JPS61225153A - Amine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Amine Derivatives This invention relates to amine derivatives, processes for their preparation and pharmaceutical compositions containing them. More particularly, the present invention relates to Co-substituted -3°≠-dihydroxyphenethylamino derivatives having pharmacological activity.

According to the present invention, there are provided compounds having the general formula, and physiologically acceptable acid addition salts, metabolically labile esters and solvates (eg, hydrates) thereof.

However, in the above formula, R is a halogen atom or a methyl, ethyl, n-propyl or n-butyl group, R2, R
5, R'l and R5 are each a hydrogen atom, or one or two of R, RSR and R5 are a methyl or ethyl group.

X is optionally substituted with an alkyl or hydroxyl group having 7 or more carbon atoms, or optionally has 7 double bonds or 37J bonds, or is an oxygen or sulfur atom or a sulfone ( -so2-) or a divalent (-NHCONH-) group optionally interposed therein, the alkylene group having 4t to 7 carbon atoms.

Y is a substituent selected from/from hydroxyl, alkyl having a carbon number of ~≠, alkoxy having a carbon number of ~≠, amino, carboxamide, alkylsulfonylamino having a carbon number of ~μ and a nitro group, and a halogen atom. A phenyl ring optionally containing a group. However, when X is optionally an alkylene chain having 7 double bonds and having a carbon number of II- to 7, Y cannot be phenyl or phenyl having 7 substituents which are halogens.

Where optical isomers may exist, formula (I) is intended to include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds having the same double bond in the alkylene chain X may exist in cis or trans form.

Within the definitions above, the term "alkyl" as a group or part of a group means that the group is straight or branched. The term "...logen" means fluorine, chlorine, bromine or iodine.

Examples of group X include -(CH2), -1-(CH2)6-1
-(CH2)7-1- (CH2)50 (CH2)5
-1-(CH2), O(CH2)2-1-(CH2),
CHOH(CH2), -1-(CH2)2CHMθ(C
H2), -1-(CI(2), S (CH2CI(,
, CH=CHCH=CHCH2-1-(CH2)2CmiC(CH2)2-1-CH2CTC(CH2), - and -(CH2)2NI(CONH(CH2)2-).

Preferred compounds of the present invention are those in which the group R1 is a chlorine atom, or more preferably a compound in which the group R1 is an alkyl group having a carbon number of 1 to λ, specifically an ethyl group.

R2 and R3 may be the same or different, but are preferably a hydrogen atom or a methyl group, more specifically R
2, R'3, R4 and R5 are each a hydrogen atom.

In a more preferred compound, X is an alkylene chain having from 7 carbon atoms, and more preferably from t to 7 carbon atoms.
This is a compound that is the alkylene button of No. 7. X has carbon number j~
7 alkylene chain, the compound is most preferably -(CH2)6-.

Another group of preferred compounds is the number of carbon atoms in which X is substituted with an alkyl (eg methyl) group or a hydroxy group! -7 alkylene chains, or/or alkylene chains with two double bonds and a carbon number of 2, or an alkylene group with a carbon number of t with an oxygen or sulfur atom or a sulfone (-SO2-) group interposed therein. It is. Particularly preferred compounds are compounds in which X is -(CI(2), S(CI(2)
, -1 more preferably -(CH2), s o2(CH
2) It is a compound that is 3-.

Y is preferably a group having the formula: However, R6 is a hydrogen atom or a group C
ONH2, R is hydrogen, more preferably R6
is a hydroxyl group, R7 hydrogen or a halogen (e.g., chlorine) atom, or an alkyl (e.g., methyl or ethyl) group having a carbon number of /≠. Particularly preferred compounds are those of formula (II) in which R6 is a hydroxyl group and R7 is a methyl or ethyl group.

One group of preferred compounds are those in which X is an alkylene chain having from 7 to 7 carbon atoms and Y is a group of formula (IIa).

However, R6 and R8 may be the same or different and are each a hydrogen atom or a hydroxy group (however,
at least 7 of R6 and R8 are hydroxy)
, R is a hydrogen atom or a halogen atom, preferably a chlorine atom, or an alkyl group having a carbon number of 1 to 3, preferably a methyl or ethyl group.

Another group of preferred compounds is an alkylene chain of ~7 carbons, in which is an alkylene chain of formula (I
This is a compound that is a group IIb).

In the above formula, R is hydrogen or a halogen atom, such as a chlorine atom, more preferably an alkyl group having from / to μ carbon atoms, specifically an ethyl group.

According to one aspect of the invention there is provided a compound of formula (I) in which each substituent is as follows.

R1: methyl, ethyl, n-propyl or n-butyl group.

R2, R3, R'l and R5: Each is a hydrogen atom, or 7 or 2 of R2, R5, R'l and R5 are methyl or ethyl groups.

X: Alkylene chain having j to 7 carbon atoms.

Y: Hydroxyl, number of carbon atoms/~≠ alkyl, number of carbon atoms/
A phenyl ring with 3 substituents selected from ~≠ alkoxy, amino and nitro groups and norogen atoms. However, Y cannot be phenyl having 7 substituents which are monologen.

According to another aspect of the invention, there are provided compounds of formula (I) in which each substituent has the following general formula:

R1: fluorine, chlorine, bromine or iodine atom.

R2, R5, R4 and R5: Each hydrogen atom (
is ) or R2, R3, R4 and/or R5
is a methyl or ethyl group.

X: Number of carbons! ~7 alkylene chains.

Y: hydroxyl, alkyl with carbon number/~l, number/~μ
a phenyl ring having / to three substituents selected from alkoxy, amino and hinitro groups and halogen atoms. However, it cannot be phenyl having seven substituents which are halogens.

Physiologically acceptable acid addition salts of compounds having formula (1) can be derived from inorganic or organic acids. Examples of such salts include hydrochloride, hydrobromide, sulfate, phosphate, benzoate, p-toluenesulfonate,
methanesulfonate, sulfamate, ascorbate, tartrate, citrate, maleate, salicylate, fumarate, succinate, lactate, glutarate,
Mention may be made of glutaconate, acetate or tricarballylate.

Preferred acid addition salts are hydrochloride and hydrobromide.

Physiologically acceptable metabolically unstable ester derivatives can be prepared by converting, for example, any of the hydroxyl groups of the cured compound having the general formula (I) into acyl groups after previously protecting other reactive groups present in the molecule. It can be formed by Examples of such esters are lower alkanoates such as acetate or pivaloate.

In addition to the above-mentioned ester derivatives, the present invention also includes within its scope forms which correspond to, for example, physiologically acceptable compounds of the general formula (1), i.e. metabolically labile esters as well as biologically acceptable forms. Physiologically acceptable compounds which are converted into cured compounds having the general formula (I) are included therein. The present invention also includes within its scope solvates, particularly hydrates of compounds having general formula (I).

In animal studies, the compounds of the present invention have been shown to reduce total peripheral vascular resistance, increase cardiac output, and lower blood pressure at low doses. The compounds of the invention have a long duration of action and are active upon oral administration.

The inventors have found that the compounds according to the invention are more potent stimulators of vascular dopamine receptors than of neuronal dopamine receptors.

The compounds according to the invention also stimulate β-adrenergic receptors.

Particularly preferred compounds according to the invention include:

≠ al -[sulfonylbis[(J,/-propanediylino), 2. /-ethanediyl]]bis[3-ethyl-/,2-benzenediol], ≠, til-[thiobis[(3,/-propanediylimino)-,2,/
-ethanediyl]]bis[3-ethyl-/,+2-benzenediol'',≠,≠'-[/,A-hexanediylbis(imino-λ,/-ethanediyl)]bis[3-ethyl-/,2 -benzenediol], and ≠-[-2
-[[A-[[,z-(3,≠-dihydroxy-comethylphenyl)ethylcoamino]hexyl]amino]ethyl]-3-ethyl/,cobenzenediol, if their physiologically acceptable salts, such as their aqueous bromide and hydrochloride salts.

The compounds of the invention can be used in the treatment or prevention of renal failure, circulatory system disorders such as hypertension, ischemic heart disease or heart disease, such as acute or congestive heart disease.

Compounds of formula (I) and their physiologically acceptable acid addition salts, solvates and metabolically labile esters are
The present invention comprises at least seven compounds of formula (I) or physiologically acceptable salts, solvates thereof suitable for use in veterinary medicine, which may be formulated for administration in a conventional manner. Also included within the scope of this invention are pharmaceutical compositions comprising compounds or metabolically unstable esters. Such compositions may be used in conventional manner in admixture with seven or more physiologically acceptable carriers or excipients.

For example, the compounds according to the invention can be formulated in a form suitable for oral, buccal, parenteral or rectal administration or administration by inhalation or inhalation. Oral administration is preferred.

Tablets and capsules for oral administration may be prepared by (a) a binder, such as starch or polyvinylpyrrolidone, having a viscosity of 14° (
b) Fillers such as lactose, microcellulose or corn starch, lubricants such as magnesium stearate or stearic acid, (→ potato starch powder, croscarmellose sodium or sodium starch glycolate) They may also contain conventional excipients such as disintegrants, wetting agents such as powder or sodium lauryl sulfate.Tablets may be coated by methods well known to those skilled in the art.Oral liquid preparations may include Liquid formulations may be present, for example, in the form of aqueous or oily suspensions, emulsions, syrups or elixirs, or as a dry product for constitution with water or other suitable vehicle before use. (to) a suspension such as sorbitol cilolaf, methylcellulose, glucose/sugar syrup or carboxymethylcellulose ()) an emulsifier such as sorbitan monooleate, (capropylene glycol or ethyl alcohol(,21!7)-ol) The compounds of the invention may also contain conventional additives such as non-aqueous vehicles (which may include edible oils), and preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid. or their salts or esters may also be formulated as suppositories containing conventional suppository bases such as cocoa butter or other glycerides.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional specifications.

The compounds of formula (I) and their physiologically acceptable acid addition salts and metabolically labile esters may be formulated for parenteral administration by bolus injection or continuous infusion. It may be present in unit dosage form in ampoules or in multi-dose containers with an added preservative. The compositions may include suspensions in oily or aqueous vehicles;
It may take the form of a solution or emulsion and may contain formulation agents such as suspending, stabilizing and/or dispersing agents. The active ingredient may also be in powder form for constitution with a suitable vehicle, eg sterile, pyrogen-free water, before use.

For administration by inhalation, the compounds according to the invention are
It is conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant such as, for example, dichlorotetrafluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or other suitable gas. In the case of pressurized aerosols, the dosage unit can be determined by attaching a valve and discharging a metered dose.

Alternatively, for administration by inhalation or inhalation, the compounds of the invention may take the form of a dry powder composition, eg, a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition may be in unit dosage form, eg, gelatin capsules or cartridges or blister packs, and the powder may be administered by inhaler or respiratory device.

When the composition consists of dosage units, the compound is
If the active compound is to be administered orally from aoo m9, each unit preferably ranges from jTv to j00T.
Conveniently it includes n9. The daily dosage used for the treatment of adults is preferably in the range 5m9 to 3g, most preferably in the range 7g to 7g, depending on the route of administration and the patient's condition, e.g. It may be administered ≠ times.

Compounds of formula (I) and their physiologically acceptable acid addition salts and metabolically labile esters are used as beta-blockers, diuretics, angiotensin-converting enzyme inhibitors, notropla agents. and can be administered in combination with other therapeutic agents such as antiemetics.

The compound of the present invention can be produced by many of the methods described below. However, unless otherwise specified, R2-R5 and X are as defined in general formula (1). , R9 and R]0 are each a hydrogen atom or a protective group, and Y1 is the general formula (I
) is as defined above or in its protected form, and Ar is a group (,2J). However, R is the same as defined for general formula (1), and n11 and RI 2 are each a hydrogen atom or a protective group. Some of the reactions described below may affect other groups in the starting material that are desired in the final product, especially when using a hydride reducing agent and where Y is a phenyl ring substituted with a carboxamide. Yes or X
This is the case when a final product with urea groups is desired and when hydrogen and metal catalysts are used for the production of compounds with ethylene or acetylene bonds. Therefore, care should be taken in normal practice to use reagents that do not adversely affect any of the groups, or to carry out the reaction as part of the process to avoid the use of these groups when they are present in the starting materials. Make it.

According to general method (1), the compound of general formula (1) is
Reduction of the compound of formula (1'fE) and optionally (2
tA) and subsequent removal of the protecting group.

Here, xl is an alkylene chain with a carbon number of λ to 1, even if it is substituted with 7 or more alkyl or hydroxyl groups, or has 7 or 2 double or triple bonds, or a carbonyl group. Even if it has an oxygen atom or a sulfur atom or a sulfone (-8o2-
) group or urea (-NHCONH-) group may be interposed therein. zl, z2, z3 and zll are each O and alkaliha C-21, C=z2 and C-25 each represent CH2, and c=z' is CR2
It is R5.

However, zl, z2, z5 Oyohi z11 slightly fewer than 7 (but not more than 1) indicates O, and when zl is O, C-22 is CH2, and t ta Z3 ka O of,! : KihaC=ZllhaCR”R5te exists.

Reducing agents that can be used are those commonly known for the reduction of amides. Suitable bulking agents for this reaction are hydrides such as lithium aluminum hydride, alane or diborane. Suitable solvents are ethers, such as terahydrofuran or dioxane, or mixtures of hydrocarbons (eg benzene) and ethers (eg diethyl ether). Reduction is from 11θ℃ to +
io.

It can be conveniently carried out at a temperature of 0.degree. C., preferably 0.degree. C. to 70.degree.

According to one general method (2), 〒 General formula (I)
Compounds of formula Ar(C)(2)2NHR9(IV) and R10N)
(Can be produced by carrying out an alkylation reaction consisting of a compound of CR2R'CR11R'Y' (V) and an alkylating agent capable of introducing a group .

For example, in one aspect of the method, formulas (IV) and (V)
can be reacted with an alkylating agent of the formula L-X-L, where L is a readily substitutable atom or group, to form compounds of the invention.

The reaction can preferably be carried out in solution in the presence of a base such as potassium carbonate or sodium hydride at a temperature within the range -0°C to +10°C. Suitable reaction solvents include (i) ethers, such as tetrahydrofuran or dioxane, (b) alcohols, such as ethanol; acetonitrile, (7-1fl) amides, such as NN-dimethylformamide, and hydrocarbons, such as benzene.

Hydrocarbylsulfonyloxy may be used.

In another embodiment of the alkylation method R9 and R10
Compounds of formula (IV) and (V), in which is hydrogen, are alkylated under reducing conditions with a compound having the formula 0T (C-Xl-CHO, where Xl is a radical as defined above), Compounds having formula (1) can be produced.

Suitable reducing agents include (a) ethanol or propane (,
27) Alkali metal or alkaline earth metal borohydrides or cyanoborohydrides using alcohols such as alcohols as solvents, such as sodium borohydride, cyanoborobitrides, or (b)alcohols such as ethanol, ethers such as dioxane or Hydrogen in the presence of a metal catalyst such as platinum, platinum oxide, palladium or rhodium using an ester such as ethyl acetate as the reaction solvent. The catalyst may be supported, for example on activated carbon, or a homogeneous catalyst such as tris-triphenylphosphine rhodium-chloride may be used. The reduction may conveniently be carried out at a temperature of -,20C to +700C, preferably at a temperature of 0C to 50C. Under conditions such that the intermediate imine compound formed can be isolated. After reduction of the imine using the above conditions, the protecting group is removed if desired to produce a compound having general formula (I).

According to another general method (3), compounds of formula (1) can be prepared by removing the protecting group of compounds of formula (Vl) (2g).

However, at least seven of R9, RIO, R11 and R12 are protecting groups, and/or the group Y1 is in a protected form.

When R9, RIO, Rll or R12 is a protecting group.

This protecting group is, for example, “grotective Φ group φ
In Organic Chemistry (Prolecti)
vs Groups in Organic Cbem
istry)” JF W McCormy (
J.

Any of the conventional protecting groups as described in F., W. McOmle (Eds.) (Plenum Press, 1971) may be used. Examples of suitable hydroxyl protecting groups represented by H11 and R112 are alkyl groups such as methyl or methoxymethyl, arylmethyl groups such as benzyl, diphenylmethyl or triphenylmethyl, heterocyclic groups such as tetrahydropyranyl. , and acyl groups such as acetyl. It will be appreciated that R and R can be taken together to form a protecting group for both hydroxyl groups, such as an alkylene group such as methylene. If there are two hydroxy groups on the right-hand side of the molecule, they are similarly preserved.

Examples of suitable amine protecting groups represented by R9 and R10 include trifluoroacetyl, t-butoxycarbonyl, trifluoroethoxycarbonyl, benzyl, benzyloxycarbonyl and x, y, 2-trichloroethoxycarbonyl groups. There is.

Protecting groups R9, R10, R11 and R12 can be removed using conventional methods to produce compounds of formula (I). For example, an arylmethyl group such as benzyl can be cleaved by hydrogenolysis in the presence of a noble metal catalyst (e.g. palladium/activated carbon) and an alkyl group protecting a hydroxyl group or an alkyl group protecting two hydroxyl groups. Dioxy groups can be cleaved under acidic conditions, for example with hydrogen bromide or boron tribromide, and acyl groups can be cleaved off by hydrolysis under basic conditions.

Y is a phenyl ring with carboxamide.

Compounds of formula (I) can be prepared by aminating the corresponding carboxylic ester. Amination is carried out using ammonia in an organic solvent such as an alcohol, e.g. methanol or ethanol, at 0°C.
to 130°C, preferably at room temperature. It is also preferred to carry out the reaction at high pressure. The carboxylic acid ester precursor can be produced by the general method (2).

When it is desired to prepare a physiologically acceptable salt of a compound of formula (I), the product of any of the above treatments is treated with a suitable acid to form the free base using conventional methods. It can be converted into salt by

Physiologically acceptable salts can also be prepared from other salts of the compounds of formula (I) with other physiologically acceptable salts using conventional methods.

Enantiomers of the compounds of the invention can be obtained by resolving the corresponding racemates using conventional means such as optically active resolving acids (e.g.
Stereochemistry of Carbo+1 Compounds
n Compounds)
Written by E. L. Eliel (Matsugrow Hill)
Me GrBw Hllll) -/RiA, 2nd year) and ``Table of Resilping Agents (
Tables of Rssolving Agent
s) J, Nis 1 HlW (S, HlW
)

Each of the methods described for the production of the compounds of the invention can be used as the last major step in the production process. It is understood that the same general methods can be used to introduce the desired group at intermediate steps in the stepwise formation of the desired compound, and that these general methods can be combined in various specifications in multi-step processes. There will be.

(3U) Compounds of formula (III) can be formed by one or more acylation reactions consisting of reaction of a suitable amine with a suitable acylating agent. Oite, Z1.
Z2. Z'-Z''o, l: and x1c are as defined in formula (m) unless otherwise specified.

For example, a compound of formula (m) in which zl is oxygen may be combined with a compound of formula (%) or a reactive derivative thereof (where X2 is optionally substituted by 7 or more alkyl or hydroxyl groups). or optionally has seven or more double or triple bonds; or an oxygen or sulfur atom or a sulfone (-SO2-) or urea (-NHCON)
I(-) groups were optionally interpolated. It can be produced by reaction with a compound (which is an alkylene compound having 3 to 3 carbon atoms).

Compounds of formula (IIT) in which z2 is oxygen are of formula (IV)
A compound of formula (m) in which z3 is oxygen can be produced by the reaction of a compound of formula (V) with a compound of formula 1 or its reactive derivative. It can be produced by reaction with a derivative.

Compounds of formula (Tll) where z4 is oxygen are of formula 1 ArC
H2CN-CX1C-NHRlo(XI)It I
It can be produced by reacting a compound of I II 1Z2z5 with a compound of formula % () or a reactive derivative thereof.

Compounds of formula (III) in which z2 and z5 are oxygen,
It can be prepared by reacting a compound of the formula (%) or a reactive derivative thereof with a compound of formula (IV) and (V).

Compounds of formula (m) in which zl and zl' are oxygen may be prepared by reaction of compounds of formulas (■) and (XII) or reactive derivatives thereof with compounds of formula %(). I can do it.

Suitable reactive derivatives of carboxylic acids for use in the above acylation reactions include acid halides or anhydrides or active esters, such as acid chlorides or bromides. Acylation with acid halides can be carried out in the presence of an acid binder such as a tertiary amine such as triethylamine or an inorganic base such as potassium carbonate. Acylation with free acid is preferably carried out in the presence of a coupling agent such as a carbodiimide such as N,N'-dicyclohexylcarbodiimide, an azide such as N,N-carbonyldiimidazole or diphenylphosphoryl azide. can. The reaction medium is preferably an anhydrous medium such as a halogenated hydrocarbon 1 such as dichloromethane or an amide such as dimethylformamide. Acylation can be carried out at a temperature of -Xl''C to 0°C.

Many compounds of general formula (■) are known.

It can be manufactured by conventional methods. Other compounds having the formula (■) can be prepared by hydrolysis of compounds having the formula ArCH2CN using conventional reaction conditions such as base hydrolysis.

The compound of formula (■) in which Z4 is oxygen is N
, N'-carbonyldiimidazole can be prepared by reacting a compound of formula (Xrl) or a reactive derivative thereof with a compound of formula (XIv) in the presence of a coupling agent such as N'-carbonyldiimidazole.

Formula (
V) The compound of formula %() (where -RLit is a group which can be reduced to amino, e.g. nitro) is reduced to a complex metal hydride, e.g. lithium aluminum hydride. It can be produced by reduction using the reaction conditions described in general method (1).

Compounds of formula (XVI) in which R14 is a nitro group can be prepared by condensing a compound of formula (%) with a suitable alkylnitro compound in the presence of a base such as ammonium acetate.

The formula in which the 2nd position of Yl is substituted with an alkyl group (Kin・TI
) are compounds of the formula (wherein R6 and R8 are as defined in formula CI) and where R and/or R are hydroxy, the protected form thereof. can be prepared by introducing an alkyl group using a strong base such as n-butyllithium and a suitable haloalkane, followed by hydrolysis under acidic conditions.

A compound having the formula (V) (wherein R2 and R5 are methyl or ethyl groups and R and R are hydrogen atoms) is a compound having the formula % formula () (where R15 is a protecting group such as a benzyl group). It can be produced by removing the protecting group from the compound (1), for example, by catalytic hydrogenolysis.

Compounds of formula (X [ , by treating a reactive derivative of the activated ester compound of formula (XX), formed with ethyl chloroformate, with an azide, such as sodium azide, and heating to about 100° C. in, for example, toluene.

The compound of formula (XX) has the formula R1602C(CH2) 2 Y' (
XXI) (wherein R16 is a protecting group as defined above) using one strong base such as n-butyllithium and an alkane such as iodomethane or ) can be manufactured by removing.

The compound of formula (XXI) has the formula HO2CCH=CHY” (XXII)
can be prepared by reducing the compound by catalytic hydrogenation as described above followed by esterification to form the protected derivative.

Compounds of formula (XXIII) can be prepared from compounds of formula (XVII) by Knebenagel reaction, ie condensation with malonic acid in the presence of a base such as piperidine and/or pyridine.

Formula (IV), (IX), (X), (XII (XII
), (Xlll), (X[V), (XV), (
XvI) The hyalkylating agents LXL and 0HCX1CHO are both known compounds and can be produced from known starting materials by conventional methods. A preferred method is illustrated in the following example.

Compounds of formula (IV) can be produced by methods (1) and (2).

(μO) Experimental example The following roadside is one that illustrates the present invention.

Temperatures are in degrees Celsius. The solution was dried using magnesium sulfate or sodium sulfate. Thin layer chromatography (5, 1.c,) was performed on silica plates. Flash column chromatography (FCC) was performed on silica (Merck 3gs).

The following abbreviations are used. THF: Tetrahydrofuran, P
d-C: palladium/activated carbon, Pd0-C palladium dioxide/activated carbon.

Intermediate 7 (dissolved in dry THF (s5, ml))
toy) was added to the borane-THF complex (1 molar THF, ml) over 5 min at Oo, then 6 min under nitrogen atmosphere.
The mixture was heated to reflux for an hour. The mixture was cooled and diluted with methanol (w
The mixture was rapidly cooled using a mi'r, then heated under reflux for 30 minutes.

The mixture was cooled, made acidic with JN hydrochloric acid, and heated again at 2θ0 for 7 hours. The mixture was treated with ethyl acetate (230 ml'J) and the organic layer was extracted with water. The aqueous extract was made basic and
Extracted with ethyl acetate. Drying, filtering and evaporating the extract yields an oil (A1) which is dissolved in ethereal methanol and treated with ethereal hydrochloric acid.
The title compound was obtained in the form of white needles, melting point /Jtj - /AJt0.

Intermediate Hirocetamidotrietheramine (,2,l, 3ml') was dissolved in dry dichloromethane (,2,l, 3ml') and intermediate, z(lZOy), in a nitrogen atmosphere.
i, zoml). The solution was cooled in a water bath. A solution of trifluoroacetic anhydride (2.2 bml) in dry dichloromethane (oml) was added slowly over a period of 1 hour. Stir the solution for 2 hours.

, 2N hydrochloric acid, f% bicarbonate, and brine, dried, and concentrated in vacuo. When the resulting oil was purified by FCC using ether/hexane (/:/) as the eluent, the title compound (
/, r7y) - melting point go-g10 was obtained.

Intermediate ni-ethyl-3,4A-dimethoxybenzeneacetic acid intermediate l(0,ri,N)-) and sodium hydroxide (AI) dissolved in ethanol (tmml) and water (xml) were dissolved in: Aμ time. The mixture was heated to reflux. The solution was evaporated in vacuo, acidified with uN hydrochloric acid and extracted with ether. The extract was washed with water, dried and evaporated. The residue was purified by FCC using ether/hexane (/:/) as eluent.
It was purified by.

The title compound (θH7rg-), melting point g target, was obtained as a white crystal.

Intermediate O (Il, 3) A, l, y-), melting point /Cr2-1041-Of-Produced from 2-methyl-3, Hiroshi-dimethoxybenzeneacetonitrile (/X@) by the method of Intermediate j.

Intermediate 7 Intermediate/(,2,O,,tp) was dissolved in dry dichloromethane (
To the solution of boron tribromide in dichloromethane (1 mol, ?oml) was carefully added in a water bath. The resulting solution was left at room temperature for 2.5 hours.

Stored in ice to cool. After another 75 minutes, the mixture was diluted with ether. The organic layer was separated, washed with brine, dried and
Evaporated. The resulting oil was dissolved in ether/cyclohexane (/: , z, , zsoml).

Filtered with high flow. R liquid in vacuum / 00 m, l
After concentrating to
-103 Q was obtained.

(Bottle) Solid potassium carbonate (1) is added to the product (1?) from step (1) dissolved in dry dimethylformamide at room temperature. Benzoyl bromide (Shihiro 75)
'l added. The mixture was stirred overnight. Added ice and water. The mixture was extracted with ether. Wash the extract with water,
Dry and evaporate. The resulting oil was purified by FCC using ether/hexane (l:/) as eluent to give the title compound (/, rxy-) as a yellow oil that slowly crystallized, melting point: -4L7. I got s0.

Intermediate r 1, A-Dibromo-3-hexyne carbon tetrabromide (#, 7y-) was dissolved in methylene chloride (70 mA), and 3-hexyne-/, 6-diol (
and j1) were added to the solution dissolved in methylene chloride (/2jml). The solution was cooled to θ°, and a solution of triphenylphosphine (/J2y-) in methylene chloride (7 omJ) was gradually added over 0.2j hours. The solution was stirred at 0° for 7 hours and then warmed to 1.21°. The dichloromethane was removed in vacuo and the residue was dissolved in ether (300
ml). The resulting suspension was filtered and evaporated to give an oil, which was purified by FCC using hexane as eluent and then hexane/ether (≠: l
) using the essence? Then, the indicated compound (
46 Hiro1) was obtained. 5, I, c, (hexane:ether-7:/) to Rf
-isoindolyl]hexanoic acid (/, 3/p) and p-aminophenethylamine (Q77y-) dissolved in dry dichloromethane (25 ml) were mixed with phenylphosphoryl azide (/l, 2 ml) and triethylamine (/ , 05ml). The resulting solution was left at room temperature for 19 hours. The mixture was treated with 2N sodium hydroxide (50ml) and extracted with dichloromethane. The extract was dried and concentrated to a semi-solid in vacuo.
Purification by FCC using ethyl acetate as eluent yields
The title compound was obtained as a pale yellow solid (3.25 L), melting point /21A-/M0.

Intermediate 10/7 was obtained in the same manner.

Intermediate IO //, 0°, from intermediate 3 (1 g, ig-) and 3,3'-oxydipropanoic acid (Hiroshi, osy).

Intermediate // 19.2°, from intermediate 3 (7,3ri1) and guoxoheptanedioic acid (2,2A f ).

Intermediate/U(Hiroshi 7) Toxyphenyl)ethyl]-3-methylhexanediamide (/, 11), melting point/! 5, 2- /,! ;3°, intermediate 2<I? -) and 3-methylhexanedioic acid (o, 31
f) from.

Intermediate/3/, 737), melting point +102-2030. intermediate j
(/, 31rf) and from intermediate Yu 3 (/, 53f).

Intermediate thickness/4tA-/'AI'-intermediate/g (9-j f
) IA −= ) a Phenylacetic acid C! r, If
/-') from.

Intermediate is (m) Intermediate, from z (z, Oy) and 3,3'-thiodipropionic acid (o,ry y-).

Intermediate/A -766°, intermediate, from 2(/P) and 3,3'-sulfonyldipropionic acid (0,jy-).

Intermediate 17 3, OfF'), melting point /71- /73°, intermediate, 2
(3,ooy) and glutaric acid (Ol 1-).

Intermediate lzacarbonyldiimidazole (/17) was added to intermediate j (:wp) dissolved in dry dichloromethane in a nitrogen atmosphere at Oo. The mixture was stirred at room temperature for 1 hour and then added slowly to a solution of A-hexanediamine (5i) in dichloromethane (sooml). The resulting solution was stirred at room temperature for 3 hours, then concentrated in vacuo. The residue was acidified (2N hydrochloric acid) and washed with ether. The aqueous layer was made basic (2N sodium hydroxide) and extracted with dichloromethane. The extract was washed with water, dried and concentrated in vacuo to give a white spiral solid.

Recrystallization from methanol/ethyl acetate yields a white powder (
xx7) The compound described above has a melting point of /3A-/3 of 0.

Intermediate 6 (4,
tiiL) t/, A-hexanediamine (/7a
y) was dissolved in a mixture of dichloromethane and dimethylformamide (/:/) and prepared by following the method of Intermediate/Solution.

Intermediate J μ-ethyl/,3-benzodioxole-j-carboxaldehyde n-butyllithium dissolved in hexane (/j
-N-(/,,?-benzodioxol-j-ylmethylene)cyclohexaneamide 7 (1007) -7 g0te dried THF (joo
The solution was stirred and added to the solution under a nitrogen atmosphere. After 13 minutes, ethyl iodide (50ml) was added.

The mixture was gradually allowed to warm up to 150°; then
Water was added and the mixture was extracted with ether. The extract was concentrated in vacuo and the concentrate was heated in 2N hydrochloric acid (,2SOrnl) on a steam bath for J minutes. The resulting solution was diluted with water and extracted with ether. When the extract is dried and evaporated, the title compound (,?, gf/-) is obtained as a pale yellow oil.
-5, 1. O, (ethane:hexane=l)R
To, I got 3.

Intermediate, 2/ midocarbonyldiimidazole (o, sa y ), intermediate x (0, x, ry) in dichloromethane (:wmJl
) was stirred and cooled and added little by little. Nitrogen was bubbled through the mixture and stirred at room temperature for 73 hours. A solution of intermediate/g in dry dichloromethane (Bml!) was slowly added to the cooled solution. Mixture at room temperature
Stir for hours. The solution was concentrated in vacuo.

The resulting solid is recrystallized from methanol.

The title compound (/g-) in the form of a white solid, melting point/Ahiro-7
A6° was obtained.

Intermediate n/23-122r' was mixed with intermediate 7g (0, -tl) and Hiro-methoxybenzeneacetic acid (0, -tl, intermediate 21
Manufactured by the method.

Intermediate physical strength Intermediate physical strength (2/,! jil-) with ethanol (4ts
The stirred suspension in hydrazine hydrate (ll, oml') was treated with hydrazine hydrate (ll, oml'). The mixture was heated to reflux for 30 minutes, producing a paste. The solvent was removed in vacuo. The residue was heated to reflux in 2N hydrochloric acid (310 ml) and cooled to room temperature. The resulting @turbidity was passed through. The permeate was washed with ethyl acetate, made basic, saturated with sodium chloride, and extracted with dichloromethane. The extract was dried and concentrated in vacuo to yield a yellow oil. A portion of this oil (Hiro, 1A7 jib) was dissolved in methanol and treated with fumaric acid (2,01rf). The resulting solution was concentrated in vacuo and the residue was crystallized from methanol/ethyl acetate to give the title compound (j
, F71i1-), melting point/At-/72°.

Intermediate Yl Intermediate/3 (j, gl 7 ) was suspended in dry pyridine 1
The dried material is treated with methanesulfonyl chloride (/, Rinim).
l). The resulting suspension was stirred at room temperature for an hour.

Concentration in vacuo yielded a paste. Add this substance to water (
roo ml) and ethyl acetate/methanol (
Purified by FCC using 20:/) as eluent. When the resulting solid was crystallized from ethyl acetate, the title compound (3,2 Otsu 1) was obtained as a white solid, melting point/10-
//l° was obtained.

Intermediate 2S Sodium hydride (30% salt dispersion, 0.7.2f
/-) was stirred in hexane for 30 minutes under nitrogen atmosphere. Dry hexane with dimethylformamide (25m
1), and a solution of the intermediate <t(rp) in dry dimethylformamide (,2,3ml) was added.
The reaction mixture was stirred at room temperature for lAS minutes and cooled. /.

6-Dibromohexane (2/, 9f) was added and the mixture was heated at 0° for 2 hours. The reaction mixture was poured into a mixture of ice and dilute hydrochloric acid and extracted with ether. The extract was washed with water, dried and concentrated in vacuo. Excess dibromohexane is removed by distillation (O0/Hg, 10
0-10!0), the title compound (lr
I got l.

Analysis Actual value C: ! 0,7. H: A, Hiroshi, N:
3. Calculated value C for C2oH2gF3BrNO3:
! ;/, 3, H: A,,! , N: 3,0 intermediate [(2,3ff)], 5, I, c, (ether:hexane, /:/) Rfo, 3, intermediate "(35'
) and/, 7-dibromohebutane (/, #p) by the method of Intermediate J.

Intermediate, 27 A mixture of thionyl chloride (/gml) and dichloromethane (ugome) was refluxed for 2 hours and evaporated in vacuo to yield a solid. +' /, A-diaminohexane (3
, xp) and anhydrous potassium carbonate (gl) were suspended in dry dichloromethane (≠□oml) and stirred.
．． The mixture was heated under reflux for 2 hours. Evaporate the solvent.

Water was added and the mixture was extracted with chloroform. Drying and evaporating the extract produces a solid.

This was triturated with a mixture of ether and hexane to give the title compound (s,!iy) as a creamy solid, melting point lt-72°.

Intermediate 2g Intermediate 20(3,tp)-malonic acid (l/-71), piperidine (15ml) and dry pyridine (3som
The mixture of l) was heated to reflux for φ hours, cooled and poured into a mixture of 2N hydrochloric acid and ice. Collect the solids that form.

Washing with water, drying, and recrystallization from ethyl acetate yielded the compound (17y-), melting point: 201iL-, 20H.
I got jo.

Intermediate, 2q Intermediate,: 1g (,!/,77') in methanol/l
/ (AOOml) was stirred over Pd-C under an atmosphere of hydrogen until hydrogen uptake ceased. The catalyst was generally removed and the P liquid was evaporated. A white solid will form.

When crystallized from ethyl acetate, the compound of title 1 (ali')
, melting point /27-/21' was obtained.

The product (J?) from step (1) was dissolved in methanol (Hirooo
ml) dissolved in concentrated sulfuric acid (IAO ml) was heated for minutes on a steam bath, cooled and poured onto a mixture of ice and water. The mixture was extracted with ether and the extracts were dried and evaporated. The residue was purified by FCC at °C using hexane/ether (7:J) as eluent to give compound 9 (/I, zP), melting point: -4° to 6°.

n-butyllithium dissolved in hexane (/, s
s mol-Ill-ml'), diisopropylamine (
A, ZajP) was dissolved in dry THF (200 ml) and added to the stirred solution at 0° under a nitrogen atmosphere. The solution was cooled to -7g0 and the product from step (11) (/Nj
-) dissolved in dry THF (200 ml), 30
It took a minute to add it. After further treatment, methyl iodide (s,
iml! ) Wohexamethylphosphoramide (ii,
qml) was added and the reaction was allowed to come to room temperature. The reaction mixture was diluted with a saturated aqueous ammonium chloride solution (
/A') and extracted with ether. The extract was washed with water, dried and evaporated. The residue was subjected to the above methylation reaction two more times using appropriately reduced amounts of reagents. Distillation of the final residue in vacuo yields the title compound (IO
,,z7),boiling point/! rO-/J, f/0. / Obtained Thor.

step (product CIO from Ill1?) and 2N sodium hydroxide (soml) in ethanol (SOme'
) was heated under reflux for 30 minutes. The solution was cooled, poured into water, acidified with 2N hydrochloric acid, and extracted with ether. The extract was dried, evaporated and the residue was dissolved in hexane/
Purified by FCC using ether (7:J) as bathing solution. Crystallization of the product from hexane gives the title compound as a white solid (2L!-), mp 7J.
-74" was obtained.

Ethyl; chloroformate (/, 1f7f) dissolved in acetone (10ml') was mixed with the product (J, 151-) from step Ov) and triethylamine (/, 1f7f).
i') was dissolved in acetone (aoml) and water (jml) and added to the stirred solution at o6. A solution of sodium azide (22(S9) L?) in water (10 min) was added and the mixture was stirred in a jo for 30 min. The mixture was diluted with water and extracted with toluene. The extract was dried, heated on a steam bath for 1 hour, and evaporated. The residue was dissolved in benzyl alcohol (2 im
1) at 100°/g h.

The mixture was then distilled in vacuo and diluted with hexane/ether (7
Purification by FCC using :3) as eluent gave the title compound (4tg-) as a colorless oil.

N1M, R1(cpc15)δ7,3A(s,tn)-
Otsu, 1 (a b, jH),! Jri(s, uH
)-j, θza ('t 'H), a, sta (b
r, m, /H), -2, rit(1,2H)-,
2jj (q, -2H), /, 3 (s, AH), /
, /-2 (5, 3a).

A solution of the product (O,-t5') from step (v) in ethanol (xml) was hydrogenated over 10% Pd-C. After 3 hours, the catalyst was removed in one portion and the P liquid was evaporated. Treatment of the residue with ethereal hydrochloric acid (O) produced a white solid, which was crystallized from methanol/ethyl acetate to give the title compound (0, lμ?), mp >3000. 5, x, c, () luene: ethanol: ammonia, 7 g: 21): 2) Rto, z202
Mercer 30 Iya-6-chloro-t-oxohexanoic acid methyl ester (I
O? ) was dissolved in dry dichloromethane (100ml), and the intermediate, 2(#)j4i) and triethylamine (,5,,gtp) were dissolved in dry dichloromethane (100M).
The reaction mixture was stirred at room temperature for 1 h, the solvent was removed in vacuo, and the residue was purified by FCC using ether as eluent, expressed as a white solid. Compound (1,y7), melting point 3
7-39° was obtained.

(if) A-(:Cnie(,2-ethyl-3,Hiro-dimethoxanoic acid) Product from step (1) (//g-L, 2N sodium hydroxide solution (-200ml) and ethanol (30ml)
0ml) of the mixture was heated to reflux at 1/1 Terama. The solution was cooled and poured into water (1000ml). The mixture was washed with ether, acidified with -2N hydrochloric acid, and then extracted with ether. The extract was washed with water and evaporated to give the title compound (T,≠1) as a white solid, melting point 0°.

Intermediate 3/ Ethyl; chloroforme) (07g7) - Intermediate 30
(2,/7?) and triethylamine (/, θ/f
l-') was dissolved in dry dichloromethane (0ml) and stirred and added at 0-jo. The reaction mixture was stirred for 70 minutes, and a solution of the intermediate, 2q (/, jl), in dry dichloromethane (:wml) was gradually added over a period of 70 minutes.

After another 20 minutes, the solution was washed with J% sodium bicarbonate solution and then with 2N hydrochloric acid. The solution was dried and evaporated to dryness. The residue was purified by FCC using ethyl acetate as eluent to give the title compound (/, 1) as a white solid, mp 103-10g, jo.

Intermediate 3 A mixture of Nini Chloro 32 μm dimethoxybenzenethanamine (2F)' + adipoyl chloride (O, rtty-) and triethylamine (i, 3 ml) was stirred in dry acetonitrile (uoml) at room temperature for 1 h. The catalyst was removed in vacuo and the residual white solid was dissolved in water for 30 min.
The mixture was stirred for a minute, collected, and dried under vacuum in a oven to obtain the compound of title 1 (25'), melting point/3 ter/610.

Intermediate 33 Methyl;j-[nee((&-(((nee(2-ethyl-3
,ll-dimethoxyphenyl)ethyl] (topmethyl-y-cyanomethyl-2-methoxybenzony)
(A%) dissolved in methanol (,2μ0 ml) was hydrogenated over Adams catalyst (0,≠2) prereduced in the presence of ethanolic hydrochloric acid (,27 ml). The catalyst P was removed and the r liquid was concentrated in vacuo. oil and trifluoroacetic anhydride (, uml) in dry dichloromethane (g
ml) was stirred at room temperature for 18 hours. The mixture was triturated with methanol and concentrated in vacuo to produce a solid.

F using ether/hexane (/:J) as eluent
Purification by CC gave the title compound (&Jp) as a white solid - melting point A/ -1,3°.

A suspension of ethyl-3,Hiro-dimethoxyphenyl)ethyl]sodium hydride (sob oil suspension, 0.2f/) in hexane was heated for 21 hours under nitrogen atmosphere for 30 minutes.
It was stirred at 0. Hexane was removed and replaced with dry dimethylformamide (!ml). The product from step (1) (/Jil) was dried in dimethylformamide (lsml)
5 was gradually added to the reaction mixture, and 10
The mixture was stirred for 1 hour. The solution is cooled to 00 and the intermediate g (
t y ) in dry dimethylformamide (j+++l)
It was treated with a solution dissolved in One reaction mixture was then diluted with 11
After heating under reflux for an hour, it was poured into ice water. Next, N-hydrochloric acid was added and the mixture was extracted with ether. Wash the extract with water and dry.

Concentrated in vacuo. The purified oil was purified twice by FCC, first using ether/hexane (/:, 2) as eluent and second time using ethyl acetate/hexane (/:l) as eluent. The title compound was obtained as a colorless oil (/,≠g-).

Analysis Actual value C: 37,2. H: Otsu, lA, H:≠
, Calculated value C for 0C33Hki2F'6N207:
jt7,2. H: A, / + N: IA, 0 person.

Example 1 Borane-THF complex (/mol/l/THF solution; 3oru
l), intermediate/! ; (2, // y-) is dried T
It was added to the solution in HF (/!rOml) at 210 ml under a nitrogen atmosphere.

The mixture was stirred under nitrogen, heated to reflux, cooled and evaporated. 2N hydrochloric acid was added to the residue, and the mixture was stirred and heated at lOθ0 for 3.6 hours. The mixture was then cooled and made basic with 1.2N sodium hydroxide. The mixture was extracted with dichloromethane and ethyl acetate. The combined extracts were washed with saturated brine, dried and evaporated to produce a viscous oil which was dissolved in methanol. Ethereal hydrochloric acid was added. Evaporate the solvent and leave a solid residue.

Recrystallization from a mixture of methanol, ethyl acetate and hexane gives the title compound (0, 7y-
), melting point /III-/It° was obtained.

The product from step (1) (≠θθ~) was dissolved in methanol (-
iml) and dissolved in water (JmJ), -2N
(carbonate)) Made basic with IJium. The mixture was extracted with ethyl acetate and the extracts were evaporated to give an oil which was dissolved in dichloromethane (30ml'). A solution of boron tribromide in dichloromethane (1 mol, r, 0rrtl),
Add slowly to the vigorously stirred solution. The resulting mixture was stirred for 78 hours at 21° under a nitrogen atmosphere and then (tl
) Cooled to θ°. Methanol was added and the resulting solution was heated to reflux for 0.7j, cooled and evaporated. The obtained solid was dissolved in absolute ethanol, and hexane was gradually added to the vigorously stirred solution.

The gum was precipitated. Remove the solvent by decantation,
The residue was dried in vacuo to give the title compound as a white foam (3 μm 9).

Analysis Measured value C: μl, /, H: A, 3-N: 3. C26HII(IN201I8'-2HBr"-
Calculated value C for 2H20: Kou 5, 3. H: A, Za, N: Hiroshi1 Example 2 Borane-THF complex (1 mol; Atn1, intermediate/
A(0, Af-) dissolved in dry THF (50 mJ) was added at θ° under a nitrogen atmosphere. The solution was stirred/g h, heated to reflux, cooled and evaporated in vacuo. 2N hydrochloric acid was added to the residue, and the mixture was stirred and heated at 7000 °C for 7 hours. As the mixture cooled, a white solid precipitated, which was collected and dried in vacuo to give the title compound (0,4'5') as a white powder, mp 2/2-2/j0.

Boron tribromide (1 mol, 9 ml) was added to the step (1) to (7) product (0,A P ) in dry dichloromethane (
The suspension was stirred and added to the suspension. The mixture was stirred at Unit 10 for 3 hours under nitrogen atmosphere. The turbid mixture was cooled to θ° and treated carefully with methanol. The solution was heated for 1 hour, cooled and concentrated in vacuo to give the title compound (0, tl) as a pale pink solid, mp 130-
133° (softened at 0o).

Analysis Actual value C: 4Z! ,j, H: A,/,
N: 33C26HIIoN206S-,2,HBr
Calculated value C for -1,jH20: In! 4LJ-
H: 44 + N 2 <', (7%.

Example 3 Borane-THF complex (Aml, 1 mol) was added to the intermediate, 2
/ (!;00ml) dissolved in dry THF (aoml) was added slowly under nitrogen atmosphere at water bath temperature. The mixture was refluxed for 20 hours, methanol was added to the cooled solution and then evaporated in vacuo. The residual was heated in 2N hydrochloric acid at reflux temperature for μ hours. Once the solution is cooled and the precipitated solids are collected and dried.

The listed compound (300~) in the form of a white powder, melting point 263° (
Decomposition) was obtained.

(11) μm [knee ((A-([knee (J, 4/-
Boron tribromide (l,, zml) dissolved in dichloromethane (yoml) was added to the product from step (1) (/, , 2fj/-) by drying the product (/,, 2fj/-) in dichloromethane (yoml).
100 ml), stirred, cooled, and heated to θ under a nitrogen atmosphere.

I added it gradually. The mixture was stirred at room temperature for 5 hours.

Added methanol. The mixture was evaporated in vacuo to produce a solid which was recrystallized from methanol/ethyl acetate to give the title compound CI? as a white powder. ), melting point/
71-/100 was obtained.

Analysis Actual value C: 30. j5, H: Aj-N:
Calculated value C for 4A, ≠ C25H38N2011-2HBr: jtO,7-H: A, I, N:
Hiroshi, 7 q6 Example (1) N,N'-bis[nee(,2-ethyl-(3
, G intermediate, 27 (j,, 2j%) in dry THF (2,
The suspension in 20 ml) was cooled to θ°, and 1 molar borane-THF complex (revised ml) was added under a nitrogen atmosphere.

The mixture was heated at reflux temperature for 3 hours. Cool the solution;
Treated with methanol and evaporated in vacuo. ! The residue dissolved in N-hydrochloric acid was heated for 20 hours and then cooled. A white solid precipitates out, which is collected and dried to give compound 1 (,
2,71r%), melting point 223-2230.

Boron tribromide (OJ77) was slowly added to the product C/f/-) from step (1) dissolved in dry dichloromethane (yoml) under a nitrogen atmosphere at θ°.
child. The mixture was then stirred at room temperature/g h, cooled to 100 ml and treated portionwise with methanol. solution.

Heat at reflux temperature for 7 hours and evaporate in vacuo.

A solid was formed which was recrystallized from methanol/ethyl acetate to give the title compound (o,ysf-
), FilA point, 20j-207e' was obtained.

Analysis Actual value C: 32.0. H: 7. /, N
:Yohiro C26H11oN2011-. Calculated value for 2HBr C: j/+j, H near, o, H:≠, 6 coefficients.

In the same manner, the compound of Example J-ta was produced.

Example j y-), melting point/g-λOO°, intermediate l(0, riO
From P).

/33- /310° Analysis Actual Measured Value C: SO1 Hiro, N Near, 0. N: Yoyu.

Br: 2! , 2 C27H112N204 ・-! Calculated value C for HBr-H20: 60,7+H: 7,2. N: 45
,3°Br: ,2! In charge of r.

Example - From t(1) (0, IP).

Example From intermediate, 2.2 (, to θ711p).

Analysis Actual value C: j/, 3. H: A, Za, N: 4
', 7C21LH56N203 m , calculated value for 2HBr C:j/, 3-H:AJ, N:3-. 0%.

From Example A(+)(,2fi').

Example 7 From intermediate lg (/, Jp).

1/jt00° analysis Actual measurement value C:≠7.2. H: A,! -N:
&, 7C2qH55N50+4 ・, 2HBr-, 2
Calculated value for /JH20 C: 1I-7, 1, H: 5,
3. N near, 0%.

From Example 7 (1) (300m9).

Examples and (7S) Melting point: 23-2'AI'.

From intermediate, 2IA(34y-).

(2,73 f/), melting point/Aj - lA 0 (min M).

Analysis Actual measurement value C: 4Lj, 2. H: A, 5,
N: ,4. ．． 2C25H3gN30+48-. 2H
Calculated values for Br-H2O C: Hiroj, 7, H: A, J
, N:A, μ section.

1 example! From r(11(2,'/-P)).

Example 2170-2≠2°, from intermediate/'1 (3,0ff).

Dough hydrate (,2,Job), melting point/Hiroj −/l/−
r'.

(7t) Analysis Actual measurement C: lAri, 2, H: AJ, N: Hiroshi, j
.

Br: 27,2 C25H3! lN2011-. Calculated value C for 2HBr-H2O: u? ,,2,H: A,I,N: l
A.5.

Br: 24.7 section.

From Example (1) (ko, oo f).

Example IO Hydrate Example ≠ Compound (4Loo■) of (1) was deoxygenated
The suspension in odorless dead hydrobromic acid (toml) was heated at reflux temperature for J hours and stirred. The mixture was flushed with a gentle stream of nitrogen. The resulting solution was cooled and evaporated in vacuo. The obtained solid was recrystallized from methanol/ethyl acetate to give the title compound (30
0m9), melting point 200-. 202° was obtained.

Analysis Measured value C: μri, 7, H: 6.7. N:≠,j
C26H11ON2011-2 HBr-//3 Et
Calculated value C for OAc: 30. Z+H
: AJ, Nko 45, 3rd person.

Example /I-/3 was carried out in two stages. The first step was carried out by the method of Example Hiro (1), and the second step was carried out by the method of Example 10.

Examples // Trihydrochloride, 5, 1. c, () Luene: Ethanol: Ammonia, 7g: xr: , 2) Rto
, from IA0 intermediate/3 (2, jtf/-).

Trihydropromide (,2,0IA7), melting point 21.1
−． 2700° analysis Actual measurement value C loss j, H:! ,Water N: A, 3C26H37N302 ・3 HB
Calculated value for r C: Hirohiro, Ri, H: A, 3. N:
From Example 5, j2//(1) (/, l' p ).

jul7 Koj Hiro-, 2sA0 (decomposition).

From intermediate 3.2 (/, j7).

(o, sb y-), melting point 19μ-/27°.

Analysis Measured value C: Hiro λ, 4L, H: 3.2-N:
≠, 3C22H2OC12N204 ・2 Calculated value C3 for HBr, 7. H: j5, 2. N: Hiroshi,
Section J.

Example/Co(1) (o, 5, y-) to Example 13 27θ−272°.

From intermediate/9 (!ff).

(7ta) do hemihydrate (3,O,zp), melting point, 24'J'-,
260'.

Analysis Measured value C: *r, 2, H: Aj-N:
4! , jC211H36N2011″-2HBr・l/
-Calculated value for 2H20・l/2MeOH
C: ≠ ff, 7, H: , 4, 2, N: 4, for example/? (1) From (4', lAP).

Example 1 Hirochloridoborane-Tl-IF complex (/MO#THF solution, v3ml
), the intermediate to (r,3of) is dried in T HF
(600 ml) at 2/° under nitrogen atmosphere.

(ZO) The mixture was stirred at reflux temperature for S, S hours under an atmosphere of 9 atoms,
Heat, cool and evaporate. 2N hydrochloric acid and THF were added to the residue and the mixture was heated at reflux for 0.15 hours and cooled. THF was evaporated. The mixture was passed through one sieve. The solid residue was washed with water and then diluted with methanol/ethyl acetate/
Recrystallization from hexane gave the title compound (j,/HiroP) as a white powder, melting point 15', 2-/3°.

The product from step (1) (O, &A, %) dissolved in methanol (/30 vtl'J) was mixed with pre-reduced 10q6Pd-C catalyst (30% (w/w) wet material/romy ) at room temperature and normal pressure until hydrogen absorption ceased. The mixture was filtered and the P solution was evaporated. The resulting gum was crystallized from methanol/ethyl acetate to give a gray crystalline form. Compound (217■)
, melting point λθJ-,zOx' (decomposition) was obtained.

Analysis Actual value C: ! Ir6.3, H near, 4. N:
! j'jC26HqON205-. Calculated value C for 2HC1-H2O: ! A, A, H: 7. A, N:
s7 Section Example/j A,! , 2 p ), melting point IAI −/13°, was prepared from the intermediate ta (5,, oy
Fl-).

Analysis Measured value C: 31.9, H: 1,3. N:
II,? , C1: /, 2.7 C27H112N205・2 Calculated value for HCI C: jri, ko + H: 8", /-N:
j, /-C1: Section /3,0 was processed into Step 8 (1) by the method of Example /I/-(II)
) (4L, 00ff).

Example 16 0-promide intermediate 31 (/,,z5c) was dissolved in dry benzene (5, om
1) was gradually added to a suspension of lithium aluminum hydride (0.4'fl) in dry ether (AOml) under nitrogen atmosphere at O to !6.
3) was added. The resulting mixture was then heated at reflux temperature for 20 hours. The mixture was cooled and treated with 1.2N sodium hydroxide solution and extracted with ether. The extract was washed with water, dried and evaporated to yield a pale brown oil.

A sample (0,-2fi') of this oil was dissolved in dry ether (
When treated with ethereal hydrochloric acid, a white solid was produced.

This was crystallized from methanol/ethyl acetate to obtain the title compound (0,/If) in the form of a white plate, melting point: 2.23-co2j0.

Lopromide (0,22y-), melting point 233-233” Analysis Actual value C: j2J, H: 7. Hiromu, N: Hiromu,
302gH+4+4N204 ・2 Calculated value C for HBr: j3.0. H near, 3. N: 屹≠Chi by the method of Example 3 (11), Example/x(1) (0
, 311f).

(Review) Example 17 Intermediate co(2,09y-) and (g)-7,A-dibromo-3-hexane<o,tiy-) were mixed with absolute ethanol (/
gml) was stirred and heated at reflux temperature for 7 hours. The ethanol was evaporated. The residual gum was dissolved in methanol and excess ethereal hydrochloric acid was added. The mixture was cooled to 0'' overnight. The resulting precipitate was collected and recrystallized in methanol/ethyl acetate to give the title compound (30/rAl) as a white powder, melting point, 2/7-collision 0. I got it.

Su[3-ethyl-1,2-benzenediol] dihydropromide hydrate (3,2,2m9), melting point 202-.
201A0 (decomposition).

Analysis Actual value C: ! ;0,2,H: A,3. N
: 4L, 3C26H36N2011-. 2HBr-H
Calculated value C for 2O: ,! TO0,2,H: A,
j5, N: Hiro, j was obtained from the product of step (1) (≠oom9) by the method of Example/(II).

In the same manner, the compounds of Example 1 were prepared.

Example/g Melting point/Hiro-/It° (decomposition).

from intermediate 2 (/, A7f) and/, A-dibromo-3-hexyne (o, plrSl-').

(Disassembly).

Analysis Actual measurement C: i, j H: j, 7. N:
3,9C26H5BN20II-,2HBr-H2O
Calculated value for C: Hiro A, 5, H: A, 0, N: Hiro,
From Section 2 Example/, r(1) (Hiroshi, 2jl).

Example 19 Chloride intermediates 2 (Y-) and (E, E)-,2, Hiro-hexadiene dial (/, /l) were dissolved in dry benzene (2,
roml) at reflux temperature for 1 hour. The solution was concentrated in vacuo. The residue in absolute ethanol (/,!0rnl) was dissolved in sodium borohydride! J Ram (i, s/
f). The reaction mixture was stirred at room temperature for 3 hours.

Diluted with water, further stirred for O, S hours, further diluted with water (g
7) and extracted with dichloromethane. The extract was dried and concentrated in vacuo. Dissolve the obtained oil in methanol,
Treated with a slight excess of ethereal hydrochloric acid. The resulting solution was concentrated in vacuo to produce a solid which was crystallized from methanol/ethyl acetate to give the title compound (j, OJg) as an off-white solid, mp rating 7-2100.

Tenkohiro0-2≠IAo (decomposition), Analysis Actual price Ci j/, 3, HI4. /, Nnige,
jC,! 6H56N20+,', Calculated value for 2HBr C+ jtJ, H+ 4.4L, N I≠, 7
blood.

was obtained from the product of step (1) by the method of Example/(Ill), except that 2N sodium carbonate was replaced by 2N sodium hydroxide.

Hide 1j Toji! -[-1[:[-((nee(,2-ethyl-3゜(♂
Z) Zuamide intermediate 3s (1,x g) and ammonia (OJr
A solution of N S, 2jTILt) in methanol was stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo to give the title compound (7 g) as a light brown oil, infrared spectrum (0%, CHBr in 5) 1NH231/
L 0.3310 (FM-1, amide (C=O)
1170 an-'hydropromide hydrate (tOOwL
9), melting point tlt-/zo (decomposition) analysis actual value C: 4t2. /, H: jJ, N
+ j, 4tC25H57N, O,” 3 HBr
” Calculated value for H2O C111,2,7,H:
1. ．． 01N: 5, OS was obtained from the product of step (1) (0.7 g) by the method of Example J(II).

Example 2 / One Piece (,21jj,2) Intermediate, 26 (/g) was dissolved in methanol (jOO++
+J) and -N sodium hydroxide (jOmA) were heated on a steam bath for 7 hours. Furthermore -)16
After warming for 7 g hours, the solution was concentrated in vacuo and the residue was extracted with ether. The extract was dried and concentrated in vacuo to give an oil. Ethereal hydrochloric acid was slowly added to this oil dissolved in dry ether. The precipitated white solid was collected and dried. Crystallization from methanol/ethyl acetate gives the title compound as a white solid (O,j/y
), the melting point was 33-23j'.

dehydrate (,2+,t 5,2) (0,1 g), melting point ir, 2-/l! 0, Analysis Actual value C+lI Ogu, HI AJ, N+
45, /, Br+, 2, 3 C27H1i2 N20II 'λ, j HBr-N
Calculated value C for 20;≠7.7, Hlbu,! ,N;≠
, 11Brt2Y) Example-? Example 2/
(+) Obtained from (O, gujg).

The examples below are of suitable formulations of compounds of the invention. The term "active ingredient" as used herein refers to a compound of the invention.

(tal) Example A - Tablet (direct compression) 1 da/tablet Active ingredient 20.0 Fine cellulose, British Pharmacopoeia /≠, O Magnesium stearate /, 0200.0 The active ingredient was passed through a 2jOμm sieve. It was sieved, blended with some excipients and compressed using lr, 1 mm punches. Compressed. Tablets of other strengths can be produced by varying the compression weight and using appropriate punches.

Tablets may be film-coated with a suitable film-forming material such as methylcellulose or hydroxypropylmethylcellulose using standard methods. Tablets may also be sugar-coated or enteric coated.

Example B - Injection for intravenous administration (weight/volume) Active ingredient /, 00 (T.2
) Water for Injections, British Pharmacopoeia Sodium chloride may be added to a total volume of 100,000 to adjust the tonicity of the solution, to maximize stability and/or to facilitate dissolution of the active ingredient. The pH may be adjusted using dilute acids or alkalis or by adding appropriate buffer salts. Antioxidant and metal chelate salts may be added.

The solution is prepared, clarified and filled into appropriately sized ampoules which are sealed by melting the glass. The injection is sterilized by heating in an autoclave using one of the acceptable cycles. Alternatively, the solution may be made sterile by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packaged in an inert atmosphere of nitrogen.

The fact that the stimulatory effect of the compounds of the present invention on vascular dopamine receptors is selective compared to the stimulatory effect on neural dopamine receptors is demonstrated by the fact that the stimulatory effect on vascular dopamine receptors is selective compared to the stimulatory effect on neural dopamine receptors. (neural dopamine receptors).

In these studies, the exemplified compounds were shown to have an overall potency at vascular dopamine receptors (dopamine-/), equipotent concentrations (
For neural dopamine receptors, it was greater than 300 (expressed as dopamine = /, expressed as isopotent concentration).

Compounds of the invention are generally non-toxic at therapeutically useful doses. For example, the compounds described in the Examples when administered orally to normal dogs at concentrations up to 10 μ/Kp:
No adverse effects were shown.

Claims (1)

Claims: 1. Compounds of formula (I) and their physiologically acceptable acid addition salts, metabolically unstable esters and solvates. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) However, R^1 is a halogen atom, methyl, ethyl,
It is n-propyl or n-butyl group. R^2, R^3, R^4 and R^5 are each a hydrogen atom, or R^2, R^3, R^4 and R
One or two of ^5 is a methyl or ethyl group. X is an oxygen or ionic atom or a sulfone (-SO_2- ) or urea (-NHC
It is an alkylene chain having 4 to 7 carbon atoms, which may have an ONH-) group interposed therein. Y is 1 to 3 substituents selected from hydroxyl, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, carboxamide, alkylsulfonylamino having 1 to 4 carbon atoms, nitro group, and halogen atom It is a phenyl ring which may have a group. However, when X is an alkylene chain having 4 to 7 carbon atoms which may have one double bond, Y is phenyl or halogen 1
It cannot be a phenyl having 5 substituents. 2. The compound according to claim 1, wherein R^1 is a methyl group, an ethyl group, or a chlorine atom. 3. The compound according to claim 1 or 2, wherein each of R^2, R^3, R^4 and R^5 is a hydrogen atom. 4, an alkylene chain having 4 to 7 carbon atoms, in which X may be substituted with one alkyl group or hydroxyl group;
or an alkylene chain having 6 carbon atoms with one or two double bonds, or an alkylene chain having 6 carbon atoms with an oxygen or sulfur atom or a sulfone (-SO_2-) group interposed therein; Range 1st to 3rd
A compound according to any one of paragraphs. 5. The compound according to any one of claims 1 to 4, wherein Y is a group having the formula ▲A mathematical formula, a chemical formula, a table, etc.▼(II). However, R^6 is a hydrogen atom or group CONH_2, R^7 is hydrogen, or R^6 is a hydroxyl group, and R^7 is hydrogen or a halogen atom or an alkyl group having 1 to 4 carbon atoms. It is. 6. The compound according to claim 5, wherein R^6 is a hydroxyl group and R^7 is a methyl or ethyl group. 7. Any one of claims 1 to 3 of the patent claim, where X is an alkylene group having 5 to 7 carbon atoms, and Y is a group of the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (IIa) Compound according to item 1. However, R^6 and R^8 may be the same or different, and are each a hydrogen atom or a hydroxyl group (however, at least one of R^6 and R^8 is hydroxy), and R^7 is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 4 carbon atoms. 8. Compound 4,4'-[sulfonylbis[(3,1-propanediylimino)-2,1-ethanediyl]Ibis[3- ethyl-1,2-benzenediol], 4,4'-[thiobis[(3,1-propanediylimino)-2,1-ethanediyl]]bis[3-ethyl-1,2-benzenediol], 4 ,4'-[1,6-hexanediylbis(imino-2
,1-ethanediyl)]bis[3-ethyl-1,2-benzenediol], and 4-[2-[6-[2-(3,4-dihydroxy-2-
methylphenyl)ethylamino]hexylamino]hexylamino]ethyl]-3-ethyl-1,2-benzenediol, and physiologically acceptable salts thereof. 9, R^1 is methyl, ethyl, n-propyl or n-
Butyl group, R^2, R^3, R^4 and R^5
are each a hydrogen atom or R^2, R^3, R
One or two of ^4 and R^5 are methyl or ethyl groups, X is an alkylene chain having 5 to 7 carbon atoms, Y is hydroxyl, alkyl having 1 to 4 carbon atoms, or 1 carbon atom It is a phenyl ring having 1 to 3 substituents selected from ~4 alkyl, C1-4 alkoxy, amino and nitro groups, and halogen atoms (provided that Y has one substituent that is halogen). phenyl), the compound according to claim 1. 10. R^1 is a fluorine, chlorine, bromine or iodine atom, and R^2, R^3, R^4 and R^5 are each a hydrogen atom, or R^2, R^3, R^ 4 and one or two of R^5 are methyl groups or ether groups, X is an alkylene chain having 5 to 7 carbon atoms, and Y is hydroxyl, alkyl having 1 to 4 carbon atoms, or 1 to 4 carbon atoms. is a phenyl ring having 1 to 3 substituents selected from alkoxy, amino and nitro groups and halogen atoms (However, Y cannot be phenyl having one substituent which is halogen), patent A compound according to claim 1. 11. A method for producing a compound according to any one of claims 1 to 10, which comprises any of the following steps (a) to (d). (a) reducing the compound of formula (III) and, if desired, removing any protecting groups present after the reduction; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) However, R^9 and R^1^0 are each hydrogen or a protecting group, and Y^1 is the group Y or its protected form. , Ar is a group ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, R^1^1 and R^1^2 are each a hydrogen atom or a protective group), and X^1 is one or more alkyl or substituted by a hydroxy group, having one or two double or triple bonds or a carbonyl group, containing an oxygen or sulfur atom or a sulfone (-SO_2-) or urea (-NHCONH-) group. It is an alkylene chain having 2 to 5 carbon atoms, which may be intercalated, and Z^1, Z^2, Z^3 and Z^4 are each 0, or the group C=Z^1, C= Z^2 or C=Z^
3 is the group CH_2, and C=Z^4 is the group CR^
2R^3 may be used (however, at least one and at most two of the groups Z^1, Z^2, Z^3 and Z^4 are 0
and when Z^1 is 0, C=Z^2 is the group CH_2, and when Z^3 is 0, C=Z^4
is the group CR^2R^3), (b) the compounds of formulas (IV) and (V) are reacted with an alkylating agent capable of introducing the group X, and, if desired, removing any protecting groups present. Ar(CH_2)_2NHR^9(IV) R^1^0NHC^2R^3CR^4R^5Y^1(V
) However, the above Ar, R^9, R^1^0 and Y^1 are as defined in step (a). (c) removing the protecting group from the compound of formula (VI); ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) However, R^9, R^1^0, R^1^1 and R^1^
At least one of 2 is a protecting group and/or
R^9, R except that the group Y^1 is in a protected form
^1^0, R^1^1, R^1^2 and Y^1 are as defined in step (a). (d) To prepare a compound of formula (I) in which Y is a phenyl ring substituted with a carboxamide group, the corresponding carboxylic acid ester is aminated and, if desired, a compound of formula (I)
or a salt thereof is optionally converted into a physiologically acceptable acid addition salt, metabolically labile ester or solvate. 12. At least one compound according to any one of claims 1 to 10, or a physiologically acceptable acid addition salt, metabolically unstable ester or solvent phase thereof; and a physiologically acceptable carrier or excipient.