JPS5838238A - Novel compound and manufacture - 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 The present invention relates to novel compounds, processes for their preparation, and compositions containing them.

According to the present invention, compounds of formula (1) 1R1 and pharmaceutically acceptable miso derivatives are provided. In the above formula, here R1 and R5, and Rg and R1 are chains -
〇■1o11-, i or R4 and R1 can form a chain -〇H2-, or Rs%R4 and R5 are each hydrogen and %"1% R1 and R4
The rest are the same and 9 are different hydrogen, alkyl or phenyl'J s R4% "7s R11 and R1
0.1t or 2 of represent hydroxy and the rest are hydrogen, X represents a chain - (C town) n- which may optionally be substituted by hydroxy, n is 1 to
is an integer of 7 and %D2 is hydrogen, alkyl, or phenyl.

nine alkyl substituted by one or more hydroxy, pyridyl, phenyl; tt is halogen;
9-alkyl substituted by 7-el substituted by alkyl, amino, alkoxy or nitro;
Alternatively, Dl is a group of Nirin, where R2 and R12t or R1 (l and R12
can form a chain -〇H2-CH2-, 9 can form a chain -1 and ILlt can form a chain -012-, and M9 can form a chain -012-
%R11 and R12 are each hydrogen, town 5R1
11, 31- and the residues of 11 are the same or different hydrogen, alkyl or 7)%R11%R14s R1! and R14's two 0.1 digits represent hydroxy and the remaining residues are represents hydrogen, or R1 and Dl together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring, provided that X is not substituted by hydroxy. 1) When R3, R4 and R5 are hydrogen, R1 and both are hydrogen or lower alkyl,
And R4b R7, ``Isn't sDt the same as Dl, where two of @ and R1 are and roxy?'') R1, R1%R4sga, R4s R7%R・and R9 are When hydrogen, % and Dl each do not represent lower alkyl or do not together with the nitrogen atom to which they are attached form a 5-membered or -i+s- 6-membered heterocyclic ring. or III)
81% "4% 'Ss R4% R7% s if Ra and R9 are hydrogen and R5 is alkyl
"2 is not the same as pl or IV) %Ill and R if R1 is phenyl
5 together form the chain -〇H2O11j-, R4
, R7, R8 and R? is hydrogen, and when n is 1,
``2 and R2 each represent hydrogen, and 9 does not represent alkyl or together form a heterocyclic ring.''

The present invention also provides compounds of formula I, and pharmaceutically acceptable derivatives thereof, as medicaments.

According to the present invention, 2! consists of the following things! Also provided is a method for making a compound of or a pharmaceutically acceptable derivative thereof.

That is, (&) 2■ DI &-NO'r1-X&-0〒21-D! ILF/
1 R4a R2& (In the formula, both 〒1 and te! are cho or O in the case that at least one of 〒1 and 〒2 represents O, and s
R1' and ha have the same meanings as R1 and R2 above, except that they may additionally represent a protecting group, and D
lm represents a group of formula V, where LSI, R41L% RAIL,
RA&, R71L.

R11L and Rya are R4a, 176% R211L
and one or two of RplL (respectively R5 except that IJ may additionally represent a protected hydroxy group)
% has the same meaning as R4, R5, R4, R7, Ra and R9.

X turtle as above except that it may additionally have a protected hydroxy group! has the same meaning as

D2m is hydrogen, alkyl, 7enyl, alkyl substituted by one or more hydro Φ7, hydroxy, pyridyl, phenyl, or halogen, Alkyl, amino, alkoxy is alkyl substituted with nitro and substituted with phenyl, or D2a is
represents a group of R10'% R11'ThR12'
s R1g'%R14"%R151L and R16* are R15a%"14'% R15a and R16&
(respectively '10%' above, except that I!l or more represents a further protected hydroxy group)
``11% R1'1.s 'IB%R14s'' having the same meaning as 18 and R+4), 7' and then if necessary t9 is optional, if desired. By removing the protecting group and converting it into a compound of the formula % formula % l, (1) formula ■ TJ1aT12-x, -a112'r4
1b (Dot in the formula) represents a group of the formula Rlb in ζ, R5b%R4b, R
1! b.

R6b%R7tl, ! j6b and R91) are Rl
tl can further represent a removable group that can increase the nucleophilicity of the nitrogen, and R4b, R71:I, R8
'1sRB%R4, -1, respectively, except that one or two of b and R91) may represent a protected hydroxy group B6.
R6s "7s"@ and has the same meaning as R9)
to react with a compound of dynamical formula I (wherein D2 is D[
K equals and R1 is equal to R1) and then must! (C) formula
R? '%'@c*Rho and hyR represents a hydroxy group, and xo can have a protected hydroxy group
@, R? > and a stone with the same meaning as X) selectively reduces the compound and formula! (wherein D2 equals Dl and both R1 groups are hydrogen) and then remove any such protecting groups if necessary or desired to form the corresponding compounds of formula I. or @) removing the protecting group from the corresponding compound of formula (1) having one or more exemplified 9-hydroxy groups or protected adenane groups and, if desired or necessary, The resulting compound of formula I can be converted into a pharmaceutically acceptable derivative thereof, or vice versa.

For method 6L), the reducing agent is electrophilic, such as diporane, or nucleophilic, such as a complex metal hydride [such as lithium, aluminum hydride or sodium (2-
methoxyethoxy)iminicum hydride]. The solvent is preferably inert to the reaction conditions. Aprotic solvents such as tetrahydrofuran, diethyl ether or 1,2-', $methoxyethane are preferred. The reaction may be carried out at about 0<0>C to 100<0>C.

When R1 and /l or RAIL represent a holding group,
The protecting group may be a hydrogenolyzable protecting group, such as a 1-phenylalkyl haze conductor, such as silane. Protecting groups may be removed, for example, by reduction using hydrogen and a suitable hydrogenation catalyst (eg palladium on charcoal).

Two of R4a, R71L% R8a and Rg& represent a protected hydroxy group, and when /l or D2& has a protected hydroxy group, the retained hydroxy group is, for example, alkoxy, It can be annealed with phenylalkoxy (eg 7-elmedoxy) or alkanoyloxy (eg ace29-toxy).

Removal of the human W protecting group depends on the nature of the holding group, but conventional techniques including acidic and basic cleavage, and hydrogenolysis can generally be used. For example, 4!41
11 Alkyl and 9 are 7 enyl alkyl groups, and 9 is a Lewis acid such as boron trihalide. When the 0g4 protecting group is an alkanoyl, which can be removed by reacting with in a chlorinated hydrocarbon solvent,
Cleavage may be accomplished using a base such as sodium hydroxide in a suitable solvent such as aqueous ethanol. Lewis bases such as pyridine/hydrochloride can be used to cleave the alkyl or phenyl alkyl groups. A 1-phenylaryl group such as benzyl may be removed by catalytic hydrogenation using a suitable catalyst such as Paszicum in a suitable solvent such as ethanol or acetic acid, preferably under pressure.

In process Cb) Ll and zl are anion-forming groups such as I.logen (e.g. chlorine or bromine) or p-
) may be luenesulfonate.

The reaction is preferably carried out in a suitable solvent in the presence of a base. The solvent can also act as a base, suitable solvents are for example pyridine (in this case no addition of a base is necessary), or ethanol or polymethylformamide (in which case a base such as bililine, triethylamine or sodium hydroxide). is preferably used). The reaction may be carried out at about 0<0>C to 100<0>C.

When R11) represents a removable group capable of increasing the nucleophilicity of the nitrogen, R1 may include, for example, p-)ruenesulfonyl or triacetyl (e.g. trichloroacetyl or trifluoroacetyl) protecting groups in K. The removal of can be carried out in the same way as described for method -).

Method (0) Reduction of K and removal of anti-reactive group are methods ←
) can be carried out in the same manner as described above.

Removal of the protecting group in method ＠) can be carried out under acidic, basic or hydrogenolytic conditions in the same manner as described for method ＠). , the amino group is suitably positioned and the nine nitro-warming group is reduced by catalytic hydrogenation, e.g. using hydrogen and A radium, preferably under elevated pressure, in a suitable solvent (e.g. ethanol). or by chemical reduction using, for example, tin and a suitable acid such as hydrochloric acid at about 0°C to 100°C.

DI & is D2a K * C < * and Rla is R2
& Ic are equal, and when 〒1 and 〒2 are both 0, the compound of formula W is 2X zloo-X, -002; fi M, where 21 and zl are the same or When a compound of formula (wherein Dl& and R11L are s?#) as defined above is reacted with a compound of the formula sell.

Good KIIll leaving groups z1 and Z2 K are, for example, halogen (e.g. chlorine, bromine), 1-aryenyl zolyl, trifluoromethanesulfonate, alkyl carbonate (e.g. ethyl or pendyl carbonate), Included are alkanoacetates, trifluoroacetate (eg, trifluoroacetate).

The reaction may be carried out in the presence of a non-nucleophilic base such as triethylamine in a solvent inert to the reaction conditions, such as a chlorinated hydrocarbon such as tetraroform.
It can be carried out between 100°C and 100°C.

The free Shun (that is, when both zl and 2! are equal to HI#ax), which is converted to NiO, reacts with, for example, thionyl chloride, ethyl chloroformate, or 4. The 000H group can be converted to 100z1 group.

If D2a is equal to or not equal to DlllL and zl or 11& is equal to or not equal to -1, then the compound of formula W has the formula ■ z1o'rl-x@-ote2z2
xi (in the formula 〒1, 'rl, X, , zl and zl
is as defined above) and the groups z1 and z2 in the molecule are expressed in any order as Natsu 2a (wherein D21L and -1 are as defined above)
By successively reacting with a compound of 1 or 2 and then, if appropriate, reacting the resulting compound with a compound of 2 or 3, a 2-M or 2-M compound can be prepared.

The compound of formula R1 (! J.

(wherein R10%R1C and xo are as defined above), a compound of formula W (wherein z1, R40, R5c, R40, R70%RI
O> YoUR? e is as defined above)).

The reaction may be carried out under the same conditions as the reaction of the compound of formula X with the compound of formula:yl.

An acid of formula xVIK may be reacted with the corresponding free acid using the same reagents and in the same manner to form the required starting material.

Compound 1 of formula ■, ■ Formula X, ■, ■, W % Are the free acids corresponding to W and the free acids corresponding to formulas known?
Alternatively, it can be prepared from known compounds using techniques known per se.

If any starting materials or intermediates have centers of polarization, these may be resolved using conventional methods.

Acid addition salts of compounds of Formula I may be prepared by reaction of the free base with a suitable acid. Acid addition salts can be converted to the corresponding free base by the action of a strong base.

The foregoing methods may produce compounds of formula 1 or derivatives thereof. It is also within the scope of the invention to treat any derivatives thus formed to liberate the free compound of formula I or to convert one derivative into another.

Compounds of formula and intermediates can therefore be separated from their reaction mixtures using conventional techniques.

Pharmaceutically acceptable derivatives of compounds of Formula I include pharmaceutically acceptable acid addition salts.

Suitable salts include salts of mineral acids, such as hydrochloric acid (eg, hydrochloric acid or hydrobromic acid), or organic acids, such as formic acid or lactic acid. The acid can be a polybasic acid, such as sulfuric acid, fumaric acid or citric acid.

Other pharmaceutically acceptable derivatives are suitable bioprecursors (prodrugs) of compound -a'r- and are readily apparent to those skilled in the art and are conventional derivatives known per se from compounds of formula I. or by methods analogous to those described above. Suitable bioprecursors include the compounds of formula I, and when the compound of formula I has a hydroxy group, esters such as carboxylic acid esters, alkanoyls such as acetyl or isobutyl, or aroyl esters such as benzoyl. be done.

Rls Rls When R4 and R11 each represent alkyl, it is preferred that they contain up to 8 and preferably up to 4 carbon atoms.

As a particular group, one or both of R1 and R2 is hydrogen or alkyl such as methyl or n-propyl, or R1 and R5° or R1 and R1
! are respectively based on M1 and M1 and M2 (in the formula R1%R41''4s R7%Gas'?s R1
0%R11%R15, R14, R15 and R14 are as defined above).

As another specific group, one of Rs and RBI is hydrogen, or R1 and R6, BI
B2 (14S R4%R7s “@s East 9%R11%”
1gs 14sR15 and R14 are as defined above.

Yet another specific group is s R4 and R11
one or both of are hydrogen, hydroxy or phenyl, or R4 and "5s or 102 (wherein Rh"6s R7% Ram "9s RlQn
R1hR14sR15 and R14 are as defined above).

In yet another group, all of R3, R4 and R11 or all of 110% R11 and R12 are 11
2 (in the formula R4s Ram Ram R9s R15s R
14s R111 and R14 are 9 as defined above) are provided.

at least one of R6, 'R7, R8 and R9;
And preferably two of them are hydroxy.

It is preferred that at least one and preferably two of RlM, "14, IJ!! and R14 are hydroxy.

It is preferred that both the adjacent pairs of I, R7% R8 and R9, /l or R11m R14, Rlg) and the adjacent pairs of '44 are hydroxy.

Compounds in which R7 is hydroxy are preferably qIIK, where n is 2 to 6, preferably 3 to 5, and I? Preferably it is iK4.

When B2 represents alkyl or optionally substituted alkyl, the alkyl moiety may have up to 8
And preferably up to 4 41-charcoal 1! may contain atoms.

, when R2 is an optionally substituted alkyl polysubstituted by enyl, the optionally substituted tzenyl moiety has from 6 to 10 carbon atoms. sell.

R2 and D! when together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring, the ring may be pyrrolidino, pyridino, morpholino or especially pyRcudino.

When the ring is biradino, the nitrogen at position 4 may be substituted with 01-06 alkyl, such as methyl.

M1 and recommendation B1 and B2% B1 and "2, 'l and 02, C
1 and I! 2, and El and 1! ! ! A compound of formula (1) containing a pair of groups is 41KFftL<, where ζ is M1, A2
, ``1% 31% OS, '2,'' 1 and 11I2 are toomaji as defined above.

Preferred 4IK compounds of Formula I are the compounds of Examples 1, 5, 12, 43-14 and 22 and pharmaceutically acceptable acid addition salts thereof.

Certain compounds of formula (2) may exist in optically active and monoisomer forms. The present invention also provides optical and male isomers of these compounds of formula (1) and mixtures thereof, including racemic mixtures thereof. It is something to do. These compounds can be resolved into their optical isomers by conventional methods.

When a carbon atom with R$, R4, Rol t or R11 is in polarization 11, its vertical atom configuration can be R or B. When the two carbon atoms are under polarization, the compound of formula
.

The compounds of Formula I, and their pharmaceutically acceptable derivatives, are useful because they have pharmacological effects in animals. That is, these compounds act on peripheral and/or central receptors. As such, they lower blood pressure, reduce heart rate and increase blood flow to certain collapsing beds, such as renal beds.

Some compounds also have effects on other adrenal receptors, and these exhibit inotropic and bronchodilatory effects. The activity of the compounds was observed in the assay system described below.

(,L) Renal blood flow in dogs, IJOM&7 and GOll
Mr. lberg's rJ, Pharmaa, Mxp
, Ther, J Vol. 151, pp. 25-31 (196
See 6th grade).

(b) Isolated ear artery of rabbit, MoOul
1OghRand and 5tory et al.
@ Pharmaa, J Vol. 49, pp. 141-142 (
(1973), and (C) IN nictitating membrane, G70rg7 and Kam rArah.

See Xnt, Pharmaodyn, J 226, 194-206 (1977).

The compounds of the present invention are useful for congestive heart failure, renal failure.

Indicated for use in the treatment of angina pectoris, ischemic heart disease, hypertension and reversible obstructive airway disease, hyperprolactinemia and also Parson's disease and other neurological disorders.

The amount administered will of course depend on the compound used, the mode of administration and the effect desired. However, in general, it is possible that the compound will reduce body weight IK#m to α05μf~50q
For humans, the indicated daily dose is 2.5μ2 to 55F, which gives satisfactory results when administered in amounts of 1μt to 750ilF, e.g. can be administered.

The novel compounds of the present invention can be used in combination or sequentially with a wide variety of other pharmaceutically active substances. If appropriate, the compound can be mixed with one or more other active substances or can be combined with other active substances (@
) may be chemically combined with one to form, for example, a salt or an ester.

The particular mixture used, the method of administration or chemically combined substances, and the proportions of active ingredients depend on the condition to be treated,
Mode of Administration 1. Mode of administration depends on a variety of factors, including the particular active ingredient and the particular patient.

Compounds that can be chemically combined with the compounds of the present invention are listed below.

I-Blocker I! Cardiac selective for I#! -Title-absorbing agents such as athene a-le (at@n*xo1), p-124-nol (
propanolol), diuretics such as thiazides such as 70C, acetylcholinesterase inhibitors such as captopril, inotropes such as amrinone, antiemetics such as sulpiride, metocloprand. (m@toolopramicls), or tombaridone (aDImp*rloneχ Compound 1 of formula I
．． and pharmaceutically acceptable derivatives thereof, if they are of the formula! It has the advantage that it is more effective in certain pharmacological models or has fewer undesirable side effects or is longer acting than compounds of similar structure.

The compounds of the invention can be administered by a variety of routes and can act systemically or locally. Therefore, the compound of the present invention can be administered to the lungs, orally to the vagina, by inhalation through the nose, from the esophagus, and from the rectum.

By local injection into the skin or other available surfaces of the body, such as by intravenous, intramuscular, intraperitoneal injection, or by surgical implantation according to the invention, a pharmaceutically acceptable adjuvant. Also provided is a pharmaceutical composition comprising preferably less than or equal to 0 and more preferably less than or equal to 50 by weight of a compound of formula (I) or a pharmaceutically acceptable derivative thereof, in admixture with a diluent or carrier. .

Examples of suitable adipants, diluents or carriers are microcrystalline cellulose, calcium phosphate, diatomaceous earth (for example lactose, dextrose or man'ol), Merck, stearin, etc. for tablets, capsules and dragees. acids, starch, sodium bicarbonate, and/or gelatin; for herbal medicines, coated with natural or hardened oils or waxes; and for inhalable compositions, crude lactose.

Chelating agents if the compound is to be used in aqueous solution! It may be necessary to incorporate masking agents such as sodium nibtate, antioxidants such as sodium metabisulfite, and buffering agents such as sodium hydrogen phosphate and sodium phosphate. Aqueous solutions typically contain up to about 10 weight percent of the novel compound and can be used for intravenous injection.

According to the invention there is further provided a method of increasing cardiac contractility in a human or non-human animal, comprising administering to the animal an effective amount of one or more compounds of the invention.

The invention is illustrated by, but not limited to, the following examples, all temperatures being at (6) degrees Celsius.

The stereochemical nomenclature is ``ohemiaalm bstraot''.
s, mxGuidaJ 1977 No. 202-212
rAppenlix from page, 8s1eation
of znmu x llamas forOhemiaa
l 8uMtano@sJ.

49- Attribution of absolute stereochemistry is given by Helmhen■・1mch@n et al.
1527 (1974), (0)
) ditto 14v7 purchase (1977), and MoD@r
m@1's "ProaesdingaOf th@8
ymposlum on DOplL! 11! ni・mug
otLiltl (8toakho1m) J (8wa
aish Pharmac@utioal Press
(published in 1982).

Example 1 (3 pieces, 8 pieces) -2,2'-(1,4-Hegosu Njiilbisa Z)] -Bime (1,2,3,4-Tetrahitada-
5,6-naphthalene sioya] ←) ' -(1,2,3,4-tetrahydro-5,
6-rimethoxy2-su7tylidene)41)-1-:y
1,2,3,4-tetrahydrone 4-5,6-simethoxy 2-tetralone (2α) in dry toluene (200 mg)
6t)>! The mixture was heated at reflux for 4 hours with continuous removal of water to form a solution of (6)-1-queerethyl 7150-one (14 wt). Evaporation of the mixture gave a brown oil (30t) containing 1,2,3,4-tetrahydro-5,6dimethoxyN-(1-phenylethyl). A solution of the iyne (21) obtained in step 1i←) in dry ethanol (250 m) was heated under atmospheric pressure (~2 days) until no further hydrogen uptake was observed. Hydrogenated over Adams catalyst (1f) at room temperature.

The solution was evaporated and evaporated to give an oil, which was dissolved in excess ethanolic Hot. Evaporation of the solution gave a dark solid which was purified by trituration with cold isopronocenol (50m) to give a colorless solid (23f).

The above reareomeric amine was subjected to high performance liquid chromatography (HFLO) on a silica column in petroleum ether/l) chloromethane (4:1).
) Partitioned by elution with a mixture containing ethylamine (1%).

Converting the free base of each diastereomer to its hydrochloride salt and crystallizing results in a diastereomeric purity of greater than 99.81 (HPLO).

11 First eluted diastereomer 9.51
, melting point 265-267°C b2 The second eluting diastereomer 6,0?
, melting point 297°C (decomposition) (o) s (-) 1t2,3. a-tetrahuman 0
-5.6-dimethoxy-2-s7talene hydrochloride A<b1> b1 (495F) in dry methanol (40M)
) was added in bulk over 1o*pa 10M [(2f) at atmospheric pressure and room temperature for 24 hours. The solution was passed through and the P solution was evaporated to give a solid which was crystallized from ethanol to give colorless prismatic crystals (582).

Melting point 270°C, [α)j' = -sal(c-als,
0H30H).

←) R(+) 1,2,3.4-nato2hydro5
, 6-Simethoxy 2-naphthalenamine hydrochloride Amine b2 (6,9
5t) +17) The solution was hydrogenated over 109GP1 catalyst (2f) at atmospheric pressure and room temperature for 78 hours. The solution was evaporated and the filtrate was evaporated to give a solid, which was crystallized from ethanol to give colorless prismatic crystals (55F
) was obtained, melting point 260℃ or higher, [α]D-+5a6(0
α2, Ol[gOH)e(・)(S) Methyl-6-(
1,2,3,4-Tetrahydro-5,6-simethoxy-2-su7talenamino)-6-oxo-hexanoate-5! S- step (0
) -t” Methyl 5-(/1-roformyl)internoate (1,
9f) was added dropwise. This solution was heated under reflux for 1 hour. The cooled solution was washed with dilute salt solution, dilute bicarbonate solution, and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to give a colorless solid, which was crystallized from toluene/petroleum ether to give colorless flakes (
&2t) to obtain melting point 115-116℃, [α]D-3
[L6(C-attack α17, (1!H50H).

C) ψ)i-(1,2,3,4-tetrahydro-5,
Solution of the 254-ster obtained in step 11 (.) in methanol (50 m) and 10 qb aqueous sodium hydroxide solution (4-). The drops were heated to reflux for 1 hour, the droplets were evaporated, cooled and acidified using dilute hydrochloric acid. Precipitate K11I in chloroform! Dissolved, washed with brine, dried over magnesium sulfate, exposed to F and evaporated to give a solid which was crystallized from ethyl acetate/petroleum ether to give colorless prismatic crystals (2,sr). . melting point 14
7-149°C, [α] D-4I17 (O-α15, O
H kudzu oi).

(g) (R book s”) -MAN'-bis(1,2
，! 5,4-tetohydro 5,6-dimetho 2-
The acid obtained in Step 1i(f) in dry dichloromethane (7 methyl)-hexane-1,6-dia 5
tr) and M,M'-carponyldiisedazole (α
The solution of 53t) was stirred at room temperature for 2 hours.

A solution of the amine (1682) obtained in step 1) (free base) in dry dichloromethane (50 mg) was added and the mixture was stirred at room temperature for 18 hours and the precipitate that formed was re-dropped into the chloroform. The organic phase was then washed with dilute hydrochloric acid, dilute sodium bicarbonate solution and brine. The organic phase was dried over Madanesicum sulfate, filtered and evaporated to give a colorless solid, which was evaporated from hot methanol. (
T! 17F), melting point 256-258°C, [a) DI-±
α1(0-(L14, OHgOIOHOj350 /
50) eｽ) (R*B*)-M, M'-BisC
1,2,3,4-nato-2-bis--5,6-dimethoxy-2-su7-tyl]-hetoxane-1,6-diadenedihydrochloride in dry tetrahydrofurin (400 mg) The solution of bis-chain 1-'' (1,3Sr) obtained at Methanol (200 m) was added to the cooled solution and evaporated to give a sticky solid; methanolic HOL was added and the suspension was heated under reflux for 4 hours. The solution was evaporated to give a colorless solid. When crystallized from methanol, colorless prismatic crystals (1,19t) were obtained.
was gotten. Melting point 260℃ or higher, [α]ゎ--Q, 5(
0 engineering α2, H2O).

←) (R*g*)-282'-(216-hexanediylbisaminoco-bis-(1,2,3,4-tetrahydro-5,6-su7talendiol) 48m aqueous hydrobromic acid solution The solution of pisuaquin (tosr) obtained in step 61I) in (50m) was heated to reflux for 2 hours under a stream of nitrogen. The solution was evaporated to dryness and the residue was crystallized from methanol and labeled as Obtaining the dihydrobromide salt of the compound as colorless prism crystals (170f)9,
Melting point 250℃ or higher, (α)” = “-1,2 (±0.4
)(0-(L18.1ito)eExample 2 The following 15 compounds were prepared in a manner similar to that described in Example 1 above.

←) (R-(RmR rate))-2,2'-(1,6-hexane-Vbis-aino]-bis-(1,2,3,4-tetrahydro-5,6-su7talediol) di Hydrobromide melting point 260℃ or higher, (a): 1m+55.8 (0-
m (L24, Ward!O).

伽)(8-(R*R率)'l-2,2-(1,6-Hexanelyylbisamino)-bis-(1,X,S,+-tetrahydro-5,6-su7 dihydrobromide] melting point 260°C or higher, (α)24-==-5al (0M1
8, [20) II Example 3 2.2'-(1,6-hexanediylbisamino)-bis-(1r2.s*a-tetrahydro-5,6-s7talendiol) 68- (a ) N, N'-bis-(1-21314-tetrahydro-5,6-simethoxy-2-su7thyl)hexane-1,6-diamidoclotetraform (15 mg) adiboylquatide <
1.1r, cLoo6m) in aa form (15m+/). ! 1,4-tetohydro5,6-simethoxy2-amino''+7talene(2,5
F.

α012M) and triethylamine (t4f.

was added dropwise into a solution of α014 M). 1 of this mixture
Stir for an hour, quench by adding water and separate the organic phase, wash with water and sulfur! Dried with gnesium. Passing the mixture and evaporating the filtrate to dryness gave a solid which was crystallized from methanol to yield the desired amide 2.
or (63%). Melting point 223-5°C.

(1)) LM'゛-bis-(1,2,3,4-tetrahydro-5,6-simethoxy-2-naphthyl)hexane-step in dry tetrahydrofuran (250sj)←
) was stirred under a nitrogen stream at 1 m [temperature], during which time the suspension of 9. Furan complex 10- was added via syringe. The resulting mixture was heated to reflux for 3 hours, cooled and additional 10-borane complex was added.

The mixture was heated under reflux overnight, during which time a clear solution was formed. The mixture was cooled and methanol was carefully added and the solution was evaporated to dryness. Methanol was added to the residue and the solution was boiled for 50 minutes. The solution was evaporated to dryness and the residue was dissolved in ether containing a few drops of ethanol. To this solution was added an excess of ethereal hydrogen chloride and the precipitated solid was filtered off, thoroughly washed with hot ethanol and dried to give the desired amine hydrochloride 1, q t (871), mp 280.
℃(min.

(C) 212'-(196-hendiylpisua))-bis-(1,2,3,4-tetrahydro-5
, 6-su7talendiol) dihydrobromide 48-dimethoxyamine obtained in step (b) in an aqueous solution of hydrogen bromide (a O-) (1,8f, 11003M
') was heated under nitrogen flow and KR flow for 3 hours.

Dissolution occurred briefly after 45 minutes, but almost immediately a white solid began to form. After -3 hours the mixture was cooled and treated with solid vrIfII. Wash this with hot methanol,
Dissolved in methanol/water and treated the solution with charcoal, filtered and evaporated the P solution to dryness. The title compound was obtained as the dihydrobromide salt. 1. IP (571)
% melting point 250°C.

Elemental analysis value as 02dH34N204 (a2ots
mole, 4.3%) 61-o% 1111 xi Br@Yi measurement value 49.7 &1 42 24.7 grave theory value 49.6
Table 5442i4 Example 4 The following compounds were prepared by a method similar to that described in Example 3 above.

2.2'-(1,4-hequinanediylbisulfate))-bis-(112,!5.4-tetohydro6.7-naphthaleneliol) dihydrobromide, melting point 260°C or higher.

Example 5 (R(R*tR*) )←)-7,7'-[1,6-heki! (a) ()-)-z, 3-bis(phenylmeth) Synthesis and division of 8-(ha)-1-phenylethylamide of (coco)bicyclo(4,2,0)-octa-1,3,5-triene-763--carboxylic acid in dry tetrahydro7ran (500 mg) (g)-2
,3-bis-(phenylmethoxy)-bicyclo(4,2
,03-octa-1,3,5-triene-7-carboxylic acid (4CLCf% 111 mol) was added to N,N'-carbonyldiimidazole (2α8v1 α
13 mos/). The reaction mixture was kept at 5°C for 5 hours and 5-(-)-1-phenylethylamine (IS, 3F, α125 mol) was added dropwise. The solution was kept at 20°C for 2 hours, then water and dichloromethane were added, the organic layer was separated, and dilute IOA,
Washing with aqueous bicarbonate and brine, drying and evaporation yielded a solid (47,5?), which was converted into a high-performance liquid using ethyl acetate/petroleum ether mixture over talica. By chromatography, two types of 7-terminals were obtained and recrystallized from ethyl acetate.

Less polar diastereomer: (RIll
l, 131)) - Natsuichi (1-72 → Luethyl) -2,
S-bis(phenylmethoxy)-bisicH[4,2,0
)-octa-1,3,5-)rien-7-carboki? Kendo, melting point 186-188℃, (1), m+1.9@(o
-15, OHOAg), J OH5 (ODOJ!!1
)-1,59PPm*More polar diastereomer: CD-(R*, u”))-Natsuichi(1-phenylethyl)-2,3-bis-(phenylmethoxy)-bicyclo-C4,2 ,0) -octa-1,3,5-)liene-7-carboxand, melting point 171-173°C, [a)
D 廓 +2 & 6 @ (o 体 α 3, OHO 羞 3), δOHB
(ODOjB) "II 1.45 Pp!lle negative) [8-(u rate, 81) )-N-(1-phenylethyl)-2,5-bis(phenylmethoxy)-bisic μ
(4,2,0)-octa-1,3,5-)rien-7-
methananne hydrochloride in dry tetrahydrochloride (330m))
(s-(R*,8*))-i r(1
52F, 2.85 f remole) was heated to 2.5F under a nitrogen stream.
IM Bo'! J N (140w1s
140 t (17 mol) and refluxed for 5 hours. After cooling, methanol and methanolic hydrogen chloride were added and the mixture was stirred overnight. The solvent is evaporated and the residue is triturated with dry ether (a
-(Bllg,B*))-Amine hydrochloride is a white crystal (
1αSt>. Melting point 171-173℃, a
(ODOIri-”&80 (1!, d), 460
(IH%d).

(c) (1s-C1m*(1t pieces [78 pieces (78
"k))))) -N,N'-bis-(1-phenylethyl)-summer, V-bisC(2,5-bis(phenylmethoxybicyclo(4,2,0)-octa-113, [8-(
R", El")]-Amine salt base salt 4.84's10
<remol) and triethylamine (503F, 30t
dichloromethane (40
A solution of adipoyl chloride (α915t, 51 lmol) in m) was added dropwise. The mixture was stirred at 20° C. overnight and poured into water. Separate the organic phase and add aqueous hydrochloric acid,
Washing with aqueous sodium bicarbonate and brine, drying and evaporation gave a colorless solid (4,82). Melting point 48
℃.

(1B-(II Shin-[II Umbrella [78 pieces (
7B”)1)]]-L6- hexanediylbis-(N
-(1-: phenylethyl) -2,5-bis(phenylmethoxy)-bicyclo(4,2,0]-octa-1,
5,5-Tri-y-7-methanamine dihydrochloride 66 [1S15 in tetrahydrofuran (100111 g)
-C1a[1u*(7s*(7s*):]))]-bisat)' (4,86F, 4.8 mol) in 1M pot (24
wt.

24 mol) and then heated under reflux for 6 hours. After cooling, methanol and methanolic hydrogen chloride were added and the solution was stirred overnight and evaporated to dryness. The residue was triturated with dry ether to give the diamine dihydrochloride (4,6f), which melted over 90t. It disassembled without any trouble.

(e) CR(R*lR”) ) (+) −y, y
'-(1,6-hexanediylbis(aminomethylene)]-bis(bicycloC4,2,0)-octa-1,3
,5-)Lien-2,3-diol) dihydrochloride The above [1B-(1R(LR) (7B (7B)))))-Diamine dihydrochloride (1t) was shaken under 5 atmospheres of hydrogen pressure at ambient temperature for 72 hours. The mixture was strained and the strained cake was extracted with hot water.

When water is evaporated ←)-diamine dihydrochloride (Q, 3f)
was gotten. Melting point 235℃ (decomposition) % [α] 9, , +
j 2.4° (0-0,15, [20).

Example 6 The following compound was prepared in a manner similar to that described in Example 5 above.

(,) Starting from (B-(R*'n*>) amide of Example 5(a), Cs-(R'',R''))-71
7'-(116-hexanediylbis(aminomethylene)]-bis(bicyclo(4,2,0)-octa-1,
3,5-triene-2,3-diol dihydrochloride was obtained.

Melting point 235°C (decomposition), [α)D--11,8 (0-0
, 15, town 0).

(11) Starting from the mixture of [s-(R ratio, B books)] and (s-(RjR”))amide of Example 5←), 2
Seken and men (R*, vessel 'l') -7,7'-[1
,6-hexanediylbis(aminomethylene)-bis(
Bicyclo-[4,2,0')-octa-1*S*5-
) Liene-2,3-diol fudihydrochloride was obtained. Melting point 2
40°C (decomposition).

Example 7 Racemic and meso (R"ta") -717' -(C
6-hexanediylbis(aminomethylene)-bis(bicyclo(4,2,0)-octa-1,s,s-triene-2,3-diol) (a) Racemic and men [R book, 8*] -N, N
'-Hequinamethylene-bis-[2,5-his(7enylmethoxy)bicycloC4,2,0]-octa-LL5-
) Liene-7-carboxamide] 2.3-bis(phenylmethoxy)-bicycloC4,2
,0)-octa-1,3,5-)liene-7-ka69-ruboni1 (0,72t) was dissolved in dry dichloromethane (
40-), cooled to -5°C and added triethylamine (0.31 Wst). This was combined with ethyl chloroformate (2wt) in dry dichloromethane (2wt).
A solution of 0.19d) was added dropwise over a period of 10 minutes. The droplets were stirred at -5°C for 1 hour and then diluted with hexane-1,6-
Diamine ((L11?) was added and the mixture was warmed to room temperature for 4 hours. The reaction mixture was diluted with water, 2!i hydrochloric acid, 2!
Wash with sodium hydroxide and saline and dry (
lia1804) L and evaporated. Recrystallization of the residue from ethanol yields purified bisamide (0,4
3F) was obtained. Melting point 155-159°C.

(b) Racemic and men (R*, 8 bottles) -7,7
'-CI,, 6-bis(achinomethylene)-bis(bicyclo(4,2,03-octa-1,5,
5-) Diene-2,3-diol dihydrochloride - Ph〇- The product of Example 7ｽ) was treated by the method described in Examples 5＠) and 5ｽ) above to obtain the title compound as the dihydrochloride salt. Ta. Melting point: 240°C (decomposed).

Example 8 7-C6-C2-phenylethyl-A)
]Methylbisic0 (4,2,O:l-octa-1,
3,5-triene-2,5-diol (a) N-(2-
phenylethyl) -y'-C(zts-his-(phenylmethoxy)-bicy/0(4,2,0)-oct1.3.5-)rien-7-yl]methyl]-hexane-1,6 -Diamide 6-oxo-6- in dry dichloromethane (25 mg)
(2-phenylethyl 2)) hexane@ (1,25
F) and N,)i'-carbonyl cyanoele (
A solution of α9t) was stirred at 20°C for 2 hours and then 2,3-his(phenylmethoxy)-bicyclo(4,2,0)-octa-
1,3,5-) Lien-7-methanadenone hydrochloride (1,9
A solution of F) and triethylamine (α5t, α7-) was added. 1 The mixture was stirred for 2 and a half hours at 20°C and water (SO-) was added. The organic phase was separated, washed with dilute hydrochloric acid, aqueous sodium bicarbonate and brine, and washed with Mg
Drying at 804 °C and evaporation afforded the desired siad as a colorless solid (2,3F). Melting point 152-155°C.

伽) N-(2-phenylethyl') -N'-[(
2,3-bix(7znylmethoxy)bicyclo(4,2,
O)-octer1.3.5-trien-7-yl]methyl)-1,4-hexanedianetrihydrochloride Example 5 (
This compound was prepared from the product of Example 8(a) using method d). Melting point 250'C or higher.

(a) 7-Cb-(2-yenylethyl-a-electron)
) Hekidylua fno] Methylbisic l:l (4,2,0
) - Otter 1. ! 5,5-) diene-2,3-diol dihydrochloride Example 8() as the dihydrochloride using the method of Example 5(.)
The title compound was prepared from the product of b).

Melting point: 208-210°C.

example ? The following compounds were prepared in a manner similar to that described in Example 8 above.

7- [: 6- [2-(3,4-dihydroxy7-ethyl)ethylamino]hexylyaelectrono]methylbicyclo(4,2,0)-octa-1,3,5-triene-2,
3-diol dihydrochloride, melting point 217°C (decomposed).

Example 10 7-(6-(2-phenylethyl ai))hekidylua Z
] Methylbicyclo[4,2,O]-octa-1,3,
5-) Diene-3,4-diol (a) N-CC5
,4-dimethoxybicyclo[4,2,0)-octa-1
,5,5-)Lien-7-I4/)Methyl13-l)-N'-(2-phenylethyl)hexane-1,6
- Diamide 6-oxo 6-(2-phenylethylaquino)hexanoic acid (a6sr) was dried with tetrahydro 7 run (220
m) under inert gas and cooled to 0-5°C. Summer 9M'-carbonyldiimidazole (412F
) for 5 minutes, then stir this mixture to 0-5
The mixture was stirred at ℃ for 3 hours. 3,4-dimethoxybicyclo(4
,2,0)-octa-1,3,5-)liene-7-methylamine hydrochloride (z9si and triethylua (4)
, 85 mg) and the mixture was incubated at room temperature for 2 hours.
Stir for hours. The resulting white precipitate was collected, washed with dry ether and dried under vacuum at 50°C. The product was crystallized from propan-2-ol to give a white solid (tyyt
) was obtained. Melting point: 150-152°C.

iF4- (b) a-((s, 4-dimethoxybicyclo(4,
2,0)-oct1*3t5-trien-7-yl)
Methyl)-M'-(2-phenylethyl)-hechusan-1,6-diaZ:/di-salt-sun-salt-tetrahydro-7-sun complex 1 mole solution 11!
(75,5-) was dissolved in tetrahydrofuran (
160wt) Medium work 1! ) into a solution of the product (aOf). The solution was heated to reflux overnight, allowed to cool to room temperature, and methanol (50 m
) was added and the mixture was refluxed for 1 hour. This suspension was concentrated to dryness to give a white solid, which was crystallized from aqueous ethanol to give white needles (&88f
) was obtained. Melting point 258-259°C.

(a) 7- (6-(2-7 EL ETILA DEN))
The product of the (4,2,0)-hydrohydride salt step (125f) was digested with KWI in dry dichloromethane (10m) and cooled to -78°C.

Boron tribromide (55-) is added and the solution is
C. for 3 hours followed by stirring at room temperature for 2 hours. methanol(
about 25-) was added and the mixture was concentrated to dryness. The resulting white solid was crystallized from dry methanol to give the title compound as the dihydrobromide salt. Melting point 210-21
4°C (decomposition).

Elemental analysis value (OzsHstMtOr2HBr) OS Hg$w% ゛Br% Actual value 5t69 6.29 all 3α16 theoretical value 52.08 442 &28 3α19 example
11 The following compounds were prepared in a manner similar to that described in Example 5 and Example 1o above.

(a) (7,7'-(1,6-hequinanediylbis(aminomethylene))]-]bis-bicyclo4.2.0
) -octa-1,3,5-triene-3,4-diol) dihydrobromide, melting point 226°C (decomposed).

(b) y -(6-C2-(3,4-dimethoxyphenyl)ethylamino]hexylatno]methylbicyclo(4,2,0)-octa-1,!5.5-)riene-3.4 -diol dihydrobromide, melting point 100-10
5℃.

Example 12 4-[2”(6-(2-phenylethyl-i])hexylano)ethyl-112-benzenediol(b)) N-(z-(s,4-dimethoxyphenyl)ethyl)-N '-(2-phenylethyl)-hexane-1,6-diaξdo〒1- 6-oxo-6- in chloromethane (3oo-)
A solution of (2-(3,4-dimethoxyphenyl)ethyl-annohexanoic acid (9,3F) and M,M'-carbonyldiimidazole (4,vor) was stirred at room temperature for 2 hours. Dichloromethane (50wt) A solution of 2-phenylethylamine (5B-) in the solution was added and the mixture was stirred at room temperature for 3 hours.

This solution was washed with 2001, water, aqueous 5-sodium bicarbonate, and water. The organic phase was dried over magnesium sulphate, filtered and evaporated to give a solid which was crystallized from ethanol (11.38F), mp 183-18
4℃.

A solution of the diand product (4941) of step VS- ← in dry tetrahydro-7 run (150 m) of While stirring under a stream of nitrogen, a 1M solution of diborane in tetrahydrofuran (4 am) was added. The solution was heated under reflux for 24 hours.

Methanol (1 oosg) was added to the cooled solution and the mixture was evaporated to dryness. The residue is methanolic H
ait (1oQj) and under reflux 1
heated for an hour. The solution was evaporated and the solid was crystallized from methanol (4.qot>, mp 28!1~
285℃.

(a) 4-C2-(6-(2-phenylethylamino)hexylamino)ethyl)-1,2-benzenediol dihydrobromide 48-Step in aqueous hydrobromic acid solution (70 m)) A solution of the shea,one product (4.75 t) was heated at reflux under nitrogen for 5 hours. The solid formed on cooling was filtered and crystallized from ethanol to give the title compound as the hydrobromide salt (51f), mp 22°7~
228℃.

Example 13 4-(2-(Jl-(2-(4-annophyl)ethyl7t-) to siluaζno)ethyl 3-1,2-benzenediol (a) y-(2-(3,4- I) Methoxy7 =
A/)ethyl)-N'-(2-(4-nitrophenyl)ethyl-hexane-L6'-1) aminodihydrochloride This compound was prepared according to the method of Example 12(b). Melting point 153-155°C.

(b) y-(2-(3,4-dimethoxyphenyl)
Formation of ethyl-2-(2-(4-aminophenyl) ethyl-hexane-1,6-diamine trihydrochloride step) 'dlc1f) solution in ethanol (5
0 m)/acetic acid (25 WIt) and hydrogenated over a palladium catalyst at 45 psi and room temperature. After hydrogen uptake ceased, the reaction mixture was warmed and the catalyst was removed briefly. Part F was evaporated to dryness and a solution of hydrogen chloride gas in methanol was added. The resulting solution was evaporated to dryness and the solid was etherified9.
Crushed ((L8t), melting point 250°C or higher.

(0) 4- (2-(6-(4-anno7el)
ethylamino)hexylamino)ethyl)-1,2-benzenediol trihydrobromide The trihydrobromide from the product of (b) processed by the method described in Example 12(0) above It was prepared as follows. Melting point 250
℃ or more.

Example 14 4-(2-(6-(2-(4-ripropheniV)ethylamino)hexylamino)ethyl)-1,2-isenzendiol 5l- (Ik) )f-(2-(3, 4-r)methoxyphenyl)ethyl)-11'-(2-(4-chlorophenyl)ethyl]-hexane-1,6-diatV Prepared using the method described in Example 12), mp 167-169°C.

N-C2-C5,4-dimethoxyphenyl)ethyl)-4'-[2-(4-chlorophenyl)ethyltohexane-1eb-1) Aone Prepared using the method described in Example 12(b), melting point 260℃ or higher.

(c), 4-C2-(6-(2-(4-chloro7
enyl)ethylamino)hexylamino)ethyl]-1
．． 2-Benzenediol dihydrobromide salt This compound was prepared as the dihydrobromide salt using the method described in Example 12(C). Melting point: 172-174°C.

Example 15 The method described in Example 12% 13 and 14 and 83- The following compounds were prepared in the same manner.

(a) 4-C2-(6-7ELA))hexylamino)ethyl) -1,2-(zendiol dihydrobromide, melting point 216-218''C0(kl) 4
- (2-(6-phenylethylamino)hexylamino)ethyl)-1,2-(nzenediol dihydrobromide, melting point 176-178°C.

(0) 4-[2-(6-(S-7dynylpropylat])hexylamino)ethyl]-1,z-benzenediol dihydrobromide, melting point 158-160°C.

4-(2-(6-(4-phenylbutyl))
)hexylazano)ethyl)-1,2-benzenediol dihydrobromide, melting point 19&5-199°C.

(e) 4-C2-(6-Aginohexylamino)ethyl)-1,2-benzenediol dihydrobromide (4-C2-C6-C-n-propylamino)
hexylamino)ethyl F) -112- is zenediol dihydrobromide, melting point 164-165°C.

ω-4-[2-(6-(M-Methyl(2-7ethylamino)hexylamino)-ethyl)-1,2-benzenediol dihydrobromide, melting point 167-169°C.

(b) 4-C2-C6-(2-phenyldicostpirua?
))hexylamino)ethyl) -1,2-benzeneliol dihydrobromide, melting point 1!15-137°C.

(1) 4-[2-(6-(2-(4-nitro-7enyl)ethylamino)hexyluate/ethyl2 1,2
-Benzenediol dihydrobromide, melting point 164°C (decomposed).

(J) 4-[2-(6-(2-(4-human diphenyl)ethylamino)hexylamino)ethyl)-
1,2-Benzeneliol dihydrobromide, melting point 260
℃ or more.

[Yes]) 4-(2-(6-(2-(4-methylphenyl)ethylamino)hexylamino)ethyl2 1,
2-benzenediol dihydrobromide, melting point 195°C (
Disassembly).

(1) 4-(2-(6-(2-(4-pyridinyl)ethylazano)hexylua())ethyl”]-1,
2-benzenediol trihydrobromide, melting point 197~
8℃.

6n) 4-(2-(6-(4-methylbi-!wodinyl)hexylamino)ethyl)-1,2-inzenediol) IJ hydrobromide, mp 197-8°C.

fFl) 4-(2-(x-methyl-6-(4-methylbiwodinyl)hexylamino)ethyl]-1,2
-Inzenediol trihydrobromide, melted at 187-190°C.

(o) 4-(2-(4-(2-yenylethylamino)butylano)ethyl) 2-penzenediol dihydrobromide, mp 251-255°C (decomposition).

ω) 4-C2-(6-(1,2,!5.4-tetohydro2-su7tylaζ)hexylamino)ethyl) -1,2-benzenediol dihydrobromide, melting point 224~ 226℃.

) 4-(2-(e-(2-phenylethylamino)octylamino)ethyl) -f, 2-benzenediol hydrobromide, mp 229-230'C.

←) 4-C2-C5-C2-7dynylethylamino)hantylamino)ethyl) -1,2-benzenediol dihydrobromide, melting point 187-189°C.

(s) s -(6-(2-(s,<-lihydroxy7el)ethylamino)hexyl]-1-phenyl-2,3,4,5-tetrahydro-1H-5- Benzazepine-7,8-5,'ol dihydrobromide, melting point 115°C (decomposed).

(t) 4-C2-(M-methyl-6-(M'-methyl-2-phenylethyl aZ))-1,2-benzenediolrihydrobromide,
Melting point: 186-188°C.

Example 16 4-[2-(6-(2-Hydroxy-2-722ethylanno)hexylua2no)ethyl-1,2-benzenediol Previous example 12 (
11) Nine summer-(2-hydroxy-2-phenylethyl)-N'-(2-("3
．． A solution of 4-bis(phenylmethoxy)phenyl)ethyl]hequinane-1,6-477t)'' (548t) was stirred under a nitrogen atmosphere while 1M tetrohydride in tetrafuran was dissolved.
A grain solution (30ml) was added and the solution was heated under reflux for 6 hours. Methanol (1
00m) was added and the mixture was evaporated to dryness. The residue is methanolic HOJ! (100 sd) and heated under reflux for 18 hours. The solution was evaporated to dryness and the residue was recrystallized from ethanol to give the title compound as the dihydrochloride salt. Colorless prismatic crystal (1,3
f), melting point 188-189°C.

Example 17 l74-C2-Cmethyl-6-(di-n-propyl72
)) hexydylaino)ethyl) -1,2-benzenediol (a) M-(2-(5,4-dimethoxyphenyl)
ethyl)-N-methyl-f,N/-di-n-propyl-
Hexane-1,6-diamide dry dimethylformamide (20 mg) Nakano 1-(2
-(3,4-dimethoxyphenyl)ethyl]-N, N'
-G-n-propyl- now no 1,6-diamide 09
The solution of t) was added to a suspension of oil-free sodium hydride (α24t) in dry dimethylformand (20m). ? , was heated at 70° C. for 1 hour. Methyl iodide (α75-) was added to the cooled suspension and the mixture was stirred at room temperature for 2 hours.

The mixture was evaporated to dryness, dissolved in ethyl acetate and the organic phase was washed with dilute hydrochloric acid, thorium carbonate solution and brine. The organic phase was dried over magnesium sulfate and
-filtration and evaporation to give a brown oil (5at).

M+406*0) M-C2-C5,4-dimethoxy7ethyl)-m-methyl-x: xl-gin
-P-tetrapyrrohexane-1,6-diamine dihydrochloride 89
- Prepared by the method described in Example 12) from the product of si point 130-132°C.

(6) 4-(2-(1#-methyl-6-(di-n
-Pro is Rua-ken]) Hekijirua-kenno) Ethyl]-1,2
- Benzenediol dihydrobromide prepared from the product of step (b) as dihydrobromide by the method described in Example 12(0), melting point 97-99°C.

Example 18 ±-4-[2-(4-hydroxy-6-(2-phenylethylaz])-hexylua2no]ethyl) -1,2
-benzenediol (a) N-(2-7ethylanno)-tetrahydro-5-oso2-7acetate2detetrahydro-5-5 in dry dichloromethane (75m)
-oxo-2-7-ethyl chloroformate (4,15F%57-) in a drop of acetic acid (&!M)90- and triethylamine (58t% S, 5xt) -10-
C. with stirring and the mixture was stirred for 45 minutes. 2-Phenylethylazun (46F) in dry dichloromethane (25m) was added and the reaction was kept at 20°C for 18 hours. Add bicarbonate to this solution) IJum water? After washing with Il, hydrochloric acid and water, drying (Mg804), evaporation and trituration with ether, the desired lactone amide (5F) was obtained as a pale cream colored solid. Melting point 8
3-85℃.

■) 3-Hydroxy-N'-[2-(3,4-rimethoxyphenyl)ethyl)-N-[2-7dynylethyl]
Lactonamide (145f) obtained in the hexane-1,6-diande step (,) and z-(s,4-ymethoxyphenyl)ethylabane (2,54F) were heated at 100°C for 1 hour under a nitrogen stream. Heated. The melt was cooled and recrystallized from ether to give the desired adhesive 11r), melting point 158-160°C.

(o) b-C2-Cs, a-dimethoxy 7-esterol)
Ethyl a
3-hexanol dihydrochloride from the previous step (in dry tetrahydroturane (150 mg))
The rear Z-do (54f) obtained in b) was heated under a nitrogen stream.
It was treated with Mborane-tetrahydro7rane (40*) and boiled under reflux for 4 hours. Cool this solution and
Methanol (25m) was added and the whole was evaporated to dryness. The residue was dissolved in methanol (50 mg) and saturated methanolic hydrogen chloride (50 sIt) at 9 and 20°C.
The mixture was stirred for 18 hours. The solvent was evaporated and the residue was triturated with ether to give the dihydrochloride salt (2,7f) as a white solid. This product decomposed at 240°C or higher without melting.

(d) 4-[2-C4-hydroxy-6-(2-
phenylethyl aZ〕)-hexyl annocoethyl)
-1,2-inzeniol dihydrobromide The dihydrochloride (2,2F) obtained in Step 1i(a) in dry dichloromethane (100-) was dissolved in triethylua (1
, 3-α94f) and stirred for 15 minutes under a nitrogen stream. The resulting suspension was cooled to -700, boron tribromide (2.2m, 5135F) was added and the mixture was allowed to warm to ambient temperature under stirring for 18 hours. Methanol (10 m) was added, the resulting solution was evaporated to dryness and the solid residue was recrystallized from 2-progol to give the title compound as the dihydrobromide salt (2,2f) as colorless needles.
obtained as. Melting point: 137-159°C.

Example 19 93-4-(2-[6-(2-(4-chlorophenyl)ethylamino] to silanoco-ethyl]-1,2-benzenediol dihydrochloride 4-(2-(6-(2- (4-Chloro-7enyl)-ethylaz-hexyl-ethyl-1,2-benzenediol dihydrobromide (50f) in a minimum amount of water K1
1 liter was dissolved and saturated sodium bicarbonate solution was added until the pH of the solution was approximately 8. The precipitated free base was washed with ice-cold water and then KJI suspended in concentrated hydrochloric acid and stirred with gentle warming until all the sticky material was dynamically replaced by a fine white solid. The suspension was cooled and filtered in ice and the precipitate was recrystallized from ethanol to give the title dihydrochloride salt (2,Of) as white crystals. Melting point: 186-188°C.

Elemental analysis value (as dihydrochloride) 94- Actual value 022502- Theoretical value oJ! 22.9311 Example 20 4-(2-(6-(2-7EELETHILA-KEN))HEXYLAZNO]ETHYL) -1,2--: Nzenediol dihydrochloride This compound is dihydrobromide in phase 1. Prepared from the salt by the method described in Example 19. Melting point 219-219, 5°C.

Example 21 1.2,3.4-tetrahydro-2"(6-(2-7dynylethyl)aminohexyl)71/-5,6-su7talendiol(&) 6-oxo-6-( 2-Phenylethylamino)hexanoic acid adipic acid monomethyl ester (241,0,15 mol) was dissolved in dry dichloromethane (SOOV) and cooled in ice water, and triethylamine (22,5 ms α
16 mole R/) was added followed by a solution of ethyl chloroformate (14,S-1115 mole) in dichloromethane (50 m) over 0 min, resulting in a S cloud! Stir for 10 min and dichloromethane:y (50 m) 77) 2-
A solution of phenylethylamino (1a8-1a16 moles) was added over 50 minutes and the resulting mixture was stirred at room temperature for 2 hours. This reaction mixture was mixed with a 2M aqueous hydrochloric acid solution (2x2oo
Wt).

Washing with aqueous 10-sodium carbonate solution (200 m) and water and evaporation under vacuum gave the crude andester. This solid was heated to reflux with a solution of potassium hydroxide (9,52F% 0.17 mol) in water (Room) for 1 hour. The cooled solution was washed with ether (200 sj), acidified and the solid was filtered. Miyakojima and drying under vacuum gave the desired And II (2il), melting point 1.
13-114°C.

This crude acid was purified by recrystallization from ethyl acetate. Melting point 114-116°C.

(t)) N-(1,213,4-tetrahydro-
5,6-Simethoxy2-su7tyl]-Iris J-(2-7
ale ethyl]hexane-1,6-dia-6-ox/-6-(2-7
(22-ethylamino) to -? ? A solution of carbonic acid (2A9t) and carbonyl 2dazole (1,60) was stirred at room temperature for 2 hours under a nitrogen stream. Dichloromethane (2Q
A solution of 1.2.3.4-tetrahydro-5,6-simethoxy 2-aminonaphthalene (2,07F) in sg) was added and the solution was stirred at room temperature for 18 hours. This solution was washed with dilute hydrochloric acid, dilute sodium carbonate solution and water. The organic phase was separated, dried over magnesium sulfate and
Filtration and evaporation gave the title compound, which was crystallized from isopropanol to give colorless -9 to 7 lake crystals (58F). Melting point 191-193
℃.

(0) Summer-C1?2tL4-tetotsuhid, CI-
5,6-Simethoxy2-naratyl)-M'-[2-7
[22-ethyl]hexane-1,6-diamine dihydrochloride borane-nat 2 in dry tetraEdofufun (200 m)
A molten solution of the hydrofuran complex (32m) and the product (45F) of the process negative was heated under reflux for 24 hours under nitrogen flow.

The solution was cooled, methanol (H)OWlt) was added and the ** was evaporated to dryness. Methanolic HOX
A solution of the residue dissolved in the solution was heated under reflux for 5 hours. The solution was evaporated to obtain a solid, which was crystallized from methanol to obtain colorless prismatic crystals (2,3f). Melting point: 265°C.

@) 1,2,3.4-tetrahydro-2-(6
-(2-phenylethyl)aminohexyl]-Adenno9
8- -5,6-su7thalene diol dihydrobromide 1 in hydrobromic acid aqueous solution (20 m)! Product of (0) (2F)
The title compound was obtained by heating to reflux for 4 hours under a gentle stream of nitrogen, evaporating the solution to dryness, and crystallizing the residue from ethanol to give the title compound as the dihydrobromide salt (2, or). Melting point 240-242
℃.

Example 22 1.2,3.4-tetrahydro-2-C6-C2-<
3.4-vhydroxyphenyl)-ethyl)aminohexyl]ino-5,6-su7talediol (P) N-(112艷14-tetrahy+70-5.
6-rimethoxy2-su7tyl)-a'-z-(3,4
-dimethoxy7-el) Ethylhexane-1,6-diamide Example 21 manufactured by the method described in 1), melting point 172-174
℃.

Cb) M-(1#2eSe4-tetohidt!-
5,6-Simethoxy2-naphthyl)-N'-, (2-
(3,4-')toxytzenyl)ethyl]hex? - 1.6-Diane dihydrochloride step-) polish preparation by the method described in Example 21 (1)), melting point 260°C.

(o) 1,2,3.4-tetrahydro 2-[6-
(2-(3,4-','hydroxy77ethyl)ethyl)
Aminohexylconono-5,6-su7talendiol dihydrobromide This compound was prepared from the product of step (b) as the dihydrobromide salt by the method described in Example 21(0). Manufactured. Melting point: 270°C.

Example 25 The following compound was prepared similarly to the method described in Example 21 above.

(a) 1.2.3.4-tetrahydro-2-(6-
(2-<3.4-dihydrodiphenyl)ethyl)
Aminohexylcoamino-6,7-sutatalendiol dihydrobromide, melting point 258-260°C.

1.2.3.4-tetrahydro-2-(6-(
2-phenylethyl)annohexyl]annoh 6.7
-su7thalediol dihydrobromide, melting point 266-2
68℃.

(Q) 1121314-Tetra upper draw 2-(4-
(2-phenylethyl)aminobutyl] 5.6
-su7thalediol dihydrobromide, melting point 250°C or higher.

(d) C2,3,4-tetrahydro-2-(8-(
5.6
-Naphthalenethiol dihydrobromide, melting point 248-2
52℃.

(・) 1.2,3.4-tetrahydro-2-(8-
(2101--X(C4-vhydroxyphenyl)ethyl)aminooctylcoamino-5,6-su7talendiol dihydrobromide, melting point 260°C.

(') 1t 2 t s , 4-tetrahydro-2
-(6-(2-phenylethyl)amino)hexylua-5-naphthalenol rihydrobromide, melting point 280°C
(Disassembly).

Example 24 M,N'-bis-(1s 2 t S $ 4-tetrahydro-5,6-simethoxy-2-naphthyl)hexane-1,6-diamine dihydrochloride 1-21 s t in acetonitrile (IQOsg)
4-Tetrahydro-5,6-simethoxy-2-su7talenamine hydrochloride (4,87f) was dissolved in acetonitrile (10
To a stirred suspension of potassium carbonate (3,Of) in a refluxing solution of 1,6-dibromohexane (2,44t) in 0m) was gradually added over 1 hour 9lOg- after the addition was complete. Refluxing was continued for 24 hours, the solution was filtered to remove inorganic salts, and the liquid was evaporated under vacuum to give an oil. Chloroform/methanol on silica (95:
5) and chromatographed with ethereal HOj, the title compound *(1,15F
) (20chi) was obtained. Melting point 275°C (decomposition).

Example 25 4-[2-(6-(z-phenylethylami])hexylamino)ethyl)-1,2-inzenediol-bis-(2-methylpropionate) dihydrochloride trifluoroacetic acid II ( 100m) 14'l)4- [
Isobutyrylprolide (12F) in a stirring droplet of 2-(6-(2-phenylethylamino)hexylamino)ethyl)-1,2-benzenediol dihydrobromide (4t) This solution was then heated at room temperature for 24 hours.
Stir for hours. Excess solvent was evaporated and the residue was treated with an aqueous solution of 7% bicarbonate. The basic mixture was thoroughly extracted with chloroform. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to give a colorless oil, which was labeled as ethereal HOjl #! & Understand
A white precipitate was obtained. This white precipitate was recrystallized from ethanol to obtain the title compound as colorless prism crystals (2.8f
) was obtained. Melting point 232-234°C.

Example 26 The following compound was prepared by a method similar to that described in Example 25.

(IL) 4-(2-(6-(2-7ethylethylamino)hexylamino)ethyl)-1,2-benzenediol-bis-benzoate dihydrochloride.

Melting point: 230°C (decomposed).

(b) 4-[2-(6-(2-phenylethylanno)hexylamino)ethyl]-1,2-penzenediol-pisua tate dihydrobromide, melting point 229
~230℃.

Example 27 Bis(phenylmethoxy) M -(2-(3,4-dihydroxyphenyl)ethyl)N'-C2-phenylethyl)-bb-hequinanediylbiscarpamate 10 in borax aqueous solution (41 of 40) 4-(2-(6)
-(z-722Vethyl aden])hexyl a2no)ethyl) A suspension of -1,2-benzeneliol (4,2F) was adjusted to pH 9 using a 2M aqueous sodium hydroxide solution. This lIi spring solution was stirred for 4 hours. Benzyl chloroformate (2.2 sd) was added and the mixture was stirred at room temperature for 2.5 hours.

105- The suspension was made acidic and the aqueous phase was extracted with ether. Separate the organic phase and add sulfur sI! ! dried with gneshikum,
-filtration and evaporation to give an oil. This oil was chromatographed on silica eluting with ditetramethane/5-0RIOI and purified by filtration.
The title compound was obtained as a pale yellow oil (2,Of).

klBw'・624゜Example Pharmaceutical preparation Intravenous preparation t Compound of Example 12 1w/sodium bisulfite 1-w/sodium sodium chloride α10611W/water
Total amount 100% and amount 2 Compound of Example 12 11w/
v Sodium metabisulfite (11%v/v
Sodium edetate (@edium metate)
αo1*v/v sodium chloride
Isotonic Amount Required 106 - Water Total Amount 10
0 - Quantity 5 Compound of Example 12
1 inch W/sodium hydrogen phosphate α94
%W/sodium maphosphate 124*
W/sodium chloride α295*W
/Masui Total amount 100 - Patent applicant Fiennes BLC - 1O'F - Continued from page 1 Priority claim @ October 9, 1981 ■ United Kingdom (GB
)■8130594 ■October 9, 1981■Britain (G'B)■8130595 @November 17, 1981■Aegis (GB)■81
34551 @R Author Francis Ince 200 Vary Road, Lokbarrow, Starshire, United Kingdom Inventor Rodney Alan Brown 260 Barton Walk, Lokbarrow East Leake, Starshire, United Kingdom Inventor John Dixon United Kingdom 5 Doppardan Avenue, Pelton, Starshire

Claims (1)

[Claims] 1) Compounds having formula I and seven pharmaceutically acceptable derivatives [
Here, in the above formula, Dl is a group of the formula ■Rp R9, and R1 and R5 are groups of R3 and R5 that can form a chain -〇H20H2-, or t or R4 and Ri can form a chain - R5% R4 and R5 are each hydrogen and s R1, RS and R4
The remainder is hydrogen, alkyl or phenyl, and 01 or 2 of R6, R7, Rfj and Rp is hydroxyl (- and the remainder is hydrogen, and X is optionally hydrogen, alkyl or phenyl). represents a chain -(OH2)n- optionally substituted by Pyridyl is substituted by phenyl and is 9 alkyl, or 9 is substituted by halogen, alkyl, anno, alkoxy or nitro, pyridyl is substituted by phenyl and is 9 alkyl, or D2 is a group of 2, where R2 and R12t or RIO and R12
and form the chain -CH2-CH2-L 5 Luke, jft
, nR, t1 and R12 may form a chain -CR2-, or Rho, R11 and R[ are each hydrogen, Ri. The remainder of R10 and R11 are the same or different and are hydrogen,
Alkyl is phenyl, R1, R14, R15
and 0.1 or 2 of R14 represents hydroxy and the remainder represents hydrogen, or R1 and D2 together with the nitrogen atom to which they are bonded represent a 5-membered or 9 represents a 6-membered O heterocycle. The formula ring is also O, which is 9! is not substituted by hydroxy and 1) Ri
, Ra and Ri are hydrogen, R1 and R2 are both hydrogen, lower alkyl and R4%, two of R7, l- and R9 are hydroxy, DI is Dl If R1, R8, R4, G, R4, R7, Ri and R1 are hydrogen, R2 and D2 each do not represent lower alkyl or they are bonded does not form a 6-membered heterocyclic ring together with the nitrogen atom, and 9 is iM) R<, R4, R1
, R4, R, R, and R9 are hydrogen and IL
If l is alkyl, D2 is not the same as Dl, or IV) If R- is 7el, then R1 and Ft
5 together form the chain -og2oa2-, R4,
R7, R. and R9 are hydrogen, n is 1,
D2 and R2 each represent hydrogen and do not represent alkyl or together form a heterocyclic ring]. 2) Said claim 1 of rounding for use as a medicine
Compounds described in Section. 3) 1 or 2 adjacent pairs of R4, R7, Ri and R1, and R11% R14, R15 and "1"
Claims 1 and 9 are the compounds according to claim 2, wherein each of the adjacent '9' pairs of 4 is human w4. 4) The compound according to any one of the preceding claims, wherein R7 is hydroxy. 5) The compound according to any one of the claims, wherein n is 5 to 5. , 6) 4-(2-(6-(2-phenylnibruamino)hexylamino)ethyl]-1,2-benzenediol, or a pharmaceutically acceptable acid addition salt thereof. Compound according to item 1. 7) (28°)-2,2'-(1,6-hexanediylbisaminoco-bis-(1,2,5,4-tetrahydro-5,6-naphthalene/diol) , (R(RiR”)) f+−) −7,7′ −(1,
6-hexyldiylbis(aminomethylene)]bis(bicyclo(4,2,0)-octa-1,3,5-)-2.35-diol), 4-42-(6-(2- (4-chloro7enyl)ethylamino)'hexyl-enyl)ethyl) -1,2-benzendiol. 1.2,5.4-tetrahydro-2-(6-(2-(3
, 4-9hydroxyphenyl)-ethyl)aminohexylamino-5.6-su7 sauce/diol, and is a pharmaceutically acceptable acid addition salt of any of these compounds. A compound according to item 1. 8) (R-(RiR”))-2t2'-(1,6-
hexanediylpisaz)]-]bisu 1,2,3.
4-tetrahydro-5,6-su7 sauce/diol], (
g-(i?i°))-2,2-(1,6-henandiylbisaz))-bis-(1,2,3,4-tetra-0-5,6-naphthalenediol), 6-2.2'-(1,6-hexanediylbis7mino)
-bis-(1,2,3,4-tetokuhydo0-5,6-naphthalenediol), 2,2'-(1,6-hexanediylbis-aino)
-bis-(1,2,3,4-tetrahydro-6,7-naphthalenediol), (8-(R?R”)) -7,7' -(1,6-hexanediylbis(aminomethylene) ]-bis(bicyclo(4,2,0)-octa-1,3,5-)diene-2,
3-diol, (n7a”)-7,7′-(1,6-hexanediylbis(aminomethylene)-bis(bicyclo(4,2,0
)-octa1.3.5-)diene-2,3-diol], 7-(6-(2-pheletheraζ))hexyluaξno]methylbisica (4,2,0) -octa-1
,3,5-)lie/-2,3-diol,enyl)-ethylamino]hexylaminocomethylbicyclo(4,2
,0)-octa-1,6,5-triair2. S-diol, 7-(6-(2-7 ethyl atom))hexylaminocomethylbicyclo(4,2yO)-octa-1,3
,5-trie/-5,4-diol, (17'-(1,
6-hexanediylbis(aminomethylene)]-bisubicyctetra(4,2,0)-octa-1,3,5-)diene-6,4-diol). 7-(6-(2-(5,4-dihydrodiphenyl)ethylamino]hexydylaino]methylbisic' (41
210)-octa-1,3,S-)rien-3,4-
Diol, 4-(2-(6-(2-(4-aminophenyl)ethylamino)hexylamino)ethyl) -1,2-benzenediol, 4-(2-(6-phenylamino)hexylamino)ethyl) -1,2-benzenediol, 4-[2-(6-phenylmethylaino)hexylamino) ether) -1,2-benzenediol, 4-(2-(6-(3-phenylpropylamino)hexylamino) ) Ethyl, l -1,2-benzenediol, 4-(2-(6-(4-phenylbutylamino)hexylamino)ethyl) -1,2-benzenediol, 4-(2-(6-AZ (hexylamino)ethyl)
-1,2-benzenediol, 4-(2-(6-(di-
n-propyla[])hexylamino)ethyl)-1,
2-benzenediol, 9-4-(2-(6-(M-methyl(2-7aleetherphino)hexylamino)-ethyl)-1,2-be/ze/diol, 4-(2- (6-(2-phenylpropylamino)hexylamino)ethyl) -1,2-benzenediol, 4-(2-(6-(2-(4-nitrophenyl)ethylamino)hexylamino)ethyl) -1 ,2-benzenediol, 4-(2-(6-(2-(4-hydroxyphenyl)ethylamino)hexylamino)ethyl)-1,2-benzenediol, 4-(2-(6-<2 -(4-methyl7enyl)ethylamino)hexylamino)ethyl)
-1,2-benzenediol, 4-(2-(6-(2-(4-pyridinyl)ethylamino)hexylamino)ethyl]-10- 1,2-benzenediol, 4-(2-(6 -(4-Methyl-6-(4-methylbi-2-diel)hexyl-aino)ethyl) -1,2-benzenediol, 4-(2=(ml-methyl-6-(4-methylbi-2-diel)-silamino)ethyl-1,2-benzene diol, 4-(2-(4-(2-phenylethylamino)butylamino)ethyl)-1,2-benzenediol, 4-(2-(6-(1,2,3,4-tetrahythro2- naphthylamino)hexylamino)ethyl)-1,
2-benzenediol, 4-(2-(8-(2-phenyletheramino)octylamino)ethyl) -1,2
-benzenediol, 4-(2-(5-(2-722ethyl-])octylamino)ether) -1,2-benzenediol, 5-(6-(2-(3,4-dihydroxyphenyl) )
ethylamino)hexyl2-1-fe=k-2,3,
4,5-tetrahytoa-1n-s-benzazebini/-
7,8-diol, 4-(2-(M-methyl-6-()
F'-MethylA/-2-722ethyl-hexyl7i-ethyl)-1,2-benzenediol, 4-(
2-(6-(2-hydroxy-2-phenylethyl az)
])Hexylamino)ethyl-1,2-benzenediol .
,2-benzenediol, 1.2,3.4-tetrahydrol-2-(6-(2-phenylethyl)aminohexyl)71-5,6-su7talediol, 1.2, 3.4-tetrahuman Q~2-(,6-(2-(
3,4-dihydroxyphenyl)ethyl)ainohexyl]atno-6,7-7talediol, 1,2,5,4-tetrahythro-2-(6-(2-72÷lethyl)aminohexyl aino- 6,7-su7tale diol, 1.2,5.4-tetrahydro-2-(4-(2-phenylethyl)inobutylcoaino-5,6-su7tale/diol. 1.2, 5.4-tetrahydro-2-(8-(2-phenylethyl)ainooctele)amino-5,6-naphthalene/diol, -1 to 5- 1.2,3.4-tetrahydro90-2-[8-( 2-(
3,4-dihydroxyphenyl)ethyl)azunooctyl]atno5,6-naphthalenediol, 1.2,5.4-tetrahydrolff-2-C6-(2-
2. A compound according to claim 1 which is a pharmaceutically acceptable acid addition salt of phenylethyl)amino]hexylua2no-5-naphthalenol or any of the compounds thereof. 9) A pharmaceutical composition comprising a compound according to any of the preceding claims in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier. fO) In preparing the compound of formula 1 or a pharmaceutically acceptable derivative thereof as described in paragraph 111g1 of the said patent claim, the following, namely 14-a) Hf1i or 0 with the condition that at least one of the moths represents 0,
R11L and R2a have the same meanings as R1 and R2 above, except that they may further represent a protecting group, and Dl
a is the formula V! 4a R? ! represents a group of L, where RHa, R4&, R5a, R4
a. RI&%R@L and Rya are R4a%R7a, RI
R5, R respectively, except that one or two of IL and Rya may represent further protected hydroxy groups.
4, has the same meaning as R5, R4, R7, R1 and R9, and has the same meaning as X above, except that xl may have an additionally protected hydroxy group; I) 2a is hydrogen; or alkyl, 7-ethyl, alkyl substituted with one or more w-d-4xy, protected 9-hydroxy, pyridyl, 7-ethyl, or hacumene, alkyl, amino , Al; is substituted with cy or nido WIK and is substituted with nine esters and is nine alkyl, or J& represents a group of the formula
21L%R1Ba, R14"s R11' and R14
1L is 31311% R14&, RH, & and one wing 14&.
11% to the above average O% except for those representing xy groups.
selectively reducing the compound of formula (b) Formula ■ L10H2-barOH@Ll ■ (I1 in the formula
1 and L! are the same and 9 are different and represent leaving groups, x
IL is as defined above) is a compound of the formula (wherein D1b represents a group of the formula ■ R6b R9b , where R4t), Rgt), R4b
, RI. -1 two R4b%R7b, R@'b sP! BiR? b is R1
'b may represent a removable group which can further increase the nucleophilicity of the nitrogen, and R4V%R7t), Rgt3 and R91)01 or 9 represent two protected human-oxy groups. Others are R1, town, R4, R5, respectively.
4)t) having the same meaning as R4, R1, RI and R1;
When compound i9 is reacted with its acid addition salt, it is obtained from formula I
(where D! is equal to Dl and R1 is equal to R1) and then! II-* or, if desired, any such protection a19 is removed by removing the removable group to form a compound of formula I, (CI) Formula X and Xo are further! One 18- or both of Ja and R26 may represent a protecting group, R4a. R7as R6o and R9 (I O 1 M9 may represent 2 protected hydroxy groups. The above R1, R2, R4 respectively except that Xc may be protected and have 9 human WΦ groups) , R5, R6, R7
, having the same meaning as R8, R1 and I) from the formula! (wherein D2 is equal to Dl and both 3g groups are hydrogen) and then remove any such protecting groups if desired to form the corresponding compounds of formula 10. or (d) removing the protecting groups from the corresponding compound of formula 1 having one or more protected 9-hydroxy groups or protected 9-2 groups and obtaining, if desired or necessary. Formula!, characterized in that it converts a compound of Formula I into a pharmaceutically acceptable derivative thereof! or a pharmaceutically acceptable derivative thereof.