JPH0310614B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel compounds, processes for their preparation, and compositions containing them. According to the invention, the formula and pharmaceutically acceptable acid addition salts thereof. Here, in the above formula, D ₁ is the formula where R ₁ and R ₅ or R ₃ and R ₅ are the chain −
CH ₂ CH ₂ − may be formed, or R ₄ and R ₅ may form a chain −CH ₂ −, or R ₃ , R ₄ and
R ₅ is each hydrogen, the remainder of R ₁ , R ₃ and R ₄ are the same or different and are hydrogen, alkyl or phenyl, two of R ₆ , R ₇ , R ₈ and R ₉ represent hydroxy; the remainder is hydrogen, X represents a chain -( _CH2 ) _o- optionally substituted by hydroxy, n is an integer from 1 to 7, and _D2 is hydrogen or Is it?
phenyl, alkyl substituted by one or more hydroxy, pyridyl, phenyl, or alkyl substituted by phenyl substituted by halogen, alkyl, amino, alkoxy or nitro; Is there?
or or D ₂ is the formula where R ₂ and R ₁₂ or R ₁₀ and R ₁₂ are the chain −
CH ₂ -CH ₂ - or R ₁₁ and R ₁₂ may form a chain -CH ₂ - or R ₁₀ , R ₁₁ and R ₁₂ are each hydrogen and R ₂ , R ₁₀ and R ₁₁
are the same or different and are hydrogen, alkyl or phenyl, 0, 1 or 2 of R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ represent hydroxy and the remainder represent hydrogen, or R ₂ and D ₂ 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 and R ₃ , R ₄ and R If ₅ is hydrogen, R ₁ and
R ₂ are both hydrogen or lower alkyl, and two of R ₆ , R ₇ , R ₈ and R ₉ are hydroxy, and D ₂ is not the same as D ₁ . The present invention also provides compounds of formula, and pharmaceutically acceptable derivatives thereof, as pharmaceuticals. According to the present invention, there is also provided a process for making a compound of the formula or a pharmaceutically acceptable acid addition salt thereof. In other words, (a) Eq. (In the formula, T ₁ and T ₂ are H ₂ or O with the condition that at least one of T ₁ and T ₂ represents O,
R ₁ a and R ₂ a have the same meanings as R ₁ and R ₂ above, except that they may additionally represent a protecting group, and D ₁ a has the formula represents a group of R ₃ a, R ₄ a, R ₅ a, R ₆ a, R ₇ a,
R ₈ a and R ₉ a are R ₃ and R 4 respectively, except that one or two of R ₆ a, R ₇ a, R ₈ a and R ₉ a may additionally represent a protected hydroxy _group . , R ₅ ,
R ₆ , R ₇ , R ₈ and R ₉ have the same meaning, X _a has the same meaning as X above except that it may additionally have a protected hydroxy group, and D ₂ a hydrogen, alkyl, phenyl, alkyl substituted by one or more hydroxy, protected hydroxy, pyridyl, phenyl, or halogen, alkyl, amino, alkoxy or alkyl substituted by phenyl substituted with nitro, or D ₂ a is of the formula represents a group of R ₁₀ a, R ₁₁ a, R ₁₂ a, R ₁₃ a,
R ₁₄ a, R ₁₅ a and R ₁₆ a are each of the above R 14 a, R 15 a and R ₁₆ a, except that one or more of R ₁₃ a, R ₁₄ a, R ₁₅ a and R 16 a may additionally represent a protected hydroxy group. ₁₀ , _R11 , _R12 , _R13 , _R14 , _R15 and _R16
(b) having the same meaning as L ₁ CH ₂ -X _a -CH ₂ L ₂ (in the formula, L ₁ and L ₂ are the same or different and represent a leaving group, and X _a is as defined above)
The compound with the formula (In the formula, D ₁ b is the formula represents a group of R ₁ b, R ₃ b, R ₄ b, R ₅ b,
R ₆ b, R ₇ b, R ₈ b and R ₉ b may represent a removable group to which R ₁ b can further increase the nucleophilicity of the nitrogen, and R ₆ b, R ₇ b, The above R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , respectively, except that one or two of R ₈ b and R ₉ b may represent a protected hydroxy group,
_{and then _ _ _ _ _} (c) by removing any such protecting or removable groups if necessary or desired to give a compound of the corresponding formula; (In the formula, R ₁ c, R ₂ c, R ₄ c, R ₅ c, R ₆ c, R ₇ c, R ₈ c,
R ₉ c and X _c may further represent one or both of R ₁ c and R ₂ c representing a protecting group;
one or two of R ₆ c, R ₇ c, R ₈ c and R ₉ c may represent a protected hydroxy group, and
The above R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , respectively, except that X _c may have a protected hydroxy group;
R ₈ , R ₉ and X have the same meanings) by selectively reducing the compound of the formula (wherein D ₂ is
D ₁ and both R ₃ groups are hydrogen) and then remove any such protecting groups if necessary or desired to give a compound of the corresponding formula; ) removing the protecting groups from a compound of the corresponding formula having one or more protected hydroxy groups or protected amine groups and, if desired or necessary, converting the resulting compound of the formula into a pharmaceutical into a sexually acceptable derivative thereof, or vice versa. In process (a), the reducing agent may be electrophilic, such as diborane, or nucleophilic, such as a complex metal hydride, such as lithium, aluminum hydride or sodium (2-methoxyethoxy)aluminum hydride. The solvent is preferably inert to the reaction conditions. Aprotic solvents such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane are preferred. The reaction may be carried out at about 0°C to 100°C. When R ₁ a and/or R ₂ a represent a protecting group,
The protecting group may be a hydrogenolyzable protecting group such as a 1-phenylalkyl derivative such as benzyl. Protecting groups may be removed, for example, by reduction using hydrogen and a suitable hydrogenation catalyst (eg palladium on charcoal). one or two of R ₆ a, R ₇ a, R ₈ a and R ₉ a represent a protected hydroxy group and/or
When D ₂ a has a protected hydroxy group, the protected hydroxy group can be, for example, alkoxy, phenylalkoxy (eg phenylmethoxy) or alkanoyloxy (eg acetoxy). Removal of the hydroxy protecting group depends on the nature of the protecting group, but conventional techniques can generally be used, including acidic and basic cleavage, and hydrogenolysis. For example, protected alkyl or phenylalkyl groups can be isolated by cleavage with a protic acid such as hydrochloric acid or hydrobromic acid at 0-150°C or with a Lewis acid such as boron trihalide in a chlorinated hydrocarbon solvent. It can be removed by reaction. When the protecting group is alkanoyl, 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 alkyl or phenylalkyl groups. 1-Phenylalkyl groups such as benzyl may be removed by catalytic hydrogenation in a suitable solvent such as ethanol or acetic acid using a suitable catalyst such as palladium, preferably under pressure. In process (b) L ₁ and L ₂ can be anion-forming groups such as halogen (eg chlorine or bromine) or p-toluenesulfonal. The reaction is preferably carried out in a suitable solvent in the presence of a base. Solvents can also act as bases.
Suitable solvents are, for example, pyridine (no addition of a salting base is necessary), or ethanol or dimethylformamide (in which case a base such as pyridine,
Preferably, triethylamine or sodium hydroxide is used). The reaction takes place at approximately 0℃~
Can be carried out at 100°C. When R ₁ b represents a removable group capable of increasing the nucleophilicity of the nitrogen, R ₁ b can be, for example, p-toluenesulfonyl or trihaloacetyl (eg trichloroacetyl or trifluoroacetyl). Removal of the protecting group in method (b) may be carried out analogously to that described for method (a). Reduction and removal of protecting groups in method (c) are methods
This can be done in the same way as described under (a). Removal of the protecting group in method (d) may be carried out analogously to that described for method (a) under acidic, basic or hydrogenolytic conditions. When D ₂ in the formula represents an alkyl group substituted by an amino-substituted phenyl, the amino group is protected by a suitably positioned nitro-protecting group, for example in a suitable solvent (e.g. ethanol), preferably under elevated pressure. It may be obtained, for example, by catalytic hydrogenative reduction using hydrogen and palladium, or by chemical reduction using, for example, tin and a suitable acid such as hydrochloric acid at about 0°C to 100°C. If D ₁ a is equal to D ₂ a and R ₁ a is equal to R ₂ a and both T ₁ and T ₂ are O, then
_A compound of formula _{XI Z 1} CO−X _a −COZ ₂ Formula XII (wherein D ₁ a and R ₁ a are as defined above). Groups Z ₁ and Z ₂ that leave well include, for example, halogen (e.g. chlorine, bromine), 1-imidazolyl,
Included are trifluoromethanesulfonate, alkyl carbonates (eg, ethyl or benzyl carbonate), or alkanoyloxy (eg, trifluoroacetoxy). The reaction may be carried out in a solvent inert to the reaction conditions, such as a chlorinated hydrocarbon such as chloroform, in the presence of a non-nucleophilic base such as triethylamine. The reaction may be carried out at about 0°C to 100°C. Free acids corresponding to formula XI (i.e. Z ₁ and Z ₂
are both equal to hydroxy) for example thionyl chloride, ethyl chloroformate or N,
Reacts with N′-carbonyldiimidazole
COOH group can be converted to -COZ ₁ group. If D ₂ a is equal to or not equal to D ₁ a and/or R ₁ a is equal to or not equal to R ₂ a, then the compound of formula Z ₁ CT ₁ −X _a −CT ₂ Z ₂ (wherein T ₁ , T ₂ , X _a , Z ₁ and Z ₂ are as defined above), the groups Z ₁ and Z ₂ in the molecule of formula XII and/or (wherein D ₂ a and R ₂ a are as defined above) followed by, if appropriate, the resulting compound with a compound of formula XII or. A compound with the formula (wherein R ₁ c, R ₂ c and X _c are as defined above) (In the formula Z ₁ , R ₄ c, R ₅ c, R ₆ c, R ₇ c, R ₈ c and
R ₉ c is as defined above). The reaction may be carried out under the same conditions as for the reaction of the compound of formula XI with the compound of formula XII above. A free acid corresponding to formula XI can be reacted with the same reagents and in the same manner as a free acid corresponding to formula XI to form the required starting material. Compounds of formula, formula XI, XII, ,
The free acids corresponding to and the free acids corresponding to the formula are known or 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 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 or derivatives thereof. It is also within the scope of this invention to treat any derivatives thus formed to liberate the free compound of formula or to convert one derivative into another. Compounds of formula and intermediates can therefore be isolated from their reaction mixtures using conventional techniques. Pharmaceutically acceptable derivatives of compounds of formula include pharmaceutically acceptable acid addition salts. Suitable salts include salts of mineral acids such as hydrohalic acids (eg hydrochloric acid or hydrobromic acid), or organic acids such as formic or lactic acid. Acids are polybasic acids,
For example, it can be sulfuric acid, fumaric acid or citric acid. Other pharmaceutically acceptable derivatives are suitable bioprecursors (prodrugs) of compounds of formula and are readily apparent to those skilled in the art and can be obtained from compounds of formula using conventional methods known per se or analogous to those described above. It is a compound that can be prepared by the method of Suitable bioprecursors include amides of compounds of formula and, when the compound of formula has a hydroxy group, esters such as carboxylic acid esters such as alkanoyls such as acetyl or isobutyl or aroyl esters such as benzoyl. When R ₁ , R ₂ , R ₄ and R ₁₁ 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 R ₁ and R ₂ is hydrogen or C ₁ -C ₆ alkyl, such as methyl or n-propyl, or R ₁ and R ₅ or R ₂ and R ₁₂ each represent a group A ₁ or A ₂ (In the formula, R ₃ , R ₄ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ ,
R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ are as defined above). As another particular group, one or both of R ₃ and R ₁₀ is hydrogen, or R ₃ and R ₅ ,
or R ₁₀ and R ₁₂ are groups B ₁ or B ₂ respectively

【formula】

[Formula] (In the formula, R ₄ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₁ , R ₁₃ , R ₁₄ ,
R ₁₅ and R ₁₆ are as defined above. Yet another specific group is R ₄ and
one or both of R ₁₁ is hydrogen, hydroxy or phenyl, or R ₄ and R ₅ or R ₁₁ and
R ₁₂ is a group C ₁ or C ₂ respectively

【formula】

[Formula] (In the formula, R ₃ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₃ , R ₁₄ ,
R ₁₅ and R ₁₆ are as defined above. Yet another group, R ₃ , R ₄ and R ₅
or all of R ₁₀ , R ₁₁ and R ₁₂ are hydrogen, and the groups E ₁ and E ₂ respectively Provided are compounds of the formula forming a moiety in which R ₆ , R ₇ , R ₈ , R ₉ , R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ are as defined above. at least one of R ₆ , R ₇ , R ₈ and R ₉ ;
And preferably two of them are hydroxy. At least one of R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆
It is preferred that 1, and preferably 2 are hydroxy. Adjacent pairs of R ₆ , R ₇ , R ₈ and R ₉ and/
Or preferably both adjacent pairs of R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ are hydroxy. Particularly preferred are compounds in which R ₇ is hydroxy. It is preferred that n is 2-6, preferably 3-5 and especially 4. When D ₂ represents alkyl or optionally substituted alkyl, the alkyl moiety may contain up to 8 and preferably up to 4 carbon atoms. When D ₂ is alkyl substituted by optionally substituted phenyl, the optionally substituted phenyl moiety is 6
May contain ~10 carbon atoms. When R ₂ and D ₂ together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring, the ring may be pyrrolidino, piperidino, morpholino or especially piperazino. When the ring is piperazino, the nitrogen in position 4 may be substituted by _C1 - _C6 alkyl, such as methyl. A ₁ and E ₂ , B ₁ and B ₂ , B ₁ and E ₂ , C ₁ and C ₅ , C ₁ and E ₂ ,
Particularly preferred are compounds of the formula containing the pair of groups E ₁ and E ₂ , where A ₁ , A ₂ , B ₁ , B ₂ ,
C ₁ , C ₂ , E ₁ and E ₂ are as defined above. Particularly preferred compounds of the formula are Examples 1, 5, 12, 14
and 22 compounds and pharmaceutically acceptable acid addition salts thereof. Certain compounds of the formula can exist in optically active and meso forms. The present invention also provides optical and meso isomers of compounds of these formulas, and mixtures thereof, including racemic mixtures thereof. These compounds can be resolved into their optical isomers by conventional methods. When a carbon atom with R ₃ , R ₄ , R ₁₀ or R ₁₁ is in a polarized state, the configuration of the carbon atom can be R or S. When the two carbon atoms are under polarization, the compound of formula can be RR, RS or SS with respect to these two centers, with the proviso that
If is not polarized, D ₂ equals D ₁ and R ₂ equals R ₁ , then the compound of formula may have the RR, SS or meso configuration. Compounds of the formula, and pharmaceutically acceptable derivatives thereof, are useful because they have pharmacological effects in animals. That is, these compounds act on peripheral and/or central dopamine receptors. As such, they lower blood pressure, reduce heart rate and increase blood flow to certain vascular beds, such as the 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. (a) Renal blood flow in dogs, see McNay and Goldberg, J.Pharmac.Exp.Ther., Vol. 151, pp. 23-31 (1966). (b) Isolated rabbit ear artery, McCullogh
Rand and Store et al., “Br.J.Pharmac.” No.
49, pp. 141-142 (1973), and (c) Cat nictitating membrane, Messrs. Gyorgy and Doda, Arch. Int. Pharmacodyn., vol. 226, pp. 194-206.
See (1977). The compounds of the invention are useful in the treatment of congestive heart failure, renal failure, angina pectoris, ischemic heart disease, hypertension and reversible obstructive airway disease, hyperprolactinemia and also Parkinson's disease and other neurological disorders. is instructed. The amount administered will, of course, vary depending on the compound used, the mode of administration and the effect desired.
However, in general, the compound is
Satisfactory results are obtained when administered in amounts of 0.05 μg to 50 mg. For humans, the total daily dose indicated is 2.5μg to 3.5g, which is e.g. 1μg to 3.5g.
It may be administered in divided doses of 750 mg. The novel compounds of the invention can be used in combination or sequentially with a wide variety of other pharmaceutically active substances. If appropriate, the compounds can be mixed with one or more other active substances or chemically combined with other active substance(s), for example to form salts or esters. The particular mixture, dosing method or chemically combined substances, and proportions of active ingredients used will depend on a variety of factors, including the condition being treated, the mode of administration, the particular active ingredient, and the patient concerned. be. Compounds that can be mixed with or chemically bonded to the compounds of the present invention are as follows. β-blockers, especially cardioselective β-blockers such as atenelol, propanol, diuretics such as thiazides such as furosemide, acetylcholinesterase inhibitors such as captopril, inotropic agents such as Amrinone, Antiemetics such as sulpiride, metoclopramide, or domperidone. Compounds of formula, and pharmaceutically acceptable derivatives thereof, may be more effective in certain pharmacological models or less likely to cause undesirable side effects than compounds of similar structure to compounds of formula. It has the advantage of being less or longer acting. The compounds of the invention can be administered by a variety of routes and can act systemically or locally. The compounds of the invention can therefore be administered by oral or nasal inhalation into the lungs, oral cavity, esophagus, rectum, topically into the skin or other available surfaces of the body, such as by intravenous injection, intramuscular injection, It can be administered by intraperitoneal injection or by surgical implant. According to the invention, it consists of preferably not more than 80% and more preferably not more than 50% by weight of a compound of formula or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Pharmaceutical compositions are also provided. Examples of suitable adjuvants, diluents or carriers are microcrystalline cellulose for tablets, capsules and dragees;
Calcium phosphate, diatomaceous earth, sugars (e.g. lactose,
dextrose or mannitol), talc, stearic acid, starch, sodium bicarbonate and/or gelatin, natural or hydrogenated oils or waxes for suppositories, and crude lactose for inhalable compositions. If the compound is to be used in aqueous solution, it may be necessary to incorporate chelating or masking agents such as sodium edetate, antioxidants such as sodium metabisulfite, or buffers such as sodium hydrogen phosphate and sodium phosphate. It can be. Aqueous solutions typically contain up to about 10% by weight 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 will be illustrated by the following examples, but the invention is not limited thereto. All temperatures are in degrees Celsius (°C). Stereochemical nomenclature is defined in “Chemical Abstracts,
"Appendix, Selection of Index Names for Index Guide" 1977, pp. 202-212.
Chemical Substances”. Absolute stereochemistry assignments are given by Helmchen et al. (a) Tet. Letters, p. 3873 (1972), (b) Ibid., p. 1527 (1974), (c) Ibid., p. 1417 (1977).
and Mr. McDermed's ``Proceedings of the
Symposium on Dopamine Agonists
(Stockholm)” (Swedish Pharmaceutical
(Published in 1982). Example 1 (R ^* S ^* )-2,2'-[1,6-hexanediylbisamino]-bis-[1,2,3,4-tetrahydro-5,6-naphthalenediol] (a) N- [1,2,3,4-tetrahydro-5,
6-dimethoxy-2-naphthylidene]-(R)-
1-Phenylethylamine 1,2,3,4- in dry toluene (200ml)
A solution of tetrahydro-5,6-dimethoxy-2-tetralone (20.6 g) and (R)-1-phenylethylamine (14 ml) was heated at reflux for 4 hours with continuous removal of water. Evaporation of the mixture gave a brown oil (30g). M ⁺ 309. (b) (RS&RR) 1,2,3,4-tetrahydro-5,6dimethoxy-N-(1-phenylethyl)naphthalenamine hydrochloride The imine obtained in step (a) (28 g) in dry ethanol (250 ml) ) was hydrogenated over Adams catalyst (1 g) at atmospheric pressure and room temperature until no further hydrogen uptake was observed (~2 days). The solution was filtered and evaporated to give an oil which was dissolved in excess ethanolic HCl. Evaporation of the solution gave a dark solid which was purified by trituration with cold isopropanol (50ml) to give a colorless solid (23g). The diastereomeric amines were resolved by high performance liquid chromatography (HPLC) on a silica column, eluting with a mixture containing triethylamine (1%) in petroleum ether/dichloromethane (4:1). Conversion of the free base of each diastereomer to its hydrochloride salt and crystallization results in a diastereomeric purity of greater than 99.8% (confirmed by HPLC). b1 9.5 g of the first eluting diastereomer,
Melting point 265-267℃ b2 6.0g of the second eluted diastereomer,
Melting point 297℃ (decomposition) (c) S(-)1,2,3,4-tetrahydro-5,
6-Dimethoxy-2-naphthalenamine hydrochloride Amine b1 (6.95) in dry methanol (400 ml)
The solution of g) was hydrogenated over 10% Pd/C catalyst (2 g) at atmospheric pressure and room temperature for 24 hours. The solution was filtered and the liquid was evaporated to obtain a solid,
This was crystallized from ethanol to obtain colorless prism crystals (3.8 g). Melting point 270℃, [α] ²⁸ _D = -60.1
(C=0.15, _CH3OH ). (d) R(+)1,2,3,4-tetrahydro-5,
6-dimethoxy-2-naphthalenamine hydrochloride Amine b2 (6.95 ml) in dry methanol (500 ml)
The solution of g) was hydrogenated over 10% Pd/C catalyst (2 g) at atmospheric pressure and room temperature for 78 hours. The solution was filtered and the liquid was evaporated to obtain a solid,
This was crystallized from ethanol to obtain colorless prism crystals (3.5 g). Melting point 260℃ or higher, [α] ²⁸ _D =
58.6 (C=0.2, _CH3OH ). (e) (S) Methyl-6-(1,2,3,4-tetrahydro-5,6-dimethoxy-2-naphthaleneamino)-6-oxo-hexanoate in step (c) in dry dichloromethane (100 ml). Methyl 5-(chloroformyl)pentanoate (1.8 g) was added dropwise into a stirring solution of the resulting amine (2.43 g) and triethylamine (2.8 ml). This solution was heated under reflux for 1 hour. The cooled solution was washed with dilute hydrochloric acid, dilute sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to give a colorless solid,
This was crystallized from toluene/petroleum ether to give colorless flakes (3.2 g). Melting point 115-116℃,
[α] ²⁴ _D = −38.6 (C = 0.17, CH ₃ OH). (f) (S) 6-(1,2,3,4-tetrahydro-5,6-dimethoxy-2-naphthaleneamino)-6-oxo-hexanoic acid Methanol (50 ml) and 10% aqueous sodium hydroxide solution (4 ml) ) A solution of the ester (3.0 g) obtained in step (e) was heated under reflux for 1 hour. The solution was evaporated, cooled and acidified using dilute hydrochloric acid. The precipitate was dissolved in chloroform, washed with brine, dried over magnesium sulfate, filtered and evaporated to give a solid which was crystallized from ethyl acetate/petroleum ether to give colorless prismatic crystals (2.5 g). Ta. Melting point 147-149℃, [α] ²⁴ _D = -
40.7 (C=0.15, _CH3OH ). (g) (R ^* ,S ^* )-N,N'-bis[1,2,3,
4-tetrahydro-5,6-dimethoxy-2-
Naphthyl]-hexane-1,6-diamide A solution of the acid obtained in step (f) (1.1 g) and N,N'-carbonyldiimidazole (0.53 g) in dry dichloromethane was stirred at room temperature for 2 hours. A solution of the amine obtained in step (d) (0.68g) (free base) in dry dichloromethane (50ml) was added and the mixture was stirred at room temperature for 18 hours. The resulting precipitate was redissolved in chloroform and the organic phase was washed with dilute hydrochloric acid, dilute sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate;
Filtration and evaporation gave a colorless solid which was purified by filtration from hot methanol (1.37g). Melting point 256-258℃, [α] ²⁵ _D = ±0.1 (C = 0.14,
_CH3OH / _CHCl350 /50). (h) (R ^* S ^* )-N,N'-bis[1,2,3,4
-Tetrahydro-5,6-dimethoxy-2-naphthyl]-hexane-1,6-diamine dihydrochloride Step (g) in dry tetrahydrofuran (400 ml)
A solution of the bisamide (1.3g) obtained in was stirred during the addition of borane (50ml, 1M solution) in tetrahydrofuran. This solution was heated under reflux for 24 hours under a nitrogen stream. Methanol (200ml) was added to the cooled solution and evaporated to give a sticky solid. Methanolic HCl was added and the suspension was heated under reflux for 4 hours. The solution was evaporated to give a colorless solid, which was crystallized from methanol to give colorless prismatic crystals (1.19 g). Melting point: 260°C or higher, [α] ²⁵ _D = -0.5 (C = 0.2, H ₂ O). (i) (R ^* S ^* )-2,2'-[2,6-hexanediylbisamino]-bis-[1,2,3,4-tetrahydro-5,6-naphthalenediol] 48% bromide A solution of the bisamine (1.05 g) obtained in step (h) in an aqueous hydrogen acid solution (50 ml) was heated under reflux for 2 hours under a nitrogen stream. The solution was evaporated to dryness and the residue was crystallized from methanol to give the dihydrobromide salt of the title compound as colorless prismatic crystals (0.70 g). Melting point 250℃ or higher, [α] ²⁸ _D =
−1.2 (±0.4) (C=0.18, _H2O ). Example 2 The following compounds were prepared in a manner similar to that described in Example 1 above. (a) [R-(R ^* R ^* )]-2,2'-[1,6-hexanediylbisamino]-bis-[1,2,3,4
-Tetrahydro-5,6-naphthalenediol dihydrobromide Melting point 260℃ or higher, [α] ²⁴ _D = +55.8 (C = 0.24,
_H2O ). (b) [S-(R ^* R ^* )]-2,2-[1,6-hexanediylbisamino]-bis-[1,2,3,4
-Tetrahydro-5,6-naphthalenediol] dihydrobromide Melting point: 260℃ or higher, [α] ²⁴ _D = -58.1 (C = 0.18,
_H2O ). Example 3 2,2'-(1,6-hexanediylbisamino)-
Bis-(1,2,3,4-tetrahydro-5,6
-naphthalenediol) (a) N,N'-bis-(1,2,3,4-tetrahydro-5,6-dimethoxy-2-naphthyl)hexane-1,6-diamide Adipoyl in chloroform (15 ml) A solution of chloride (1.1g, 0.006M) in chloroform (15
1,2,3,4-tetrahydro-5,6 in ml)
-dimethoxy-2-aminonaphthalene (2.5g,
0.012M) and triethylamine (1.4g,
0.014M) solution. 1 of this mixture
Stirred for an hour, quenched by adding water and the organic phase was separated, washed with water and dried over magnesium sulphate. The mixture was filtered and the liquid was evaporated to dryness to give a solid which was crystallized from methanol to yield 2.0 g (63%) of the desired amide. melting point
223~5℃. (b) N,N'-bis-(1,2,3,4-tetrahydro-5,6-dimethoxy-2-naphthyl)hexane-1,6-diamine dihydrochloride Step (a) in dry tetrahydrofuran (250 ml) )
The suspension of the amide (2.0 g) obtained above was stirred at room temperature under nitrogen flow, while 10 ml of 1M borane/tetrahydrofuran complex was added via a syringe. The resulting mixture was heated to reflux for 3 hours, cooled and an additional 10 ml of 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 30 minutes. The solution was evaporated to dryness and the residue was dissolved in ether containing a few drops of ethanol. Add excess ethereal hydrogen chloride to this solution and filter the precipitated solid, wash thoroughly with hot ethanol and dry to obtain the amine hydrochloride salt.
1.9g (87%) was obtained. Melting point: 280℃ (decomposition). (c) 2,2'-(1,6-hexanediylbisamino)-bis-(1,2,3,4-tetrahydro-
5,6-Naphthalenediol) dihydrobromide A suspension of dimethoxyamine (1.8 g, 0.003 M) obtained in step (b) in 48% aqueous hydrogen bromide solution (80 ml) was heated under a nitrogen stream. Heated under reflux 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 the solids were filtered off. This was washed with hot methanol, dissolved in methanol/water and the solution was treated with charcoal, filtered and the liquid was evaporated to dryness. The title compound was obtained as the dihydrobromide salt. 1.1g (57%), melting point 250℃. Elemental analysis value as C ₂₆ H ₃₆ N ₂ O ₄ (H ₂ O 1.5 mol,
4.3%) C% H% N% Br% Measured value 49.7 6.1 4.2 24.7 Theoretical value 49.6 6.5 4.4 25.4 Example 4 The following compound was prepared by a method similar to that described in Example 3 above. 2,2'-(1,6-hexanediylbisamino)-
Bis-(1,2,3,4-tetrahydro-6,7
-naphthalene diol) dihydrobromide, melting point
260℃ or higher. Example 5 [R(R ^* ,R ^* )](+)-7,7'-[1,6-hexanediylbis(aminomethylene)]-bis(bicyclo[4.2.0]-octa-1,3, 5-triene-
(2,3-diol) (a) (+)-2,3-bis(phenylmethoxy)
Synthesis and resolution of S-(-)-1-phenylethylamide of bicyclo[4.2.0]-octa-1,3,5-triene-7-carboxylic acid (±)- in dry tetrahydrofuran (500 ml)
2,3-bis-(phenylmethoxy)-bicyclo[4.2.0]-octa-1,3,5-triene-7-
Carboxylic acid (40.0 g, 0.11 mol) was dissolved in N,N'-carbonyldiimidazole (20.8
g, 0.13 mol). This reaction mixture was
C. for 3 hours and S-(-)-1-phenylethylamine (15.3 g, 0.125 mol) was added dropwise. The solution was kept at 20°C for 2 hours and then water and dichloromethane were added. The organic layer was separated, washed with dilute HCl, aqueous bicarbonate and brine, dried and evaporated to give a solid (47.3g). This amide mixture was prepared using ethyl acetate/ethyl acetate on silica.
It was resolved by preparative high performance liquid chromatography using a petroleum ether mixture. Two fractions were obtained and recrystallized from ethyl acetate. Less polar diastereomers: [S-(R ^* ,
S ^* )]-N-(1-phenylethyl)-2,3-bis(phenylmethoxy)-bicyclo[4.2.0]-octa-1,3,5-triene-7-carboxamide, melting point 186-188°C , [α] _D = +1.9° (C = 0.3,
_CHCl3 ), _δCH3 ( _CDCl3 )=1.39ppm. More polar diastereomers: [S-(R ^* ,
R ^* )]-N-(1-phenylethyl)-2,3-bis-(phenylmethoxy)-bicyclo-[4.2.0]-
Octa-1,3,5-triene-7-carboxamide, melting point 171-173°C, [α] _D = +25.6° (C = 0.3,
_CHCl3 ), _δCH3 ( _CDCl3 )=1.45ppm. (b) [S-(R ^* ,S ^* )]-N-(1-phenylethyl)-2,3-bis(phenylmethoxy)-bicyclo[4.2.0]-octa-1,3,5-triene -7-Methanamine hydrochloride [S-(R ^* ,S ^* )]-amide (13.2
g, 2.85 mmol) was treated with 1M borane in tetrahydrofuran (140 ml, 140 mmol) under nitrogen and boiled under reflux for 5 hours. After cooling, methanol and methanolic hydrogen chloride were added and the mixture was stirred overnight. Evaporation of the solvent and trituration of the residue with dry ether gives
-(R ^* ,S ^* )]-Amine hydrochloride is a white crystal (10.5
g) was obtained. Melting point 171-173℃, δ
( _CDCl3 ) = 6.80 (1H, d), 6.60 (1H, d). (c) [1S−[1R ^* [1R ^* [7S ^* (7S ^* )]]]] −N, N'
−
Bis-(1-phenylethyl)-N,N'-bis[(2,3-bis(phenylmethoxybicyclo[4.2.0]-octa-1,3,5-triene-7)
-yl]-methyl]-hexanediamide [S-(R ^* ,S ^* )]-amine hydrochloride (4.84 g, obtained in step (b) above) in dichloromethane (80 ml),
10 mmol) and triethylamine (3.03 g,
Adipoyl chloride (0.915 mmol) in dichloromethane (40 ml) into a stirred solution of
g, 5 mmol) was added dropwise. The mixture was stirred at 20° C. overnight and poured into water. The organic phase was separated, washed with aqueous hydrochloric acid, aqueous sodium bicarbonate and brine, dried and evaporated to give a colorless solid (4.8g). Melting point 48℃. (d) [1S − [1R ^* − [1R ^* [7S ^* (7S ^* )]]]] -1,
6
-Hexanediylbis-[N-(1-phenylethyl)-2,3-bis(phenylmethoxy)-bicyclo[4.2.0]-octa-1,3,5-triene-7-methanamine] dihydrochloride Tetrahydrofuran [1S−[1R ^* ] in (100ml)
−[1R ^* [7S ^* (7S ^* )]]]]-Bisamide (4.86 g,
4.8 mmol) was treated with 1M borane in tetrahydrofuran (24 ml, 24 mmol) under nitrogen 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. Trituration of the residue with dry ether gave diamine dihydrochloride (4.6 g), which decomposed without melting above 90°C. (e) [R(R ^* ,R ^* )](+)-7,7'-[1,6-hexanediylbis(aminomethylene)]-bis(bicyclo[4.2.0]-octa-1,3 ,5-triene-2,3-diol) dihydrochloride [1S-[1R ^* [1R ^* [ 7S ^* (7S ^* )]]]]-diamidine hydrochloride (1 g) was shaken under 3 atmospheres of hydrogen pressure at ambient temperature for 72 hours. The mixture was filtered and the percake was extracted with hot water. Evaporation of water gave (+)-diamine dihydrochloride (0.3g).
Melting point 235°C (decomposition, [α] ³⁰ _D = +12.4° (C = 0.15,
_H2O ). Example 6 The following compound was prepared in a manner similar to that described in Example 5 above. (a) Starting from the [S-(R ^* ,R ^* )]amide of Example 5(a), [S-(R ^* ,R ^* )]-7,7'-[1,6-hexanediylbis (aminomethylene)]-bis(bicyclo[4.2.0]-octa-1,3,5-triene-2,3 diol dihydrochloride was obtained. Melting point
235℃ (decomposition), [α] ³⁰ _D = -11.8 (C = 0.15,
_H2O ). (b) [SR ^* , S ^* )] and [S-
(R ^* , R ^* )] Starting from a mixture of amides, racemic and meso (R ^* , S ^* )-7,7′-[1,6-
Hexanediylbis(aminomethylene)-bis(bicyclo-[4.2.0]-octa-1,3,5-triene-2,3-diol) dihydrochloride was obtained.
Melting point: 240℃ (decomposition). Example 7 Racemic and meso (R ^* , S ^* ) −7,7′−[1,6
-hexanediylbis(aminomethylene)-bis(bicyclo[4.2.0]-octa-1,3,5-triene-2,3-diol) (a) racemic and meso(R ^* ,S ^* )-N, N'-hexamethylene-bis-[2,3-bis(phenylmethoxy)bicyclo[4.2.0]-octa-1,
3,5-triene-7-carboxamide] 2,3-bis(phenylmethoxy)-bicyclo[4.2.0]-octa-1,3,5-triene-7-
Carboxylic acid (0.72g) Dry dichloromethane (40
ml) and cooled to -5°C and triethylamine (0.31 ml) was added. To this was added dropwise a solution of ethyl chloroformate (0.19ml) in dry dichloromethane (2ml) over a period of 10 minutes. The solution was stirred at -5°C for 1 hour and hexane-
1,6-diamine (0.11 g) was added and the mixture was warmed to room temperature for 4 hours. The reaction mixture was washed with water, 2N hydrochloric acid, 2N sodium hydroxide and brine, dried (Na ₂ SO ₄ ) and evaporated.
The residue was recrystallized from ethanol to give purified bisamide (0.43 g). Melting point 155-159
℃. (b) Racemic and meso (R ^* , S ^* ) −7,7′−[1,
6-hexanediylbis(aminomethylene)-
Bis(bicyclo[4.2.0]-octa-1,3,5
-triene-2,3-diol]dihydrochloride The product of Example 7(a) was treated as described in Examples 5(d) and 5(e) above to give the title compound as the dihydrochloride salt. Melting point: 240℃ (decomposition). Example 8 7-[6-(2-phenylethylamino)hexylamino]methylbicyclo[4.2.0]-octa-1,
3,5-triene-2,3-diol (a) N-(2-phenylethyl)-N'-[[2,3
-bis-(phenylmethoxy)-bicyclo[4.2.0]-octa-1,3,5-triene-7
-yl]methyl]-hexane-1,6-diamide 6-oxo- in dry dichloromethane (25 ml)
A solution of 6-(2-phenylethylamino)hexanoic acid (1.25 g) and N,N'-carbonyldiimidazole (0.9 g) was stirred at 20°C for 2 hours and then dissolved in dry dichloromethane (20 ml). 2,3
-bis(phenylmethoxy)-bicyclo [4.2.0]
-octa-1,3,5-triene-7-methanamine hydrochloride (1.9 g) and triethylamine (0.5
g, 0.7 ml) was added. This mixture at 20℃
Stir for 2.5 hours and add water (50ml). The organic phase was separated, washed with dilute hydrochloric acid, aqueous sodium bicarbonate and brine, dried over _MgSO4 and evaporated to give the desired diamide as a colorless solid (2.3g). Melting point 125-155℃. (b) N-(2-phenylethyl)-N'-[[2,3
-bis(phenylmethoxy)bicyclo [4.2.0]
-oct-1,3,5-trien-7-yl]
Methyl]-1,6-hexanediamine dihydrochloride This compound was prepared from the product of Example 8(a) using the method of Example 5(d) above. Melting point over 250℃. (c) 7-[6-(2-phenylethylamino)hexylamino]methylbicyclo[4.2.0]-octa-1,3,5-triene-2,6-diol dihydrochloride of Example 5(e) The title compound was prepared from the product of Example 8(b) above as the dihydrochloride salt using the method. melting point
208-210℃. Example 9 The following compounds were prepared in a manner similar to that described in Example 8 above. 7-[6-[2-(3,4-dihydroxyphenyl)
ethylamino]hexylamino]methylbicyclo[4.2.0]-octa-1,3,5-triene-2,
3-diol dihydrochloride, melting point 217°C (decomposed). Example 10 7-[6-(2-phenylethylamino)hexylamino]methylbicyclo[4.2.0]-octa-1,
3,5-triene-3,4-diol (a) N-[(3,4-dimethoxybicyclo[4.2.0]
-oct-1,3,5-trien-7-yl)
Methyl]-N'-(2-phenylethyl)hexane-1,6-diamide 6-oxo-6-(2-phenylethylamino)
Hexanoic acid (8.65 g) was dissolved in dry tetrahydrofuran (220 ml) under inert gas and
Cooled to 5°C. N,N'-carbonylimidazole (6.12 g) was added over 5 minutes and the mixture was stirred at 0-5°C for 3 hours. 3,4-
dimethoxybicyclo[4.2.0]-octa-1,3,
5-triene-7-methylamine hydrochloride (7.98
g) and triethylamine (4.85ml) were added sequentially and the mixture was stirred at room temperature for 2 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 (8.77 g
I got it. Melting point 150-152℃. (b) N-[(3,4-dimethoxybicyclo[4.2.0]
-oct-1,3,5-trien-7-yl)
[Methyl]-N'-(2-phenylethyl)-hexane-1,6-diamine dihydrochloride Step (a) A 1 molar solution (75.5 ml) of the borane-tetrahydrofuran complex in tetrahydrofuran (160 ml) under an inert atmosphere of the product (8.0 g). The solution was heated at reflux overnight, allowed to cool to room temperature, and methanol (50ml) was carefully added. After all effervescence had ceased, methanolic hydrogen chloride (50ml) was added and the mixture was refluxed for 1 hour. The suspension was concentrated to dryness to give a white solid, which was crystallized from aqueous ethanol to give white needles (6.88 g). melting point
258-259℃. (c) 7-[6-(2-phenylethylamino)hexylamino]methylbicyclo[4.2.0]-octa-1,3,5-triene-3,4-diol dihydrobromide Step (b) ) product (3.25g) was dissolved in dry dichloromethane (10ml) and cooled to -78°C. Boron tribromide (3.5ml) was added and the solution was stirred at -78°C for 3 hours, then at room temperature for 2 hours. Methanol (approximately 25ml) 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 210-214℃ (decomposition). Elemental analysis value (as C ₂₃ H ₃₂ N ₂ O ₂・2HBr) C% H% N% Br% Actual value 51.69 6.29 5.11 30.16 Theoretical value 52.08 6.42 5.28 30.19 Example 11 Same method as described in Example 5 and Example 10 above The following compound was prepared. (a) (7,7′-[1,6-hexanediylbis(aminomethylene)]-bis-bicyclo[4.2.0]
-octa-1,3,5-triene-3,4-diol) dihydrobromide, melting point 226°C (decomposed). (b) 7-[6-[2-(3,4-dihydroxyphenyl)ethylamino]hexylamino]methylbicyclo[4.2.0]-octa-1,3,5-triene-3,4-diol diol Hydrochloride, melting point
100-105℃. Example 12 4-[2-(6-(2-phenylethylamino)hexylamino)ethyl]-1,2-benzenediol(a) N-[2-(3,4-dimethoxyphenyl)ethyl]- N'-[2-phenylethyl]-hexane-1,6-diamide 6-oxo-6-(2-(3,4-dimethoxyphenyl)ethyl-aminohexanoic acid (9.3 g) in dry dichloromethane (300 ml) and N, N′−
A solution of carbonyldiimidazole (4.90g) was stirred at room temperature for 2 hours. A solution of 2-phenylethylamine (3.8ml) in dichloromethane (50ml) was added and the mixture was stirred at room temperature for 3 hours. The solution was washed with 2NHCl, water, 5% aqueous sodium bicarbonate, and water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give a solid, which was crystallized from ethanol (11.38
g). Melting point 183-184℃. (b) N-[2-(3,4-dimethoxyphenyl)ethyl]-N'-[2-phenylethyl]-hexane-1,6-diamine dihydrochloride Step (a) in dry tetrahydrofuran (150 ml)
A solution of the diamide product (4.94 g) was stirred under nitrogen while a 1M solution of diborane in tetrahydrofuran (48 ml) was added. This solution was heated under reflux for 24 hours. Methanol (100ml) was added to the cooled solution and the mixture was evaporated to dryness. The residue was dissolved in methanolic HCl (100ml) and heated under reflux for 1 hour. The solution was evaporated and the solid crystallized from methanol (4.90g). Melting point 283-285℃. (c) 4-[2-(6-(2-phenylethylamino)
Hexylamino)ethyl]-1,2-benzenediol hydrobromide A solution of the diamine product of step (b) (4.75 g) in 48% aqueous hydrobromic acid (70 ml) was refluxed under nitrogen. The mixture was heated for 3 and a half hours. The solid formed on cooling was filtered and crystallized from ethanol to give the title compound as the dihydrobromide salt (3.1
g). Melting point 227-228℃. Example 13 4-[2-(6-(2-(4-aminophenyl)ethylamino)hexylamino)ethyl]-1,2-
Benzenediol (a) N-[2-(3,4-dimethoxyphenyl)ethyl]-N'-[2-(4-nitrophenyl)ethyl]-hexane-1,6-diamine dihydrochloride This compound is Example 12 Prepared by method (b).
Melting point 153-155℃. (b) N-[2-(3,4-dimethoxyphenyl)ethyl]-N'-[2-(4-aminophenyl)ethyl]-hexane-1,6-diamine trihydrochloride Product of step (b) A solution of (1 g) was dissolved in a mixture of ethanol (50 ml)/acetic acid (25 ml) and hydrogenated over a palladium catalyst at 45 psi and room temperature. After hydrogen uptake ceased, the reaction mixture was warmed and filtered to remove the catalyst. The liquid 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 triturated with ether (0.8g). Melting point over 250℃. (c) 4-[2-(6-(4-aminophenyl)ethylamino)hexylamino)ethyl]-1,2
-Benzenediol trihydrobromide Salt Prepared as the trihydrobromide salt from the product of step (b) by the method described in Example 12(c) above. melting point 250
℃ or more. Example 14 4-[2-(6-(2-(4-chlorophenyl)ethylamino)hexylamino)ethyl]-1,2-
Benzenediol (a) N-[2-(3,4-dimethoxyphenyl)ethyl]-N'-[2-(4-chlorophenyl)ethyl]-hexane-1,6-diamide as described in Example 12(a) Prepared using the method. Melting point 167-169
℃. (b) N-[2-(3,4-dimethoxyphenyl)ethyl]-N'-[2-(4-chlorophenyl)ethyl]-hexane-1,6-diamine The method described in Example 12(b) Prepared using Melting point over 260℃. (c) 4-[2-(6-(2-(4-chlorophenyl)
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℃. Example 15 The following compounds were prepared similarly to the methods described in Examples 12, 13 and 14 above. (a) 4-[2-(6-phenylamino)hexylamino)ethyl]-1,2-benzenediol dihydrobromide, mp 216-218°C. (b) 4-[2-(6-phenylmethylamino)hexylamino)ethyl]-1,2-benzenediol dihydrobromide, melting point 176-178°C. (c) 4-[2-(6-(3-phenylpropylamino)hexylamino)ethyl]-1,2-benzenediol dihydrobromide, melting point 158-160
℃. (d) 4-[2-(6-(4-phenylbutylamino)
hexylamino)ethyl]-1,2-benzenediol hydrobromide, melting point 196.5-199°C. (e) 4-[2-(6-amino-hexylamino)ethyl]-1,2-benzenediol dihydrobromide, mp 201-202°C. (f) 4-[2-(6-(di-n-propylamino)
hexylamino)ethyl]-1,2-benzenediol dihydrobromide, melting point 164-165°C. (g) 4-[2-(6-(N-methyl(2-phenylethylamino)hexylamino)-ethyl]-
1,2-benzenediol dihydrobromide, melting point 167-169°C. (h) 4-[2-(6-(2-phenylpropylamino)hexylamino)ethyl]-1,2-benzenediol dihydrobromide, melting point 135-137°C (i) 4-[2 -(6-(2-(4-nitrophenyl)
ethylamino)hexylamino)ethyl]-1,
2-benzenediol dihydrobromide, melting point
164℃ (decomposition). (j) 4-[2-(6-(2-(4-hydroxyphenyl)ethylamino)hexylamino)ethyl]
-1,2-benzenediol dihydrobromide,
Melting point over 260℃. (k) 4-[2-(6-(2-(4-methylphenyl)
ethylamino)hexylamino)ethyl]-1,
2-benzenediol dihydrobromide, melting point
195℃ (decomposition). (l) 4-[2-(6-(2-(4-pyridinyl)ethylamino)hexylamino)ethyl]-1,2
-Benzenediol trihydrobromide, melting point
197-8℃. (m) 4-[2-(6-(4-methylpiperazinyl)hexylamino)ethyl]-1,2-benzenediol trihydrobromide, melting point 197-8
℃. (n) 4-[2-(N-methyl-6-(4-methylpiperazinyl)hexylamino)ethyl]-
1,2-benzenediol trihydrobromide,
Melting point 187-190℃. (o) 4-[2-(4-(2-phenylethylamino)butylamino)ethyl]-1,2-benzenediol dihydrobromide, melting point 251-255°C
(Disassembly). (p) 4-[2-(6-(1,2,3,4-tetrahydro-2-naphthylamino)hexylamino)ethyl]-1,2-benzenediol dihydrobromide, melting point 224-226 ℃. (q) 4-[2-(8-(2-phenylethylamino)octylamino)ethyl]-1,2-benzenediol dihydrobromide, melting point 229-230
℃. (r) 4-[2-(5-(2-phenylethylamino)pentylamino)ethyl]-1,2-benzenediol dihydrobromide, melting point 187-189
℃. (s) 3-[6-(2-(3,4-dihydroxyphenyl)ethylamino)hexyl]-1-phenyl-2,3,4,5-tetrahydro-1H
-3-Benzazepine-7,8-diol dihydrobromide, melting point 115°C (decomposed). (t) 4-[2-(N-methyl-6-(N'-methyl-2-phenylethylamino)hexylamino)ethyl]-1,2-benzenediol dihydrobromide, melting point 186~ 188℃. Example 16 4-[2-(6-(2-hydroxy-2-phenylethylamino)hexylamino)ethyl]-1,
2-Benzenediol Previous example in dry tetrahydrofuran (100ml)
N-(2
-Hydroxy-2-phenylethyl)-N'-[2
-(3,4-bis(phenylmethoxy)phenyl)
Ethyl]hexane-1,6-diamide (3.48g)
The solution was stirred under nitrogen while a 1M solution of diborane in tetrahydrofuran (30ml) was added and the solution was then heated under reflux for 6 hours. Methanol (100ml) was added to the cooled solution and the mixture was evaporated to dryness. The residue was dissolved in methanolic HCl (100ml) and heated to 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 prism crystal (1.3g), melting point
188-189℃. Example 17 4-[2-(N-methyl-6-(di-n-propylamino)hexylamino)ethyl]-1,2-benzenediol (a) N-[2-(3,4-dimethoxyphenyl) )ethyl]-N-methyl-N',N'-di-n-propyl-hexane-1,6-diamide N- in dry dimethylformamide (20 ml)
[2-(3,4-dimethoxyphenyl)ethyl]-
N,N'-di-n-propyl-hexane-1,6
-A solution of diamide (3.9g) was added to a suspension of oil-free sodium hydride (0.24g) in dry dimethylformamide (20ml). this mixture
Heated at 70°C for 1 hour. Methyl iodide (0.75ml) 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, dilute sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to give a brown oil (3.8g). M+406. (b) N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-N',N'-di-n-propyl-hexane-1,6-diamine dihydrochloride of step (a) The product was prepared by the method described in Example 12(b). Melting point 130-132℃. (c) 4-[2-(N-methyl-6-(di-n-propylamino)hexylamino)ethyl]-1,
2-Benzenediol dihydrobromide salt Prepared as the dihydrobromide salt from the product of step (b) by the method described in Example 12(c) above. Melting point 97~99
℃. Example 18 ±-4-[2-[4-hydroxy-6-(2-phenylethylamino)-hexylamino]ethyl]-
1,2-Benzenediol (a) N-(2-Phenylethylamino)-tetrahydro-5-oxo-2-furanacetamide Tetrahydro-5-oxo-2-furan-acetic acid (5.5 ml) in dry dichloromethane (75 ml) g) and triethylamine (3.8 g, 5.3 ml) was added dropwise with stirring at -10° C. and the mixture was stirred for 45 minutes. Phenylethylamine (4.6 g) in dry dichloromethane (25 ml) was added and the reaction was heated to 20°C.
It was held for 18 hours. The solution was washed with aqueous sodium bicarbonate, hydrochloric acid and water to give the desired lactone amide (3.5 g) as a pale cream solid after drying (MgSO ₄ ) and evaporation and trituration with ether. Melting point 83-85℃. (b) 3-Hydroxy-N'-[2-(3,4-dimethoxyphenyl)ethyl]-N-[2-phenylethyl]hexane-1,6-diamide Lactonamide obtained in step (a) ( 3.45 g) and 2-(3,4-dimethoxyphenyl)ethylamine (2.54 g) were heated at 100° C. for 1 hour under a nitrogen stream. The melt was cooled and triturated with ether and the resulting solid was recrystallized from ethanol to yield the desired diamide (5.1 g). Melting point 158
~160℃. (c) 6-[2-(3,4-dimethoxyphenyl)ethylamino]-1-[2-phenylethylamino]-3-hexanol dihydrochloride from step (b) in dry tetrahydrofuran (150 ml). The diamide obtained in (3.4 g) was treated with 1M borane-tetrahydrofuran (40 ml) under nitrogen and boiled under reflux for 4 hours. The solution was cooled, methanol (25ml) was added and the whole was evaporated to dryness. The residue was dissolved in methanol (50
ml) and saturated methanolic hydrogen chloride (50 ml) and stirred at 20°C for 18 hours. The solvent was evaporated and the residue was triturated with ether to give the dihydrochloride salt (2.7g) as a white solid. This material decomposed at temperatures above 240°C without melting. (d) 4-[2-[4-hydroxy-6-(2-phenylethylamino)-hexylamino]ethyl]
-1,2-Benzenediol dihydrobromide The dihydrochloride (2.2 g) obtained in step (c) in dry dichloromethane (100 ml) was treated with triethylamine (1.3 ml, 0.94 g) and under a nitrogen stream. 15 below
Stir for a minute. The resulting suspension was cooled to −70°C,
Boron tribromide (2.2 ml, 5.85 g) was added and the mixture was allowed to warm to ambient temperature under stirring for 18 hours. Methanol (10ml) was added, the resulting solution was evaporated to dryness and the solid residue was recrystallized from 2-propanol to give the title compound as the dihydrobromide salt (2.2g) in colorless needles. Melting point 137~
139℃. Example 19 4-[2-[6-[2-(4-chlorophenyl)ethylamino]hexylamino]-ethyl]-1,2-
Benzenediol dihydrochloride 4-[2-[6-[2-(4-chlorophenyl)-
ethylamino]hexylamino]ethyl]-1,
2-benzenediol dihydrobromide (3.0g)
was dissolved in a minimum amount of water 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 suspended in concentrated hydrochloric acid and stirred with gentle warming until all sticky material was 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 (2.0 g) as white crystals. Melting point 186-188℃. Elemental analysis value (as dihydrochloride) Actual value Cl 23.02% Theoretical value Cl 22.93% Example 20 4-[2-[6-(2-phenylethylamino)hexylamino]ethyl]-1,2-benzenediol di Hydrochloride This compound is obtained from the corresponding dihydrobromide salt in Example 19.
Prepared by the method described. Melting point 219-219.5
℃. Example 21 1,2,3,4-tetrahydro-2-[6-(2-
phenylethyl)aminohexyl]amino-5,
6-Naphthalenediol (a) 6-oxo-6-(2-phenylethylamino)hexanoic acid Adipic acid monomethyl ester (24 g, 0.15 mol) was dissolved in dry dichloromethane (500 ml) and cooled in ice water; Triethylamine (22.3 ml, 0.16 mol) was added followed by ethyl chloroformate (14.3 ml, 0.15 mol) in dichloromethane (50 ml).
mol) solution was added over 30 minutes. The resulting suspension
Stir for 30 minutes and dissolve 2-phenylethylamine (18.8 ml, 0.16 mol) in dichloromethane (50 ml).
solution was added over 30 minutes and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 2N aqueous hydrochloric acid (2x200ml), 10% aqueous sodium carbonate (200ml) and water and evaporated under vacuum to give the crude amide ester. This solid was heated at reflux with a solution of potassium hydroxide (9.52g, 0.17mol) in water (300ml) for 1 hour. The cooled solution was washed with ether (200ml), acidified and the solid was isolated by filtration and dried under vacuum to give the desired amic acid (26.1g). Melting point 113-114
℃. The crude acid was purified by recrystallization from ethyl acetate. Melting point 114-116℃. (b) N-[1,2,3,4-tetrahydro-5,
6-dimethoxy-2-naphthyl]-N'-[2-
Phenylethyl]hexane-1,6-diamide A solution of 6-oxo-6-(2-phenylethylamino)hexanoic acid (2.49 g) and carbonyldiimidazole (1.62 g) in dry dichloromethane (100 ml) was added under a stream of nitrogen. The mixture was stirred at room temperature for 2 hours. 1,2, in dichloromethane (20ml)
3,4-tetrahydro-5,6-dimethoxy-2
A solution of -aminonaphthalene (2.07 g) 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 sulphate, filtered and evaporated to give the title compound, which was crystallized from isopropanol to give colorless flakes of crystals (3.8g). Melting point 191-193℃. (c) N-[1,2,3,4-tetrahydro-5,
6-dimethoxy-2-naphthyl]-N'-[2-
Phenylethyl]hexane-1,6-diamine dihydrochloride Borane-tetrahydrofuran complex (32 ml) in dry tetrahydrofuran (200 ml) and process
A solution of the product (b) (3.5 g) was heated to reflux under nitrogen for 24 hours. The solution was cooled, methanol (100ml) was added and the solution was evaporated to dryness. A solution of the residue dissolved in methanolic HCl was refluxed for 5 minutes.
heated for an hour. This solution was evaporated to obtain a solid,
This was crystallized from methanol to obtain colorless prism crystals (2.3 g). Melting point 265℃. (d) 1,2,3,4-tetrahydro-2-[6-
(2-Phenylethyl)aminohexyl]-amino-5,6-naphthalenediol dihydrobromide A solution of the product of step (c) (2 g) in aqueous hydrobromic acid (20 ml) was slowly flushed with nitrogen. The mixture was heated under reflux for 4 hours. The solution was evaporated to dryness and the residue was crystallized from ethanol to give the title compound as the dihydrobromide salt (2.0 g) in the form of colorless prismatic crystals.
obtained as. Melting point 240-242℃. Example 22 1,2,3,4-tetrahydro-2-[6-(2-
(3,4-dihydroxyphenyl)-ethyl)aminohexyl]amino-5,6-naphthalenediol (a) N-[1,2,3,4-tetrahydro-5,
6-dimethoxy-2-naphthyl]-N'-2-
(3,4-dimethoxyphenyl)ethylhexane-1,6-diamide Prepared by the method described in Example 21(a). Melting point 172-174
℃. (b) N-[1,2,3,4-tetrahydro-5,
6-dimethoxy-2-naphthyl]-N'-[2-
(3,4-dimethoxyphenyl)ethyl]hexane-1,6-diamine dihydrochloride Prepared from the product of step (a) by the method described in Example 21(b). Melting point 260℃. (c) 1,2,3,4-tetrahydro-2-[6-
(2-(3,4-dihydroxyphenyl)ethyl)aminohexyl]amino-5,6-naphthalenediol dihydrobromide This compound is obtained from the product of step (b) as the dihydrobromide salt. Prepared by the method described in Example 21(c).
Melting point 270℃. Example 23 The following compound was prepared in a manner similar to that described in Example 21 above. (a) 1,2,3,4-tetrahydro-2-[6-
(2-(3,4-dihydroxyphenyl)ethyl)aminohexyl]amino-6,7-naphthalenediol dihydrobromide, melting point 258-260
℃. (b) 1,2,3,4-tetrahydro-2-[6-
(2-Phenylethyl)aminohexyl amino-6,7-naphthalenediol dihydrobromide, melting point 266-268°C. (c) 1,2,3,4-tetrahydro-2-[4-
(2-Phenylethyl)aminobutyl]amino-5,6-naphthalenediol dihydrobromide, melting point 250°C or higher. (d) 1,2,3,4-tetrahydro-2-[8-
(2-Phenylethyl)aminooctyl]amino-5,6-naphthalenediol dihydrobromide, melting point 248-252°C. (e) 1,2,3,4-tetrahydro-2-[8-
(2-(3,4-dihydroxyphenyl)ethyl)aminooctyl]amino-5,6-naphthalenediol dihydrobromide, melting point 260°C. Example 24 N,N'-bis-(1,2,3,4-tetrahydro-5,6-dimethoxy-2-naphthyl)hexane-1,6-diamine dihydrochloride 1,2,3 in acetonitrile (100 ml) ,4
-tetrahydro-5,6-dimethoxy-2-naphthalenamine hydrochloride (4.87 g) in 1,6-dibromohexane (2.44 g) in acetonitrile (100 ml).
g) of potassium carbonate (3.0 g) in a refluxing solution of
g) was gradually added to the stirred suspension over 1 hour.
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. Chromatography on silica eluting with chloroform/methanol (95:5) and trituration with ethereal HCl gave the title compound (1.15 g) (20%). melting point 275
°C (decomposition). Example 25 4-[2-(6-(2-phenylethylamino)hexylamino)ethyl]-1,2-benzenediol-bis-(2-methylpropionate) dihydrochloride Trifluoroacetic acid (100ml) Middle 4-[2-(6
-(2-phenylethylamino)hexylamino)
Isobutyryl bromide (12 g) was added to a stirred solution of ethyl]-1,2-benzenediol dihydrobromide (4 g). This solution was then stirred at room temperature for 24 hours. Excess solvent was evaporated and the residue was treated with aqueous sodium bicarbonate solution. 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,
Treatment of this with ethereal HCl gave a white precipitate. This white precipitate was recrystallized from ethanol to obtain the title compound as colorless prism crystals (2.8 g). Melting point 232-234℃. Example 26 The following compound was prepared by a method similar to that described in Example 25. (a) 4-[2-(6-(2-phenylethylamino)
hexylamino)ethyl]-1,2-benzenediol-bis-benzoate dihydrochloride, melting point
230℃ (decomposition). (b) 4-[2-(6-(2-phenylethylamino)
hexylamino)ethyl]-1,2-benzenediol-bis-acetate dihydrobromide,
Melting point 229-230℃. Example 27 Bis(phenylmethoxy)N-[2-(3,4-dihydroxyphenyl)ethyl]N'-[2-phenylethyl]-1,6-hexanediylbiscarbamate 10% borax aqueous solution (4 g in 40 ml) Middle 4-[2-
(6-(2-phenylethylamino)hexylamino)ethyl]-1,2-benzenediol (4.2
The suspension in g) was adjusted to pH 9 using a 2N aqueous sodium hydroxide solution. This suspension was stirred for 4 hours. Benzyl chloroformate (2.2ml) was added and the mixture was stirred at room temperature for 2.5 hours. The suspension was made acidic and the aqueous phase was extracted with ether. The organic phase was separated, dried over magnesium sulphate, filtered and evaporated to give an oil. This oil was coated on silica gel with dichloromethane/
Purification by chromatography eluting with 5% CH ₃ OH gave the title compound as a pale yellow oil (2.0 g). MS m/e624. Example A Pharmaceutical Preparation Intravenous Preparation 1 Compound of Example 12 1% w/v Sodium Metabisulfite 1% w/v Sodium Chloride 0.106% w/v Water Amount to make 100% of total volume 2 Compound of Example 12 1% w/v v Sodium metabisulfite 0.1%w/v sodium edetate
0.01% w/v Sodium chloride Amount necessary to achieve isotonicity Water Amount to make the total volume 100% Compound of 3 examples 12 1% w/v Sodium hydrogen phosphate 0.94% w/v Sodium phosphate 0.24% w/v Sodium chloride 0.295 %w/v Water Volume taken as 100% of total volume Pharmacology Test Example Renal vascular resistance is calculated from measurements of renal blood flow and blood pressure in pentobarbitone anesthetized dogs. An adult beagle dog (10-15 kg) of either sex is given pentobarbitone sodium (30 mg/kg, intravenous).
After the patient was anesthetized and intubated to create a pneumothorax, artificial respiration was performed using a constant-stroke volumetric pump. Measurements of canine renal blood flow (RBF) were prepared by modifying the method of McNay and Goldberg (1966) as described by Brown et al. (1983). RBF is an electromagnetic flow probe (2.5-3.00mm Narco
Recorded from the left renal artery using
Blood pressure (BP) was recorded from a pressure transducer (Gaeltec, 5F) at the tip of a catheter placed in the descending aorta via the left carotid artery. Renal vascular resistance (RVR) was recorded continuously by electronically dividing mean BP by mean RBF. Agonists and agonists were administered directly (intraarterially) into the renal artery with a constant infusion of saline (0.1 ml/min) by a ZIG needle bent at a right angle and the distal end inserted into the renal artery.
Injected. Saline was injected constantly throughout the experiment to keep the needle lumen open. Phenoxybenzamine (10 mg/Kg, iv over 1-1.5 hours) was injected to irreversibly block alpha-adrenoceptors. In some dogs, non-selective β-
Adrenoceptor agonist, prolanolol (0.5 mg/Kg and 0.25 mg/Kg/hour intravenously)
while in other dogs, a selective β ₂ -adrenoceptor antagonist, ICI118551, was administered.
(Bilski et al., 1983) was injected (0.2 mg/Kg/hour, intra-arterial). prejunctional DA ₂ −
The receptor was administered hourly (500 μg/Kg,
(intravenous) haloperidol (Shepperson et al.,
(1982) or by the specific _DA2 -receptor blocker domperidone (Kohli et al., 1983) at a dose of 0.1 mg/Kg ^-1 (intravenously). Following the establishment of a control renal vasodilator response, the effects of dopexamine and dopamine (intra-arterial) at a dose of 10 μg/Kg (intravenous)
retested after _DA1 -receptor blockade caused by SCH23390 (Hilditch et al., 1984). The dose of test compound and dopamine required to reduce RVR by 20% (referred to as the ED ₂₀ dose)
Calculated before and after _DA1 -receptor blockade. _DA2 -Receptor Activity (Rabbit Ear Artery) Prejunctional dopamine _DA2 -receptor agonist activity was detected as inhibition of nerve-derived vasoconstriction in rabbit isolated auricular arteries (Brown and O'conner, 1981). Transect the central auricular artery and prepare the following composition (mM):
Placed in an organ bath containing Krebs-Henseleit solution: NaCl 117.6, KCl 5.4, _NaHCO3 25.0,
_CaCl2 2.55, _MgSO4 1.12, _NaH2PO4 0.9, glucose _11.1 . 5% _CO2 in _O2 was bubbled at 37<0>C. This solution also perfused the artery at a rate of 3 ml/min and contained propranol (10 ^-6 M) and cocaine (5 x 10 ^-5 M) to inhibit the absorption of β-adrenoceptor and neuron catecholamines, respectively. I cut it off. In some experiments it was established that the absorption of neuron is important with the exception of cocaine. A regular series of field stimuli (1 to
As a result of nerve-derived vasoconstriction caused by 3Hz, 0.5ms pulse width 70V for 10 seconds every 2.5 minutes,
A short period of vasoconstriction (increased perfusion pressure) was induced. In each experiment, 6,7-ADTN ( ₂ -amino-6,
7-dihydroxy-1,2,3,4-tetrahydronaphthalene) was used. Each agonist was added extraluminally to the bath 1.5 minutes before stimulation and the dose was increased after each response to obtain a cumulative dose-response. next
Agonist effects were tested at least 20 min after pretreatment with the DA ₂ -receptor agonists metoclopramide (2.5 × 10 ⁻⁶ M, Hope et al., 1978) or sulpiride (10 ⁻⁶ M, Brown and O′conner, 1981). . The effects of test compounds and 6,7-ADIN were re-examined in some studies in the absence of antagonist to test reproducibility of responses. β ₁ -Adrenoceptor Activity (Guinea Motu Atrium) β ₁ -Adrenoceptor activity was assessed as an increase in the rate of spontaneous atrial contraction, which is sensitive to antagonism by propranolol (10 ⁻⁶ M). Paired atria were removed from male guinea pigs and Krebs containing cocaine (5 x 10 ^-5 M) to prevent absorption.
-Henseleit solution (95% O ₂ ; 5% CO ₂ at 37°C)
It was allowed to slide spontaneously under diastolic tension of 2 g. Insometric contractions were recorded by a Grass transducer and used to trigger a long-term cardiac monitor. Test compounds were added cumulatively directly into the bath containing the posterior atrium to determine the response to isoprenaline. Note the concentration of isoprenaline and test drug required to increase the actual rate to 50% of the maximum value of isoprenaline. Potency is expressed as isoprenaline ratio. The maximum effect of the test drug is expressed as the ratio of the maximum amount of isoprenaline that yields intrinsic activity (IA). _β2 -adrenoceptor activity (guinea pig trachea) Agonist activity for _β2 -adrenoceptor was suspended in a 25 ml bath containing Krebs-Henseleit solution (95% _O2 ; ₅ % CO2, 37°C). It was evaluated in isolated tracheal chains of guinea pigs. The chain was connected to a Grass force transducer to record isometric tension and placed under a static tension of 2 g. The bath solution contained atenolol (4×10 ⁻⁶ M) and phentramine (10 ⁻⁵ M) to block β ₁ - and α-adrenoceptors, respectively. 17α-estradiol (5×10 ⁻⁵ M) prevented both neuron and β-neuron extrasorption mechanisms (Salt, 1972). The tissue was repeatedly administered a supramaximal dose of albutamol (10 ^-5 M) and then washed several times, resulting in stable spontaneous tone. Salbutamol was then added cumulatively until maximum relaxation was obtained. Following regeneration of Toll, this procedure was repeated with the test compound and maximal relaxation was determined by addition of supramaximal amounts of salbutamol. Relaxation produced by the test agonist was expressed as a ratio of the salbutamol-induced maximal relaxation rate. Salbutamol, unlike isoprenaline, is β2 _- specific and has 1/6 the activity of isoprenaline, so the activity of the isoprenaline ratio can be calculated. Potency is expressed as the isoprenaline ratio, and the maximum effect of the test compound is
Salbutamol and therefore isoprenaline are cited as the specific activity of the ratio. Receptor Selectivity Receptor titer ratios are used to calculate receptor selectivity. All comparisons were performed using equimolar concentrations of either the hydrobromide or hydrochloride salts of the test compounds. In separate experiments, the hydrobromide and hydrochloride salts of the compound of Example 12 of the present invention were shown to have quite equivalent pharmacological effects. n represents the number of test animals used for each measurement. Unless otherwise indicated, all
The DA ₁ study was conducted using one test animal,
All DA ₂ , β ₁ and β ₂ studies were performed using two test animals.

【table】

TABLE Compounds of the invention have been shown to be used in the treatment of acute congestive heart failure. This is of considerable importance in the treatment of heart failure, since the DA ₁ receptor agonist properties lead to a reduction in afterload and improve renal blood flow and excretory function. DA ₁
Excessive activity at other receptors relative to activity at one receptor can cause problems.
For example, excessive DA ₂ receptor stimulation causes vomiting, excessive β ₁ adrenoceptor stimulation causes bradycardia and arrhythmia, and excessive β ₂ adrenoceptor stimulation causes shunting of blood to skeletal muscles and muscle tremors. leading to. However, since small amounts of DA ₂ receptor and β ₂ adrenoceptor stimulation can be potentiated after a reduction in load, this is considered beneficial. Therefore, the DA ₁ /DA ₂ and DA ₁ /β ₂ ratios are
The properties of the DA ₁ receptor should be favorable and give an indication of the usefulness of the compound in the treatment of acute depressive heart failure. Many of the compounds of the invention do not exhibit detectable activity as _β1 agonists. Those shown, such as the compound of Example 12, have only weak activity.
Known compounds A and B and Example 12 of the present invention
The difference in intrinsic activity (IA) defined above between
This is well illustrated by the graph shown in FIG. 1 (in which ΔHR represents changes in heart rate). That is, the maximum increase in heart rate that occurs in the case of known compounds A and B is 105 and 122 beats per minute, respectively, whereas the maximum increase in heart rate that occurs in the case of Example 12 of the invention is 16 beats per minute. It was hot. This lack of β ₁ activity is a very clear advantage of the compounds of the invention. Toxicity test Compound of Example 20 of the present invention (4-[2-[6-
(2-phenylethylamino)hexylamino]
ethyl]-1,2-benzenediol dihydrochloride)
As a result of testing _the acute toxicity of
(mouse iv) and 30-50mg/Kg (rat iv)
It was hot. The _LD50s of other compounds of the invention were also comparable.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the change in heart rate versus the dose of the test compound.

Claims (1)

[Claims] 1 formula and pharmaceutically acceptable acid addition salts thereof [wherein D ₁ is the formula a group in which R ₁ and R ₅ or R ₃ and R ₅ can form a chain -CH ₂ CH ₂ -, or R ₄ and R ₅ can form a chain -CH ₂ -, or R ₃ , R ₄ and R ₅ are each hydrogen, and R ₁ , R ₃ and R ₄
the rest are the same or different and are hydrogen, alkyl or phenyl, two of R ₆ , R ₇ , R ₈ and R ₉ represent hydroxy and the rest are hydrogen,
X represents a chain -(CH ₂ ) _o - optionally substituted by hydroxy, n is an integer from 1 to 7, and D ₂ is hydrogen, alkyl or phenyl; is alkyl substituted by one or more hydroxy, pyridyl or phenyl, or by phenyl substituted by halogen, alkyl, amino, alkoxy or nitro, or D ₂ is the formula where R ₂ and R ₁₂ or R ₁₀ and R ₁₂ can form a chain -CH ₂ -CH ₂ -, or R ₁₁ and
R ₁₂ may form a chain -CH ₂ -, or R ₁₀ ,
R ₁₁ and R ₁₂ are each hydrogen, the remainder of R ₂ , R ₁₀ and R ₁₁ are the same or different and are hydrogen, alkyl or phenyl, and R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ are 0, 1 or 2 represent hydroxy and the rest represent hydrogen, or R ₂ and
D ₂ 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 and R ₃ , R If ₄ and R ₅ are hydrogen,
R ₁ and R ₂ are both hydrogen or lower alkyl, and two of R ₆ , R ₇ , R ₈ and R ₉ are hydroxy, and D ₂ is not the same as D ₁ ]. 2. The above-mentioned claim in which one or two adjacent pairs of R ₆ , R ₇ , R ₈ and R ₉ and adjacent pairs of R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ are all hydroxy. A compound according to item 1 in the range. 3. A compound according to claim 1 or 2, wherein _R7 is hydroxy. 4. The compound according to any one of the claims, wherein n is 3 to 5. 5 4-[2-(6-(2-phenylethylamino)
Hexylamino)ethyl]-1,2-benzenediol, or a pharmaceutically acceptable acid addition salt thereof. 6 (R ^* S ^* )-2,2'-[1,6-hexanediylbisamino]-bis-[1,2,3,4-tetrahydro-5,6-naphthalenediol], [R(R ^* , R ^* )](+)-7,7'-[1,6-hexanediylbis(aminomethylene)]bis(bicyclo[4,2,0]-octa-1,3,5-triene-2, 3-diol), 4-[2-(6-(2-(4-chlorophenyl)ethylamino]hexylamino)ethyl]-1,2
-benzenediol, 1,2,3,4-tetrahydro-2-[6-(2
-(3,4-dihydroxyphenyl)-ethyl)aminohexyl]amino-5,6-naphthalenediol, or a pharmaceutically acceptable acid addition salt of any of the compounds thereof. 1
Compounds described in Section. 7 [R-(R ^* ,R ^* )]-2,2'-[1,6-hexanediylbisamino]-bis-[1,2,3,4
-tetrahydro-5,6-naphthalenediol], [S-(R ^* ,R ^* )]-2,2-[1,6-hexanediylbisamino]-bis-[1,2,3,4-
Tetrahydro-5,6-naphthalenediol], 2,2'-(1,6-hexanediylbisamino)
-bis-(1,2,3,4-tetrahydro-5,
6-naphthalenediol), 2,2'-(1,6-hexanediylbisamino)
-bis-(1,2,3,4-tetrahydro-6,
7-naphthalenediol), [S-(R ^* ,R ^* )]-7,7'-[1,6-hexanediylbis(aminomethylene)]-bis-bicyclo[4,2,0]-octa- 1,3,5-triene-2,3-diol, (R ^* ,S ^* )-7,7'-[1,6-hexanediylbis(aminomethylene)]-bis-bicyclo[4,2,0 ]-octa-1,3,5-triene-
2,3-diol], 7-[6-(2-phenylethylamino)hexylamino]methylbicyclo[4,2,0]-octa-1,3,5-triene-2,3-diol, 7 -[6-[2-(3,4-dihydroxyphenyl)-ethylamino)hexylamino]methylbicyclo[4,2,0]-octa-1,3,5-triene-2,3-diol, 7 -[6-(2-phenylethylamino)hexylamino]methylbicyclo[4,2,0]-octa-1,3,5-triene-3,4-diol, (7,7'-[1, 6-hexanediylbis(aminomethylene)]-bis-bicyclo[4,2,0]
-octa-1,3,5-triene-3,4-diol), 7-[6-[2-(3,4-dihydroxyphenyl)ethylamino]hexylamino]methylbicyclo[4,2,0] -octa-1,3,5-triene-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-phenylmethylamino)hexylamino)ethyl]-1,2- Benzenediol, 4-[2-(6-(3-phenylpropylamino)
hexylamino)ethyl]-1,2-benzenediol, 4-[2-(6-(4-phenylbutylamino)
hexylamino)ethyl]-1,2-benzenediol, 4-[2-(6-amino-hexylamino)ethyl]-1,2-benzenediol, 4-[2-(6-(di-n-propyl) amino)hexylamino)ethyl]-1,2-benzenediol, 4-[2-(6-(N-methyl(2-phenylethylamino)hexylamino)-ethyl]-1,2
-benzenediol, 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-methylphenyl)ethylamino)hexylamino)ethyl]-1,2
-benzenediol, 4-[2-(6-(2-(4-pyridinyl)ethylamino)hexylamino)ethyl]-1,2-benzenediol, 4-[2-(6-(4-methylpiperazinyl) hexylamino)ethyl]-1,2-benzenediol, 4-[2-(N-methyl-6-(4-methylpiperazinyl)hexylamino)ethyl]-1,2-
Benzenediol, 4-[2-(4-(2-phenylethylamino)
butylamino)ethyl]-1,2-benzenediol, 4-[2-(6-(1,2,3,4-tetrahydro-2-naphthylamino)hexylamino)ethyl]-1,2-benzenediol, 4-[2-(8-(2-phenylethylamino)
octylamino)ethyl]-1,2-benzenediol, 4-[2-(5-(2-phenylethylamino)
pentylamino)ethyl]-1,2-benzenediol, 3-[6-(2-(3,4-dihydroxyphenyl)ethylamino)hexyl]-1-phenyl-
2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol, 4-[2-(N-methyl-6-(N'-methyl-2
-phenylethylamino)hexylamino)ethyl]-1,2-benzenediol, 4-[2-(6-(2-hydroxy-2-phenylethylamino)hexylamino)ethyl]-1,
2-benzenediol, 4-[2-(N-methyl-6-(di-n-propylamino)hexylamino)ethyl]-1,2-
Benzenediol, (+)-4-[2-[4-hydroxy-6-(2-
phenylethylamino)-hexylamino]ethyl]-1,2-benzenediol, 1,2,3,4-tetrahydro-2-[6-(2
-Phenylethyl)aminohexyl]amino-
5,6-naphthalenediol, 1,2,3,4-tetrahydro-2-[6-(2
-(3,4-dihydroxyphenyl)ethyl)aminohexyl]amino-6,7-naphthalenediol, 1,2,3,4-tetrahydro-2-[6-(2
-Phenylethyl)aminohexyl]amino-
6,7-naphthalenediol, 1,2,3,4-tetrahydro-2-[4-(2
-phenylethyl)aminobutyl]amino-5,
6-naphthalenediol, 1,2,3,4-tetrahydro-2-[8-(2
-Phenylethyl)aminooctyl]amino-
5,6-naphthalenediol, 1,2,3,4-tetrahydro-2-[8-(2
-(3,4-dihydroxyphenyl)ethyl)aminooctyl]amino-5,6-naphthalenediol, or a pharmaceutically acceptable acid addition salt of any compound thereof.
Compounds described in Section. 8 formula or a pharmaceutically acceptable acid addition salt thereof [wherein D ₁ is the formula a group in which R ₁ and R ₅ or R ₃ and R ₅ can form a chain -CH ₂ CH ₂ -, or R ₄ and R ₅ can form a chain -CH ₂ -, or R ₃ , R ₄ and R ₅ are each hydrogen, and R ₁ , R ₃ and R ₄
the rest are the same or different and are hydrogen, alkyl or phenyl, two of R ₆ , R ₇ , R ₈ and R ₉ represent hydroxy and the rest are hydrogen,
X represents a chain -(CH ₂ ) _o - optionally substituted by hydroxy, n is an integer from 1 to 7, and D ₂ is hydrogen, alkyl or phenyl; is alkyl substituted by one or more hydroxy, pyridyl or phenyl, or by phenyl substituted by halogen, alkyl, amino, alkoxy or nitro, or D ₂ is the formula where R ₂ and R ₁₂ or R ₁₀ and R ₁₂ can form a chain -CH ₂ -CH ₂ -, or R ₁₁ and
R ₁₂ may form a chain -CH ₂ -, or R ₁₀ ,
R ₁₁ and R ₁₂ are each hydrogen, the remainder of R ₂ , R ₁₀ and R ₁₁ are the same or different and are hydrogen, alkyl or phenyl, and R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ are 0, 1 or 2 represent hydroxy and the rest represent hydrogen or R ₂ and
D ₂ 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 and R ₃ , R If ₄ and R ₅ are hydrogen,
R ₁ and R ₂ are both hydrogen or lower alkyl, and two of R ₆ , R ₇ , R ₈ and R ₉ are hydroxy, and D ₂ is not the same as D ₁ A therapeutic agent for depressive heart palsy, comprising a composition of the following mixed with a pharmaceutically acceptable adjuvant, diluent or carrier. 9 formula and pharmaceutically acceptable acid addition salts thereof [wherein D ₁ is the formula a group in which R ₁ and R ₅ or R ₃ and R ₅ can form a chain -CH ₂ CH ₂ -, or R ₄ and R ₅ can form a chain -CH ₂ -, or R ₃ , R ₄ and R ₅ are each hydrogen, and R ₁ , R ₃ and R ₄
the rest are the same or different and are hydrogen, alkyl or phenyl, two of R ₆ , R ₇ , R ₈ and R ₉ represent hydroxy and the rest are hydrogen,
X represents a chain -(CH ₂ ) _o - optionally substituted by hydroxy, n is an integer from 1 to 7, and D ₂ is hydrogen, alkyl or phenyl; is alkyl substituted by one or more hydroxy, pyridyl or phenyl, or by phenyl substituted by halogen, alkyl, amino, alkoxy or nitro, or D ₂ is the formula where R ₂ and R ₁₂ or R ₁₀ and R ₁₂ can form a chain -CH ₂ -CH ₂ -, or R ₁₁ and
R ₁₂ may form a chain -CH ₂ -, or R ₁₀ ,
R ₁₁ and R ₁₂ are each hydrogen, the remainder of R ₂ , R ₁₀ and R ₁₁ are the same or different and are hydrogen, alkyl or phenyl, and R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ are 0, 1 or 2 represent hydroxy and the rest represent hydrogen, or R ₂ and
D ₂ 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 and R ₃ , R If ₄ and R ₅ are hydrogen,
R ₁ and R ₂ are both hydrogen or lower alkyl, and two of R ₆ , R ₇ , R ₈ and R ₉ are hydroxy, and D ₂ is not the same as D ₁ ] In manufacturing the following, that is, the formula (wherein T ₁ and T ₂ are H ₂ or O with the proviso that at least one of T ₁ and T ₂ represents O, R ₁ a and R ₂ a are It has the same meaning as R ₁ and R ₂ above, and D ₁ a is the formula represents a group of R ₃ a, R ₄ a, R ₅ a, R ₆ a, R ₇ a,
R ₈ a and R ₉ a are R ₃ , R ₄ , R 9 a respectively, except that one or two of R ₆ a, R ₇ a, R ₈ a and R ₉ a may represent a further protected hydroxy group. ₅ , _R6 ,
has the same meaning as R ₇ , R ₈ and R ₉ , Xa has the same meaning as above except that it may have a further protected hydroxy group, D ₂ a is hydrogen,
Alkyl, phenyl, alkyl substituted by one or more hydroxy, protected hydroxy, pyridyl, phenyl, or by halogen, alkyl, amino, alkoxy or nitro is alkyl substituted by substituted phenyl, or
or D ₂ a is the formula represents a group of R ₁₀ a, R ₁₁ a, R ₁₂ a, R ₁₃ a,
R ₁₄ a, R ₁₅ a and R ₁₆ a each represent the above R 10 except that one or more of R ₁₃ a, R ₁₄ a, R ₁₅ a and R ₁₆ a may represent a further protected hydroxy _group . , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ ) and then remove any protecting groups if necessary or desired. and, if desired or necessary, converting the resulting compound of formula into a pharmaceutically acceptable acid addition salt thereof. Method. 10 formula and pharmaceutically acceptable acid addition salts thereof [wherein D ₁ is the formula a group in which R ₁ and R ₅ or R ₃ and R ₅ can form a chain -CH ₂ CH ₂ -, or R ₄ and R ₅ can form a chain -CH ₂ -, or R ₃ , R ₄ and R ₅ are each hydrogen, and R ₁ , R ₃ and R ₄
the rest are the same or different and are hydrogen, alkyl or phenyl, two of R ₆ , R ₇ , R ₈ and R ₉ represent hydroxy and the rest are hydrogen,
X represents a chain -(CH ₂ ) _o - optionally substituted by hydroxy, n is an integer from 1 to 7, and D ₂ is hydrogen, alkyl or phenyl; is alkyl substituted by one or more hydroxy, pyridyl or phenyl, or by phenyl substituted by halogen, alkyl, amino, alkoxy or nitro, or D ₂ is the formula where R ₂ and R ₁₂ or R ₁₀ and R ₁₂ can form a chain -CH ₂ -CH ₂ -, or R ₁₁ and
R ₁₂ may form a chain -CH ₂ -, or R ₁₀ ,
R ₁₁ and R ₁₂ are each hydrogen, the remainder of R ₂ , R ₁₀ and R ₁₁ are the same or different and are hydrogen, alkyl or phenyl, and R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ are 0, 1 or 2 represent hydroxy and the rest represent hydrogen, or R ₂ and
D ₂ 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 and R ₃ , R If ₄ and R ₅ are hydrogen,
R ₁ and R ₂ are both hydrogen or lower alkyl, and two of R ₆ , R ₇ , R ₈ and R ₉ are hydroxy, and D ₂ is not the same as D _{1 [ _ _ _ _ _} A compound of the formula (In the formula, D ₁ b is the formula represents a group, where R ₁ b, R ₃ b, R ₄ b, R ₅ b,
R ₆ b, R ₇ b, R ₈ b and R ₉ b may represent a removable group in which R ₁ b can further increase the nucleophilicity of the nitrogen, and R ₆ b, R ₇ b, R ₈ R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , respectively, except that one or two of b and R ₉ b may represent a protected hydroxy group.
and R ₉ ) or its acid addition salt.
D ₂ equals D ₁ and R ₁ equals R ₂ ) and then removing any such protecting or removable groups if necessary or desired;
and, if desired or necessary, converting the resulting compound of formula into a pharmaceutically acceptable acid addition salt thereof. . 11 formula and pharmaceutically acceptable acid addition salts thereof [wherein D ₁ is the formula a group in which R ₁ and R ₅ or R ₃ and R ₅ can form a chain -CH ₂ CH ₂ -, or R ₄ and R ₅ can form a chain -CH ₂ -, or R ₃ , R ₄ and R ₅ are each hydrogen, and R ₁ , R ₃ and R ₄
the rest are the same or different and are hydrogen, alkyl or phenyl, two of R ₆ , R ₇ , R ₈ and R ₉ represent hydroxy and the rest are hydrogen,
X represents a chain -(CH ₂ ) _o - optionally substituted by hydroxy, n is an integer from 1 to 7, and D ₂ is hydrogen, alkyl or phenyl; is alkyl substituted by one or more hydroxy, pyridyl or phenyl, or by phenyl substituted by halogen, alkyl, amino, alkoxy or nitro, or D ₂ is the formula where R ₂ and R ₁₂ or R ₁₀ and R ₁₂ can form a chain -CH ₂ -CH ₂ -, or R ₁₁ and
R ₁₂ may form a chain -CH ₂ -, or R ₁₀ ,
R ₁₁ and R ₁₂ are each hydrogen, the remainder of R ₂ , R ₁₀ and R ₁₁ are the same or different and are hydrogen, alkyl or phenyl, and R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ are 0, 1 or 2 represent hydroxy and the rest represent hydrogen, or R ₂ and
D ₂ 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 and R ₃ , R If ₄ and R ₅ are hydrogen,
R ₁ and R ₂ are both hydrogen or lower alkyl, and two of R ₆ , R ₇ , R ₈ and R ₉ are hydroxy, and D ₂ is not the same as D ₁ ] In manufacturing the following, that is, the formula (In the formula R ₁ c, R ₂ c, R ₄ c, R ₅ c, R ₆ c, R ₇ c, R ₈ c,
R ₉ c and Xc further include the fact that one or both of _{R 1} c and R ₂ c may represent _a protecting group;
The above R ₁ , R ₂ , R ₄ , respectively, except that one or two of R ₈ c and R ₉ c may represent a protected hydroxy group, and Xc may have a protected hydroxy group. R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and X have the same meanings) by selectively reducing compounds of formula (where D ₂ is equal to D ₁ and both R ₃ groups hydrogen) and then removing any such protecting groups if necessary or desired and converting the resulting compound of formula to a pharmaceutically acceptable acid thereof, if desired or desired. A process for preparing a compound of formula or a pharmaceutically acceptable acid addition salt thereof, characterized in that it is converted into an addition salt.