JPH0141627B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a novel drug with valuable pharmacological properties.
Azatetracyclene and its acid addition salts, its
Manufacturing method and containing this new substance as an active ingredient
related to pharmaceutical formulations and their applications.
Ru. Azatetracyclene according to the present invention is expressed by the following formula:
Equivalent to. [R in the formula₁is a hydrogen atom, lower alkyl group, carbon
cycloalkyl lower alkyl having up to 10 atoms
group, lower alkenyl group, lower alkynyl group,
-Lower alkylamino lower alkyl group, hydroxy
cy lower alkyl group, alkoxy lower alkyl group,
Alkanoyloxy lower alkyl group, lower alkyl
ruthio lower alkyl group or phenyl lower alkyl group
and ring A is unsubstituted or
is a halogen atom with atomic number up to 35, lower alkyl
group, hydroxyl group, lower alkoxy group, alkali
Noyloxy group, lower alkylthio group, triflu
Substituted with an omethyl group or a cyan group,
X is an oxygen atom, a sulfur atom, a methylene group, a direct bond
or subexpression (R in the formula₃is a hydrogen atom or a lower alkyl group
) is a divalent residue represented by , and Y is directly
represents a bond, Z represents a sulfur atom or a vinylene group
vinegar〕 Acid addition salts of the compound of the above formula (), especially pharmacology
Acid addition salts which are recognized as
It's an elephant. The above definition of formula () as well as the following
By the way, lower groups have a maximum of 8 carbon atoms, especially
It should be understood as the maximum group of 4. R₁especially 1 to 6 carbon atoms as a lower alkyl group
Contains elementary atoms. Can be linear or branched
can. These lower alkyl groups are e.g. methyl
group, ethyl group, propyl group, isopropyl group,
thyl group, isobutyl group or t-butyl group.
Ru. As a cycloalkyl lower alkyl group, the residue is
R₁especially contains 4 to 8 carbon atoms. For example,
Chlopropylmethyl group, cyclobutylmethyl group or
and especially the cyclopentylmethyl group, cyclohexyl
silmethyl group, further e.g. cyclopropylethyl
group, cyclobutylethyl group, cyclopentylethyl group
group, cyclohexylethyl group is cycloalkyl
It is mentioned as a lower alkyl group. Residue R as lower alkenyl group₁Particularly 3~
Contains 4 and especially 3 carbon atoms. Lower Arkeni
As a group, for example, an allyl group or a 2-methylaryl group.
Examples include ru groups. R as lower alkynyl group₁Especially propargi
Examples include ru groups. residue R₁di-lower alkylamino lower as
In an alkyl group, the nitrogen atom is at least
separated from the ring nitrogen atom by two carbon atoms
There is. This group is especially suitable for up to 10 carbons, especially 4 to 6 carbons.
Contains elementary atoms. The lower alkyl group in this substituent is
Straight chain ones are preferred. An example is the basis for the whole thing.
For example, diethylamino-butyl group, -propyl group, or
or -ethyl group, dimethylamino-butyl group, -
The ethyl group and especially the dimethylaminopropyl group
can give. residue R₁to hydroxy lower alkyl group as
in which the hydroxyl group has at least two carbons
separated from the ring nitrogen atom by an atom. this
The radicals contain 2 to 8, especially 2 to 6 carbon atoms.
This hydroxyl chain, which can be linear or branched,
The class alkyl group is, for example, 1-methyl-2-hydroxy
ethyl group, 2-hydroxypropyl group, 1-
or 2-methyl-2-hydroxypropyl group and
and especially 2-hydroxyethyl and 3-hydroxypropanol.
Lopil can be given. residue R₁lower alkoxy lower alkyl as
In the group, the oxygen atom has at least two carbon atoms.
separated from the ring nitrogen atom by a child. This base
contains, for example, 3 to 10 carbon atoms, especially 3 to 6 carbon atoms.
nothing. As this lower alkoxy lower alkyl group
is, for example, 2-methoxypropyl group, 2- or
3-ethoxypropyl group, 2- or 3-propyl group
Xypropyl group, 3-isopropoxypropyl group
and especially 2-methoxy- or 2-ethoxye
The middle 3-methoxypropyl group is used as a chill group.
It can be opened. residue R₁Alkanoyloxy lower alkyl as
In the kill group, the oxygen atom has at least two carbon atoms.
Separated from the ring nitrogen atom by an elementary atom. child
The radicals include, for example, 3 to 21 and especially 4 to 11 carbon atoms.
Including children. This group is, for example, 2-formylethyl
group, 2-acetyloxyethyl group, 2-propio
Nyloxyethyl group, 2-acetyloxypropyl group
group, 2-methyl-3-acetyloxypropyl
group or 2- or 3-propionyloxypro
Pyl group and especially 3-acetyloxypropyl
and 3-octanoyloxypropyl group.
It will be done. residue R₁lower alkylthio lower alkyl as
In the group, the atoms have at least two carbon atoms.
Separated from the ring nitrogen atom by an elementary atom. child
The group contains, for example, 3 to 10 carbon atoms, especially 3 to 6 carbon atoms.
including. This lower alkylthio lower alkyl group is
Especially methylthioethyl group or 3-methylthiop
An example is the lopyl group. Ring A can have one or many substituents.
Wear. However, this ring still has the following substituents
It is preferable to have only one. i.e. atomic number
Up to 35 halogen atoms, 4 or more chlorine atoms
Lower alkyl groups with carbon atoms such as ethyl
group, propyl group, isopropyl group, butyl group,
Sobutyl group, t-butyl group as middle methyl
groups, hydroxyl groups, lower atom groups of up to 4 carbon atoms
alkoxy groups such as ethoxy groups, propoxy groups,
Sopropoxy group, butoxy group, isobutoxy group, etc.
and middle methoxy group, alkanoyloxy group
For example, formyloxy group, propionyloxy group
and especially the acetyloxy group, up to 4 carbons
Lower alkylthio groups with atoms such as ethylthio
group, propylthio group, isopropylthio group, butylthio group
As a ruthio group, the middle methylthio group and also
Substituents such as trifluoromethyl group or cyanogen group
It is. X is a subexpression When representing a divalent residue represented by R₃
is a hydrogen atom or a lower alkali of up to 4 carbon atoms
Kill groups such as propyl, butyl, isobutyl
group, and the middle group is a methyl group or an ethyl group.
It is preferable. Salts of the compound of formula () are primarily acid addition salts, especially acid addition salts.
Examples include acid addition salts that are accepted for medicinal purposes. for example
Non-hydrochloric acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid
Organic acids or organic acids such as organic carboxylic acids or
Sulfonic acids e.g. methanesulfonic acid, ethanesulfonic acid
acid, 2-hydroxyethanesulfonic acid, acetic acid,
Malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,
Succinic acid, fumaric acid, maleic acid, benzoic acid, salt
Lycylic acid, phenylacetic acid, mandelic acid or ene
It is a salt with bonic acid, etc. New azatetracyclene and
The acid addition salts of Biso have valuable pharmacological (e.g. central
It has the property of acting on the nervous system. This compound
First of all, things suppress the central nervous system and calm excitement.
(stimulant amphetamine antagonist) has excellent action
There is. This can be proven based on pharmacological experiments.
can be done. In other words, this compound is a stimulant.
0.1 to 25 mg/Kg to house mice in resistance test
When given by injection or orally, it has an excitatory-depressant effect.
[Niemegeers and Janssen:
Arzneimittelf orschung. Volume 24, page 45 (1974)
reference〕. The antagonizing effect of amphetamine is responsible for the infarction effect.
Compared to other countries, it is relatively small. Therefore, this new
The compound is used for the treatment of excited states, as a tranquilizer, and as an antipsychotic.
Can be applied as a target and excitatory-inhibitory compound
can. The invention particularly relates to compounds of formula () as follows:
It is something to do. That is, in formula () R₁
is hydrogen atom, lower alkyl group, up to 8 carbon atoms
cycloalkyl lower alkyl group, lower alkyl group with
Kenyl group, lower alkynyl group, di-lower alkyl group
Amino lower alkyl group, hydroxy lower alkyl group
group, lower alkoxy lower alkyl group, alkanoyl
ruoxy lower alkyl group, lower alkylthio lower
Alkyl group or phenyl lower alkyl group
and ring A is unsubstituted or atomic
Halogen atoms up to number 35, lower alkyl groups,
Droxyl group, lower alkoxy group, lower alkyl
For thio, trifluoromethyl or cyanide groups
Therefore, it is monosubstituted, and X is an oxygen atom.
Is it a child, sulfur atom, methylene group, or a direct bond?
or subexpression (R in the formula₃is a hydrogen atom or a lower alkyl group
) is a divalent residue represented by , and Y is directly
It is a tangential bond, and Z is a sulfur atom or a vinylene group.
In certain compounds and their salts, especially acid addition salts
Concerning the salts of lentils that are approved for medicinal purposes.
It is. The present invention firstly proposes that in formula () R₁is a hydrogen field
children, lower alkyl groups such as methyl group, ethyl group,
Isopropyl and n-butyl groups, 4 carbon atoms
~8 cycloalkyl lower alkyl groups
cyclopentylmethyl group and cyclohexyl
Methyl group, lower alkenyl group such as allyl group, lower
alkynyl groups such as propargyl group, di-lower
Alkylamino lower alkyl group e.g. dimethyl alkyl group
Minoethyl group and 3-dimethylaminopropyl
groups, hydroxy lower alkyl groups such as 2-hydro
xyethyl group and 3-hydroxypropyl group,
Lower alkoxy lower alkyl groups such as 3-methoxy
C- and 3-ethoxypropyl groups, alkanoids
3-acetyloxy lower alkyl group such as 3-acetyloxy
Cypropyl group and 3-octanoyloxypro
Pyr group, lower alkylthio lower alkyl group e.g.
2-methylthio- and 2-ethylthioethyl
groups, 3-methylthio- and 3-ethylthio-pro
Pyr group or phenyl lower alkyl group e.g. ben
Zyl group and phenylethyl group, and ring A is a
unconverted or halogens up to atomic number 35
atom, lower alkyl group, hydroxyl group, lower
Alkoxy group, lower alkylthio group, trifluoro
substituted by a methyl group or a cyan group.
, X is an oxygen atom, a sulfur atom, a methylene group, a direct
A subexpression that is a tangential combination (R in the formula₃is a hydrogen atom or 4 carbon atoms
Lower alkyl groups with especially methyl and ethyl groups
be) is substituted with a divalent residue represented by
Therefore, Y is a direct bond and Z is a sulfur atom or vinyl
Compounds with ren group and their salts
Acid addition salts Acid addition salts approved for medicinal purposes
It is related to. The present invention particularly provides R in the formula ()₁is a hydrogen atom,
lower alkyl groups such as methyl or ethyl groups,
cycloalkyl lower alkyl having 4 to 8 carbon atoms
Kyl groups, such as cyclopentylmethyl groups and
Chlorhexylmethyl group, lower alkenyl group e.g.
Allyl group, lower alkynyl group e.g. propargyl
Group, di-lower alkylamino lower alkyl group example
dimethylaminoethyl group and 3-dimethylaminoethyl group
Minopropyl group, hydroxy lower alkyl group example
2-hydroxyethyl group and 3-hydroxy
Examples of propyl group, lower alkakoxy lower alkyl group
For example, 3-methoxypropyl group, alkanoyloxy
Lower alkyl group such as acetoxypropyl group or
and 3-octanoyloxypropyl group, lower a
lukylthio lower alkyl group e.g. 2-methylthio
Ethyl group, 3-methylthiopropyl group or Fe
Nyl lower alkyl groups such as benzyl and fe
Is it a nylethyl group and ring A is unsubstituted?
or chlorine atom, bromine atom methyl group, hydroxy
group, methoxy group, methylthio group or cyan group
X is an oxygen atom, sulfur
Atom, methylene group, direct bond or moiety
formula (R in the formula₃is a hydrogen atom or a methyl group or
(ethyl group) is substituted with a divalent residue represented by
, Y is a direct bond and Z is a sulfur atom or bicarbonate
Compounds with nylene groups and their salts, especially acidification
Regarding acid addition salts approved for medicinal purposes:
It is something to do. The present invention is based on R₁is low grade
Alkyl groups such as methyl or ethyl groups, or
is a cyclopentylmethyl group and ring A is a
unconverted or chlorine atoms, methyl groups,
Substituted by a toxy group or a cyan group
Moreover, it is because Y is a direct bond and Z is a sulfur
In ring A of the compound which is an atom or vinylene group
Preferably it is substituted at the 7-position. and
X may be an oxygen atom, a sulfur atom, or a methylene group.
is a partial expression (R in the formula₃is a hydrogen atom, methyl group or ethyl group
) is a divalent residue represented by , and Y is directly
It is a tangential bond and Z is a sulfur atom or a vinylene group.
The present invention relates to compounds that such compounds
For example, 3-methyl-2,3,4,5-tetrahydrogen
Dro-1H-dibenzo [2,3:6,7] Chiepi
No[4,5-d]azepine, 3-methyl-2,
3,4,5-tetrahydro-1H-dibenzo [2,
3:6,7] Oxepino [4,5-d] Azepino
3-methyl-7-cyano-2,3,4,5-
Tetrahydro-1H-dibenzo [2,3:6,7]
Thiepino[4,5-d]azepine, 3-methyl-
1,2,3,4,5,10-hexahydro-diben
Zo [3,4:6,7] Cyclohepta [1,2-
d] azepine or 3-(2,3,4,5-tet
Lahydro-1H-dibenzo[2,3:6,7]
epino[4,5-d]azepine-3-yl) pro
Panol and their salts are recognized medicinally.
It is an acid addition salt. Compounds of formula () are made by known methods. vinegar
For example, the expression [A, X, Y and Z in the formula () are
has the same meaning as The reactive ester of diethanol represented by the formula [R in the formula₁has the same meaning as in the expression ()
By reacting with a compound represented by
You can get it. Reactive ester of diethanol with the above formula ()
As a base, esters of strong inorganic acids such as bis-salts are used.
Hydrohydride ester, bis-hydriodide ester
or especially hydrobromide esters or hydrogen bromide-
Hydrochloric acid ester can be applied to this
Ru. Furthermore, strong organic acids such as methanesulfone
acid, benzenesulfonic acid, p-chloro- or p-
-bromobenzenesulfonic acid or p-toluene
Corresponding diethyl acids of sulfonic acids such as sulfonic acids
You can use steal. of the compound of formula ()
These diesters are preferably prepared in a suitable inert solvent.
It is best to carry out the reaction at a reaction temperature of 20 to 130°C. No
Active solvents include, for example, benzene or toluene.
Hydrocarbons such as, halogens such as chloroform
hydrocarbons, ethanol and especially methanol
Lower alcohols, ethers or dioxins such as
Etheric liquids such as sun, as well as acetate
methyl ethyl ketone or diethyl ketone
alkanones such as or mixtures of these solvents
For example, benzene-methanol is suitable. 1 mole of diester of diethanol of the above formula ()
using the molar equivalent of the free base of formula () and 1 molar equivalent of the free base of formula ().
In the reaction according to the invention, two molar equivalents of acid are split
but it is preferably bound to an acid binder.
stomach. A suitable acid binder is potassium carbonate.
Alkali carbonates, such as umum, or sodium hydroxide
alkaline water such as um or potassium hydroxide
Excess of oxide or compound of formula (), and
is pyrimidine and especially triethylamine or
Tertiary compounds such as N-ethyl-diisopropylamine
It is an organic base. Direct starting materials i.e. reactive diexes of formula ()
Stel is obtained from the corresponding diethanol in the usual way.
By esterification or by converting hydroxy groups to halo
It is created by replacing it with a gen atom. one
Diethanol is the corresponding diacetic acid methyl ester
reduction with lithium aluminum hydride from
made by. Diacetate methyl ester is equivalent
diacetonitrile to methanol and 2 molar equivalents
To make while introducing hydrogen chloride using a large amount of water.
Can be done. Diacetonitrile is the corresponding bis-
(bromomethyl) - compound from sodium cyanide
It can be obtained from Furthermore, a compound of formula () can be obtained by another method.
can be done. i.e. the expression [In the above formula, A, X, Y and Z are the same as above.
has the meaning of R₁′ is the above R₁has the same meaning as
(However, if the alkanoyloxy lower alkyl group is
(excluding), Q₁and Q₂are, independently of each other, oxygen atoms
or represents two hydrogen atoms (however, Q₁and Q₂of
At least one is an oxygen atom) This reduction can be carried out using lithium aluminum hydride or
Hydrogen such as diborane or aluminum hydride
This is advantageously carried out using a compound complex. as its solvent
diethyl ether, tetrahydrofuran, di-
oxy, ethylene glycol dimethyl ether or
or diethylene glycol dimethyl ether.
Preferably, an ethereal liquid is used. reaction temperature
The temperature should be preferably 0° to 100°C or depending on the reaction medium used.
Boiling point. Make diborane separately and introduce it.
or sodium borohydride and trifluoride
In-situ reaction process from boron ether complex compound
It can also be made with lithium aluminum hydride
In addition, aluminum chloride is added for reactions using aluminum.
An activator such as can be used. N-substituted lactam as raw material of formula ()
- and imide compounds are N-unsubstituted formulas
By substituting the corresponding compound in ()
can be made. This N-substituted compound has the formula
R₁―OH (this R′₁is the above R′₁From the meaning of hydrogen field
corresponding hydroxylation of
It can be made using a known method using a reactive ester of a compound.
I can do it. N--Unsubstituted imide of formula () is formula
Obtained from the compound (). i.e. hydrogen bromide
By forming an azepine ring with
made by treatment with formamide
Ru. diethyl ether or tetrahydrofuran
by hydride complexes in ethereal solvents such as
From this imide by partial reduction,
A lactam is produced. In connection with the reaction according to the invention, optionally:
Change the compound of formula () to another compound of formula ()
A series of transformations are performed. residue R₁is a hydrogen atom, and the compound of formula () is
In some cases R₁reaction product with other meanings
You can also change it to . So, for example, the N-substitution is the formula R〓₁-OH (this R〓₁teeth
R above₁Also the meaning of excluding the hydrogen atom from the meaning of
using reactive esters of alcohols corresponding to
or the equivalent aldehyde under reducing conditions.
This is done by reacting with hydrogen or ketones.
be exposed. R₁Compounds of formula () where is a hydrogen atom and formula R〓
-The reaction of OH with a hydroxy compound is carried out in a solvent.
The reaction temperature is 20 to 130℃, especially the boiling point of the solvent.
It is preferable. Reactive esters include, for example, chlorides or
halides such as bromide, as well as o- or
p-Toluenesulfonic acid-methyl ester or
- Sulfonic acid esters such as ethyl esters
or as dimethyl sulfate or diethyl sulfate
Sulfuric acid esters can be used. acid binder and
For example, an alkali metal such as potassium carbonate
Carbonates, alkaline hydroxides such as sodium hydroxide
or for example pyridine or N-ethyldi
A tertiary organic base such as isopropylamine is suitable.
ing. Suitable solvents are
Inert substances such as benzene or toluene
hydrocarbons such as methanol and ethanol
Alkanols such as acetone or methyl
Alkanones such as ethyl ketone. Formula R〓₁-Aldehyde equivalent to alcohol of OH
and ketones are, for example, lower aliphatic aldehydes or
Ketones, lower free, esterified or ethers
Hydroxyoxoalkane or S
It is an oxoalkanecarboxylic acid that has been esterified.
These aldehydes or ketones and the above formula
Reaction product obtained during reaction with compound ()
substances can be reduced in the same reaction process, i.e. in succession.
I can do it. Formaldehyde or acetaldehyde
Ketones like unaaldehyde or acetone
For example, the compound of formula () above is always inert.
heated to about 30-100℃ in a neutral solvent, and at the same time
i.e., the reaction mixture is subsequently mixed with water in the presence of a catalyst.
Add element. Methanol or ethanol is used as a solvent.
Alcohol such as Le is suitable and suitable
A noble metal catalyst, for example, palladium attached to charcoal, is used as a catalyst.
Alloy skeletons such as aluminum or Raney nickel
It is a medium. For reductive alkylation instead of hydrogen in the presence of a catalyst
Other reducing agents such as formic acid can also be used. child
The above compound of formula () can be converted to the above compound by a modification of
type of aldehyde or ketone especially formal
Heat the dehyde and its ingredients without a solvent as much as possible.
Ru. To substitute this N-with an alkyl group, R₁is hydrogen
The reaction product, which is an atom, is first acylated and then
This is done by reducing the carbonyl group.
This reduction can be carried out using lithium aluminum hydride or di
This is done with hydride complexes such as borane.
It's advantageous. As a solvent, diethyl ether,
Trahydrofuran, dioxane, ethylene glyco
dimethyl ether or diethylene glyco
ethereal liquids such as dimethyl ether
It is preferable to use The reaction temperature is preferably 0° to 100°.
°C or the boiling point of the reaction medium used. diborane
Either make it separately and introduce it, or use hydrogenation.
Sodium boronate and boron trifluoride ether complex
You can make it on the spot. Furthermore, in some cases R₁is hydroxy lower a
R₁is an esthetician
Compounds that are hydroxy lower alkyl groups
It can be acylated to even substances. This acylation can be performed, for example, with carboxylic anhydrides or
20~ using the corresponding carbonyl halide
It can be carried out at a reaction temperature of 100°C. acid is minute
The cleavage causes condensation to proceed automatically, making it an example of a third organic base.
Adding pyridine to the reaction mixture as an acid binder
It is better to Using excess tertiary organic base as a solvent
You can also do that. In addition, benzene and tomato are used as solvents.
Hydrocarbons such as luene or chloroform
It is also possible to add halogenated hydrocarbons such as Furthermore, in some cases R₁is phenyl lower a
R₁is a hydrogen field
Hydrogenolysis into reaction products, which are children.
You can also do it. This hydrogenolysis is carried out using ordinary hydrogenation catalysts.
for example palladium on charcoal or platinum oxide.
The use of precious metal catalysts such as charcoal or
Catalysts such as rhodium on aluminum oxide
or alloy framework catalysts such as Raney nickel.
Depending on use, methanol, ethanol or
in an inert organic solvent such as oxane at room temperature and normal pressure.
or at a moderately elevated temperature of up to about 100°.
(or) at an increased pressure of approximately 100 bar.
I can. Furthermore, X is a subexpression (R in the formula₃is a hydrogen atom) A compound of formula () which is a divalent residue represented by
R₃For other reaction products where is a lower alkyl group
You can also change it. This conversion reaction converts the above reaction products into a solvent and a base.
Reactive lower alkyl esters in the presence of condensing agents
It is preferable to react with Reactive esters include, for example, chlorides or
halides such as bromide, as well as o- or
p-Toluenesulfonic acid methyl ester or
- Sulfonic acid esters such as ethyl esters or
is a sulfuric acid ester such as dimethyl sulfate or diethyl sulfate.
You can use tell. As a basic condensing agent
Alkali metal alkano such as potassium t-butyrate
Corresponding amide such as lat, sodium amide
Sodium hydride or lithium hydride
Metal hydrides such as aluminum are suitable. Appropriate melting
The medium is one that is inert under the reaction conditions, such as benzene.
Hydrocarbons such as carbon and toluene, as well as tetrahydrogen
Dorofuran, dioxane, ethylene glycol di
ethereal liquids such as methyl ether
Phosphoric acid - hexamethyltriamide or dimethyl
It is an amide such as formamide. This conversion reaction first transforms the above reaction product into an acyl
and then reduce the carbonyl group.
It can be done. This reduction reaction is preferably performed with a hydride.
As a hydride, diborane is used as an ethereal reaction medium.
For example, tetrahydrofuran, dioxane, ethylene
glycol dimethyl ether or diethylene
Preferably carried out in glycol dimethyl ether.
Delicious. The reaction temperature is, for example, -20 to +80℃, especially 0
℃ to room temperature. This requires Jibola
For example, boron trifluoride ether complex compound and water
For example, from sodium borohydride to the solution used in the reaction.
Either make it separately in a medium and add it as a solution, or
For example in diethylene glycol dimethyl ether
It can be prepared as a gas and charged into the reaction mixture, or it can be
Or you can make it on the spot. Depending on the respective reaction conditions and starting materials, the final product
The product may be used in free form or in its salt form.
These objects can be obtained from each other in the usual way.
or other salts. i.e. obtained
From acid addition salts, e.g. with bases or with basic ion exchangers.
The free compound is obtained by treatment with a converting agent, or
The free base of formula () can be combined with an organic or inorganic acid, especially
To make medicinal salts such as those mentioned above.
Converted to acid addition salts by reaction with a suitable acid.
I can do it. The salt of this new compound can also be used for purification purposes.
Can be done. For example, converting a free compound into its salt.
and in some cases purified
can be prepared and converted back into the free compound. play
The relationship between the free form and the salt form of this new compound is
Since it is always secret, it is not mentioned so far as a free compound.
In this section and below, in some cases,
Its meaning and purpose can be explained in the same way for the corresponding acid.
I want to be The present invention also relates to the following embodiments of this manufacturing method.
It is something to do. In other words, in a certain step of this manufacturing method
Starting from the compound obtained as an intermediate, the remaining
process or incorporate this process at some stage.
Stop or make starting materials under reaction conditions
or the reactants may be
One such embodiment is in the form of a salt. In carrying out the method of the invention, it is preferable that
The final product groups listed below are particularly recommended.
Starting materials should be used to reach the final product.
It is possible. This new compound can be used in pharmaceutical formulations such as:
It can be used in the form of an effective amount of the active substance
administered orally (e.g. internally) or parenterally.
inorganic or organic solid or liquid suitable for
In some cases, medicinal carrier materials may be used.
This includes: i.e. the active substance as a diluent
For example, lactose, dextrose, sucrose, manni
Toll, sorbitol, cellulose and (also
) Glycine and lubricants such as diatomaceous earth and tal
stearic acid and its salts such as stearin
Magnesium acid or calcium stearate
Tablets containing polyethylene glycol and/or polyethylene glycol
tablets or gelatin capsules are used. Tablets are magnesium aluminum silicate,
Starch such as sorghum, wheat, rice or waste, gelatin
Chin, tragacanth, methylcellulose, sodium
mucarboxymethylcellulose and/or
It also contains binders such as polyvinylpyrrolidone,
and optionally starch, agar, alginic acid
or a squirting agent such as sodium alginate,
and/or foaming mixtures or adsorbents, dyes.
Also includes spices, seasonings and sweeteners. Yet again
of new medicinally active compounds can be administered by injection (e.g. intravenous injection).
It is also used in the form of injection preparations or injectable solutions. child
Solutions such as are isotonic aqueous solutions or suspensions.
This may be available, for example, as a lyophilized formulation.
The active substance alone or a carrier substance such as mannitrate
Contains at any time and is made into a solution before use.
It is preferable that there be. This pharmaceutical preparation is sterile
and (or) e.g. preservatives, stabilizers, wetting agents.
and/or emulsifiers, solubilizers, osmotic pressure regulators
may contain salts and/or PH buffers for
Wear. The preparation may also be supplemented with other pharmacological agents if desired.
May contain chemically valuable substances, but are not known
methods such as conventional mixing methods, granulation methods, sugar coating
to be made by method, solution method or freeze-drying method
and contains about 0.1 to 100%, especially 1 to 5%
However, lyophilized products contain up to 100% of the active substance. throw
Dosage depends on application method, species, age and individual condition.
Varies, but is accepted as a free base or medicinally
The daily dose of salt is generally about 0.1 mg for warm-blooded animals.
and 10mg/Kg, but for warm-blooded animals weighing approximately 70Kg.
It is about 0.01g to 0.5g. Examples are provided below to further illustrate the invention.
show. Temperature is given in °C. Example 1 10,11-bis-[2-(methylsulfonyloxy)
C)-ethyl]-5H-dibenzo[a,d]
Anhydrous alcocontaining 21.8 g (0.05 mol) of loheptene
7.4% ethanol of ethylamine in 200 ml of solution.
35 ml (2.6 g, 0.06 mol) of diisoplast solution
Lopylethylamine 15.5g (0.125mol)
and boil the reaction mixture under reflux for 18 hours.
Ru. The reaction mixture is then concentrated using a water pump vacuum.
Dissolve the residue in 300 ml of methylene chloride and
This solution was sequentially added to 2N sodium hydroxide solution and
Wash with 100ml of water each. methylene chloride solution
Concentrate to approximately 50 ml with a water jet pump and add 4N air.
Adding 15 ml of hydrochloric acid solution produces 3-ethyl
Ru-1,2,3,4,5,10-hexahydro-di
benzo[3,4:6,7]cyclohepta[1,2
-d] Azepine hydrochloride precipitates, melting point 296-299°. The melting point of this methanesulfonate is 220~221°
It is. This starting material can be made as follows
Ru. In other words, a method similar to the items described in Example 5.
by. 5H-dibenzo[a,d]cycloheptene-10,
11-Diacetonitrile 27g (0.1mol), methanol
5H from 400ml of water, 3.8ml of water and dry hydrogen chloride.
Dibenzo[a,d]cycloheptene-10,11-di
Acetic acid dimethyl ester. Melting point 104-106° (hexane
from) 5H-dibenzo[a,d]-10,11-diacetic acid di
33.6g (0.1mol) of methyl ester and lithium hydride
7.6 g (0.2 mol) of aluminum in anhydrous diethyl
solution contained in ether 1 and 5H-diben
Zo[a,d]cycloheptene-10,11-dietano
Rules. Melting point 154-156° (from acetone) 5H-dibenzo[a,d]cycloheptene-10,
28.0g (0.10mol) of 11-diethanol and pyridine
Methanesulfonic acid chloride in a solution contained in 120ml
16.8 ml (25.2 g, 0.22 mol) at a reaction temperature of -5°
Add. Then at 0° for 30 minutes and then at 15-25° for 1 hour.
Stir. The reaction mixture was mixed with 600ml of methylene chloride.
Next, add 5N hydrochloric acid and ice in a separate filter.
Shake with 400ml of water each. Separate the methylene chloride solution
Dry over magnesium sulfate and aspirate
Concentrate by evaporation. 10, 11-bis- [2-
(methylsulfonyloxy)-ethyl]-5H-di
Benzo[a,d]cycloheptene is a colorless concentrated liquid
remains as oil. The following are made in a similar way: 3-methyl-1,2,3,4,5,10-hexa
Hydro-dibenzo[3,4:6,7]cyclohep
Ta[1,2-d]azepine-methanesulfonic acid
Salt, melting point 189-191℃. The starting materials for this are 10, 11-
Bis-[2-(methylsulfonyloxy)-ethyl
]-5H-dibenzo[a,d]cycloheptane
21.8g (0.05mol), 6.3% ethanolic methyl
30 ml (1.9 g, 0.06 mol) of amine solution and di
Sopropyl-ethylamine 15.5g (0.125mol)
It is. 3-benzyl-1,2,3,4,5,10-hex
sahydro-dibenzo[3,4:6,7]cyclohe
Pta[1,2-d]azepine hydrochloride, melting point 265~
270°. The raw material for this is 10,11-bis-[2-(methylene)
rusulfonyloxy)-ethyl]-5H-diben
zo[a,d]cycloheptene 21.8g (0.05mol),
6.2 g (0.06 mol) of benzylamine and diiso
Propylethylamine 15.5g (0.125mol)
Ru. Example 2 3-benzyl-1,2,3,4,5,10-hex
sahydro-dibenzo[3,4:6,7]cyclohe
Pta[1,2-d]azepine hydrochloride 19.4g (0.05
mol) and 2 g of 5% Pb-carbon in methanol
Add 900ml of suspension to 770ml at normal pressure and 40 to 50°.
Hydrogenate until hydrogen is absorbed. Next is Nutsuchi
Strain the catalyst with step E and evaporate the filtrate with an aspirator.
Ru. 1, 2, 3, 4, 5, 10 remaining as a residue
xahydro-dibenzo[3,6:6,7]cyclo
Hepta[1,2-d]azepine hydrochloride crude product
When recrystallized from tanol, it has a melting point of 295-300°. To make this the free base, methylene chloride 250
Suspend the hydrochloride salt in ml and concentrate ammonia solution
Add 100ml and shake. methylene chloride solution
are separated and concentrated until crystallization begins. Next
When hexane is added to 1, 2, 3, 4, 5, 10-
hexahydro-dibenzo[3,4:6.7]cyclo
Hepta[1,2-d]azepine crystallizes. melting point
190~191°. To convert the free base to methanesulfonate,
Add a theoretical amount of meth to the free base dissolved in methylene chloride.
mix with sulfonic acid. and add ether
Then, 1,2,3,4,5,10-hexahydro-
dibenzo[3,4:6,7]cyclohepta[1,
2-d] Azepine-methanesulfonate precipitates
do. Melting point: 269-271°. Example 3 10,11-bis-[2-(methylsulfonyloxy)
C)-ethyl]-5H-dibenzo[a,d]
43.6g (0.1mol) of loheptane in absolute ethanol
Add (aminoethyl) to the solution dissolved in 400ml.
Loheptane 11.9g (0.12mol) and diisopropyl
-Add 32.3g (0.25mol) of ethylamine and mix the reaction.
Boil the mixture under reflux for 20 hours. reaction mixture
Concentrate with an aspirator and dissolve the residue in methylene chloride.
Dissolved in 150ml and 500ml of pentane, the solution was sequentially 2N
200ml each of sodium hydroxide solution and water
Wash with Next, add 200ml of 2N hydrochloric acid to the organic phase.
When heated, the hydrochloride is separated into particles. crystal
To filter it with Nutsuchie and use it as the free base
Suspend the hydrochloride in 300 ml of methylene chloride and add
Add 100ml of concentrated ammonia solution and shake. Methyl chloride
The solution is separated and concentrated until crystallization begins.
Then add hexane and 3-(cyclopliers)
methyl)-1,2,3,4,5,10-hexahyl
Dro-dibenzo[3,4:6,7]cyclohepta
[1,2-d]Azepine melting point 141-142° crystallizes
Ru. To convert this to methanesulfonate, salt
Dissolve the group in methylene chloride and add a theoretical amount of methanesulfate.
Adding fonic acid and adding ether to it gives 3-
(cyclopentylmethyl)-1,2,3,4,5,
10-hexahydro-dibenzo [3,4:6,7]
Cyclohepta[1,2-d]azepine-methane
Sulfonate melting point 248-249° precipitates. Example 4 1,2,3,4,5,10-hex made in Example 2
sahydro-dibenzo[3,4:6,7]cyclohe
Pta[1,2-d]azepine 26.1g (0.1 mol)
92 g (2 mol) of formic acid and 30% formua under ice cooling.
mixed with 20 g (0.2 mol) of rudehyde, and 95~
Stir at 100° for 1 hour. Then pour it over ice water.
and add 10N sodium hydroxide aqueous solution to it.
Make it alkaline. The separated base is diluted with methylene chloride.
and concentrate the methylene solution until crystallization begins.
do. Then, when hexane is added, 3-methyl-
1,2,3,4,5,10-hexahydro-diben
Zo [3,4:6,7] Cyclohepta [1,2-
d] Azepine with a melting point of 144-146° crystallizes. methane
To convert the sulfonate salt, convert the base into methylene chloride.
and add a theoretical amount of methanesulfonic acid to it.
I can do it. And when ether is added, 3-methyl-
1,2,3,4,5,10-hexahydro [3,
4:6,7] cyclohepta [1,2-d] azepi
Methanesulfonate melting point 189-191° is precipitated.
Ru. Example 5 10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-dibenzo[b,f]thiepin
Dissolve 4.56g (0.01mol) in 50ml of absolute ethanol
1.3 g (0.12 mol) of benzylamine
and diisopropyl-ethylamine 3.25 g (0.025
mol) and boil the reaction mixture under reflux for 18 h.
Ru. After cooling in an ice bath, the crystals separate. Nutsuchi that
and a small amount of isopropanol and
Wash with water. What's inside Nutsuchie is 3-Benji.
Ru-2,3,4,5-tetrahydro-1H-dibe
Nzo [2,3:6,7] Chiepino [4,5-d]
Azepine melting point is 149°-150°. To convert to hydrochloride, add 3.0 g of base to 100 g of acetone.
ml and in ether with stirring.
Add 2.2ml of 4N hydrochloric acid. and the solution becomes cloudy easily
Add ether until it looks like this. 3-Benzyl
2,3,4,5-tetrahydro-1H-dibenzo
[2,3:6,7] Thiepino [4,5-d]-a
Zepine hydrochloride crystallizes and has a melting point of 241-242°. This raw material can be made in the following ways:
Ru. Dibenzo[b,f]thiepin-10,11-diacetic acid
58g (0.2mol) of tonitrile and 800ml of methanol
Suspend in 7.5 ml of water with stirring. and
Cool to 0-5° in an ice bath. I dried here for an hour.
Passing in hydrogen chloride produces a clear solution. gas
The temperature should be maintained between 5 and 20° during heating.
The reaction mixture was then heated for 1 hour at room temperature and then for 4 hours.
Stir further under reflux while bringing to a boil. that
Evaporate completely in a rotary evaporator. A
Dissolve the ether solution in water and 2N sodium chloride.
Completely washed with Da solution and dried over sodium sulfate.
evaporates into Dissolve the oily residue in methanol,
When cooled to 0°, dibenzo[b,f]thiepin-
10,11-Diacetic acid methyl ester crystallizes. this
Strain it through a Nutsuchie and dry it under reduced pressure at 50℃ to find the melting point.
Shows 84-86°. Lithium hydride in 400ml of anhydrous diethyl ether
Oysters were added to a suspension of 7.6 g (0.2 mol) of sodium chloride.
While stirring, keep moisture out and store under nitrogen atmosphere.
Dibenzo[b,f]thiepin-10 within 1 hour,
11-Diacetic acid dimethyl ester 35.4g (0.1mol)
in anhydrous diethyl ether is added dropwise.
do. Boil the reaction mixture under reflux for 16 h at
Ru. After cooling to 0~5°, add 130ml of water to the reaction mixture.
Add dropwise. The organic phase is then separated and water
Wash and dry with sodium sulfate to a small volume.
Evaporate until Then dibenzo[b,f]thi
Pin-10,11-diethanol crystallizes, melting point 131
~133° is shown. Dibenzo[b,f]thiepin-10,11-dieta
Add 15 g (0.05 mol) of alcohol to 60 ml of pyridine at room temperature.
Melt and stir in an ice-salt bath to bring the reaction temperature up to
Methanesulfonic acid chloride 8.4 ml (12.6 g,
0.11 mol) is added dropwise. The reaction mixture was then heated at 0°
Stir for 30 minutes, then at 15-25° for 1 hour. after that
Add 500ml of methylene chloride to a separating filter.
Then, shake it sequentially with 2N hydrochloric acid and 400ml of water. salt
Separate the dichloromethane solution and hydrate over magnesium sulfate.
Dry and evaporate with an aspirator. as a remainder
10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-dibenzo[b,f]thiepin
The melting point is 107-108°. Example 6 In the same manner as in Example 5, using the corresponding raw materials, the following
compounds are produced. A 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-dibenzo[b,f]thiepi
22.7g (0.05mol), 2-phenylethylamine
7.3 g (0.06 mole) and diisopropyl
16.25 g (0.125 mol) of ethylamine was added to anhydrous ethyl alcohol.
3-(2-phenyl-
ethyl)-2,3,4,,5-tetrahydro-
1H-dibenzo [2,3:6,7]chiepi)
[4,5-d]Azepine is obtained, with a melting point of 96~
99° (from acetonitrile). Methanesulfonic acid
The salt is 161-164° (from absolute ethanol). B 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-2-methoxy-dibenzo
[b, f] - Thiepin 24.2g (0.05 mol), methi
1.85g (0.06mol) and diisopropylene
Pyrethylamine 16.25g (0.125mol) anhydrous
From the liquid contained in ethanol, 7-methoxy-3
-Methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]thiepino
[4,5-d]Azepine is obtained with a melting point of 108-112°
(from acetone). Hydrochloride has a melting point of 220-224° (anhydrous
(from ethanol). C 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-2-methylthio-dibenzo
[b, f] Thiepin 25.0 g [0.05 mol), (ami
cyclopentane 6.0g (0.06mol)
and diisopropylethylamine 16.25g
(0.125 mol) of anhydrous ethanol containing 7-
Methylthio-3-(cyclopentylmethyl)-
2,3,4,5-tetrahydro-1H-diben
Zo [2,3:6,7] Thiepino [4,5-d]
Crude product of azepine is obtained, melting point is methanesulfate
phonate 206-209° (from absolute ethanol). D 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-2-methyl-dibenzo
[b, f] Thiepin 23.4g (0.05 mol), methyl
1.85 g (0.06 mol) of amine and diisopropylene
Contains 16.25g (0.125mol) of ruethylamine
From water ethanol, 3,7-dimethyl-2,
3,4,5-tetrahydro-1H-dibenzo
[2,3:6,7] Thiepino [4,5-d] a
A crude product of zepin is obtained. Hydrochloride has a melting point of 265
~268° (from absolute ethanol). E 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-2-bromo-dibenzo
[b, f] Thiepin 26.7g (0.05 mol), methyl
1.85 g (0.06 mol) of amine and diisopropylene
Contains 16.25g (0.125mol) of ruethylamine
From water ethanol, 7-bromo-3-methyl-
2,3,4,5-tetrahydro-1H-diben
Zo [2,3:6,7] Thiepino [4,5-d]
Crude product of azepine is obtained, the hydrochloride has a melting point of 280°
(Decomposition) (from absolute ethanol) F 9,10-bis-[2-(methylsulfonyl)
xy)-ethyl]phenanthrene 21.1g (0.05
mol), 1.85 g (0.06 mol) of methylamine and
Diisopropyl-ethylamine 16.25g
(0.125 mol) of anhydrous ethanol containing 3-
Methyl-2,3,4,5-tetrahydro-1H
- Fuenanthro [9,10-d] azepine obtained
Its melting point is 142-145° (from acetone).
The melting point of methanesulfonate is 242-244° (ethanol
). G 4,5-bis-[2-(methylsulfonyl)
xy)-ethyl]-naphtho[1,2-b]thio
Phene 21.4g (0.05mol), Methylamine 1.85g
(0.06 mol) and diisopropyl-ethyl acetate
From 16.25 g (0.125 mol) of amine, 3-methyl-
2,3,4,5-tetrahydro-1H-thieno
[2', 3': 1, 2] Naphtho [4, 5-d] Azeh
A crude product of pin is obtained, the melting point of the hydrochloride is 273 ~
280° (decomposition) (from methanol). H 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-dibenz[b,f]oxe
Pin 21.9g (0.05mol), Methylamine 1.85g
(0.06 mol) and diisopropyl-ethyl acetate
From 16.25 g (0.125 mol) of amine, 3-methyl-
2,3,4,5-tetrahydro-1H-diben
Z [2,3:6,7] Oxepino [4,5-
d] Azepine was obtained, with a melting point of 147-149° (acetate
from nitrile). Melting point of hydrochloride 282-285° (anhydrous
from ethanol). I 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-dibenz[b,f]oxe
Pin 21.9g (0.05mol), isopropylamine
3.5g (0.06mol) and diisopropyl-ether
From 16.25 g (0.125 mol) of thylamine, 3-i
Sopropyl-2,3,4,5-tetrahydro-
1H-Dibenz [2,3:6,7] Oxepino
[4,5-d]Azepine is obtained, melting point 125 ~
128° (from acetonitrile). Melt of maleate
Point 175-177° (from acetone). K 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-5-ethyl-5H-diben
Z[b,f]Azepine 23.3g (0.05 mol), medicinal
1.85 g (0.006 mol) of thylamine and diiso
Propyl-ethylamine 16.25g (0.125mol)
From, 3-methyl-10-ethyl-1,2,3,
4,5,10-hexahydro-dibenz [b,
f] Azepino [4,5-d] Azepine melting point 99 ~
100° (from toluene) is obtained. oxalate
The melting point of is 180-183° (from absolute ethanol).
Ru. L 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-5-ethyl-5H-diben
Z [b, f] azepine 23.3g (0.05 mol), a
3.4 g (0.06 mol) of rylamine and diisopropylene
Lopylethylamine 16.25g (0.125mol)
et al., 3-allyl-10-ethyl-1,2,3,
4,5,10-hexahydro-dibenz [b,
f] Azepino [4,5-d] Azepine melting point 100
~101° (from hexane) is obtained. of hydrochloride
Melting point: 245-248° (absolute ethanol/acetone)
et al). M 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-5H-dibenz[b,f]
Azepine 21.9g (0.05mol), Methylamine 1.85
g (0.06 mol) and diisopropyl-ethyl
From 16.25 g (0.125 mol) of amine, 3-methyl
-1,2,3,4,5,10-hexahydro-di
Benz [b, f] azepino [4,5-d] aze
A pin melting point of 121-124° (from methanol) was obtained.
Ru. Melting point of methanesulfonate: 263-266° (anhydrous
(from ethanol/acetone). and N 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-5H-dibenz[b,f]
Azepine 21.9g (0.05mol), (aminoethyl)
- 6.0 g (0.06 mol) of cyclopentane and di
Isopropyl-ethylamine 16.25g (0.125mol)
from 3-(cyclopentylmethyl)-
1,2,3,4,5,10-hexahydro-dibe
[b, f] azepine [4,5-d] azepine
of pentane, melting point 72-75° (from pentane).
Melting point of methanesulfonate: 271-274° (methanol
(from Le) The raw material can be made as follows. [For B] 2-methoxy-10,11-bis
(bromomethyl)-dibenzo[b,f]thiepin
42.3g (0.1mol) and in 500ml acetonitrile
of sodium cyanide 11.8 g [0.24 mol) to 2
-Methoxy-dibenzo[b,f]thiepin-10,
11-Diacetonitrile melting point 198-200° (acetonitrile
) is obtained from Lil. 2-Methoxy-dibenzo[b,f]thiepin-
31.8 g (0.1 mol) of 10,11-diacetonitrile
400ml of tanol, 3.8ml of water and dry hydrogen chloride
et al., 2-methoxy-dibenzo[b,f]thiepin
-10,11-Diacetic acid dimethyl ester melting point 96-98°
(from toluene) is obtained. 2-Methoxy-dibenzo[b,f]thiepin-
10,11-diacetic acid dimethyl ester 38.5g (0.1mol)
) and hydrogenated lithium in anhydrous diethyl ether 1
2-Metho from 7.6 g (0.2 mol) of aluminum
xy-dibenzo[b,f]thiepin-10,11-di
Ethanol melting point 116-119° (ethyl acetate/hexane
) can be obtained. 2-Methoxy-dibenzo[b,f]thiepin-
32.8 g (0.1 mol) of 10,11-diethanol and
Methanesulfonic acid chloride in 120ml of pyridine
25.2g (0.22mol) to 10,11-bis[2-
(methylsulfonyloxy)-ethyl]-2-methane
The crude product of toxy-dibenzo[b,f]thiepine is
can get. [For C] 2-methoxythio-10,11-
Bis(bromomethyl)-dibenzo[b,f]thie
44.2 g (0.1 mol) of pin and 500 g of acetonitrile
11.8g (0.24mol) of sodium cyanide in ml
2-Methylthio-dibenzo[b,f]thiepin
-10,11-diacetonitrile melting point 204-206° (acetic acid
) is obtained from ethyl. 2-Methylthio-dibenzo[b,f]thiepin
33.4 g (0.1 mol) of 10,11-diacetonitrile,
400ml of tanol, 3.8ml of water and dry hydrogen chloride
et al., 2-methylthio-dibenzo[b,f]thiepi
N-10,11-diacetic acid dimethyl ester melting point 85~
86° (from pentane) is obtained. 2-Methylthio-dibenzo[b,f]thiepin
-10,11-diacetic acid dimethyl ester 40.0g (0.1
mol) and hydrogenated phosphorus in anhydrous diethyl ether.
From 7.6 g (0.2 mol) of thium aluminum
Chilthio-dibenzo[b,f]thiepin-10,11
-Diethanol melting point 58-60° (diethyl ether?
) are obtained. 2-Methylthio-dibenzo[b,f]thiepin
-10,11-diethyl 34.5g (0.1mol) and pyridine
25.2g methanesulfonic acid chloride in 120ml
(0.22 mol) and 10,11-bis[2-(methyl
Sulfonyloxy)-ethyl]-2-methylthio
-A crude product of dibenzo[b,f]thiepine was obtained.
Ru. [For D] 2-methylthio-10,11-bi
Su-(bromomethyl)-dibenzo[b,f]]
Epine 41.0g (0.1mol) and acetonitrile
Sodium cyanide 11.8g (0.24 mol) in 500ml
Tokara 2-methyl-dibenzo[b,f]thiepin
-10,11-diacetonitrile melting point 198~200° (acetonitrile
tonitrile) is obtained. 2-Methyl-dibenzo[b,f]thiepin-
30.2 g (0.1 mol) of 10,11-diacetonitrile,
400ml of tanol, 3.8ml of water and dry hydrogen chloride
2-Methyl-dibenzo[b,f]thiepin-
10,11-Diacetic acid dimethyl ester melting point 76-77° (Metal
(from tanol) is obtained. 2-Methyl-dibenzo[b,f]thiepin-
36.9 g (0.1 mole) of 10,10-diacetic acid dimethyl ester
) and hydrogenated lithium in anhydrous diethyl ether 1
7.6 g (0.2 mol) of aluminum and 2-metal
Chill-dibenzo[b,f]thiepin-10,11-di
Ethanol melting point 126-129° (from acetonitrile)
is obtained. 2-Methyl-dibenzo[b,f]thiepin-
31.2g (0.01mol) of 10,11-diethanol and piri
25.2g methanesulfonic acid chloride in 120ml gin
(0.22 mol), 10,11-bis-[2-(metal)
Tylsulfonyloxy)-ethyl]-2-methyl
-A crude product of dibenzo[b,f]thiepine was obtained.
Ru. [For E] 2-bromo-10,11-bis
(bromoethyl)-dibenzo[b,f]thiepin
-10,11-diacetonitrile, melting point 200-204° (A
from setonitrile) is obtained. 2-bromo-dibenzo[b,f]thiepin-
36.7 g (0.1 mol) of 10,11-diacetonitrile and
400ml methanol, 3.8ml water and dry hydrogen chloride
From 2-bromo-dibenzo[b,f]thiepin-
10,11-Diacetic acid dimethyl ester, melting point 90-93°
(from absolute ethanol) is obtained. 2-bromo-dibenzo[b,f]thiepin-
43.3 g (0.1 mole) of 10,11-diacetic acid dimethyl ester
) and lithium hydride in anhydrous diethyl ether
7.6 g (0.2 mol) of aluminum and 2-bromine
-dibenzo[b,f]thiepin-10,11-dieta
Nol, melting point 166-169° (from diethyl ether)
is obtained. 2-bromo-dibenzo[b,f]thiepin-
37.7 g (0.1 mol) of 10,11-diethanol and
Methanesulfonic acid chloride in 120ml of pyridine
25.2g (0.22mol) and 10,11-bis[2-
(methylsulfonyloxy)-ethyl]-2-b
Lomodibenzo[b,f]thiepin, melting point 94~
96° (from benzene/ether) is obtained. [For F] Phenanthrene-9,10-di
Acetonitrile [S.Hauptmann: Chem.Ber.93，
2604 (1960)] 25.6 g (0.1 mol) and methanol
400ml of water, 3.8ml of water and dry hydrogen chloride.
Nanthrene-9,10-diacetic acid-dimethyl ester
A melting point of 143-145° (from methanol) was obtained.
Ru. Phenanthrene-9,10-diacetic acid-dimethyl ester
Stell 32.2g (0.1mol) and anhydrous diethyl ether
7.6 g of lithium aluminum hydride in 1
(0.2 mol) and phenanthrene-9,10-die
Tanol, melting point 175-177° (from methanol) is obtained.
It will be done. Phenanthrene 9,10-diethanol 26.6g
(0.1 mol) and methanesulfate in 120 ml of pyridine
25.2 g (0.22 mol) of phonoyl chloride and 9,10
-bis-[2-(methylsulfonyloxy)-e
Chill]-phenanthrene, melting point 157-159° (acetate
) is obtained from nitrile. [For G] 4,5-dimethyl-benzo
[f] Thieno [2,3-b] Thiepin 122g (0.5
mol) and 100 g of potassium hydroxide.
Boil under reflux under a nitrogen atmosphere. reaction mixture
Cool the mixture to 20°, dilute with 800ml of water, and add petroleum ether.
Extract with file. Separate the organic phase, wash with water and dilute with sodium sulfate.
Dry over thorium and concentrate. The remainder is 4,5-
dimethyl-naphtho[1,2-b]thiophene
When recrystallized from tanol, it has a melting point of 88-90°. 4,5-dimethyl-naphtho[1,2-b]thio
106 g (0.5 mole) of phene in 2.5 g of carbon tetrachloride
Dissolve and dissolve N-bromosuccinimide 178g
(1 mol) is added. Ultraviolet lamp in nitrogen atmosphere
Boil the reaction mixture while stirring while irradiating the
Heat until hot. All the N- at the bottom of the melter
Bromosuccinimide floating in solution
Continue boiling until it changes to acid imide. That time is long
It takes 20 minutes. Now add 400ml of water to the reaction mixture.
In addition, the crystallized 4,5-bis(bromemet)
filter)-naphtho[1,2-b]thiophene
do. A melting point of 202-204° is obtained. Bis-bromomethyl-naphtho[1,2-b]thi
Offene 37.0g (0.1mol) and sodium cyanide
Acetonitrile 500 containing 11.8 g (0.24 mol)
ml and Naphtho[1,2-b]thiophene-4,
5-Diacetonitrile, melting point 250-251° (acetone
) is obtained. Naphtho[1,2-b]thiophene-4,5-di
Acetonitrile 26.2g (0.1mol), methanol
From 400ml, 3.8ml water and dry hydrogen chloride, knaf
[1,2-b]thiophene-4,5-diacetic acid di
Methyl ester, melting point 136-138° (methanol or
) are obtained. Naphtho[1,2-b]thiophene-4,5-di
Acetic acid dimethyl ester 32.8g (0.1mol) and anhydrous
Lithium aluminum hydride in diethyl ether 1
7.6 g (0.2 mol) of Naphtho[1,2-
b] Thiophene-4,5-diethanol, melting point
163-166° (from acetone) is obtained. Naphtho[1,2-b]thiophene-4,5-di
in 27.2 g (0.1 mol) of etator and 120 ml of pyridine.
25.2g (0.22mol) of methanesulfonic acid chloride and
to 4,5-[2-(methylsulfonyloxy)
-ethyl]-naphtho[1,2-b]thiophene,
A melting point of 132-135° (from methylene chloride) is obtained. [For H) and I)] 10, 11-bis-
(bromomethyl)-dibenz[b,f]oxepi
in 38 g (0.1 mole) and 500 ml acetonitrile.
from 11.8g (0.24mol) of sodium cyanide
Dibenz[b,f]oxepin-10,11-diacetate
Tonitrile, melting point 176-178° (from methanol)
can get. dibenz[b,f]oxepin-10,11-dia
Setonitrile 27.2g (0.1mol), methanol 4400
ml, dibenz from 3.8 ml of water and dry hydrogen chloride
[b,f] Oxepin-10,11-dimethyl acetate
Ester, melting point 65-67° (from pentane) obtained
Ru. dibenz[b,f]oxepin-10,11-divinegar
33.8 g (0.1 mol) of acid dimethyl ester and anhydrous dimethyl ester
Lithium aluminum hydride in ethyl ether 1
7.6 g (0.2 mol) and dibenz [b, f]
Oxepin-10,11-diethanol, melting point 138~
140° (from acetone) is obtained. dibenz[b,f]oxepin-10,11-jie
Tanol 28.2g and methanesulfonic acid chloride
from 120 ml of pyridine containing 25.2 g (0.22 mol)
10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-dibenz[b,f]oxepi
A melting point of 112-114° (from methylene chloride) was obtained.
Ru. [For K) and L)] 5-acetyl-
10,11-bis-(bromomethyl)-5H-diben
Z[b,f]azepine 42.1g (0.1 mol) and
Sodium cyanide in 500ml of acetonitrile
11.8g (0.24mol) and 5-acetyl-5H-di
Benz[b,f]azepine-10,11-diacetoni
Tolyl, melting point 183-185° (from benzene) is obtained.
Ru. 5-acetyl-5H-dibenz[b,f]aze
Pin-10,11-diacetonitrile 31.3g (0.1mol)
), 400 ml of methanol, 3.8 ml of water and dry chloride
Hydrogen and 5-acetyl-5H-dibenz [b,
f] Azepine-10,11-diacetic acid dimethyl ester
mol., melting point 123-124° (from toluene). 5-acetyl-5H-dibenz[b,f]aze
Pin-10,11-diacetic acid dimethyl ester 37.9g
(0.1 mol) and 150 ml of anhydrous tetrahydrofuran
7.6g (0.2 mole) of lithium aluminum hydride in
) and 5-ethyl-5H-dibenz [b, f]
Azepine-10,11-diethanol, melting point 102~
105° (from ether) is obtained. 5-Ethyl-5H-dibenz[b,f]Azepi
in 120 ml of 10,11-diethanol and pyridine.
25.2g (0.22mol) of methanesulfonic acid chloride and
to 10,11-bis-[2-[methylsulfonylo
xy)-ethyl]-5-ethyl-dibenz[b,
f] Azepine, melting point 140-143° (from toluene)
can get. [For M) and N)] 5-acetyl-
5H-dibenz [b, f] azepine-10,11-di
Acetic acid dimethyl ester 37.9g (0.1 mol) and anhydrous
Lithium aluminum hydride in diethyl ether 1
7.6 g (0.2 mol) of Ni and 5H-dibenz
[b,f]Azepine-10,11-diethanol, fused
A point of 180-182° (from acetone) is obtained. 5H - dibenz [b, f] azepine - 10, 11 -
28.1g (0.1mol) of diethanol and 120ml of pyridine
25.2g (0.22mol) of methanesulfonic acid chloride in
) and 10,11-bis-[2-(methylsulfonate)
Nyloxy)-ethyl]-5H-dibenz[b,
f] Azepine, melting point 140-142° (from toluene)
can get. Example 7 7-methoxy-3-methyl-2,3,4,5-
Tetrahydro-1H-dibenzo [2,3:6,7]
Thiepino[4,5-d]azepine (this is shown in Example 6)
16.2g (0.05mol) and
Add a mixture of 140 ml of 48% aqueous hydrobromic acid under reflux.
Boil for 2 hours, stirring. Next, adjust this to 20°
Cool to 7-hydroxy precipitated here
3-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]thiepino[4,
5-d] Filter the azepine hydrobromide and
Dissolve this in 160 ml of a 6% methanol aqueous solution.
Add concentrated ammonia water to this solution to form phenol.
Make it alkaline with talaine. instructor
free 7-hydroxy-3-methyl-2,3,
4,5-tetrahydro-1H-dibenzo [2,
3:6,7]thiepino[4,5-d]azepine
Crystallizes. When this is recrystallized with acetonitrile,
Shows a melting point of 216-218°. To convert to methanesulfonate, this base
Dissolve 9.3g (0.03mol) in 380ml of acetone.
2.88 g of methanesulfonic acid while stirring into the solution of
(0.03 mol) is added. Then, 7-hydroxy
C-3-methyl-2,3,4,5-tetrahydro
-1H-dibenzo[2,3:6,7]thiepino
[4,5-d]Azepine methanesulfonate crystals
It shows a melting point of 282-286°. Example 8 7-bromo-3-methyl made by Example 6
-2,3,4,5-tetrahydro-1H-diben
Zo [2,3:6,7] Thiepino [4,5-d] a
Zepin 18.6g (0.05mol) and dimethylformamide
10.7 g (0.12 mol) of cuprous cyanide in 20 ml of
Stir the mixture in a nitrogen atmosphere for 22 hours.
Heat to 180°. Then cool to 30° and add chloride
of ethylene diamine diluted with 100 ml of ethylene.
Add 50ml of 50% aqueous solution. Then separate the organic phase
washed with water, dried over sodium sulfate, and evaporated.
let The crystalline residue is 7-cyano-3-methyl
-2,3,4,5-tetrahydro-1H-diben
Zo [2,3:6,7] Thiepino [4,5-d] a
Zepin and recrystallized from hexane/ethyl acetate
and a melting point of 154-157°. To convert to methanesulfonate, this base
Dissolve 9.6g (0.03mol) in 50ml of acetone,
2.88 g (0.03 mol) of methanesulfonic acid is added to this solution.
Add while stirring. 7 crystallizes here
-cyano-3-methyl-2,3,4,5-tetra
Hydro-1H-dibenzo[2,3:6,7]thie
Pino[4,5-d]azepine-methanesulfonic acid
As a salt, it has a melting point of 247-250°. Example 9 2,3,4,5-tetra in 50 ml of anhydrous pyridine
Hydro-1H-dibenzo[2,3:6,7]thie
Pino[4,5-d]azepine-3-propanol
While stirring into a solution containing 16.9g (0.05mol)
12.2 g of octanoyl chloride (0.075
mol) dropwise. At this time, the temperature is maintained between 0 and 5 degrees.
dripping It is then stirred for a further 20 hours at room temperature.
The reaction mixture was then poured onto ice water and the ether
Extract with file. Separate the organic phase, wash with water and sulfuric acid
Dry over sodium and evaporate completely. oily
3-octanoyloxypropyl as a residue
2,3,4,5-tetrahydro-1H-dibenzo
[2,3:6,7]thiepino[4,5-d]adze
You will get a pin. Dissolve 21.5g of crude base in 150ml of acetone.
4.2 ml of anhydrous oxalic acid in 22 ml of absolute alcohol
Add a solution containing g (0.047 mol). At this time
3-octanoyloxypropyl-2,3,4,
5-tetrahydro-1H-dibenzo [2,3:6,
7] Thiepino[4,5-d]azepine-oxalic acid
Salt crystallizes. This is recrystallized from absolute ethanol
It shows a melting point of 157-162°. The following can be made in a similar way: 2,3,4,5-tetrahydro-1H-diben
Zo [2,3:6,7] Thiepino [45-d] Azepi
Contains 16.9g (0.05mol) of 3-propanol
50ml of anhydrous pyridine and 5.9g (0.075mol) of acetyl chloride
) and 3-acetoxypropyl-2,3,
4,5-tetrahydro-1H-dibenzo [2,
3:6,7]thiepino[4,5-d]azepine
can get. This oxalate has a melting point of 156-160° (no
(from water and ethanol). Example 10 75ml of 7.4% absolute ethanol solution of ethylamine
(equivalent to 0.012 mol), diisopropylethyl acetate
3.25 g (0.025 mol) of amine, 50 ml of absolute ethanol and
and 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-dibenzo[b,f]thiepin
(This is made according to Example 5) 4.5g (0.01 mole)
) and the whole in a closed tube for 20 hours.
Heat to 90°. After cooling the reaction mixture methylene chloride
Rinse 250ml and separate into a filter.
Add 50ml of 2N sodium hydroxide solution and 50ml of water.
Shake next. The methylene chloride solution is vaporized using an aspirator.
Crude 3-ethyl-2, which is emitted and precipitated,
3,4,5-tetrahydro-1H-dibenzo [2,
3:6,7]thiepino[4,5-d]azepine
Convert to hydrochloride as follows: i.e. color
3.1 g of the remaining sticky oil is dissolved in methylene chloride.
and 4N ethereal hydrochloric acid solution.
Add 3ml of liquid. 3-ethyl-2,3,4,5-
Tetrahydro-1H-dibenzo [2,3:6,7]
Thiepino[4,5-d]azepine-hydrochloride is
It sinks in the tell. Strained 1 degree ethanol at Nutsuchie
Recrystallize from alcohol/ether. Methanesulfonic acid
The melting point of salt is 212-214°. Example 11 Lithium hydride in 1 anhydrous diethyl ether
In a suspension containing 14.6 g (0.38 mol) of aluminum
Within 20 minutes while stirring in a nitrogen atmosphere,
3-methyl-1 in 500 ml of water diethyl ether,
5-dihydro-2H-dibenzo [2,3:6,7]
Thiepino [4,5-d]azepine-2,4 (3H)
- Add a suspension containing 32.1 g (0.1 mol) of dione.
Ru. At this time, the temperature is maintained at 20-30°. then react
Boil the mixture under reflux for another 15 minutes, then
Cool to 0-5°. 75ml ethyl acetate then 150ml water
Excess hydrogenation solution is removed by carefully adding dropwise
Decomposes thium aluminum. Separate the organic phase
and extracted multiple times with 5% methanesulfonic acid.
Phenolic the acidic extract with concentrated ammonia water.
If the rain shows alkalinity, the crude
3-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]thiepino[4,
5-d] Azepine separates as oil. this coarse salt
The groups were extracted with ether, the organic phase was separated and washed with water.
and completely evaporated after drying over sodium sulfate.
Ru. Dissolve the residue in 50 ml of petroleum ether and bring to 0°
cool. Then, a pure base with a melting point of 83-86° crystallizes out.
do. Melting point of methanesulfonate is 256-258°
be. Starting material 3-methyl-1,5-dihydro-
2H-dibenzo[2,3:6,7]thiepino[4,
5-d] Azepine-2,4(3H)-dione is the following
It can be made like this. 1,5-dihydro-2H-dibenzo [2,3:
6.7] Thiepino[4,5-d]Azepine-2,4
(3H)-dione, which was prepared as described in Example 6.
30.7 g (0.1 mol) and methyl iodide
Contains 16.6g (0.12mol) in 1 methylene chloride
Add tetrabutylammonium hydroxide to the solution in 45 ml of water.
Droxide 28.5g_~solution nitrogen gas containing 0.11 mol)
Add dropwise within 30 minutes while stirring in ambient air.
The temperature then rises to 20° to 25°. Then the reaction mixture
Stir for another 5 hours at room temperature, then add water
Add 250ml. Separate the organic phase, wash with water and add sulfuric acid
Dry over sodium and evaporate completely. crystalline
Stir the residue with 50 ml of absolute ethanol, then add
Strain through a sieve and wash with absolute ethanol. Living
The product is 3-methyl-1,5-dihydro-2H-di
Benzo [2,3:6.7] Thiepino [4,5-d]
With azepine-2,4(3H)-dione, melt after drying.
The point is 216-222°. Example 12 Aluminum chloride in 100ml anhydrous diethyl ether
In an ice-cold solution containing 4 g (0.03 mol) of
Lithium aluminum hydride in 75 ml of water diethyl ether
A suspension containing 1.14 g (0.03 mol) of
In a bare atmosphere, with moisture excluded, and the reaction temperature is 5° or less.
Stir to thicken, being careful not to let it rise to the top.
Charge again. Then 500ml of anhydrous diethyl ether
1,3,4,5-tetrahydro-2H-dibe in it
Nzo [2,3:6,7] Chiepino [4,5-d]
Containing 2.93g (0.01mol) of azepin-2-one
Add the suspension and boil the mixture under reflux for 24 hours.
Ru. After cooling it to 0~5°, I decided to drop 10ml of water.
Therefore, carefully decompose the excess aluminum hydride.
do. Now separate the organic phase and add twice 30 ml of water each time.
Wash, dry over sodium sulphate and evaporate. Residue
2,3,4,5-tetrahydro-1H-
Dibenzo [2,3:6.7] Thiepino [4,5-d]
Azepine is obtained. This is reconstituted from methanol.
When crystallized, it has a melting point of 142-143°. methanesulfone
The melting point of the acid salt is 305-307°. Starting material 1,3,4,5-tetrahydro-
2H-Dibenzo [2,3:6.7] Thiepino [4,5
-d] Azepine-2-one is made as follows.
be able to. 10,11-bis-(bromomethyl)-dibenzo
(b, f) 198 g (0.5 mol) of Thiepin was added under nitrogen feces.
in acetonitrile 2.5% while stirring in an ambient atmosphere.
Dissolve at 50°. Add this solution to 180 ml of distilled water.
A solution containing 59g of sodium anhydride was dropped within 10 minutes.
add In this case, the internal
Maintain temperature at 50°. This reaction mixture was then converted into
Stir for another 30 minutes at temperature and then ice
Charge 1.5 liters of water. Here dibenzo [b, f]
Thiepin-10,11-diacetonitrile crystallizes
Ru. Strain the gray crystals through a Nutsuchie, add water, and then acetate.
Wash with tonitrile and then vacuum dry at 60°.
Shows a melting point of 205-207°. Dibenzo[b,f]thiepin-10,11-diacetic acid
145 g (0.5 mol) of tonitrile to 2.75 g of methylene chloride
Stir to dissolve. Add 5~ to this solution
Introduce dry hydrogen bromide for 30 min with ice cooling at 7°.
Ru. Yellow crystals separated from the reaction mixture after several hours.
do. Then stop introducing hydrogen bromide and continue for 30 minutes.
Stir at 5-70°. Now add about half of the solvent to
The reaction mixture is evaporated in vacuo. Does it remain?
Strain the boiled crystals through a Nutsuie filter and dissolve them in methylene chloride.
Wash thoroughly and dry the pale yellow crystals at 60° under reduced pressure.
Ru. 2-Amino-4-bromo- thus obtained
1H-dibenzo[2,3:6.7]thiepino[4,5
-d]Azepine-hydrobromide as a crude product
further processed. 2-amino-4-bromo-1H-dibenzo [2,
3:6.7] Thiepino [4,5-d] Azepine
90g (0.2mol) of drobromide, dimethylformua
Stir 1.5% of Mido and 1.3% of Water in a nitrogen atmosphere.
Boil under reflux for 2 hours while stirring. Then anti
The reaction mixture was diluted with 800 ml of water at 90-100° and
Cool on ice to 5°. At this time, 1,5-dihydro-2H
- Dibenzo [2,3:6.7] Thiepino [4,5-
d] Azepine-2,4(3H)-dione crystallizes
Ru. Strain this through a sieve and mix well with water and acetone.
After washing and drying at 100° vacuum, this crude product
shows a melting point of 253-256°. Anhydrous diethyl ether 3.5 and anhydrous tetra
Lithium aluminum hydride in 350ml of hydrofuran
In a suspension containing 22.8 g (0.6 mol) of
Hydro-2H-dibenzo[2,3:6.7]thiepino
[4,5-d]Azepine-2,4(3H)-dione
61.4g (0.2mol) in 200ml of anhydrous diethyl ether
While stirring the suspension contained in the nitrogen atmosphere
Add within 30 minutes. In this case, the temperature is kept at 20~30°.
One. The reaction mixture was then boiled under reflux for another 24 hours.
Then cool to 0-5°. ethyl acetate 150
ml then carefully dropwise add 300 ml of water.
Decompose excess lithium aluminum hydride. Yes
Separate the organic phase and wash it several times, first with 2N hydrochloric acid and then with water.
Wash well and dry over sodium sulfate until completely evaporated.
let 1,3,4,5-tetrahydride as a residue
Lo-2H-dibenzo [2,3:6.7] Thiepino
[4,5-d]Azepin-2-one is obtained and melted.
Points 195-198° are shown. Example 13 2,3,4,5-tetrahydro-1H-diben
Zo [2,3:6.7] Thiepino [4,5-d] Aze
8.38 g (0.03 mol) of pin in 6 ml of 85% formic acid.
Melt at 40-50° while stirring. 35% in this solution
Add 2.4 ml of formaldehyde solution. then
Stir further for 12 hours at 95-100°. Next, this anti-
The reaction mixture was cooled to 20°, diluted with 100 ml of water and concentrated.
With ammonia water, with phenolphthalein, with alkaline
be sure to demonstrate In this way, crude 3-methyl
-2,3,4,5-tetrahydro-1H-diben
Zo [2,3:6.7] Thiepino [4,5-d] Aze
The pin separates as oil. This crude base is dissolved in ether.
The organic phase was separated, washed twice with water and diluted with sodium sulfate.
Dry over thorium and evaporate completely. this base
is converted to methanesulfonate as follows:
Ru. Dissolve 8.4g (0.03mol) of crude base in 40ml of acetone.
then carefully add 2.6 g of methanesulfonic acid.
Add. Then here is 3-methyl-2,3,4,
5-tetrahydro-1H-dibenzo [2,3:
6.7] Thiepino[4,5-d]Azepinemethane
The sulfonate crystallizes out from absolute ethanol.
When recrystallized, it has a melting point of 256-258°. Example 14 2,3,4,5-tetrahydro-1H-diben
Zo [2,3:6.7] Thiepino [4,5-d] Aze
Add 8.38g (0.03mol) of pin to 80ml of 50% acetic acid.
Dissolve while stirring. Add acetic anhydride to this solution at the same time.
Add 8.16g (0.08mol) and leave at room temperature for 12 hours.
Ru. The reaction mixture was then completely evaporated on a rotary evaporator.
and dissolve the residue in ether. This ether solution
Dilute the solution once with acid and once with 2N sodium hydroxide aqueous solution.
and washed twice with water, and then with sodium sulfate.
This ether solution is completely evaporated after drying on
It will be done. Here, 3-acetyl-2,3,4,5-te
Torahydro-1H-dibenzo [2,3:6.7] Thie
Pino[4,5-d]azepine remains as a yellow oil.
Ru. Convert 9.4g of this crude acetyl compound into anhydrous diethyl
Dissolve in 150ml of ether and add this solution to anhydrous diethyl
Lithium aluminum hydride in ether 50ml
within 1 hour into a suspension containing 1.6 g (0.042 mol)
Add dropwise. At this point, the reaction mixture begins to boil.
Ru. Boiling is then continued under reflux for another 6 hours. cold
After bringing the temperature to 0-5°, add 40 ml of water to this reaction mixture.
is added dropwise and the organic phase is separated. wash this with water
and completely evaporated after drying over sodium sulfate.
Dissolve the oily residue in 10ml of acetone and cool to -10°.
3-ethyl-2,3,4,5-tetrahydro
-1H-dibenzo[2,3:6,7]thiepino
[4,5-d]Azepine, melting point 106-107° crystallizes
Ru. Methanesulfonate was prepared as described in Example 7.
It has a melting point of 212-214° (from ethanol). Example 15 The following final product is made analogously to Example 12. 1,3,4,5-tetrahydro-2H-thieno
[2', 3': 2, 3] [1] Benzothiepino [4, 5
-d]Azepine-2-one and 1,2,3,5-te
Tolahydro-4H-thieno [2′,3′:2,3] [1]
Benzothiepino[4,5-d]azepine-4-o
2,3,4,
5-tetrahydro-1H-thieno [2', 3': 2,
3] [1] Benzothiepino [4,5-d] azepi
with a melting point of 119-120° (from diethyl ether).
It will be done. Starting material 1,3,4,5-tetrahydro
-2H-thieno [2', 3': 2, 3] [1] Benzothi
epino[4,5-d]azepine-2-one and 1,
2,3,5-tetrahydro-4H-thieno [2',
3′] [1] Thiepino [4,5-d] Azepine-4
- The mixture with ion is prepared as follows in the same way as in the production of raw materials in Example 12.
It can be made like this. 4,5-bis-(bromomethyl)-thieno
[2,3-b] [1] Benzothiepine 201g (0.5 mo
) to Chieno [2,3-b] [1] Benzochie
Pin-4,5-diacetonitrile, melting point 170~
172° (from acetonitrile) is obtained. Thieno [2,3-b] [1] Benzothiepine-
From 147g (0.5mol) of 4,5-diacetonitrile
2-amino-4-bromo-1H-thieno [2', 3':
2,3] [1] Benzothiepino [4,5-d] a
Zepine-hydrobromide and 4-amino-2-bro
Mu-5H-thieno [2', 3'-2, 3] [1] Benzo
Thiepino[4,5-d]azepine-hydrochloride
A mixture of 3 and 5 hydride is obtained as crude product. 2-amino-4-bromo-1H-thieno [2′,
3′:2,3] [1] Benzothiepino [4,5-d]
Azepine-hydrobromide and 4-amino-2-bromide
Romu-5H-Chieno [2', 3': 2, 3] [1] Ben
Zothiepino[4,5-d]azepine-hydrobro
From 92 g (0.2 mol) of the mixture with mido, 1,5-
Dihydro-2H-thieno [2′,3′:2,3] [1]
Benzothiepino[4,5-d]azepine-2,4
(3H) - dione, melting point 215-218° (methanol or
) are obtained. 1,5-dihydro-2H-thieno [2′,3′:2,
3] [1] Benzothiepino [4,5-d] azepi
62.6 g (0.2 mol) of 2,4(3H)-dione
et al., 1,3,4,5-tetrahydro-2H-thie
ノ[2′,3′:2,3][1]Benzothiepino[4,
5-d] Azepine-2-one and 1,2,3,5-
Tetrahydro-4H-thieno [2′,3′:2,3]
[1] Benzothiepino[4,5-d]azepine-
A mixture of 4-ones is obtained as crude product. Example 16 The following final product is made analogously to Example 13. 2,3,4,5-tetrahydro-1H-thieno
[2', 3': 2, 3] [1] Benzothiepino [4, 5
-d] 3-Methyl from 14.3g (0.05mol) of azepine
Ru-2,3,4,5-tetrahydro-1H-thie
ノ[2′,3′:2,3][1]Benzothiepino[4,
5-d] Azepine is obtained as a crude product. Mail
Tansulfonate has a melting point of 208-209° (anhydrous ethanol).
). Example 17 The following final product is made analogously to Example 14. 2,3,4,5-tetrahydro-1H-thieno
[2', 3': 2, 3] [1] Benzothiepino [4, 5
-d] 14.3g (0.05mol) of azepine to 3-ethyl
Ru-2,3,4,5-tetrahydro-1H-thie
ノ[2′,3′:2,3][1]Benzothiepino[4,
5-d] Azepine, melting point 127-129° (acetone or
) are obtained. Methanesulfonate has a melting point of 209
~211° (from absolute ethanol). Example 18 The following compound is prepared in the same manner as in Example 11 using appropriate raw materials.
You can get things. 3-[3-(dimethylamino)-propyl]-
1,5 dihydro-2H-dibenzo [2,3:6,
7] Thiepino [4,5-d]Azepine-2,4
(3H)-dione 39.3g (0.1 mol) and diethyl anhydride
14.6g lithium aluminum hydride in ether
(0.38 mol), 3-[3-(dimethylamino)
-Propyl]-2,3,4,5-tetrahydride
Lo-1H-dibenzo[2,3:6,7]thiepino
[4,5-d]azepine is obtained as a crude product,
Its dihydrochloride has a melting point of 285-289° (decomposed). 3-[3-(dimethylamino)-propyl]-
1,5-dihydro-2H-thieno [[2′,3′:2,
3] [1] Benzothiepino [4,5-d] azepi
39.9 g (0.1 mol) of 2,4(3H)-dione and nothing
Lithium aluminum hydride in water diethyl ether
14.6 g (0.38 mol) of 3-[3-dime]
thylamino)-propyl]-2,3,4,5-te
trahydro-1H-thie) [2', 3': 2, 3] [1]
Benzothiepino[4,5-d]azepine is crudely produced.
Obtained as an object. Dihydrochloride has a melting point of 265-270° (min.
solution) is shown. 3-[3-(dimethylamino)-propyl]-
5,10-dihydro-dibenzo [3,4:6,7]
Cyclohepta[1,2-d]azepine-2,4-
(1H,3H)-dione 37.4g (0.1 mol) and anhydrous dione
Lithium aluminum hydride in ethyl ether
From 14.6g (0.38mol), 3-[3-(dimethylene)
Ruamino)-propyl]-1,2,3,4,5,
10-hexahydro-dibenzo [3,4:6,7]
Cyclohepta[1,2-d]azepine, melting point 80~
82° (from pentane) is obtained. Dihydrochloride has a melting point
It has approximately 315° (decomposition). This raw material can be made in the following way. aa 1,5-dihydro-2H-dibenzo [2,
3:6,7]thiepino[4,5-d]azepine
-2,4(3H)-dione 30.7g (0.1mol) was newly added.
Distilled 3-(dimethylamino)-propylene
14.6g (0.12mol) of chloride and anhydrous toluene
6.9 ml of anhydrous toluene to the suspension contained in 600 ml.
Contains 2.3g (0.1mol) of lithium amide
The suspension was boiled under reflux under a nitrogen atmosphere.
Add dropwise within 2 hours while stirring. reaction mixture
Keep things boiling for 20 hours under reflux and then leave in the room
Cool to warm. Add 100ml of water and separate the organic phase.
3 times with 50 ml of 10% methanesulfonic acid.
Extract. Flush the acidic extract with concentrated ammonia water.
Enolphthalein shows alkalinity
do. At this time, 3-[3-(dimethylamino)
-Propyl]-1,5-dihydro-2H-dibe
Nzo [2,3:6,7] Chiepino [4,5-
d] Azepine 2,4(3H)-dione becomes crystalline
To separate. This is recrystallized in ether/pentane
It shows a melting point of 102-103°. Methanesulfonate is made as follows.
Ru. 30 g (0.076 mol) of base in 75 ml of acetone
Dissolved methanesulfonic acid 7.3g (0.076 mole)
Add carefully. At this time, 3-[3-(jime)
thylamino)-propyl]-1,5-dihydro
-2H-dibenzo[2,3:6,7]thiepino
[4,5-d]Azepine 2,4(3H)-dione
-Methanesulfonate crystallizes. This is meta
When recrystallized from nol, melting point is 270-275° (decomposition)
shows. The following compounds are made in the same way. bb 1.5-dihydro-2H-thieno [2', 3': 2,
3] [1] Benzothiepino [4,5-d] aze
Pin-2,4(3H)-dione 31.2g (0.1mol),
3-(dimethylamino)-propyl chloride
14.6g (0.12mol) and lithium amide 2,
3g (0.1 mol) and 3-[3-(dimethyl
amino)-propyl]-1,5-dihydro-
2H-thieno [2', 3': 2, 3] [1] Benzothi
Epino[4,5-d]azepine-2,4 (3H)
-dione, melting point 117-119° (from acetone)
It will be done. The melting point of hydrochloride is 224-227° (anhydrous ethano
). and cc 5,10-dihydro-dibenzo [3,4:6,
7] Cyclohepta[1,2-d]azepine-
2,4(1H,3H)-dione 28.9g (0.1mol),
3-(dimethylamino)-propyl chloride
14.6g (0.12mol) and 2.3g lithium amide
(0.1 mol) and 3-[3-(dimethylamine)
-propyl]-5,10-dihydro-diben
Zo [3,4:6,7] Cyclohepta [1,2-
d]Azepine-2,4-(1H,3H)-Gio
A melting point of 113-115° (from hexane) was obtained.
Ru. The melting point of hydrochloride is 265-268° (absolute ethanol
). 5,10-dihydro-dibenzo [3,4:6,
7] Cyclohepta [1,2-d] azepine-2,
4-(1H,3H)-dione is the same as the raw material in Example 14.
It is made by 10,11-bis-(bromomethyl)-5H-dibe
Nzo[a,d]cycloheptene (German patent publication
(see Specification No. 2125654) in acetonitrile 2.5
What it contains and 59g of sodium cyanide (1.2 mole)
) and 5H-dibenzo[a,d]cyclohep
Thene-10,11-diacetonitrile, melting point 217~
220° (from acetonitrile) is obtained. 5H-dibenzo[a,b]cycloheptene-10,
135 g (0.5 mol) of 11-diacetonitrile was added to
Dry hydrogen bromide is applied to what is contained in tyrene 2.75.
2-Amino-4-bromo-1,10-dihyde
Rhodibenzo[3,4:6,7]cyclohepta
[1,2-d] Crude azepine-hydrobromide
product is obtained. 2-amino-4-bromo-1,10-dihydro-
dibenzo[3,4:6,7]cyclohepta[1,
2-d] Azepine-hydrobromide 86.5g (0.2
mol), dimethylformamide 1.5 and water 1.3
Tokara 5,10-dihydro-dibenzo [3,4:
6,7]cyclohepta[1,2-d]azepine-
2,4(1H,3H)-dione, melting point 265-268° (A
) is obtained from Seton. Example 19 In the same manner as Example 5, use the corresponding raw materials to form the following formula.
You can make compounds. 10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-dibenzo[b,f]thiepin
22.7g (0.05mol), n-butylamine 4.4g
(0.06 mol and diisopropylene in absolute ethanol)
Pyrethylamine 16.25g (0.125mol) to 3
-Butyl-2,3,4,5-tetrahydro-1H
-dibenzo[2,3:6,7]thiepino[4,5
-d] Azepine, melting point 107-108° (from acetone)
is obtained. The melting point of methanesulfonate is 218 ~
220° (from absolute ethanol). 10,11-bis-[2-[methylsulfonylox
c)-ethyl]-dibenzo[b,f]thiepin
22.7g (0.05mol), allylamine 3.4g (0.06mol)
) and diisopropyl in absolute ethanol.
16.25g (0.125mol) of ethylamine and 3-a
Lyle-2,3,4,5-tetrahydro-1H-di
Benzo[2,3:6,7]thiepino[4,5-
d] Azepine is obtained as a crude product. methane
Sulfonate has a melting point of 25-227° (anhydrous ethanol or
). 10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-dibenzo[b,f]thiepin
22.7g (0.05mol), propargylamine 3.3g
(0.06 mol) and diisopropylene in absolute ethanol.
Lopylethylamine 16.25g (0.125mol)
3-propynyl-2,3,4,5-tetrahydride
Lo-1H-dibenzo[2,3:6,7]thiepino
[4,5-d]azepine is obtained as a crude product,
The methanesulfonate has a melting point of 218-221° (anhydrous ester).
(from tanol). 10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-dibenzo[b,f]thiepin
22.7g (0.05 mol), (aminomethyl)-cyclope
6.0g (0.06mol) of tantan and absolute ethanol
16.25g of diisopropyl-ethylamine inside
(0.125 mol) and 3-(cyclopentylmethyl
)-2,3,4,5-tetrahydro-1H-di
Benzo[2,3:6,7]thiepino[4,5-
d] Azepine, melting point 113-115° (absolute ethanol or
) is obtained, and the melting point of methanesulfonate is 248
~252° (from absolute ethanol). 10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-dibenzo[b,f]thiepin
22.7g (0.05 mol), (aminomethyl)-cyclohe
6.7 g (0.06 mol) of xane and absolute ethanol
16.5g of diisopropyl-ethylamine inside
(0.125 mol) and 3-(cyclohexylmethylene)
)-2,3,4,5-tetrahydro-1H-di
Benzo[2,3:6,7]thiepino[4,5-
d] Azepine, melting point 113-115° (from acetone)
The resulting methanesulfonate has a melting point of 256-258° (no
(from water and ethanol). 10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-dibenzo[b,f]thiepin
22.7g (0.05mol), ethanolamine 3.7g
(0.06 mol) and diisopropylene in absolute ethanol.
Lopylethylamine 16.25g (0.125mol)
1,2,4,5-tetrahydro-3H-diben
Zo [2,3:6,7] Thiepino [4,5-d] a
Zepine-3-ethanol, melting point 157-159° (aceto
) is obtained, and methanesulfonate has a melting point of
Shows 194-198° (from absolute ethanol). 10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-dibenzo[b,f]thiepin
22.7g (0.05mol), 3-aminopropanol 4.5
g (0.06 mol) and diiso in absolute ethanol
16.25 g (0.125 mol) of propyl-ethylamine and
from 1,2,4,5-tetrahydro-3H-dibe
Nzo [2,3:6,7] Chiepino [4,5-d]
Azepine-3-propanol, melting point 120-132°A
) from setone) and methanesulfonate is fused.
Point 181-183° (from absolute ethanol). 10,11-bis-[2-(methanesulfonyloxy)
c)-ethyl]-dibenzo[b,f]thiepin
22.7g (0.05mol), 3-methoxypropylamine
5.4 g (0.06 mol) and absolute ethanol
Diisopropyl-ethylamine 16.25g (0.125mol)
) and 3-(3-methoxypropyl)-2,
3,4,5-tetrahydro-1H-dibenzo [2,
3:6,7]thiepino[4,5-d]azepine
Obtained as a crude product, its methanesulfonate salt
has a melting point of 213-216° (from absolute ethanol). 10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-dibenzo[b,f]thiepin
22.7g (0.05mol), 3-(methylthio)-pro
6.3 g (0.06 mol) of pyramine and anhydrous ethano
16.25 g of diisopropyl-ethylamine in a
(0.125 mol) and 3-[3-(methylthio)
-Propyl]-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]thiepino[4,
5-d] Azepine is obtained as a crude product. Mail
Tansulfonate has a melting point of 212-214° (anhydrous ethanol).
(from Le). 10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-dibenzo[b,f]thiepin
22.7g (0.05mol), 2-(methylthio)-ethyl
5.5 g (0.06 mole) and anhydrous ethanol
16.25g diisopropyl-ethylamine in
(0.125 mol) and 3-[2-(methylthio)
-Ethyl]-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]thiepino[4,
5-d] Azepine, melting point 91-92° (from pentane)
is obtained, and methanesulfonate has a melting point of 218-220°
(from absolute ethanol). 10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-2-chloro-dibenzo[b,
f] Thiepin 24.5g (0.05mol), methylamine
1.85g (0.06mol) and diiso in methanol
16.25 g (0.125 mol) of propyl-ethylamine and
From, 7-chloro-3-methyl-2,3,4,5
-Tetrahydro-1H-dibenzo [2,3:6,
7] Thiepino[4,5-d]azepine is the crude product
The melting point of the hydrochloride is 226-268° (anhydrous ether).
from Tanol). 10,11-bis-[2-(methylsulfonyloxy)
c)-ethyl]-2-chloro-dibenzo[b,
f] Thiepin 24.5g (0.05 mol), (aminomethyl
)-cyclopentane 6.7g (0.06mol) and
Diisopropyl-ethylamide in absolute ethanol
16.25 g (0.125 mol) of 7-chloro-3-
(cyclopentylmethyl)-2,3,4,5-te
Trahydro-1H-dibenzo [2,3:6,7]
Thiepino[4,5-d]azepine, melting point 123~
126° (from acetone) is obtained. Methane sulfo
phosphate has a melting point of 195-198° (from absolute ethanol).
Motsu. The raw material for the last two final products is that
They can be made in the same manner as Example 5 and Example 12, respectively.
Wear. 2-chloro-10,11-bis-(bromomethyl)
-Dibenzo[b,f]thiepin 43.1g (0.1mol)
and sodium cyanide in 500 ml of acetonitrile
From 11.8g, 2-chloro-dibenzo [b,f]
Thiepin-10,11-diacetonitrile, melting point 207
~210° (from chloroform) is obtained. 2-chloro-dibenzo[b,f]thiepin-
32.3 g (0.1 mol) of 10,11-diacetonitrile,
400ml of tanol, 3.8ml of water and dry hydrogen chloride
et al., 2-chloro-dibenzo[b,f]thiepin-
10,11-Diacetic acid-dimethyl ester, melting point 111~
113° (from methanol) is obtained. 2-chloro-dibenzo[b,f]thiepin-
10,11-diacetic acid dimethyl ester 38.9g (0.1mol)
) and lithium hydride in anhydrous diethyl ether.
7.6g (0.2mol) of aluminum and 2-k
Lordibenzo [b, f] Thiepin-10,11-di
Ethanol, melting point 152-154° (from ethyl acetate)
can get. 2-chloro-dibenzo[b,f]thiepin-
33.3g (0.1mol) of 10,11-diethanol and piri
25.2g of methanesulfonyl chloride in 120ml of gin
(0.22 mol), 10,11-bis-[2-(metal)
(methylsulfonyloxy)-ethyl-2-chloro-
Dibenzo[b,f]thiepin, melting point 118-120° (dibenzo
(from ethyl ether) is obtained. Example 20 10,11-bis[2-methylsulfonyloxy-
ethyl]-dibenzo[b,f]oxepin 21.9g
A solution in 250 ml of absolute alcohol containing (0.05 mol)
and 6 g (0.06 mole) of aminomethylcyclopentane.
) and diisopropylethylamine 16.25g
(0.125 mol) and the reaction mixture was refluxed for 18 hours.
It flowed. After cooling in an ice bath, aspirate the precipitated crystals.
Collect, then add a small amount of isopropanol and pen
Washed with tan. This crystalline product has a melting point of 99~
3-(cyclopentylmethyl)- with a temperature of 101℃
2,3,4,5-tetrahydro-1H-dibenzo
[2,3:6,7] Oxepino [4,5-d] -
It's azepine. The melting point of methanesulfonate is
The temperature was 280℃ (decomposition). 10,11-bis[2-(methylsulfonyloxy)
c)-ethyl]-dibenzo[b,f]oxepine
21.9g (0.05mol), 3-aminopropanol 4.5
g (0.06 mol) and diisopropylethylamine
From absolute ethanol containing 16.25g (0.125mol)
Starting from the melting point 59-61℃ (pentane) in a similar manner
(recrystallized from) 1,2,4,5-tetrahydro-
3H-dibenzo[2,3:6,7]oxepino
[4,5-d]Azepine-3-propanol is obtained
It was done. Melting point of methanesulfonate: 188-192℃
(Recrystallized from absolute ethanol). Example 21 Under stirring, 3-methyl-1,2,3,4,5,10
-hexahydrodibenzo[b,f]azepino
[4,5-d] Azepine with hexametapol 130ml
and 130 ml of anhydrous toluene were dissolved. lightly
By cooling, maintain the temperature at 18-20℃
Contains 7.8g (0.2mol) of sodium amide
Add a suspension of 24 ml of anhydrous toluene to this solution over 15 minutes.
dripped into. Simultaneously introduce a drying stream of nitrogen into this reaction solution.
The ammonia generated through the process was expelled. dripping
When the addition is complete, continue stirring for 30 minutes,
Then, maintain the temperature at 18-20℃ by cooling with ice.
14.2g of methyl iodide
(0.1 mol) of a solution in 100 ml of anhydrous toluene containing 15
It was dripped over a period of minutes. Stir the reaction mixture for an additional 15 minutes.
Stir, then add a mixture of 2 ml of water and 400 ml of toluene.
I poured it slowly inside. Separate the organic layer and the aqueous layer.
Extracted with toluene. Combine the combined organic layers with water.
Washed, dried with potassium carbonate and completely evaporated to dryness.
Ta. 3,10-dimethyl-1, which is a crystalline residue
2,3,4,5,10-hexahydro-dibenzo
[b, f] Azepine [4,5-d] Azepine
When recrystallized from tanol, it has a melting point of 197-199℃.
did. Methanesulfonate has a melting point of 231-233℃.
Ivy (recrystallized from ethanol). The starting materials were prepared according to the procedure described in Example 6K.
It was obtained as follows. That is, 5-acetyl
-10,11-bis(bromomethyl)-5H-diben
Zo[b,f]Azepine 42.1g (0.1mol) and Shea
acetate containing 11.8 g (0.24 mol) of sodium chloride.
From 500ml of nitrile, 5-acetyl-5H-dibene
Zo[b,f]azepine-10,11-diacetonitri
[Melting point: 183-185℃ (recrystallized from benzene)]
was gotten. Also, 5-acetyl-5H-diben
Zo[b,f]azepine-10,11-diacetonitri
31.3g (0.1mol), methanol 400ml, water 3.8ml
and dry hydrogen chloride, dimethyl [5-acetyl
-5H-dibenzo[b,f]azepine-10,11-
Diacetate] [Melting point: 123-124℃ (Toluene or
(recrystallized)] was obtained. Also, dimethyl [5-
Acetyl-5H-dibenzo[b,f]azepine-
10,11-diacetate] 37.9 g (0.1 mol) and
Anhydrous tea containing 7.6g of lithium aluminum hydride
From 150ml of trahydrofuran, 5-ethyl-5H-
Dibenzo[b,f]azepine-10,11-dietano
[Melting point: 102-105℃ (recrystallized from ether)]
was gotten. Also, 5-ethyl-5H-dibenzo
[b, f]Azepine-10,11-diethanol 30.9
g (0.1 mol) and methanesulfonyl chloride 25.2 g
From 120 ml of pyridine containing (0.22 mol), 10,11-
Bis-[2-(methylsulfonyloxy)-ethyl
]-5-ethyl-5H-dibenzo[b,f]a
Zepine [Melting point: 140-143℃ (recrystallized from toluene)
crystal)] was obtained. Also, dimethyl [5-acetyl
Ru-5H-dibenzo[b,f]azepine-10,11
-Diacetate] 37.9g (0.1 mol) and hydrogenated
Anhydrous diethyl containing 7.6g lithium aluminum
From ether 1, 5H-dibenzo[b,f]a
Zepine-10,11-diethanol [Melting point: 180-182
°C (recrystallized from acetone)] was obtained. Also,
5H-dibenzo[b,f]azepine-10,11-di
28.1g (0.1mol) of ethanol and methane chloride
Pyridine 120 containing 25.2 g (0.22 mol) of Ruphonyl
ml to 10,11-bis-[2-(methylsulfony)
ruoxy)-ethyl]-5H-dibenzo[b,f]
Azepine [Melting point: 140-142℃ (recrystallized from toluene)
crystal)] was obtained. Also, 10, 11-bis-[2-
(methylsulfonyloxy)-ethyl]-5H-di
Benzo[b,f]azepine 21.9g (0.05mol),
1.85 g (0.06 mol) of methylamine and diisopropylene
From 16.25 g (0.125 mol) of pyruethylamine, 3
-Methyl-1,2,3,4,5,10-hexahydride
Rhodibenzo [b, f] Azepino [4,5-d]
Azepine [Melting point: 121-124℃ (Re-used from methanol)
crystal)] was obtained. Melting of methanesulfonate
Point: 263-266℃ (from absolute ethanol/acetone
recrystallization). Example 22 The following compounds were prepared according to Example 6H with the corresponding starting materials.
It was obtained using That is, 10, 11-bis-
[2-(methylsulfonyloxy)-ethyl]-
2-chlorodibenzo[b,f]oxepin 23.6g
(0.05 mol), methylamine 1.85g (0.06 mol) and
Contains 16.25g of diisopropylethylamine.
From water ethanol to 7-chloro-3-methyl-
2,3,4,5-tetrahydro-1H-dibenzo
[2,3:6,7] Oxepino [4,5-d] a
Zepine [Melting point: 174-176℃ (recrystallized from toluene)
crystal)] was obtained. Melting point of hydrochloride: 279-281℃
(Recrystallized from absolute ethanol). Starting material 10,11-bis-[2-(methyl
Sulfonyloxy)-ethyl]-2-chloro-di
Benzo[b,f]oxepine was added to the procedure of Example 6H.
Therefore, it could be obtained as follows. 10,11-bis-(bromomethyl)-2-chloro
-Dibenzo[b,f]oxepin 20.7g (0.05mol)
) and sodium cyanide 5.9g (0.12mol)
From 250 ml of acetonitrile containing 2-chloro-
Dibenzo[b,f]oxepin-10,11-diacetic acid
Tonitrile [Melting point: 227-230℃ (from ethanol)
Recrystallization)] was obtained. Also, 2-chloro-dibe
Nzo[b,f]oxepin-10,11-diacetoni
Tolyl 15.3g (0.05mol), methanol 200ml,
From 1.9 ml of water and dry hydrogen chloride, crude dimethyl
-Chloro-dibenzo[b,f]oxepin-10,
11-Diacetate] (oil) was obtained. Also,
dimethyl[2-chloro-dibenzo[b,f]oxy
Sepine-10,11-diacetate] 18.7g (0.05mol)
) and lithium aluminum hydride 3.8g (0.1
From 500 ml of diethyl ether containing
-Chloro-dibenzo[b,f]oxepin-10,
11-Diethanol (oil) was obtained. Also,
2-chloro-dibenzo[b,f]oxepine-
15.8g (0.05mol) of 10,11-diethanol and salt
Pi containing 12.6 g (0.11 mol) of methanesulfonyl
From 60 ml of lysine, crude 10,11-bis-[2-(methylene)
rusulfonyloxy)-ethyl]-2-chloro-
Dibenzo[b,f]oxepin (oil) is obtained.
It was. Example 23 The following compounds are prepared according to Examples 5 and 6E with the corresponding
Obtained using starting materials. A 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-dibenzo[b,f]thiepi
22.7g (0.05mol), propylamine 3.3g
(0.06 mol) and diisopropylethylamine
From absolute ethanol containing 16.25g, 3-pro
Pill-2,3,4,5-tetrahydro-1H-
Dibenzo [2,3:6,7] Thiepin [4,6
-d] Azepine [melting point 128-130℃ (acetone or
(recrystallized)] was obtained. Methanesulfonate
Melting point: 181-183℃ (recrystallized from absolute ethanol)
Akira). B 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-2-bromo-dibenzodi
Benzo[b,f]thiepin 26.7g (0.05mol),
(aminomethyl)cyclopentane 6g (0.06mol)
) and diisopropylethylamine 16.25g
(0.125 mol) to 7-bromo3-(cyclope
methylmethyl)-2,3,4,5-tetrahydride
Lo-1H-dibenzo [2,3:6,7] Chiepi
No[4,5-d]Azepine [Melting point: 120-123℃
(recrystallized from ethanol)] was obtained. C 10,11-bis-[2-(methylsulfonyl)
xy)-ethyl]-2-bromo-dibenzo
[b, f] Thiepin 26.7g (0.05 mol), ethyl
2.7 g (0.06 mol) of amine and diisopropyl
From 16.25 g (0.125 mol) of ethylamine to crude 7-
Bromo-3-ethyl-2,3,4,5-tetra
Hydro-1H-dibenzo[2,3:6,7]
Epino[4,5-d]azepine was obtained. Example 24 While stirring, 7-bromo-3-ethyl-2,3,
4,5-tetrahydro-1H-dibenzo [2,
3:6,7]thiepino[4,5-d]azepine
19.3 g (0.05 mol) (prepared according to Example 4),
Dime containing 10.7g (0.12mol) of copper cyanide ()
Add a mixture of 20 ml of chillformamide to a nitrogen atmosphere.
The mixture was heated to 180°C for 22 hours. Then, reaction mixture
Cool the material to 30 °C, dilute with 100 ml of methylene chloride,
Treated with 50 ml of 50% ethylenediamine aqueous solution. Next
Then, separate the organic layer, wash with water, and apply over sodium sulfate.
and further dried. Crystallinity of residue 7-
Cyano-3-ethyl-2,3,4,5-tetrahy
Dro-1H-dibenzo [2,3:6,7] Chiepi
No[4,5-d]azepine has a melting point of 154-156℃.
(recrystallized from hexane/ethyl acetate). 10g base to convert to methanesulfonate
(0.03 mol) in 50 ml of acetone, then
Add methanesulfonic acid to this solution while stirring.
When 2.88g (0.03mol) is added, 7-cyano-3
-Ethyl-2,3,4,5-tetrahydro-1H
-dibenzo[2,3:6,7]thiepino[4,5
-d] Azepine methanesulfonate crystallized
[Melting point: 220-223°C). 7-cyano-3-(cyclo
pentylmethyl)-2,3,4,5-tetrahydride
Lo-1H-dibenzo[2,3:6,7]thiepino
[4,5-d]Azepine [Melting point: 170-172℃ (Metal)
(recrystallized from tanol)] is 7-bromo-3-
(cyclopentylmethyl)-2,3,4,5-te
Trahydro-1H-dibenzo [2,3:6,7]
Thiepino [4,5-d] azepine 22g (0.05mol)
) and copper cyanide () 10.7g (0.12mol)
Obtained in the same manner from 20 ml of dimethylformamide containing
I was able to Melting point of methanesulfonate:
203-206℃ (recrystallized from absolute ethanol. Example 25 3-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]thiepino[4,
5-d] 0.02g of azepine methanesulfonate
The containing tablets are made as follows. Dispensing (for 10000 tablets): 3-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]thiepino
[4,5-d]Azepine methanesulfonate
200.00g Lactose 200.80〃 Potato starch 354.70〃 Stearic acid 10.00〃 Talc 200.00〃 Magnesium stearate 2.50〃 Colloidal silica 32.00〃 Sufficient amount of ethanol 3-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]thiepino[4,
5-d] Azepine methanesulfonate, lactose and
Stearing a mixture of 194.70g of bibare starch
Moisten the sieve with an ethanolic solution of phosphoric acid and
Make it into granules. After drying, the remaining potatoes
Starch, talc, magnesium stearate
and colloidal silica and pour this mixture.
Make it into 0.1g tablets. In some cases
The notches for division make it even thinner and suitable for taking.
It can be added to tablets. Example 26 3-methyl-7-cyano-2,3,4,5-te
Trahydro-1H-dibenzo [2,3:6,7]
Thiepino[4,5-d]azepine methanesulfone
Sugar-coated tablets containing 0.005 g of acid salt are made as follows.
It will be done. Dispensing (for 10,000 sugar-coated tablets) 3-methyl-7-cyano-2,3,4,5-te
Trahydro-1H-dibenzo [2,3:6,7]
Thiepino[4,5-d]azepine methanesulfo
50.00g Lactose 175.90〃 Stearic acid 10.00〃 Colloidal silica 56.60〃 Talc 165.00〃 Potato starch 20.00〃 Magnesium stearate 2.50g Sucrose (crystal) 502.28〃 Sierra Tsuk 6.00〃 Gum Arabic 10.00〃 Dye 0.22〃 Titanium dioxide 1.50〃 Sufficient amount of ethanol 3-methyl-7-cyano-2,3,4,5-te
Trahydro-1H-dibenzo [2,3:6,7]
Thiepino[4,5-d]azepine-methanesulfo
Ethanol solution of phosphate, lactose and stearic acid
Granules are made from the liquid. After drying this, colloid
Lika, talc, potato starch and steari
Mix with magnesium chloride and press into sugar-coated cores.
Ru. Next, add sucrose, cilantro, and arabic.
A concentrated white pigment made from pigments, dyes, and titanium dioxide.
Sprinkle and dry. Thus the weight of 0.100g
Dragee-coated tablets with Example 27 3-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]oxepino
[4,5-d) Capsules containing azepine hydrochloride are
It is made as follows. Dispensing (for 1000 capsules) 3-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]oxepino
[4,5-d]Azepine hydrochloride 20.0g Lactose 253.00〃 Gelatin 2.00〃 Corn starch 10.00〃 Talc 15.00〃 Sufficient amount of water 3-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]oxepino
[4,5-d] Mixing azepine hydrochloride with lactose,
This mixture is evenly moistened with an aqueous solution of gelatin.
Pass this through a suitable sieve (e.g. 1.2 to 1.5 mm coarse mesh)
Pass through a mesh-width sieve to make granules. This granule
Mix with dry corn starch and talc.
and put this into a hard gelatin capsule (size 1)
Pack evenly. Example 28 3-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3,:6,7]thiepino
[4,5-d]Azepine methanesulfonate 0.01
An aqueous injection solution containing g/ml was prepared as follows.
It will be done. Dispensing (for 1000 ampoules) 3-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]thiepino
[4,5-d]Azepine methanesulfonate
10.0g Sufficient amount of water 3-methyl-2,3,4,5-tetrahydro-
1H-dibenzo[2,3:6,7]thiepino[4,
5-d] Add azepine methanesulfonate to 1000ml of water
The solution contained therein is filled into ampoules and sterilized.
The ampoule contains a 1% solution of this active substance. Test results A Ant of the compound produced in the above example
Phetamine antagonism, [Niemegeers and
Janssen: Arzneimittel-Forschung. Vol. 24, p. 45.
(1974)] and the results are as follows:
Shown in the table.

【table】

[Table] C Conclusion The above compounds ~ all generally had good amphetamine antagonistic effects (stimulatory or excitation suppressing effects), and among these, compounds and XII had good values above average. Toxicity test results Regarding the compounds shown in the table below, their toxicity (orientierenden Toxizitaten), DL ₅₀ value (mg/Kg
mice, intraperitoneal administration) were evaluated by standard methods.

【table】

[Table] Conclusion According to the evaluation of LD ₅₀ in mice, the compounds of the present invention listed in the above table submitted to the test ~
All of the compounds showed good or very good non-toxicity, and especially compounds 6 and 6.
The somewhat lower values for XII are more than compensated for by the better than average values in the evaluation of amphetamine antagonism.

Claims (1)

[Claims] 1 Formula (): [In the formula, R ₁ is a hydrogen atom, a lower alkyl group, a cycloalkyl lower alkyl group having 10 or less carbon atoms, a lower alkenyl group, a lower alkynyl group, a (di-lower alkylamino) lower alkyl group, a hydroxy lower alkyl group, an alkoxy lower alkyl group,
It is an alkanoyloxy lower alkyl group, a lower alkylthio lower alkyl group, or a phenyl lower alkyl group, and Ring A is unsubstituted or a halogen atom with an atomic number of 35 or less, a trifluoromethyl group, a lower alkyl group, or a hydroxy group. , lower alkoxy group,
is substituted by a lower alkylthio group or a cyano group, and X is an oxygen atom, a sulfur atom, a methylene group, a direct bond, or has subformula (a): (R ₃ in the formula is a hydrogen atom or a lower alkyl group), Y is a direct bond, and Z is a vinylene group or a sulfur atom] Clen and its addition salts. 2 R ₁ is a hydrogen atom, a lower alkyl group, a cycloalkyl lower alkyl group having 4 to 8 carbon atoms, a lower alkenyl group, a lower alkynyl group, a (di-lower alkylamino) lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group an alkyl group, an alkanoyloxy lower alkyl group, a lower alkylthio lower alkyl group, or a phenyl lower alkyl group, and ring A is unsubstituted, or a chlorine atom, a bromine atom, a methyl group, a hydroxy group, a methoxy group,
is substituted with a methylthio group or a cyano group, and X is an oxygen atom, a sulfur atom, a methylene group, or has the subformula (a): (In the formula, R ₃ is a hydrogen atom, a methyl group, or an ethyl group), Y is a direct bond, and Z is a sulfur atom or a vinylene group. Azatetracycline of formula (I) according to item 1 and a pharmaceutically acceptable acid addition salt thereof. 3 R ₁ is a lower alkyl group or a cyclopentylmethyl group, and Ring A is unsubstituted, or
substituted with a chlorine atom, a methyl group, a methoxy group or a cyano group, and X is an oxygen atom, a sulfur atom, a methylene group, or has subformula (a): (R ₃ in the formula is a hydrogen atom, a methyl group, or an ethyl group) is a divalent residue represented by: Y is a direct bond and Z is a sulfur atom or a vinylene group Claim 1 Azatetracycline of the formula () and its pharmaceutically acceptable acid addition salts as described in 2. 4 3-Methyl-2,3,4,5-tetrahydro-1H-dibenzo[2,3:6,7]thiepino[4,5-d]azepine, the azatetracyst according to claim 1. Clen and its pharmaceutically acceptable acid addition salts. 5 3-Methyl-2,3,4,5-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-d]azepine; Clen and its pharmaceutically acceptable acid addition salts. 6 3-methyl-7-cyano-2,3,4,5-
Tetrahydro-1H-dibenzo[2,3:6,7]
Azatetracycline and its pharmaceutically acceptable acid addition salt according to claim 1, which is thiepino[4,5-d]azepine. 7. The aza according to claim 1 which is 3-methyl-1,2,3,4,5-10-hexahydro-dibenzo[3,4:6,7]cyclohepta[1,2-d]azepine. Tetracycline and its pharmaceutically acceptable acid addition salts. 8 3-(2,3,4,5,tetrahydro-1H
-Dibenzo[2,3:6,7]thiepino[4,5
-d] azepin-3-yl)propanol and a pharmaceutically acceptable acid addition salt thereof according to claim 1. 9 Formula (): [In the formula, R ₁ is a hydrogen atom, a lower alkyl group, a cycloalkyl lower alkyl group having 10 or less carbon atoms, a lower alkenyl group, a lower alkynyl group, a (di-lower alkylamino) lower alkyl group, a hydroxy lower alkyl group, an alkoxy lower alkyl group,
It is an alkanoyloxy lower alkyl group, a lower alkylthio lower alkyl group, or a phenyl lower alkyl group, and Ring A is unsubstituted or a halogen atom with an atomic number of 35 or less, a trifluoromethyl group, a lower alkyl group, or a hydroxy group. , lower alkoxy group,
is substituted by a lower alkylthio group or a cyano group, and X is an oxygen atom, a sulfur atom, a methylene group, a direct bond, or has subformula (a): (R ₃ in the formula is a hydrogen atom or a lower alkyl group), Y is a direct bond, and Z is a sulfur atom or a vinylene group] and a method for producing its salt, the formula (): (In the formula, rings A, X, Y and Z have the meanings described above.) A reactive diester of diethanol represented by the formula (): (wherein R ₁ has the meaning given above) and, if desired, convert the resulting free compound into a salt, and/or if desired, convert the resulting salt into a free compound or other A method characterized by converting the salt into a salt. 10 Formula (′): [In the formula, R ₁ ' is a hydrogen atom, a lower alkyl group, a cycloalkyl group having 10 or less carbon atoms, a lower alkenyl group, a lower alkynyl group, a (di-lower alkylamino) lower alkyl group, an alkoxy lower alkyl group , a lower alkylthio lower alkyl group, or a phenyl lower alkyl group, and Ring A is unsubstituted or a halogen atom with an atomic number of 35 or less, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylthio group, a tri- substituted by a fluoromethyl group or a cyano group, and X is an oxygen atom, a sulfur atom, a methylene group, a direct bond, or has subformula (a): (R ₃ in the formula is a hydrogen atom or a lower alkyl group), the residue Y is a direct bond, and Z is a sulfur atom or a vinylene group] A method for producing cyclen and its salt, comprising the formula ('): [Wherein, R ₁ ', rings A, X, Y and Z have the meanings described above, and Q ₁ and Q ₂ independently represent an oxygen atom or two hydrogen atoms (provided that (at least one of Q ₁ and Q ₂ is an oxygen atom)] and, if desired, convert the resulting free compound into a salt, and/or, if desired, convert the resulting salt into a free compound or A method characterized by converting it into another salt. 11 Formula (): [In the formula, R ₁ is a hydrogen atom, a lower alkyl group, a cycloalkyl lower alkyl group having 10 or less carbon atoms, a lower alkenyl group, a lower alkynyl group, a (di-lower alkylamino) lower alkyl group, a hydroxy lower alkyl group, an alkoxy lower alkyl group,
an alkanoyloxy lower alkyl group, a lower alkylthio lower alkyl group, or a phenyl lower alkyl group, and ring A is unsubstituted or a halogen atom with an atomic number of 35 or less, a lower alkyl group, a hydroxy group, a lower alkoxy group, substituted by a lower alkylthio group, a trifluoromethyl group or a cyano group, and X is an oxygen atom, a sulfur atom, a methylene group, a direct bond or a substituent (R ₃ in the formula is a hydrogen atom or a lower alkyl group), the residue Y is a direct bond, and Z is a sulfur atom or a vinylene group] A pharmaceutical formulation for the treatment of excitatory conditions comprising cyclen and its pharmaceutically acceptable acid addition salt and a pharmaceutical carrier. 12 R ₁ is a hydrogen atom, a lower alkyl group, a cycloalkyl lower alkyl group having 4 to 8 carbon atoms, a lower alkenyl group, a lower alkynyl group, a (di-lower alkylamino) lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group an alkyl group, an alkanoyloxy lower alkyl group, a lower alkylthio lower alkyl group, or a phenyl lower alkyl group, and ring A is unsubstituted, or a chlorine atom, a bromine atom, a methyl group, a hydroxy group, a methoxy group,
is substituted with a methylthio group or a cyano group, and X is an oxygen atom, a sulfur atom, a methylene group, or has the subformula (a): (R ₃ in the formula is a hydrogen atom, a methyl group, or an ethyl group.) Azatetra of the formula () in which Y is a direct bond and Z is a sulfur atom or a vinylene group. 12. A pharmaceutical formulation according to claim 11, comprising cyclen and its pharmaceutically acceptable acid addition salt and a pharmaceutical carrier. 13 R ₁ is a lower alkyl group or a cyclopentylmethyl group, Ring A is unsubstituted or substituted with a chlorine atom, methyl group, methoxy group, or cyano group, and X is an oxygen atom , a sulfur atom, a methylene group, or a subformula (
a): (R ₃ in the formula is a hydrogen atom, a methyl group, or an ethyl group.) Azatetra of the formula () in which Y is a direct bond and Z is a sulfur atom or a vinylene group. 12. A pharmaceutical formulation according to claim 11, comprising cyclen and a pharmaceutically acceptable acid addition salt thereof and a pharmaceutical carrier. 14 3-Methyl-2,3,4,5-tetrahydro-1H-dibenzo[2,3:6,7]thiepino[4,5-d]azepine, 3-methyl-2,3,4,5-tetrahydro ―
1H-dibenzo[2,3:6,7]oxepino[4,5-d]azepine, 3-methyl-7-cyano-2,3,4,5-tetrahydro-1H-dibenzo[2,3:6, 7]
Thiepino[4,5-d]azepine, 3-methyl-1,2,3,4,5,10-hexahydro-dibenzo[3,4:6,7]cyclohepta[1,2-d]azepine, or 3-(2,3,4,5,tetrahydro-1H-
Dibenzo[2,3:6,7]thiepino[4,5-
d] azepin-3-yl)propanol, and a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical carrier. pharmaceutical preparations.