 2-benzyloxy-6-hydroxyiminol-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one in the manner described in Reference Example 25-b) and recrystallization of the product from chloroform-n-hexane 9.3 g of 6-acetamido-2-benzyloXY-1-nitro-6,7,8,9- ■ tetrahydro-SH-benzocyclohepten-S-one in the form of colorless Needles with a melting point of 125-126 ° C were obtained.

Elemental analysis for C _on II _{or .iT o} 0 _r Calculated: C 65.20; H.'5.47; H, 7.61 Found: C, 65.135 K 5.50; II, 7.45

Nuclear Magnetic Resonance Spectrum (DMSO-d ^ -) δ:

1.87 (3H, s), 5.30 (2H, s), 7.32 (lH, d), 7.33 (5H, s), 7.75 (IH, d)

609812/1006

c) 6 - Acetamido-2-benzyloxy-1-nitro-6,7,8,9-tetrahydro-5H-benzocycloliepten-5-one (H, 8 g) is reacted in the manner described in Reference Example 25-c). By add from water to the yellow syrup obtained, a yellow precipitate is formed, which is filtered off and purified by column chromatography is purified on silica gel using chloroform-methanol (50: 1) as the eluent, wherein 2.1 g of cis-6-acetamido-2-benzyloxy-1-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol can be obtained in the form of a powder.

Nuclear Magnetic Resonance Spectrum (DMSO-dg) δ:

1.80 (3H, s), 4.78 (lH, d, J = 5Hz), 5.22 (2H, s), 5.72 (lH, d),

7.10 ^ 1H ^ d), 7.32 (6H, s and d)

Elution is continued with chloroform-methanol (50: 1.5), powdery trans-6-acetamido-2-benzyloxy-1-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol is obtained. By recrystallization from chloroform-n-hexane 4.3 g of colorless needles with a melting point of 175 to 176 ° C. are obtained.

Elemental analysis for .Gp _n HppNpO, - ·} έΗ _ο 0 Calculated: _ C 63.31; H 6.11; N, 7.39 Found: * C_ 63.58; H 5.91; N, 7.10 Nuclear Magnetic Resonance Spectrum (DMSO-d--) δ:

1.80 (3H, s), 4.72 (lH, dxd, - J = 4-Hz, 7Hz), 5.22 (2H, s), 5.5O (lH, d), 7.10 (lH, d), 7.35 (6H, s), 7.53 (lH, d)

d) The trans-acetamido alcohol derivative prepared in accordance with section (c) (4.1 g) is reacted in the manner described in Reference Example 25-b). After cooling it will the reaction mixture is adjusted to pH 9-10 with concentrated hydrochloric acid to cause crystallization. The crystals are filtered off, washed with water, dried and recrystallized from methanol, whereby

609812/1006

2.8 g of trans-e-amino - ^ - benzyloxy-1-nitro-G, 7,8,9-tetrahydro-5H-benzocyclohepten-5-ol from melting point 167 to 169 ° C can be obtained.

Elemental analysis for C ^ oHpgNpCL Calculated: C 65.84; H 6.14; N 8.53 Found: C, 65.73; H 6.07; N_ 8.37 Nuclear Magnetic Resonance Spectrum (DMSO-d, -) δ:

4.42 (lH, d, J = SHz), 5.2O (2H, s), 7.13 (lH, d), 7.35 (5H, s), 7.67 (lH, d) .__

e) To a solution of 0.82 g of the trans-amino alcohol prepared in accordance with section (d) in 40 ml of acetone, 10 ml Tetrahydrofuran, 15 ml of ethanol and 0.3 ml of concentrated hydrochloric acid are added in portions to 1.2 g of lithium cyanoborohydride-dioxane complex given with stirring at room temperature. After 30 minutes, 0.5 ml is concentrated to the solution Hydrochloric acid and, after a further 20 minutes, added 0.4 g of reducing agent, whereupon the mixture overnight is left in the refrigerator. The mixture is evaporated under reduced pressure, the residue with Ethyl acetate extracted and the extract evaporated, leaving 0.9 g of trans ^ -Benzyloxy-ö -isopropylamino-1-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol as a reddish oil which confirms to be p-toluenesulfonate will. Recrystallization from acetone turns colorless Needles with a melting point of 172 to 174 ° C were obtained.

Elemental analysis for C ₂₁ H ₂₆ N ₂ O ^ 'Cr ₇ HgO ₅ S

Calculated: C 61.97; H, 6.32; N 5.16 Found: C ... 62.01; H, 6.14; N_ 5.12 Nuclear Magnetic Resonance Spectrum (DMSO-d) 6:

1.23 (3H, d), 1.32 (3H, d), 2.3O (3H, s), 4.97 (lH, d), 5.27 (2H, s), 7.37 (5H, s) ---

609812/1006

E.g. for example 29

a) To a solution of 3.1 g of 2-benzyloxy-l-nitro-6,7,8,9 + tetrahydro-SH-benzocyclohepten-S-one in 30 ml of ethanol and 10 ml of tetrahydrofuran are given 3.5 g of Raney nickel. The mixture is refluxed in an oil bath while a solution of 2 ml of hydrazine hydrate in. 5 ml of ethanol is added dropwise. After filtering off the Catalyst, the filtrate is concentrated under reduced pressure to a volume of about 20 ml. The residue 1 ml of concentrated hydrochloric acid is added. The solution is diluted with 100 ml of diethyl ether, 2.5 g 1-Amino-2-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one hydrochloride can be obtained in the form of needles with a melting point of 167 to 170 ° C. Nuclear Magnetic Resonance Spectrum (DMSO-cU) δ:

5.28 (2H, s) _s 7.1-7.7 (7H, m), 9.32 (3Hj3reit)

b) The hydrochloric obtained in accordance with section (a) (2.5 g) is dissolved in 40 ml of dimethylformamide and 3 ml of pyridine. 1.5 ml of trifluoroacetic anhydride are added to the mixture added at room temperature. After 30 minutes, the reaction mixture is poured into 400 ml of ice water and extracted with chloroform. The solvent is evaporated and the residue is recrystallized from benzene-n-hexane, wherein 2.9 g of 2-benzyloxy-1-trifluoroacetamido-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one in the form of colorless needles with a melting point of 138-14O ° C can be obtained.

Nuclear Magnetic Resonance Spectrum (CDC ^ -,) δ: 5.10 (2H, s). _f 6.90 (lH, d), 7.38 (5H, s), 7.75 (lH, d), 8.1 (1H, broad)

c) To a solution of 10.2 g of 2-benzyloxy-1-trifluoroacetamido-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one

in 200 ml of acetone 13.8 g of anhydrous potassium carbonate

B0981? / 100S

nat and 3.8 ml of methyl iodide. The mixture will stirred overnight at room temperature. The precipitate formed is filtered off and the filtrate is reduced to min- ' evaporated under the current pressure. The residue is with Chloro-i form extracted, the chloroform extract washed with water and the solvent evaporated. Ethanol is added to the residue, 9.4 g of 2-B'enzyloxy-1- (N-methyltrif luoroacetamido} -6, 7,8,9-tetrahydro-5H-benzocyclohepten-5-one as pale yellow rods with a melting point of 101-102 ° C. Nuclear Magnetic Resonance Spectrum (CDC ^ -,) δ:

3.23 (3H, s), 5.15 (2H, s), 6.98 (lH, d), 7.35 (5H, s), 7.83 (lH, d)

Reference example 30

a) By reacting 6.4 g of 2-benzyloxy-1- (N-methyltrifluoroacetamido) -6,7,8 , 9-tetrahydro-5H-benzocyclohepten-5-one 7.0 g of 2-benzyloxy-1- (N-methyltrifluoroacetamido) -6-hydroxyimino-6,7,8,9-tetrahydro-SH-benzocyclohepten-5-one are obtained in the manner described in reference example 25-a) obtained in the form of a yellow oil.

b) By converting 7.0 g of the hydroxyimino derivative prepared in accordance with section (a) to the reference In the manner described in Example 25-b), 7.3 g of 6-acetamido-2-benzyloxy-1- (N-methyItrifluoroacetamido) -6,7,8,9-tetrahydro-SH-benzocyclohepten-S-one are obtained obtained in the form of a brown oil.

Nuclear Magnetic Resonance Spectrum (DMSO-d) δ:

1.92 (3H, s), 3.22 (3H, s), 4.8 (lH, m), 5.22 (2H, s) ,. 7.20 (IH, d), 7.AO (5H, s), 7.83 (1H ₁ CL), 8.2 (1H, broad)

c) By converting 2.2 g of the acetamido derivative obtained in accordance with section (b) to that in reference example 25-c) described way, 2.1 g of an oil are

609812/1006

hold which was subjected to column chromatography on silica gel using chloroform as the eluent will. The oily substance obtained is recrystallized from methanol, whereby 100 mg of trans-6-acetamido-2-benzyloxy-1- (N-methy1trifluoroacetamido) -6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol can be obtained as colorless platelets with a melting point of 206-208 ° C.

Nuclear Magnetic Resonance Spectrum (DMSO-cU) δ:

1.87 (3H, s) / 3.15 (3H, s), 4.70 (lH, dxd, J = 4Hz, 8Hz), 5.10 (2H, s)

By adding diethyl ether to the mother liquor, 1.8 g of a mixture of the cis and trans derivatives are obtained.

Reference example 31

In the manner described in Reference Examples 14 to 18, 2-benzyloxy-5,6-N-tert-butylimino-1-methylamino-GjVjSjS-tetrahydro-SH-benzocycloheptene is obtained in the form of a brown oil from 2-benzyloxy-l- (N-methyltrifluoroacetamido) -6, 7,8,9-tetrahydro-5H-benzocyclohepten-5-one.

Nuclear Magnetic Resonance Spectrum (CDC-C) δ:

l.O7 (9H, s), 2.67 (3H, s), 1.2-3.2 (8H, m) -, 3.7 (1H, broad) 5.00 (2H, s), 6.73 (lH, d), 6.97 (lH, d), 7.3O (5H, s)

Reference example 32

a) To a solution of 1.0 g of methyl 2-benzyloxy-5-oxo-6,7,8,9-tetrahydro-SH-benzocycloheptene-1-carboxylate 1.1 g of pyridinium hydrobromide perbromide are in 30 ml of chloroform given. The mixture is stirred first at 0 C and then at room temperature for a total of 1.5 hours. The reaction mixture is then poured into ice water and extracted with chloroform. The extract is made with water

6Ö9812 / 10Ö6

washed, dried and evaporated, leaving 1.39 g a brown oil can be obtained. The chromatographic separation of the oil on silica gel (solvent benzene Ethyl acetate (4: 1) gives 840 mg of methyl 2-benzyloxy-6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene carboxylate in the form of a pale yellow oil.

Nuclear magnetic resonance spectrum (CDC-O 6:

5.88 (3H, s), 4.78 (lH, t, J = 6Hz), 5.14- (2H, s), 6.87 (lH, d), 7.33 (5H, s), 7.63 (lH, d)

b) To a solution of methyl 2-benzyloxy-6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate 6.5 g of benzylmethylamine are added to 60 ml of acetonitrile and 20 ml of tetrahydrofuran. The mixture is 4 hours heated on the reflux condenser.

The reaction mixture is evaporated under reduced pressure and the residue is dissolved in 150 ml of ethanol. 5.9 g of sodium borohydride are added to the solution. The mixture is stirred for 4 hours at room temperature. To Addition of acetic acid to decompose the excess hydride, the resulting mixture is reduced Evaporated pressure. Benzene and water are added to the residue. The separated benzene layer is washed with water

washed, dried and evaporated under reduced pressure to give 6.23 g of a crude product be made by chromatography on silica gel and recrystallization is purified from a mixture of chloroform and η-hexane, whereby 629 mg of trans-methyl-2-benzyloxy-6- (N-benzy1-N-methy1amino) -5-hydroxy-6,7,8,9-tetrahydro-SH benzocycloheptene-1-carboxylate is obtained in the form of colorless crystals with a melting point of 121-122 ° C.

609812/1008

Elemental analysis for C _OQ H-, _n O _{/ r} N

do? l '+

Calculated: e 75.48; H 7.01; N 3.14 Found: C 75.21; H 6.85; N 3.04

Nuclear magnetic resonance spectrum (CDC <£) δ 2.07 (3H, s), 3.5O (2H, s), 3.86 (3H, s), 4.9l (lH, d, J = 6Hz), 5.02 (2H, s), 6.73 (lH, d), 7.26 (5H, s), 7.29 ' (5H, s), 7.45 (lH, d)

c) The N-benzyl derivative obtained in accordance with section (b) (481 mg) is reacted in the manner described in Example 24-d), whereby 511 mg of crude trans-2-benzyloxy-6- (N-benzyl-N-methylamino) -1-hydroxymethy1-6,7,8,9 -tetrahydro-SH-benzocyclohepten-S-ol in the form of a pale yellow oil.

Nuclear Magnetic Resonance Spectrum (CDC ^ _x ) §:

1.3-2.0 (4H, treit), 2.1O (3H, s), 2.5-3.3 (3H, m), 3.52 (2H, s), 3.7-4.1 (2H, broad), 4.81 (2H, s), 4.90 (lH, d, J = 7Hz), 5.02 (2H, s), 6.80 (lH, d), 7.3! ( 5H, s), 7.35 (5H, s), 7.46 (lH, d).

Reference example 33

a) cis-6-Acetamido-2-benzyloxy-1-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (2.1 g) is reacted in the manner described in Reference Example 25-b), wherein 1.9 g of cis-6-amino-2-benzyloxy-1-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol can be obtained as a pale brown powder.

Nuclear Magnetic Resonance Spectrum (DMSO-cL) δ:

1.4-2.l (4H, m), 2.4-3.2 (3H, m), 3.6 (3H, _b horse), 4.83 (1H, s), 5.20 (2H, s), 7.10 (lH, d), 7:35 (5H, s), 7.48 (lH, d)

809812 / 100e

b) To a solution of 1.5 g of the cis-amino alcohol prepared according to section (a) in methanol 0.5 ml of concentrated hydrochloric acid is added. The mixture is evaporated to dryness. The residue is again in 10 ml of methanol dissolved. After adding 1.1 g of cyclobutanone, the mixture is stirred for some time at room temperature and treated in the manner described in Reference Example 28-d). The brown oil obtained is poured onto a pebble gel column applied. From the fraction eluted with chloroform containing 1% methanol, 350 mg of cis - ^ - Benzyloxy-S-cyclobutylamino-l-nitroe ^ jS ^ -tetrahydro-SH-benzocyclohepten-S-ol obtained as a brown oil.

Nuclear magnetic resonance spectrum (CDC / -,) δ:

1.3-2.4 (10H, m), 2.5-3.7 (5H, m), 4.3 (lH, m), 4-.78 (lH, d, J = 3Hz), 5.i5 (2H, s), 6.9ü (lH, d), 7.37 (5H, s), _ 7.4-3 (IH, d)

Reference example 34

To an ice-cooled solution of 181 mg of methyl-2-benzytoxy-6-hydroxyimino-5-oxo-6 , 7,8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate in 7 ml of ethanol 37 mg of sodium borohydride are added all at once with stirring. After stirring for 1 hour with the same Temperature, the mixture is neutralized with acetic acid and the solvent is distilled off. The residue will extracted with ethyl acetate and washed with water, dried and evaporated, leaving a white Solid is obtained. By recrystallizing this crude product from a mixture of chloroform and η-hexane gives 150 mg of methyl 2-benzyloxy-5-hydroxy-6-hydroxyimino-6,7,8,9-tetrahydro-5H-benzocycloheptene carboxylate obtained from melting point 1O2-1O3 ° C.

609012 / IOOe

Nuclear Magnetic Resonance Spectrum (CDC-C) δ:

1.52-2.17 (2H, m>, 2.25-3.12 (4H, m), 3.85 (3H, s), 5.03 (2H, s), 5.26 (lH, s), 6.0 (2H, broad., S), 6.62 -6.83 (IH, m), 7.22-7 Λ7 (6H)

example 1

In a mixture of 50 ml of water and 10 ml of methanol, 0.5 g of 1,2-dihydroxy-6-isopropylamino-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-one hydrobromide is added at 0.2 g Reduced platinum oxide as a catalyst. After the uptake of hydrogen has ceased, the catalyst is filtered off. After adding 50 ml of methanol, the filtrate is concentrated under reduced pressure at a temperature of not more than 40.degree. The residue is mixed with diethyl ether and the G _e mixture allowed to stand to give a syrup separates which gradually crystallized. The crystals are filtered off, 370 mg of 1,2, S-trihydroxy-e-isopropylamino-S, 7,8,9-tetrahydro-SH-benzocycloheptene hydrobromide being obtained as an amorphous powder with a melting point of 145-150 ° C. (decomposition).

Elemental analysis for C ^ H ^ O ^ N «HBr

Calculated: ^c 50.61; H 6.67; W 4.22

Found: ^C, 50.28; H 6.97; N 4.23

Example 2

250 mg of 1,2-dihydroxy-6- (α-methyl phen ^1- ethylamino) -6,7, e ^ -tetrahydro-SH-benzocyclohepten-5-one hydrobromide are added to 5 ml of methanol. 0.3 g of sodium borohydride are added in small portions with stirring. The mixture is reacted for 3 hours at room temperature with stirring. The methanol is distilled off under reduced pressure. After adding water, the residue becomes

609812 / $ 100

by adding dropwise in-hydrochloric acid to pH 5 adjusted and extracted with chloroform. The extract is dehydrated. After adding 1 equivalent of methanolic Fumaric acid solution, the solvent is distilled off under reduced pressure. The residue will recrystallized from methanol diethyl ether, 0.1 g of 1,2,5-trihydroxy-6- (o (-methylphenylethylamino) -6, 7,8,9-tetrahydro-51-i-benzocycloheptene fumarate with a melting point of 118-125 ° C (decomp.). This product is a mixture of the cis and trans isomers.

_{Elemental analysis} for C 0n H ₀ E- (X ₂ NC, .ELO ,. Calculated: _c 65.00: H 6.59; N 3.16

Found: _c 64.4-9; H 6.18; N 2.98

Examples 3 to 10

In the manner described in Examples 1 and 2, the products listed in Table 3 are obtained from the corresponding products Raw materials produced.

O NHR _x

609812/1008

Table 3

at
game OH ^R 5 Reduction
procedure salt Enamel
point, ⁰ C
(Decomp.)
etc. OCH ₃ H cataly-
tables
reduction Hydro
bromide Mass spec
dream
m / e,
209.191 4th OH H Watrium
borohydride free 140-142 OCH,
5 ^CH 2 ~ C3 dto. Fuma—
advice Crowds
spectrum
m / e
299,281,
91 6th OBz O It Il II9-I3O 7th OBz CH ^
CHCH ^) Il free 85-95 8th It Hydro-
^ chloride 177-182

Bz = benzyl

609812/1008

Examples 9 and 10

In the manner described in Example 1, the products listed in Table 4 are obtained from the corresponding products Raw materials produced.

CH ^ C

NHE

Table 4

I.
Lead
game Source material ^Z 2 product .Melting point,
⁰ C, etc. 9 ^B 3 H ^E 3 115-125 ° C
(Decomp.) 10 ^CH 2O ^CH 2 ~ O ^CH 2-O Mass spectrum
m / e
25I, 233 CH-,
3 CH-,
3

Example 11

A solution of 1 g of 1,2-dibenzyloxy-6-oxyimino-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-one in 25 ml of anhydrous tetrahydrofuran is added dropwise to a mixture of 0.8 g of lithium aluminum hydride and 12 ml of anhydrous tetrahydrofuran are added. The mixture becomes 1.5 Heated for hours on the reflux condenser. After cooling, 100 ml of tetrahydrofuran and a small amount of a 10% aqueous sodium hydroxide solution added in small portions. The supernatant is made by decanting removed and the remaining precipitate washed several times with diethyl ether. The supernatant and wash liquids are pooled, dehydrated and through

609812/1006

Freed from solvent by distillation. The residue is crystallized from ethyl acetate-petroleum ether, whereby 0.3 g of cis-e-amino-1,4-dibenzyloxy-S-hydroxy-e, 7,8,9-tetrahydro-SH-benzocycloheptene with a melting point of 139-141l.

Elemental analysis for Coc-H ^ nON,

Calculated: C 77.09; H 6.99; N 3.60

Found: C. 77.12; H 6.93; N 3.62

Example 12

Add to a mixture of 2 ml of water and 2 ml of methanol 150 mg of 6-benzyloxycarbonylamino-1,2-bis-benzyloxycarbonyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one given. After adding 150 mg of platinum oxide, the catalytic reduction is carried out at normal pressure, until no hydrogen is absorbed. The catalyst is filtered off and an equivalent amount of methanolic Fumaric acid added to the filtrate. At temperatures not exceeding 30.degree. C., the mixture is reduced under reduced pressure Pressure restricted. Diethyl ether is added to the residue. The mixture is left to stand and the crystals formed filtered off, whereby 30 mg of 6-amino-1,2,5-trihydroxy-6,7,8 , 9-tetrahydro-5H-benzocycloheptene fumarate with a melting point of 185-19O ° C. This product is a mixture of the trans and cis isomers.

Elemental analysis for C-, -, H-. t = O, N "C ^ ELO.
Calculated: c 55.38; H 5.89; N 4.37 Found: c ■ 56.06; H 5.68; N 4.38

609812 / 100S

2S36509

Example 13

0.5 g of cis-6-amino-1,2-dibenzyloxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene are added to 20 ml of benzene solved. 3 g of benzaldehyde and a small amount of ethanolic hydrochloric acid are added to the solution. In a equipped with a dehydration device, the mixture is refluxed for 3 hours, whereupon the benzene is distilled off and crude 1,2-dibenzyloxy-6-benzylideneamino-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene is obtained. This product is dissolved in 15 ml of methanol. With the addition of a catalytic Amount of ethanolic hydrochloric acid and Ig lithium cyanoborohydride, the reaction is 3 hours at room temperature carried out. After adding 10 ml of 10% hydrochloric acid the mixture is stirred for 10 minutes and, after adding 50 ml of water, washed with diethyl ether with 10% strength neutralized aqueous sodium hydroxide solution and extracted with chloroform. The extract is dehydrated and narrowed. Ethanolic hydrochloric acid and diethyl ether are added to the residue, 0.2 g of cis-6-benzylamino-1,2-dibenzyloxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride with a melting point of 177-182 ° C (decomp.).

Elemental analysis for C, ~ H, -, 0-, N * HC €

t> c- 00 0

Calculated: _c 74 ^ 47; H 6.64; N 2.71 Found: _c 74.61; H 6.44; N 2.85

Example 14

To a solution of 130 mg of lithium aluminum hydride in 15 ml of anhydrous tetrahydrofuran are 0.7 g of 6-cyclohexylcarbonylamino-1,2-dimethoxy-6,7,8,9-tetra_ given hydro-5H-benzocyclohepten-5-one. The mixture is refluxed for 4 hours. The reaction mixture is acidified with 10% hydrochloric acid, with chloroform

609812/1006

washed, alkaline with 10% sodium hydroxide solution made and extracted with diethyl ether. The extract is dehydrated and after adding 1 equivalent concentrated methanolic fumaric acid. A 1: 1 mixture of diethyl ether and petroleum ether is added to the residue, wherein 0.4 g of e-cyclohexylmethylamino-S-hydroxy-1,2-dimethoxy-6,7,8,9-tetrahydro-SH-benzocycloheptene fumarate with a melting point of 115-125 ° C.

Example 15

1 g of cis-6-amino-1,2-dibenzyloxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene is dissolved in 40 ml of methanol. 3.5 g of benzyl methyl ketone and then 1.2 g of lithium cyanoborohydride are added in small portions to the solution. The mixture is stirred for 2 hours, after which the methanol is distilled off. The residue is extracted with diethyl ether and the extract is purified by column chromatography on silica gel (developing solvent benzene-ethyl acetate = 9: 1), 0.4 g of cis-1,2-dibenzyloxy-5-hydroxy-6- (α-methyl phen ^ _- , a thy I amino) -6, 7,8,9-tetrahydro-SH-benzocycloheptene can be obtained in the form of an amorphous powder with a melting point of 85-95 C.

Elemental analysis for C - ,,. ILt-A ₇ N

Λμ. .5 / a.

Calculated: C 80.44; H 7.35; N, 2.76 Found: C, 80.18; H 7.13; N, 2.95

Example 16

0.4 g of 6-amino-5-hydroxy-1,2-dimethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene are added to 10 ml of methanol solved. 4 g of cyclohexanecarbaldehyde, a catalytic one, are added to the solution Amount of ethanolic hydrochloric acid and 1 g of lithium cyanoborohydride added. The mixture is at 3 hours Leave room temperature for the reaction. 10 ml of 10% aqueous hydrochloric acid solution are added to the reaction mixture and, after stirring for 10 minutes, 5.0 ml of water

609812/1006

given. The mixture is washed with diethyl ether, neutralized with 10% aqueous sodium hydroxyl solution and extracted with chloroform. The extract is dried and concentrated under reduced pressure. A small amount of ethanol and 0.2 g are added to the residue Fumaric acid and then diethyl ether and petroleum ether added, with 0.4 g of 6-cyclohexylmethylamino-5-hydroxy-1,2-dimethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene fumarate with a melting point of 115-125 ° C (decomp.).

Elemental Analysis for Cp ₀ H ^ -, 0 ^ N * C ^ H ^ 0 ^ · H ₂ O Calculated: _c 61.65; H 7.98; N 3.00 Found: c 6.1.34; H 7.81; N 2.78

Example 17

In 30 ml of methanol, 0.2 g of 6-amino-5-hydroxy-1,2-dimethoxy-6,7, e ^ -tetrahydro-SH-benzocyclohepten and Dissolved 1.5 g of methoxyacetaldehyde. The reduction is carried out with 0.5 g of 5% palladium-on-carbon as a catalyst The catalyst is filtered off and the filtrate is concentrated. 1 equivalent of ethanol is added to the residue Given fumaric acid solution. The ethanol is distilled off and 10 ml of diethyl ether are added to the residue. The powdery precipitate formed is filtered off, 0.15 g of 5-hydroxy-1,2-dimethoxy-6- (2-methoxyethylamino) -6,7,8 ^ -tetrahydro-SH-benzocycloheptene fumarate can be obtained in the form of a hygroscopic colorless powder.

Elemental Analysis for C ^ iW O ^ N · C ₄ H ^ O ₄ Calculated: c 58.35; H 7.10; N. 3 Found: C 57.99; H 7.35; N 3

609812/1006

Nuclear magnetic resonance spectrum (DFiSO-dg, 100 MHz: δ 3.3, 3.7, 3.9.

Examples 18-22

The compounds listed in Table 5 are obtained by reducing alkylation of the appropriate starting materials in the manner described in Examples 15 and 16 prepared.

^E l

ρ - JA ^ - \ Carbonylver-2 T 'if> b indu ng

OH NH ₂ OH

60 9 8 12/100 6

Table 5

at
game Carbonyl
binding E-] -E-] ⁼ Ep ^B ? salt
(Configuration) Melting point, C.
(Decomp.) 18th Benzaldehyde OBz ^CH 2 ~ Ö Hydrochloride
(ice cream) 177-182 19th Cyclohexanone OCH ₃ OCH ₂ -O Fumarate 125-135 20th Cyclohexenone OCH ₇ , It Fumarate 125-135 21 acetone OH .CH
CH °
^S CHL Hydrobromide 145-150 22nd äensylmethyl-
ketone OH CH-,
CH-CH _? - <Q> Fumarate
(ice cream) 137

Bz = benzyl

CO

K)

cn

CD

cn ο

CD

Example 23

In the manner described in Example 17, 1,2-dimethoxy-6-oxyimino-6,7,8,9-th trahydro-BH-benzocycl.ohepten-S-one in the presence of cyclohexanone and platinum oxide catalytically reduced, whereby 6-cyclohexylamino-1,2-dimethoxy-6,7,8,9-tetrahydro-SH-benzocyclohepten-B-ol with a melting point of 128-135 ° C.

Example 24

650 mg of 1,2-dibenzyloxy-5,6-tert-butylimino-6,7,8,9-tetrahydro-SH-benzocycloheptene are dissolved in 30 ml of dioxane solved. 36 ml of 5% strength sulfuric acid are added to the solution. That The mixture is left to stand for 3 days at room temperature. The reaction mixture is made with sodium hydrogen carbonate neutralized and then extracted with chloroform. The extract is dehydrated and concentrated. The residue is purified by column chromatography on silica gel (benzene-acetone = 9: 1), whereby 300 mg of trans-1,2-di-benzyloxy-6-tert.-butylamino-S-hydroxy-ö, 7,8,9-tetrahydro- 5H-benzocycloheptene can be obtained in the form of crystals with a melting point of 91-95 ° C.

Elemental analysis for ΟοοΗ ^ Ο-, Ν

Calculated: C 78.17; H 7.92; N 3.14 Found: C 78.87; H 7.56; N 3.11

Examples 25 to 29

In the manner described in Example 24, the compounds listed in Table 6 are obtained from the corresponding compounds 5,6-imino derivatives produced.

609812/1006

pi

I _x /

OH NHR,

Table 6

at
game Ri ⁼ Ri ⁼ Rp H salt
(Configuration) Enamel
point, ° _c
(Decomp.) 25th OH CH,
-CH < ⁵
CH,
0 Hydrobromide 145-150 26th OCH, -H free 140-142 27 OBz -CHCH ₂ - ^ free ■ 85 - 93 28 OCH, -O Fumarate 119-130 29 OH -C (CH ₅ ) ₃ Fumarate
(trans) 215-216

Bz = B enz yl

Example 30

In 30 ml of dioxane, 0.5 g of 1,2-diacetyloxy-5,6-tert-butylimino-6, VjSjS-tetrahydro-SH-benzocycloheptene are added solved. 36 ml of 5% strength sulfuric acid are added to the solution. That The mixture is left to stand for 3 days. The reaction mixture is neutralized with sodium hydrogen carbonate and with n-butanol extracted. The extract is dehydrated, and after adding 1 equivalent of fumaric acid, the n-butanol is distilled off. The residue is made from methanol-diethyl ether

609812/1006

recrystallized, whereby 0.2 g of 6-tert-butylamino-1,2,5-trihydroxy-6,7,8, g-tetrahydro-SH-benzocycloheptene fumarate with a melting point of 212-213 ° C (decomp.).

Elemental analysis for ^ cH 0 ^ N- ¹ / £ (C _{/ +} H _{/ +} 0 ^ -HpO) Calculated: c 61.43; H 7.58; N 4.21 Found: C 61.19; H 7.39; N 4.27

Example 31

700 mg of trans-1,2-D.ibenzylo.xy-6-tert-butylamino-S-hydroxy-G, 7,8,9-tetrahydro-5H-benzocycloheptene are dissolved in 15 ml of methanol solved. The catalytic reduction is carried out at normal pressure in the presence of 700 mg of 10% palladium carbon carried out as a catalyst. When no more hydrogen is absorbed, the catalyst is filtered off, whereupon 1 equivalent of methanolic fumaric acid solution is added to the filtrate and the methanol is distilled off. Of the The residue is recrystallized from methanol-diethyl ether, with 430 mg of trans-6-tert-butylamino-1,2,5-trihydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene fumarate with a melting point of 215-216 ° C (decomp.).

Elemental analysis for C ₁₅ H ₂₅ O ₃ N _{7 + 442} ) Calculated: C 61.43; H 7.58; N, 4.21 Found: C, 61.16; H 7.78; N 3.94 Examples 32 to 40

In the manner described in Example 31, the products listed in Table 7 are prepared with the aid of the following Reaction produced:

609812/1006

BzO

BzO

OH NHR

Fumarate

NHR.

Bz: benzyl

Table 7

example product configuration Enamel
point, C
(Decomp.) 32 R ^ ice cream 137 CE,
-CHCH ₂ - (Q * ice cream 197-200 34 -H trans 183-185 35 -H trans 210-212 36 -CH ₅ ice cream 176-178 37 ice cream 186-189 38 CH-,
-CH < ³
CH-,
3 trans 184-186 39 CH-,
-CH < ⁵
CH-, trans 140-145 40 CH ₃
-CHCH ₂ - ^ - OH trans 169-171 -O

60981 2/1006

Examples 41 and 42

The following in Table 8 under the column "Product" The compounds mentioned are converted from the compounds mentioned under the "Starting material" column to those in Example 31 described manner produced.

Table 8

Example]

42

Output compound

OCH

CH ^ O

OH N-CH, ι 3

Bz

OCOOBz

product
(Salt)

OCH

GE ₇ Q

i .NHCH ^

(Fumarate)

OH NHCOOBz OH

(Fumarate)

Melting point, ⁰ C (dec.)

etc.

Mass spectrum
(m / e), ( ⁺ )

185-190

Bz = benzyl

Example 43

300 mg of cis-6-acetylamino-1,2,5-triacetyloxy-6,7,8, g-tetrahydro-SH-benzocycloheptene are added to 3 ml of methanol given, whereupon 3 ml of 10% hydrochloric acid are added. That The mixture is heated to 90 ° C. for 1 hour and then concentrated under reduced pressure. The residue is with Neutralized sodium hydrogen carbonate and extracted with n-butanol. The extract is dehydrated. After adding

609812/10 0 6

the solvent is distilled off from 1 equivalent of fumaric acid. Diethyl ether is added to the residue. The deposited crystals are obtained from methanol-diethyl ether recrystallized, with 100 mg of cis-6-amino-1,2,5-trihydroxy-6 , -7, 8, 9-tetrahydro-5H-benzocycloheptene umarate vom Melting point 197-2OO ° C can be obtained.

Example 44

100 mg of 6- (N-cyclohexyl-N-trifluoroacetylamino) -5-trifluoroacetyloxy-1,2-dimethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene are added to 5 ml of 1% strength hydrochloric acid given. The mixture is heated to 60 ° C. for 45 minutes. The reaction mixture is concentrated under reduced pressure and the Neutralized residue with sodium hydrogen carbonate and extracted with chloroform. The extract is dehydrated and the solvent is distilled off. The residue is uniform by adding 50 mg of fumaric acid and one a small amount of ethanol dissolved. By adding diethyl ether, 100 mg of δ-cyclohexylamino-S-hydroxy-1,2-di- methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene fumarate from Melting point 119-128 ° C obtained.

Example 45

230 mg of 1,2-dibenzyloxy-6- (N-benzyl-N-trifluoroacetylamino) -5-trifluoroacetyloxy-6,7,8,9-tetrahydro-5H-benzocycloheptene are dissolved in 3 ml of methanol solved. 3 ml of 1% strength aqueous sodium hydroxide solution are added to the solution. The mixture is heated to 60 ° C. for 1 hour and then concentrated under reduced pressure and extracted with chloroform. The extract is dehydrated and freed from the solvent by distillation. The residue is in a small amount Ethanol hydrochloric acid dissolved. Diethyl ether is added to the solution. The crystals formed in this way are filtered off, whereby 80 mg of 6-benzylamino-1,2-dibenzyloxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene hydrochloride obtained from melting point 177 to 182 ° C (decomp.)

609812/1006

2536503

will.

Example 46

A mixture of 1 g of 1,2-dibenzyloxy-6-ethoxycarbonylamino-6,7,8,9 ~ tetrahydro-5H-benzocyclohepten-5-one, 1 g of lithium aluminum hydride and 50 ml of tetrahydrofuran is heated for one hour with stirring on the reflux condenser. To After cooling, 100 ml of diethyl ether and 10 ml of water are added to the reaction mixture. The organic layer will separated, dried and concentrated under reduced pressure. By adding diethyl ether to the residue Crystals formed are recrystallized from methanol, 0.3 g of trans-1,2-dibenzyloxy-6-methylamino-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-ol can be obtained in the form of colorless crystals with a melting point of 153-154 ° C.

Elemental analysis for C ^ H ^ O ^ N

Calculated: C 77.59; H. 7.24; N 3.47

Found: C 77 Λ3; H 7.19; N 3.41

Nuclear magnetic resonance spectrum (100 MHz, CDCl.,) 6: 4.36 (1H, d, J = 8 Hz)

Examples 47 and 48

0.5 g trans-1,2-dibenzyloxy-6-ethoxycarbonylamino-6,7,8,9 tetrahydro-SH-benzocyclohepten-S-ol is based on the example 46 described manner, where 0.2 g of trans-1,2-dibenzyloxy-6-methy1amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol can be obtained. The mixed melting point and the infrared spectrum determine that the product with the product prepared according to Example 46 is identical.

In the same way, the cis-isomer becomes the above said starting compound cis-1,2-dibenzyloxy-6-methylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol obtained in the form of colorless crystals with a melting point of 136-139 ° C.

609812/1006

Elemental analysis for '26 ^ 29 ^ 3 ^ Calculated: ^C 77.39; H 7 _; 2Ψ; Ν 3Λ7 Found: ^c 76.75; H_ 6.96; N 3.22

Nuclear magnetic resonance spectrum (100 MHz, CDCl-) ^ 4.77 (IH, d, J = 2 Hz)

Examples 49-52

In the manner described in Example 15, the products mentioned in Table 9 by reducing the corresponding starting materials produced.

Ausqanasmaterial product

OBz OBz

BzO - ^ Sr ^ \ ^H 2 BzO

Carbonyl

connection ' _0H " _NHR

609812/1006

Table 9

ο co OO

O O σ>

example Carbonyl compound
manure product ^Ie 3 configuration S a.l ζ: Melting point, ⁰ C
(Decomp.) 4-9 acetone -CH,
-CH ^5
X CH,
3 ice cream free 150-153 50 acetone .CH
-CH °
^N CH,
3 trans Fumarate 207-208 51 p-hydroxybenzyl
methyl ketone CH,
-CHCH ₂ - ^ - OH trans Fumarate 203-206 52 Cyclobutanone O trans Fumarate 210-212

-ο -j

Bz = benzyl

Example 53

1.7 g of 1,2-dibenzyloxy-5,6-tert-butylimino-6,7,8,9-tetrahydro-5H-benzocycloheptene are added to 50 ml of anhydrous dioxane solved. A solution of 0.39 g of sulfuric acid in 10 ml of dioxane is added dropwise to the solution. That The mixture is stirred for 2 hours at room temperature. After adding 100 ml of diethyl ether to the mixture, the The supernatant is discarded and the residue is left to stand overnight after adding 100 ml of dioxane and 50 ml of water. The mixture obtained is neutralized over sodium bicarbonate and extracted with chloroform. the the separated chloroform layer is dried and concentrated under reduced pressure. The chromatographic Purification of the residue on a silica gel column with subsequent production of the oxalate in a manner known per se Manner gives 0.38 g of trans-1,2-dibenzyloxy-6-tert-butylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-oloxalate in the form of colorless crystals with a melting point of 167-169 ° C.

Elemental analysis for ^ 2 ^t ^ " ⁷ ₎ ^c P '^' ⁽ ^ 2 ^ '2 ^ ^{> lJ} r Calculated: C, 69.51; H 6.96; N 2.62

Found: C, 69.24; H 6.9 ^; N 2.85

Example 54

A mixture of 1.35 g of trans-6-acetylamino-1,2-dibenzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol and 12 g of sodium hydroxide in 70 ml of ethanol and 20 ml of water is 5 Heated for hours on the reflux condenser. After cooling, the mixture is poured into an excess amount of water and extracted with chloroform. The organic layer is separated, dried and concentrated under reduced pressure. After adding diethyl ether to the residue, 0.8 g of trans-6-amino-1,2-dibenzyloxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-oil separates from melting point 181-183 ° C Fo rm voη far mere n

60981 11 1006

Crystals.

Elemental analysis for C _{2 cH 20} O ₇ -N ·} £ Η ₂ 0

Calculated: C 75.35; H 7.08; N 3.52

Found: C 75.32; H 7.19; N 3.44

By adding p-toluenesulfonic acid to a solution this product in methanol becomes a p-toluenesulfonate of the above-mentioned 6-amino derivative formed, which crystallizes on addition of diethyl ether to the solution. Melting point 165-168 ° C.

Elemental analysis for C _or -H _or , 0 ^ N'C ₀ H ₀ O ^ S

dr) c- (t> r <-> y

Calculated: C 68.43; H 6.28; N 2.49

Found: C 68.00; H 6.15; N 2.61

Nuclear magnetic resonance spectrum (100 MHz CL - DMS0 + D ₂ O) δ: 4.73 (lH, d, J = IOHz)

Example 55 ,

In the manner described in Example 54, 0.33 g of trans-6-amino-1,2-dibenzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol from 0.5 g of trans-1,2-dibenzyloxy-6-ethoxycarbonylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol obtain. The product is identical to the product prepared according to Example 54.

Example 56

To a solution of 322 mg of methyl 6-acetamido-2-benzyloxy-5-oxo-6,7,8, S-tetrahydro-SH-benzocycloheptene-carboxylate 200 mg of lithium aluminum hydride are added to 10 ml of tetrahydrofuran. The mixture is 3 hours heated on the reflux condenser, whereupon ethyl acetate, ethanol and water are added one after the other. the the separated organic layer is dried and evaporated to give 350 mg of a residue which then by preparative chromatography (silica gel)

609812/1006

is cleaned. The silica gel layer on which the desired compound is adsorbed is removed and the compound is eluted with a mixture of chloroform and methanol (volume ratio 9: 1). By Evaporation of the solvent gives 76 mg of trans-2- benzyloxy-6-ethylamino-1-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol obtained as a viscous oil.

Nuclear Magnetic Resonance Spectrum (CDC-C) δ:

1.10 (3H, t), 2.88 (3Hwide, s), 4-.4A (IH, d, J = 8Hz), 4.80 (2H, s), 5.06 (2H, s), 6.81 (lH, d), 7.3 ^ (5H, s), 7.64- (lH, s)

Example 57

In a mixture of 40 ml of acetone and 10 ml of methanol, 710 mg of trans-e-amino ^ -benzyloxy-1-methylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol solved. 0.4 ml of concentrated hydrochloric acid are added to the solution. The mixture will stand for some time at room temperature left, whereupon 1.1 g of lithium cyanoborohydride — dioxane— Complex can be added to the mixture in small portions. The reaction mixture is 2 hours at room temperature stirred, mixed with water and stirred for some time, whereupon the solvent under reduced Pressure is distilled off. The residue is then dissolved in ethyl acetate and washed with water. Evaporation of the solvent under reduced pressure gives 620 mg of a brown oil. By Recrystallization from a mixture of benzene and η-hexane becomes trans-2-benzyloxy-6-isopropylamino-l-methyl - amine-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-oil in Obtained in the form of colorless needles with a melting point of 92 to 95 C.

Nuclear magnetic resonance spectrum of its hydrochloride (DMSO-dg) δ :

1.22 (5H, d), 1.32 (3H, d), 2.63 (3H, s), 4-.85 (lH, d, J = SHz), 5.08 (2H, b), 5.8 (3H, broad), 6.78 (lH, d), 6.97 (lH, d),

609812/1006

Example 58

620 mg of trans-e-Amino ^ -benzyloxy-1-nitro-δ, 7,8,9-tetrahydro-5H-benzocyclohepten-5-ol are dissolved in a mixture of 15 ml of ethanol and 5 ml of methanol and over 76 mg of 10% palladium carbon as a catalyst at normal Hydrogenated under pressure and normal temperature. The catalyst is filtered off and the filtrate under reduced pressure Pressure concentrated to dryness. The residue is dissolved in methanol. After adding 400 mg of fumaric acid, the mixture concentrated. The crude product obtained is redissolved in water. The by adding tetrahydrofuran Crystals deposited for the solution are recrystallized from water, 108 mg of trans-1,6-diamino-2-hydroxy-5,7,8,9-tetrahydro-SH-benzocyclohepten- ■ 5-ol can be obtained in the form of colorless rods with a melting point of 240 ° C. (decomp.).

Nuclear magnetic resonance spectrum of the free base (DMSO-dg) 8 l 4.28 (IH, d, J = 8 Hz).

Elemental Analysis for C ₁₁ H ₁₆ N ₂ O ₂ ^ (C ^ H ^ O.) Calculated: _c 58.63; H 6.81; N 10.52 Found: _c 58.41; H 6.77; N 10.37

Examples 59 to 61

In the manner described in Example 58, the products listed in Table 10 are obtained by catalytic hydrogenation obtained from the corresponding starting materials.

Starting material product

\ jr- Hi- OH ^ O ~ xy rr \ üv ~ -t »" IT \....

⁶ 5 2 r T>. If I> (fumarate)

609812/1006

Table IC

O O

Z >

(SO

example CH,
Γ.ττ / ί
CH ₂
0 Configu
ration Appearance of the crystals
(Solvent for
Recrystallization) Melting point, ⁰ C
(Decomp.) NMR spectrum of the
free base
(DMS0-d _c ) (P. J)
Ί
> 59 CH ₂
ι 9
-C-CH ₅
CH-,
0 trans colorless rods
(Methanol-water-ether) 215 4.27 (lH, d, J = 8Hz) 60 -ο trans colorless platelets
(Ethanol ether) 225 4.05 (lH, d, J = 8Hz) 61 ice cream colorless platelets
(Methanol ether) 220 4.60 (lH, s, wide)
IN
C.
- -. t,

(J)

O CO

Example 62

430 mg trans-e-amino ^ -benzyloxy-l-methylamino-e, 7,8,9- tetrahydro-SH-benzocyclohepten-S-ol are in one Mixture of 15 ml of tetrahydrofuran and 15 ml of methanol and dissolved over 245 mg of 10% palladium carbon at normal pressure and normal temperature until hydrogen is no longer absorbed. The catalyst is filtered off and the filtrate was evaporated under reduced pressure. The residue is dissolved in methanol and a small amount Amount of n-propanol dissolved. After adding 300 mg of fumaric acid to the solution, the mixture is coated with activated charcoal treated. By adding diethyl ether to the filtrate, 185 mg of trans-6-amino-2-hydroxy-1-methylamino-6,7,8, g-tetrahydro-SH-benzocyclohepten-S-ol-fumarate are separated as a white precipitate.

Elemental _analysis for C-, _Ο Η Ί 0N ₀ O ₀ -Cy ₁ H, 0, * CH _n OH-JaH 0 Calculated: c 56.27; H 7.26; N 6.72 Found: c 56.00; H 7.67; N 6.88

Nuclear magnetic resonance spectrum of the free base (DMSO-dg) S: 4.32 (IH, d, J = 8 Hz)

Examples 63-73

In the manner described in Example 62, the products listed in Table 11 are obtained by catalytic hydrogenation of the corresponding starting materials.

Starting material product

(Fumarate)

OH NHR ^ OH NHR,

60981 2/1006

Tabel

ο cd οο

For example -NHCH _x ^E 3 <onfigura—
bion Appearance of the crystals
(Solvents for
crystallization) Enamel
point, oc
(Decomp.) Nuclear magnetic
Resonance spectrum
(DMSO-d _c ) ο
b 63 -NHCH,
3 CH,
-CH < ⁵
CH-,
3 trans colorless prisms
(Water-methanol-ether) 211 free ease
4-.4O (lH, d, J = 8Hz) & 4 -CHgOH CH,
I 3
-C-CH,
ι 3
CH _x trans colorless rods
(Water tetrahydrofuran) 235 free base
4.18 (lH, d, J = 8Hz) 65 -CHgOH -CgH ₅ trans colorless fine crystals
(Ethanol ether) 193 free base
4.58 (IH, d, J = SHz) 66 -CHgOH CH,
-C-CH,
ι 5
CH ₂
3 trans colorless fine crystals
(Ethanol) 212-213 free base
4.17 (lH, d, J = 8Hz) 67 -CH < ⁵
CH,
3 ice cream colorless fine crystals
(Ethanol diethyl ether) 195-205 Fumarate
4.84 (s)

Table 11 (cont.)

example C.
^ιΧ 1 = ^Λ 1 CH,
-CH <5
CH, Configu
ration ice cream appearance of the crystals
(Solvents for
crystallization) Enamel
point, ^
(Decomp.) Nuclear magnetic
Resonance spectrum
(DMSO-d ₆ ) 68 -CHgOH -O trans trans colorless fine crystals
(Ethanol diethyl ether) 197 free base
4.82 (lH, d, J = 8Hz) 69 -CHgOH - dto. 185 - 70 -CHgOH CH ₃ t ^ -
-CHCH _p - / 3-0CH ^ 1 colorless fine crystals
(Isopropanol) 110 - 71 -CHgOH CH ₃
-CHCHgH ^ colorless fine kri
stalls
(Isopropanol
Acetonitrile) 138 - 72 -CHgOH -H colorless granules
(Isopropanol
Acetonitrile) 171 free base
4.79 (s) 73 -CHgOH -O colorless, fine platelets
(Ethanol diethyl ether) 197-199 Fumarate
4.95 (lH, d, J = 8Hz)

Example 74 j

i 511 mg of trans -2-benzyloxy-6- (N-benzyl-N-methylamino) -lhydroxymethyl 1-6,7,8,9-tetrahydro-5H-benzacyclohepten-5-ol are dissolved in 30 ml of ethanol and over 500 mg of 10% palladium carbon overnight at normal pressure and normal temperature hydrogenated. The catalyst is filtered off and the filtrate under reduced pressure to Evaporated dry. The residue is dissolved in 10 ml of ethanol. 80 mg of fumaric acid are added to the solution. The mixture is stirred for some time and concentrated to about 5 ml under reduced pressure.

By adding about 30 ml of diethyl ether to the concentrate, trans ^ -hydroxy-1-hydroxymethyl-o-methylamino-6 , 7, e ^ -tetrahydro-SH-benzocyclohepten-S-olfumarate precipitated, which is filtered off to give 222 mg of the compound having a melting point of 105-108 ° C. (decomp.) will.

Elemental analysis for C _1x H

Calculated: ^ 59.20-, H, 7.29; N, 4.60 Found:. _c? 59.27; H, 7.64; N, 4.01 Nuclear Magnetic Resonance Spectrum (DMSO-d, -) δ:

2.5O (3H, s), 4.50 (2H, s), 6.4l (lH, s), 6.62 (lH, d), 7.04 (lH, d)

Example 75

In a solution of 9 g of sodium hydroxide in 20 ml of water and 50 ml of ethanol, 2.6 g of 6-acetamido-2-benzyloxy-1- (N-methyltrifluoroacetamido) -6,7,8,9-tetrahydro-5H-benzocycloheptene-5-oil are obtained solved. The resulting solution is refluxed for 2 hours and then cooled adjusted to pH 3 with concentrated hydrochloric acid. The ethanol is distilled off under reduced pressure and the remaining aqueous layer with ethyl acetate

609812/1006

wash, adjusted to pH 9 to IO with potassium carbonate and after adding a saturated sodium chloride solution with a mixture of chloroform and ethyl acetate (4: 1) extracted. Evaporation of the solvent from the extract under reduced pressure gives a yellow oil, which crystallizes in colorless platelets after the addition of ethanol. The crystals are filtered off and washed with ethanol, 1.2 g of trans-6-amino-2-benzyloxy-1-methylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol with a melting point of 150-151 ° C.

Nuclear Magnetic Resonance Spectrum (CDC ^) δ:

2.67 (5H, s), 4.48 (1H ₁ Cl, J = SHz), 5.08 (2H, s), 6.82 (lH, d), 7.37 (lH, d), 7

Example 76

To a solution of 2.1 g of 2-benzyloxy-5,6- (N-tert-butylimino) -1-methylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene 0.9 g of acetic acid are added to a mixture of 60 ml of dioxane and 10 ml of water. The received Solution is refluxed for 75 minutes and then left to cool, whereupon 1.5 g of potassium carbonate and 20 ml of water are added to the reaction mixture. The dioxane is distilled off under reduced pressure. The remaining aqueous solution is extracted with benzene and the extract is washed with water, dried and evaporated under reduced pressure to give 2.0 g of a brown oil. By chromatographic purification of the oil on silica gel using a mixture of chloroform and methanol (100: 1) 1.0 g of trans-2-benzyloxy-6-tert-butylamino-1-methylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol is used as the eluent obtained as a brown oil.

609812/1008

Nuclear magnetic resonance spectrum. (CDC ^) δ

l.O8 (9H, s), 1.3-2.8 (6H, m), 2.68 <3H, s), 3 -, ^ 4.32 (lH, d, J = SHz), 5.08 (2H, s), 6.8 ₅ ( lH, d), 7.35 (lH, d),

Example 77

645 mg of methyl trans-6-amino-2-benzyloxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate are added to a mixture of 30 ml of cold methanol and 10 ml of tetrahydrofuran and 0.9 ml of cyclobutanone and then 1.0 g of lithium cyanoborohydride-dioxane complex given in small portions while stirring. The mixture is stirred for an additional 20 hours, and methanol and tetrahydrofuran are distilled off.

Ethyl acetate and water are added to the residue. The organic layer is separated, washed with water, dried and evaporated to dryness. In 3 ml of anhydrous tetrahydrofuran, 360 mg of des Dissolved residue. The solution is added dropwise to a mixture of 100 mg of lithium aluminum hydride and 3 ml given anhydrous tetrahydrofuran. The reaction mixture is refluxed for 2 hours and then treated with water and extracted with ethyl acetate. The extract is washed with water, dried and used for Evaporated dry. The residue is recrystallized from ethyl acetate, trans-2-benzyloxy-6-cyclobutylamino-1-hydroxymethy1-6,7,8, S-tetrahydro-SH-benzocyclohepten-5-ol is obtained in the form of colorless platelets with a melting point of 137-141 ° C.

Nuclear Magnetic Resonance Spectrum ^

'4.37 (1H, d, J = 8.4Hz), 4.78 (2H, s), 5.06 (2H, s), 6.82

, 7.2O-7.5O (5H, m), 7.65 (lH, d, J = 8.

6 0 9 8 1 11 1 0 0.8

Example 78

500 mg of trans-methyl-6-amino-2-benzyloxy-5-hydroxy-6,7,8, g-tetrahydro-SH-benzocycloheptene-1-carboxylate
with 40 ml of acetone to that described in Example 77
Wise reacted, whereby 376 mg of trans-2-benzyloxy-l-hydroxymethyl-6-isopropylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol in the form of a pale brown oil
can be obtained.

Nuclear Magnetic Resonance Spectrum (DMSO-cL-) δ:

O.93 (3H, t, J = 6Hz), 4-A2 (lH, d, J = 8Hz), 4.63 (2H, s), 5.08 (2H, s), 6.87 (lH, d, J = 8.5Hz), 7.23-7.62 (6H, m)

Example 79

tetrahydro SH-benzocycloheptene-1-carboxylate fumarate
are reacted with 40 ml of acetone in the manner described in Example 77, with 215 mg of cis-2-benzyloxy-1-hydroxymethyl-6-isopropylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol having a melting point of 134- 138 C.

Elemental analysis for C _oo H _OQ 0, N Calculated: C 74.33; H 8.22; N 3.94 Found: C 73.91; H 8.23; N 3.64-

Example 80

520 mg of trans-methyl-6-amino-2-benzyloxy-5-hydroxy-6,7, -8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate are reacted with 4 g of cyclohexanone in the manner described in Example 77, 379 mg of trans-2-benzyloxy-6-cyclohexylamino-1-hydroxymethy1-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol in the form of a pale yellow oil.

609812/1006 '

Nuclear Magnetic Resonance Spectrum (CDC- ^) δ: 4.34 (lH, d, J = 8Hz), 4.78 (2H ₁ S), 5.05 (2H, s), 6.82 (1H, d, J = 8.5Hz), 7.38 (5H, s), 7.65 (lH, d, J = 8.5Hz)

Example 81

To a suspension of 600 mg trans-methyl-6-amino-2-benzyloxy-5-hydroxy-f) , 7,8, ^ tetrahydro-SH -benzocycloheptene-1-carboxylate 1.2 g of methyl p-methoxybenzyl ketone are dissolved in 15 ml of benzene and 0.1 ml of 5% alcoholic hydrochloric acid. The resulting mixture is 2 days at Stirred room temperature, the solvent evaporated under reduced pressure and the residue in a Dissolved mixture of 30 ml of tetrahydrofuran and 30 ml of ethanol. 800 mg of lithium cyanoborohydride-dioxane complex are added to the solution within 20 minutes while stirring given. The mixture is stirred for a further 2 hours at room temperature. The reaction mixture is then with concentrated hydrochloric acid slightly acidified and. the solvent is distilled off. The residue is taking further dried under high vacuum and redissolved in anhydrous tetrahydrofuran. This solution becomes lithium aluminum hydride added in excess, whereupon the mixture is refluxed for 3.5 hours.

Ethyl acetate and water are added to the reaction mixture. The ethyl acetate layer is separated with Washed water, dried and evaporated to dryness. By chromatographic purification of this residue on a silica gel column using chloroform-methanol (3: 1) as elution solvent, 166 mg trans-2-benzyloxy-l-hydroxymethyl-6- (4-methoxy-a-methyl-

phenäthy1} amino-6,7,8, g-tetrahydro-SH-benzocyclohepten- · 5-one obtained as a pale yellow oil.
Nuclear Magnetic Resonance Spectrum (CDC ^ _7. ) Δ:

1.03 (3H, d, J = 6Hz), 3.77 (3H, s), 4.40 (lH, d, J = 8Hz), 4.80 (2H, s), 5.11 (2H, s), 6.70-7.80 (llH, m)

609812 / 1Q06

Example 82

500 mg of trans-methyl-δ-amino-1-benzyloxy-S-hydroxy-δ, 7, -8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate will

with 1, 'O g of methyl p-hydroxybenzyl ketone on the game 81 described manner implemented, with 78 mg of 2-benzyloxy-1-hydroxymethy1-6- (4-hydroxy-a-methylphen— ethyl) amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol in the form of a pale yellow GI (analysis by thin layer chromatography shows that the Product is a mixture of the cis and trans isomers).

Nuclear Magnetic Resonance Spectrum (CDC ^ -,) δ:

1.01 (3H, d, J = 6Hz), 4.32C - # H, d, J = 7Hz), 4.67 (- # H, s), 4.76 (2H, s), 5.0J (2H, s), 6.62-7.03 (5H, m), 7.20-7.70 (6H, m)

Example 83

Methyl 1-2-benzyloxy-6-hydroxyimino-5-oxo-6,7,8,9-tetrahydro-SH-benzocycloheptene-1-carboxylate is dissolved in 10 ml of acetic acid and hydrogenated over 500 mg of Raney nickel at normal temperature and normal pressure. The reaction mixture is filtered under flowing nitrogen so that the filtrate falls into 0.4N hydrochloric acid, the is used in a slight excess. The filtrate obtained in this way is evaporated under reduced pressure and finally dried under high vacuum, whereby 280 mg of crude methyl G-amino ^ -benzyloxy-S-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-1-carboxylate be obtained in the form of a yellowish green solid. The crude product is treated with lithium aluminum hydride for 3.5 hours treated in 10 ml of tetrahydrofuran, which is heated on the reflux condenser.

Ethyl acetate and water are added to the reaction mixture. The organic layer is separated and taken under

60981 2/1008

evaporated to dryness under reduced pressure. The residue is purified by passing it through a silica gel column and from a mixture of chloroform and diethyl ether recrystallized, whereby 102 mg of trans-6-amino-2-benzyloxy-1-hydroxymethy1-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-ol from melting point 138 to 140 ° C can be obtained.

Example 84

In a mixture of 10 ml of xylene and 5% ethanol Hydrochloric acid is 660 mg of trans-6-Amino_2-benzyloxy-1-nitro-6,7,8 ^ -tetrahydro-SH-benzocyclohepten-S-ol and 1.1 g of cyclohexanone dissolved. The solution is kept in an oil bath at 110-115 ° C overnight. That Water formed during the reaction becomes an azeotropic after the addition of 30 ml of benzene to the reaction mixture Removed mixture with benzene. After the solvent has been evaporated from the reaction mixture, trans-2-benzyloxy-6-cyclohexylideneamino-1-nitro-6,7,8,9-tetrahydro-SH-benzocyclbhepten-S-ol hydrochloride is obtained obtained as a brown powder, which is dissolved in 20 ml of methanol and immediately over 250 mg of 10% palladium carbon and 200 mg of platinum dioxide is hydrogenated. After the reaction has ended, the catalysts are filtered off. The filtrate is concentrated, whereby 450 g of a red syrup are obtained. After adding an aqueous potassium carbonate solution to the syrup the mixture is extracted with ethyl acetate. The extract is dried and again under reduced pressure constricted. Adding benzene to the red syrup remaining as residue gives 145 mg of trans-1-amino-6-cyclohexylamino-2-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol obtained in the form of a powder.

Nuclear Magnetic Resonance Spectrum (DMSO-ü) 6:

1.0-3.2 (18H, m), 4.0-5.5 (5H; broad) _? 4.28 (lH, d, J = SHz), 6.52 (lH, d, J = SHz), 6.67 (lH, d, J = SHz)

6 0 9 8 12/1006

After adding 200 mg of fumaric acid and diluting with diethyl ether and allowing the methanolic solution to stand (10 ml) of the 'prepared in the manner described Powder in a cold place is the fumarate of the above compound (190 mg) in the form of yellow plat- i

ο '

Chen obtained with a melting point of 165 ° C. (decomp.). |

Example 85

To a solution of 450 mg of methyl 2-benzyloxy-5-hydroxy-6-hydroxyimino-6,7,8, g-tetrahydro-SH-benzocycloheptene-carboxylate 4 ml of anhydrous acetic acid are added to 10 ml of pyridine. The mixture is at overnight Room temperature stirred. The reaction mixture obtained is concentrated under reduced pressure and the residue dissolved in 2 ml of anhydrous tetrahydrofuran. 20 ml of an approximately 1 molar diborane solution are added to the solution given in tetrahydrofuran, whereupon the mixture is refluxed for 2 hours. After cooling it will aqueous 3N sodium hydroxide solution was added to the mixture and the tetrahydrofuran was distilled off. The residue Ethyl acetate and a small amount of water are added and the organic layer is decanted separated, washed with aqueous sodium chloride solution and dried. In conclusion, that will Solvent distilled off, whereby 331 mg of 6-amino-2-benzyloxy-1-hydroxymethy1-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (Mixture of cis and trans isomers) can be obtained in the form of a white powder.

Nuclear Magnetic Resonance _{Spectrum (CDC ^ 2.} ) Δ: 4.45 (4-H, d, J = S.5Hs), 4.79 (-, 2.5H, s.), 5.00 (2H, s), 6.6 ~ 7.7 (7H, m )

Example 86

860 mg of trans-methyl-2-benzyloxy-6-N-tert-butylamino-5-hydroxy-6,7,8, g-tetrahydro-SH-benzocycloheptene-1-carboxylate in 60 ml of anhydrous tetrahydrofuran are with

6098 12/100 6

430 mg of powdered lithium aluminum hydride for 4 hours heated on the reflux condenser under dry nitrogen. After adding 20 ml of ethyl acetate, 50 ml of methanol and The reaction mixture is filtered with 20% strength aqueous sodium hydroxide and the filtrate under reduced pressure concentrated and the residue extracted with ethyl acetate.

The extract is washed with water and evaporated to dryness under reduced pressure. By addition of a mixture of benzene and η-hexane are 451 mg of crystalline trans-2-benzyloxy-6-tert.-butylamino-1- hydroxymethyl-6, 7,8, 9-tetrahydro-5H-benzocyclohepten-5-ol obtained from melting point 130 to 131 ° C.

Elemental analysis for Ορ-, Η -, -, Ο-, Ν Calculated: C 74.76; H 8.46; N 3.79

Found: C 74.76; H 8.51; N 3.53

Nuclear Magnetic Resonance Spectrum (GDC ^) δ

1.04 (9H, s), 4.26 (lH, d, J = 9Hz)

Example 87

To a solution of 150 mg of cis-methyl-6-amino-2-benzyl oxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1 carboxylate (melting point 142.5-144 ° C) in 10 ml of anhydrous tetrahydrofuran is lithium aluminum hydride in Excess given. The mixture is refluxed for 3 hours, whereupon ethyl acetate and water dem Reaction mixture is added and the separated organic layer is dried and evaporated, whereby 116 mg of cis-6-amino-2-benzyloxy-1-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol can be obtained in the form of an oil.

Nuclear Magnetic Resonance Spectrum (CDC ^ -,

4.7K2H ₊ lH, treit), 4.95 (2H, s), 6.63 (lH, d, J = SHz), 7.08-7.47 (6H).

609812/1006

Example 88

62o mg of methyl trans-6-amino-2-benzyloxy-5-hydroxy-6,7,8,9-tetrahydro-SH-benzocycloheptene-1-carboxylate are reacted in the manner described in Example 86. After the excess reducing agent by adding ethyl acetate and water has been added, the reaction mixture is concentrated to remove volatile constituents and then extracted with a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1: 1). The extract will washed with a saturated sodium chloride solution, dried over magnesium sulfate and then evaporated, whereby

56o mg trans-6-amino-2-benzyloxy-1-hydroxymethyl-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-ol in the form of a white powder with a melting point of 142 to 144 ° C (recrystallized from ethanol) can be obtained.
Nuclear Magnetic Resonance Spectrum (in DMSO-dg) ¹ ^

4.409 (1H, d, J = 8Hz), '4.62 (2H, s), 5.07 (2H, s). Elemental analysis for C-, g ^ -zNO ^

calculated: C 72.82; H 7.40; N 4.47

found: _G 72.34 .; H 7.38; N 4.41

Example 89

450 mg of trans-6-amino-2-benzyloxy-1-hydroxymethyl-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-ol are reacted in the manner described in Example 6 2, with 32o mg of trans-6-amino-2-hydroxy-1-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol can be obtained in the form of a white powder. The powder is recrystallized from ethanol, whereby crystals of melting point 158OC (decomp.) are obtained.

Nuclear magnetic resonance _{spectrum (j_ n} DMso-d) δ ° 4.32 (lH, d, J = SHz), 4.52 (2H, s), 6.58 (lH, d, J = SHz), 7.20 (Hi, d, 8Hz).

609812 / 100e

Melting point of the fumarate (recrystallized from ethanol):

above 28o ° C.

Elemental analysis for C ₁₂ H ₁₇ NO ₃ * 1/2 (C ₄ H ₄ O ₄ ) calculated: C 59.78; H. 6.81; N 4.98 found: C. 59.60; H 6.89; N 4.97

Example 9o

2.0 g of trans-6-amino-2-benzyloxy-1-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol and 2, ο ml of cyclobutanone are in a mixture of 2o ml of ethanol and 1o ml of tetrahydrofuran solved. 1.54 g of lithium cyanoborohydride are added to this solution and 6.5 ml of a 5% ethanolic chlorine

i given hydrogen solution. The mixture is stirred for 6 4 hours at room temperature. The mixture is poured into 700 ml of ice water and the resulting solution is strongly acidified with concentrated hydrochloric acid and, after it has been stirred for some time, made alkaline with potassium carbonate and finally extracted with ethyl acetate. The extract is washed successively with water and a saturated sodium chloride solution and dried. Removal of the solvent under reduced pressure gives a brown oil which is applied to a silica gel column and then eluted with 4,000 ml of chloroform-methanol (80: 1). The eluate is evaporated to give trans-2-benzyloxy-6-cyclobutylamino-1-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol in the form of a pale yellow powder.
Nuclear magnetic resonance _{spectrum (^ n} DMS0 ~ d) δ

1.5-2.3 (13H ₉ IIi), 3.0-3.7 (3H, m), 4.45 (lH, d, J = SHz).

1.1 g of the trans-cyclobutylamino alcohol obtained in this way are over 4oo mg of 10% palladium carbon in a mixture of 3o ml of tetrahydrofuran and 3o ml of methanol

609812/1006

Normal pressure and normal temperature hydrogenated until no more hydrogen is absorbed. The catalyst is filtered off and evaporate the filtrate to dryness to give 0.8 g of a yellow solid. By recrystallization the solid from methanol becomes trans-1-amino-ö-cyclobutylamino - ^ - hydroxy-e, 7,8,9-tetrahydro-5H-benzocyclohepten-5-ol obtained in the form of colorless flakes with a melting point of 168 to 170 ° C.

Nuclear Magnetic Resonance Spectrum /. _ ,, ". , ν

1.4-3.4 (l4H _f m), 4.13 (5H, broad), 4.35 (lH, d, J = SHz), 6.55 (lH, d, J = 8Hz), 6.68 (lH, d, J = 8Hz).

Melting point of the fumarate (crystallized from methanol-diethyl ether): 216 ° C (decomp.).

Elemental analysis for C ₁₅ H ₂₂ N ₂ O ₂ calculated: C, 63.73; H 7.55? N 8.75

found: C 63.55; H 7.70; N 8.75

609812/1006

Example 91

Below are some examples of dosage forms in which the products according to the invention for example used as bronchodilators.

A) tablets

1) trans-6-cyclobutylamino-1,2,5-trihydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene 1.5 mg

2) lactose 90.0 mg

3) corn starch 38.0 mg

4) Magnesium stearate 0.5 mg

130.0 mg per tablet

After thoroughly mixing the ingredients (1) and (2) with
26 mg of corn starch, the mixture is granulated with a paste made from 7 mg of corn starch. The magnesium stearate and the remaining 5 mg of corn starch are added to the granules, whereupon the mixture becomes one
Tablet of 7 mm diameter is pressed.

B) capsules

1) 1) trans-6- (4-Hydroxy- ^ iL- me thy Ip hen ä thy 1) -

amino-1,2,5-trihydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene 1.5 mg

2) lactose 144.0 mg

3) Microcrystalline Cellulose 70.0 mg

4) Magnesium stearate 4.5 mg

220.0 mg per capsule

All ingredients are mixed well and placed in a hard gelatin capsule size # 3 (described in Pharmacopoeia of Japan, 8th Edition).

609812/1 006

C) solution for injection

1) trans-6-isopropylamino-1,2,5-trihydroxy

. 0.2 mg

2) sodium chloride 9 mg

3) chlorobutanol 5 mg

4) sodium bisulfite 1 mg

All components are dissolved in distilled water in such an amount that 1.0 ml of solution (pH 5.0) can be obtained. The solution is filled into an amber-colored ampoule. The atmosphere in the ampoule will replaced by nitrogen. All work steps are carried out under sterile conditions.

D) inhalants

1) trans-6-cyclobutyl-2-hydroxy-1-hydroxymethyl 1-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol 1.0 g

2) glucose 5.0 g

The two ingredients are dissolved in sterile distilled water in an amount such that 100.0 ml Solution can be obtained, which is then filtered through a membrane filter with a porosity of 0.22, u.

4) Aerosol for inhalation

1) trans 1-hydroxy-e-isopropylamino-1-methylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol 1.5 g

2) corn oil 1.0 g

3) Sorbitan trioleate 0.5 g

4) Freon 12-Freon 11 (weight ratio

1: 1) to 100 g

The compound is homogeneously dispersed in the mixture of corn oil and sorbitan trioleate to form the concentrate. The concentrate and the propellant (4) are then filled into the metal can under increased pressure.

609812/1006

Claims (44)

Claims 1) Compounds of the formula in the R ^. an optionally substituted amino group, a lower alkyl radical substituted by hydroxyl groups or an optionally protected one Hydroxyl group, R- an optionally protected one Hydroxyl group and R ^. Hydrogen or an optionally substituted hydrocarbon radical, and their salts. 2) acid addition salts of the compounds according to claim 3) Compounds according to claim 1, characterized in that R ^ is an unprotected hydroxyl group. 4) Compounds according to claim 1, characterized in that R ^ is a protected hydroxyl group. 5) compounds according to claim 1 to 4, characterized in that that the protecting group of the protected hydroxyl group is an aralkyl radical. 6) Compounds according to claim 1 to 5, characterized in that the protective group of the protected Hydroxyl group is a benzyl group. 7) Compounds according to claim 1, characterized in that R ,. is an amino group. 8) Compounds according to claim 1, characterized in that Ry. is a substituted amino group. 9) compounds according to claim 1 and 8, characterized 609812/1006 indicates that the substituent of the substituted amino group is a lower alkyl radical. 10) Compounds according to claim 9, characterized in that the lower alkyl radical is a methyl radical or ethyl radical is. 11) Compounds according to claim 1, characterized in that R ^ is a lower substituted with hydroxyl groups Is an alkyl radical. 12) Compounds according to claim 1 and 11, characterized in that the one having a hydroxyl group substituted lower alkyl is hydroxymethyl. 13) Compounds according to claim 1 to 12, characterized in that Rp is an unprotected hydroxyl group is. 14) Compounds according to claim 1 to 12, characterized in that R "is a protected hydroxyl group is. 15) compounds according to claim 14, characterized in that that the protecting group of the protected hydroxyl group is an aralkyl radical. 16) Compounds according to claim 14 and 15, characterized in that the aralkyl radical is a benzyl radical is. 17) Compounds according to claim 1 to 16, characterized in that R- is hydrogen. 18) compounds according to claim 1 to 16, characterized in that that R- is an optionally substituted hydrocarbon radical. 19) Compounds according to claim 18, characterized in that the substituent of the substituted carbon 60 98 12/1006 hydrogen radical is a hydroxyl group or is lower alkoxy. 20) compounds according to claim 1 to 18, characterized in that that the hydrocarbon radical is an optionally substituted lower alkyl radical is. 21) Compounds according to claim 1 to 18, characterized in that the hydrocarbon radical is a Cycloalkyl radical with a 3 to 7-membered ring. 22) Compounds according to claim 1 to 18, characterized in that the hydrocarbon radical R-, is an optionally substituted aralkyl radical. 23) Compounds according to claim 1 to 18, characterized in that the hydrocarbon _{radical R 3 is} an aryl radical. 24) Compounds according to claim 1 to 18, characterized in that the hydrocarbon radical R ,. a Cycloalkylalkyl radical, the cycloalkyl radical of which has a 3 to 7-membered ring. 25) Compounds according to claim 1 to 24 in the form of the trans isomers. 26) Compounds according to claim 1 to 24 in the form of the cis isomers. 27) Compounds according to claim 1 to 24 in the form of mixtures of the trans and cis isomers. 28) trans-6-isopropylamino-1,2,5-trihydroxy-6,7,8,9-tetrahydro-SH-benzocycloheptene. 29) trans-6-cyclobutylamino-1,2,5-trihydroxy-6,7,8,9- tetrahydro SH-benzocycloheptene. 609812/1006 30) trans-6- (4-hydroxy-o (-methylphenethyl) -amino-1,2, b-trihydroxy-6,7,8, g-tetrahydro-SH-benzocycloheptene. 31) trans-6-ethylamino-2-hydroxy-1-hydroxymethyl-6, 7,8,9; - tetrahydro-SH-benzocyclohepten-S-ol. ! 32) trans-2-hydroxy-1-hydroxymethyl-6-isopropylamino- 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol. 33) trans-δ-cyclobutylamino ^ -hydroxy-1-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol. 34) trans-2-hydroxy-1-hydroxymethyl-6- (4-hydroxy - </.- methyl! phenethyl) amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-oil. 35) trans-2-hydroxy-1-hydroxymethy1-6- (4-methoxyVl- methylpher.ethyl) -amino-6, 7,8,9-tetrahydro-5H-benzocyclohepten-5-ol. 36) trans ^ -Hydroxy-e-isopropylamino-1-methylamino-6,7,8, g-tetrahydro-SH -benzocyclohepten-S-ol. 37) trans -1-amino-2-hydroxy-6-isopropylamino-6,7,8,9-tetrahydro-SH-benzocyclohepten-S-ol. 38) trans -1-amino-6-cyclobutylamino-2-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol. 39) Pharmaceutical preparations containing at least one compound according to claim 1 as active ingredient to 38 or their physiologically acceptable salts with a pharmaceutically acceptable carrier. 40) Process for the preparation of compounds of the formula 60981 2/1006 in which R ^ is an optionally substituted amino group, a lower alkyl radical substituted by hydroxyl groups or an optionally protected hydroxyl group, R "is an optionally protected hydroxyl group, R _{3 is} hydrogen or an optionally substituted hydrocarbon radical, or their salts, characterized in that compounds of the formula in which R. is an optionally substituted amino group, a lower alkyl radical substituted by hydroxyl groups, a group reducible to one of these groups or an optionally protected hydroxyl group, R- has the meaning given above, A. a group of the formula -NHR ₃ (in which R _{3 has} the meaning given above) or a _{group reducible to -NHR 3} and X is a group of the formula ^> C = 0 or / CH-OH with the proviso that in cases in which A ^ is a group of the formula - Is NHR ₃ , X is / C = O. 41) Process for the preparation of compounds of the formula NHCH in which R ^ is an optionally substituted amino group lower alkyl radical substituted with hydroxyl groups or an optionally protected one Hydroxyl group, R "an optionally substituted Hydroxyl group, R. hydrogen or a lower alkyl radical and R, - hydrogen or an optionally 609812 / 10Ό6 _ 1o5 - substituted hydrocarbon radical including the case in which R ₄ and R ₅ together with the adjacent carbon atom form a ring group ι, or salts of these compounds, thereby; characterized in that one compounds of the formula in which Rp has the meaning given above, R. a optionally substituted amino group, a lower alkyl radical substituted with hydroxyl groups, a group reducible to one of these groups or an optionally protected hydroxyl group, A "is an amino group or a group which can be reduced to an amino group, and X for J ^ C = O or J ^ CH-OH stands in the presence of a carbonyl compound the formula ^R 5 is, in which R. and R ₁ - have the meanings given above, reduced. 42) Process for the preparation of compounds of the formula OH NHiU in which R ^ is an optionally substituted amino group, one substituted with hydroxyl groups 609812/1006 Alkyl radical or an optionally protected hydroxyl group, R "an optionally protected one Hydroxyl group, R ~ hydrogen or an optionally substituted hydrocarbon radical, or their salts, characterized in that compounds the formula -, b in which R ^ is an optionally substituted amino group, a lower alkyl radical substituted with hydroxyl groups, one to one of these groups is a hydrolyzable group or an optionally protected hydroxyl group and R1 and R2 are the above Have the meanings mentioned, hydrolyzed. 43) Process for the preparation of compounds of the formula in which R _{1 is} an optionally substituted amino group, a lower alkyl group substituted by hydroxyl groups or an optionally protected hydroxyl group, Rp is an optionally protected hydroxyl group, R. is a hydrogen atom or an optionally substituted hydrocarbon group, or their salts, characterized in that compounds of formula 609812/1006 OZ ₁ NE, in which R ^ is an optionally substituted amino group, a lower alkyl radical substituted with hydroxyl groups, one by a reaction to Removal of the protective group in one of these groups convertible group or an optionally protected group Is hydroxyl group, Rp and -OZ .. optionally are protected hydroxyl groups, Zp is hydrogen or a protecting group and R-. the above has the stated meaning with the proviso that at least one protective group is present in the formula, subjected to a reaction to remove the protective group. 44) compounds of the formula in R. an optionally substituted amino group, an alkyl radical substituted by lower alkyl radicals, a group reducible to one of these groups or an optionally protected hydroxyl group, Rp an optionally protected hydroxyl group, A. a group of the formula -NHR ₃ (in which R- is hydrogen or is an optionally substituted hydrocarbon radical) or a group which can be reducible to -NHR. and X is ^ C = O or / CH-OH with the proviso that in cases in which A. is a group of the formula -NHR ₃ , X is ^ C = O. 609812/1006