JPS61103892A - N6-acenaphthyladenosines and analogues - 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 N6-naphthyl-, decalinyl- and tetralinyl-adenosines have been described in the literature, which also have coronary vasodilatory effects. N6-naphthyladenosine is the West German patent No. 1,
No. 670,116. N6-[Decalinyl, Tet51J 2A/.

Quinolinyl and isoquinolinyltmethyladenosines are described in German Patent No. 2,139,107, and tetranyl or tetrahydronaphthyladenosine/ are also described in German Patent No. 2,402,804. ing. U.S. Pat. No. 4,501,735 fully discloses N6-(1 and 2-benzocycloalkyl)adenosines. The benefits of each include increased coronary blood flow or beneficial circulatory effects. None of these references teach or make obvious the acenaphthyladenosine and analogs of the present invention.

The compounds of the invention use novel N6-side chains on adenosine, such as acenaphthyl and its analogues, and have valuable antihypertensive and coronary vasodilator effects.

That is, the present invention provides the formula X' Y (wherein = is optionally a double bond or a single bond; n=
6 from 0 to 4: X, X', Y, Y' are each independently ■, OI(,] ~ rogene, amino, nitro, lower alkyl, lower alkoxy or trifluoromethi, ν: p1= 41. Lower alkyl, OB or lower alkoxy; B2 is H or halogen: R2'
, B3' and Fls'=H.

low pine alkanoyl, benzoyl, or lower alkyl,
benzoyl substituted by lower alkoxy, norogen or hatrifluoromethyl: R2' and E5' together represent 2/, 5/-ingropylidene?
and all diastereomers and pharmaceutically acceptable acid addition salts thereof.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (1) above and a pharmaceutically acceptable carrier, and Formula I according to the above definition in dosage series form for mammals
It also relates to a method of treating hypertension or coronary blood flow (eg in angina) in said animal, comprising administering a compound of the invention. What is the therapeutically effective amount for those suffering from high blood pressure and angina? Containing mammals.

in an amount effective to treat blood pressure or angina.

In compounds of formula I, the term "lower alkyl" refers to 1 to
Straight-chain or branched alkyl having 6 carbon atoms, such as methyl, ethyl, globyl, isopropyl, butyl, 5ec-f-tyl, isobutyl, tart-butyl, amyl, isoamyl, neopentyl, hexyl, etc., including gold.

Halogen includes in particular fluorine, chlorine or bromine.

Lower alkoxy is 0-alkyl (having 1 to 6 carbon atoms as defined above for "lower alkyl").

Lower alkanoyl has 1 to 6 in the alkyl chain as defined above.
carbon atoms? It is a straight-chain or branched-d-alkyl group.

Compounds of formula (1) are useful in both free base form and acid addition salt form. Either form is within the scope of this invention. In fact, the use of the salt form is comparable to the use of the base form. Suitable pharmaceutically acceptable salts within the scope of the present invention include:
Mineral acids such as hydrochloric acid and sulfuric acid: and those derived from organic acids such as ethanesulfonic acid, benzenesulfone ml, p-)lue, sulfo/acids, respectively, hydrochloride, sulfate, ethanesulfonate, benzenesulfonate, p-
−) luenesulfone −) sudo.

Acid addition salts of the basic compounds include converting the free base into a suitable [1-
The salt is isolated by dissolving it in an aqueous or aqueous-alcoholic solution or other suitable solvent and evaporating the bath, or by reacting the free base and the acid in an organic solvent (in which case The salts can be obtained by direct separation or by concentration of the solution).

Compounds of the invention can have asymmetric carbon atoms.

The invention relates to individual enantiomers or noastereomers.
and mixtures thereof. Individual enantiomers or noastereomers can be prepared and isolated by methods known in the art.

A preferred embodiment of the present invention is represented by the formula (1) (in the formula x, x', Y,
Y' is hydrogen; and n, R, R1, F12',
Rsl and R5' are as defined above).

Another preferred embodiment of the present invention is the formula (1) (wherein x, x'
, Y, Y' and F+1 are hydrogen, n is zero, and ]2, R2', P5' and R51 are as defined above).

Another preferred embodiment is the formula (1) (wherein X, X', Y
, Y' and R1G are hydrogen, n is zero, R2 is hydrogen, and R2', B3' and B51 are as defined above.

Another preferred embodiment is the formula (X in the formula).

X', Y, Y', B1 and B2 are hydrogen, n=0
and R2', R5' and psl are hydrogen, acetyl, benzoyl, or E2' and R5' together may represent impropylidene).

A special embodiment includes R6-(acenaphthyl)adenosine or a pharmaceutically acceptable salt thereof.

The compound of formula (II) can be prepared in an inert solvent, such as an alcohol, or an aprotic solvent, such as trimethylformamide, in an amount of from about 25 to about 1
It can be conveniently synthesized by reacting 6-valopurinlyseside of formula (1) with the required acenaphthylamine of formula (1) at 60°C for 1 to 48 hours. The addition of a base such as triethylamine or calcium carbonate to neutralize the hydrogen halide formed as a reaction by-product can be beneficial, but this can also be achieved by using an additional equivalent of the aryl alkylamine. It can be carried out. It is also convenient, but not necessary, to protect the acetate or epenzoate ester, which can be removed using ammonium hydroxide or sodium methoxy Pt after synthesis of the I7 lanose hydroxyl group 2H6-substituted adenosine. The reaction is shown as follows.

■m In the formula, Hal is halogen, preferably chlorine or bromine, and Y, Y', X, X', B1, n.

B2', F15' and l"15' are as defined for Formula I.

The starting compound, the amine of the formula It can be prepared by converting it to an oxime and then reducing the oxime, for example by Raney nickel catalytic hydrogenation.

Other starting materials are known or can be prepared by known methods.

Compounds of formula I are suitable for adenosine receptors (conveniently A1 and A
2 receptors) have been found to have varying affinities. These compounds are useful as antihypertensive agents for the treatment of hypertension.

Pharmacological evaluation, adenosy/receptor binding-A1 receptor affinity (FI
Preparation of membranes from the cerebellum and brainstem upper eyelids of male Long-range rats (150-20(1)) Brinkman
50 volumes of ice-cold no 5 M Tris-HCZ buffer (pH 7,7
) for 20 seconds (setting number 6), then 10
min 2 G, 000 X f (5orvallFIC
-2), and centrifuged at 4°C. The supernatant was discarded and resuspended and centrifuged as before. This belene) t-2 international units/d of adenosine deaminase (
20− containing sigma tag m>”r from the revised intestinal mucosa
of Tris-HCt buffer and incubated at 37°C for 60 minutes, then at 0°C for 10 minutes. This homocyne was centrifuged again.

And the final pellet is ice-cold Q, 05 M Tr.
It was resuspended in is-HC1 buffer (pH 7.7) to a concentration of 20 my/m based on the original wet tissue weight and used immediately.

Assay conditions Tissue homocyne) (1011q/mt)? 1.0 gM (5H, l) with or without the test substance
-N6- Cyclohexyladenosine ((5H)-CH
A) 2 containing CL 05 M Tris-HCt
The cells were incubated for 1 hour at 25° C. in a buffer solution (pH 7.7) (6 sets). The incubation volume was 2. Unbonded (3H)-CHA was transferred to Whatman glass fiber (
GF/B) was separated by high-speed filtration under reduced pressure through a filter 27.

The filters were heated to 5-M ice-cold Q, 05M Tris-H
Rinsed three times with C2 buffer (pH 7,7). The radiolabeled ligand t-101tj retained on the filters was measured by liquid scintillation spectrophotometry after shaking the filters for 1 hour or more in a Peckman-Retysolp HP scintillation cocktail on a mechanical shaker.

Calculated non-specific binding f 1 was defined as the binding that occurs in the presence of mM theophylline. 50 specific binding (ICso
) The inhibitory test substance concentration was determined by non-JlI type computer curve fitting. Scatchard (
5catchard) Plot the radioligand binding amount (mol/tissue) total c1m***υJ e/))
Calculated by linear regression of the line obtained by plotting the free radiation vs. Free radioligand was defined as the concentration of radioligand added to the incubation mixture (in nM) since the amount of bound radioligand is a small fraction of the total amount added.

The Hill coefficient was calculated by performing a linear regression of the line obtained by multiplying the logarithm of the bound radioligand. Maximum number of binding sites (BmaX) was calculated from k-scan charts.

Adenosine receptor binding-A2 receptor affinity (I'tBA
2) 200-500 tissue specimens? Male 8prague-Dawley
Rat brain f was purchased from Pe1-Freez. Lo
n'g-Evans type with hooded hair (hoo
ded ) male rat (Blue Spruce Farm
Fresh brains (purchased from S. et al.) gave essentially the same results.

The brains were brought out of the freezing state and then kept on ice to dissociate the striatum. Striatal t10 volume ice-cold 50 mM Tris
-HCt (PH7 at 25°C, 7, pHa26 at 5°C (
Polytron PT-1 for 30 seconds in Tris)
0 (Brinkmann) i (set to 5).

The suspension was centrifuged for 10 minutes at 1so,oooxt,
Throw away the skim, that belen)? 10 volumes of ice-cold T-shirt as mentioned above
resuspended in RIS, centrifuged again, resuspended at a ratio of 1-15M, and stored in plastic fissure vials at -70°C (stable for at least 6 months). If necessary, the tissue should be brought back to room temperature from the frozen state and treated with Polytr.
on and kept on ice until use.

Incubation conditions All incubations were carried out using 5 μm of original tissue weight of rat striatal membranes, 4 nM of (AH)-N-ethyladenokune-5'-hypertoxamide ((3H)NECA), 1.
N6-cyclopentyladenosine at 50°C (to eliminate all A1 receptor binding), MgCl2.0 at IQmM.
For 60 minutes at 25° C. in a glass tube (12×75 im) containing 1-Tris f with 1 unit/g of adenosine deaminase and 1 tidimethyl sulfoxide.

N6-cyclopentyladenosine deficiency 0,02 N HC
Dissolve the solution at a concentration of 10mM in 100ml and dilute it in Tris. Stock solutions and diluted solutions of N6-cyclopentyladenosine could be stored at -20°C for several months. Test compound: Dimethyl sulfoxide VC10r on the same experimental day.
Dissolved in nM concentration and dimethyl sulfoxide at 1
The final incubation concentration was diluted 1:00.

Control incubations used an equal volume (10 μt) of tunomethyl sulfoxide, but the resulting dimethyl sulfoacetate concentration did not affect binding. (3H) NEC
A k Diluted to 40 nM in Tris. Membrane suspension (5mg70.79ml) G'! Total final concentration in each case was 10mM.
and sufficient MgC42 and adenosine deaminase to provide cL1 unit/1. For test compounds with IC5o values lower than 1 μM, the order of addition is test compound (10 μt), N6-cyclopentyladenosine (100 μt), (5H)NECA (100 μt).
t), f and membrane ([179m) and Toshika. 111M
Larger ICs.

Value and limited water solubility? The addition order for the test compounds (the contents i- are the same) is the test compound, membrane, N6-cyclopentyladenosine, and (3a) NgcA.
Toshitomo. After all additions were completed, the tube racks were vortexed and then incubated for 60 minutes at 25° C. in a shaking water bath.

In the middle of incubation, vortex the tube rack for a certain period of time.

Incubation was carried out under reduced pressure at 2.4 an CkF/
The process was terminated by filtration through the B filter.

Each tube was filtered in seven stages. Briefly, the contents of the tube were poured into a filter, added to 4 water-cooled Tris tubes, the contents were poured into the filter, and the filter was washed twice with 4 mj of ice-cold Tris. Filtration was completed in approximately 12 seconds.

Place the filter in a scintillation vial and add 8d F.
Ormula 947 scintillation fluid was added and the vials were left overnight, shaken, and counted in a liquid scintillation counter at 40% efficiency.

Data Analysis Non-specific binding was defined as binding in the presence of 100 μM N6-cyclopentyladenosine, and specific binding was defined as total binding minus non-specific binding. The rcso was calculated by weighted nonlinear least squares curve fitting to the mass action equation:

Y=T-8・□D+ where Y is the bound cpm, T is the total bound cpm in the absence of drug, S is the specific bound cpm in the absence of drug, and D&D of the drug. and K is the IC5o of the drug.

The weighting factor was calculated under the assumption that the standard deviation is proportional to the predicted value of Y. In this computer analysis, non-specific binding was treated as an extremely high (infinite) concentration of drug.

Adenosine A for N6-acenaphthyl abrasi/
The IC5o' value (nM) for 1 and A2 receptor affinity is 6
40 (for RBA-1), and 95.0 (iA-
for 146-(1-acenaphthylenylmethyl)adenosine) and 92 (for RBA-1).
and 63 (for BBA-2); and N6-
((1,2-dihydro-1-acenaphthylenyl)methyl)adenosine was kX 6 (relative to RBA-1) and 24 (RBA-2).

Evaluation of antihypertensive effect (Tomo R5) The usefulness of the compounds of the present invention as antihypertensive agents is demonstrated by standard pharmacological test method 1, for example, the effect of producing a significant decrease in mean arterial blood pressure in conscious rats. This test method is described below.

Direct monitoring of aortic blood pressure and heart rate from awake rats Continuous monitoring of pulsatile blood pressure (BP) from unrestrained awake rats surgically equipped with a polyethylene cannula using a computerized data capture scheme
er assisted data capture
Scheme (abbreviated as CADO8) K. °The basic elements of this method are cannula intubation and CADOS.

Method (1) of tiletamine HCL and zolazepam 13CL:
1 mixture) (20-40 w9/kg, intramuscularly) and the descending aorta was exposed through a midline incision. A cannula made from polyethylene tubing is inserted through the small puncture hole below the renal artery and into the aorta.

The puncture hole was made using a 23G disposable needle after applying forceps to a certain section of the aorta above and below the puncture site. P
E I DO (0,861!HID) body and PE50
A cannula consisting of a tip (0,58,, ID) was attached to a trocar, inserted through the entire abdominal muscle, passed subcutaneously along the dorsal midline, and exited between the ears. The cannula was moored between the abdominal muscle and the scalula (5calulaa).
3-〇 Braided suture). The midline incision was made with continuous simple sutures (4-0 chronic
)) Close it in two steps (first muscle, then skin). Each rat was then administered 30,000 units of penicillin subcutaneously at 7'C (penicillin G sterile suspension).

A harness designed to provide full cannula protection to the rat and give the rat relative freedom of movement.
s)-spring-universal joint assembly? I installed it. The puller is made from nylon hook/loop tape glued to a metal plate, and a spring wire (1B-
8 stainless steel) to a brass universal joint. Each polyethylene cannula is connected to a spring and connected through a universal joint to a pressure-quadrant juicer (Model P25Gb, Statham Instrument).
NTS) and an infusion pump (Sage model 254-7: 0rion B) using a PE100 tube.
(manufactured by e5earch). During the study, each rat received a continuous slow infusion of heparinized saline solution (24
About 400 per hour! or 40 units of heparin) to prevent blood clot formation. Additional “flushes” of the cannula with heparinized saline were performed when the aortic pulse pressure (systolic pressure minus diastolic pressure) was below 25 mHg. Pulse blood pressure and heart rate sounds were monitored at 1 minute intervals by two laboratory microcomputers connected directly to the data concentrator computer. Data were first stored on the data concentrator disk and then analyzed and reported by the main research computer. The overall scheme consists of modulation of the primary signal from the pressure transducer, primary data of 1-minute values of systolic, diastolic and mean blood pressure and heart rate by the laboratory microcongiator. The author was responsible for all computer-based storage, analysis, and report writing for the main research.

The transducer was connected to an analog signal conditioning module. These modules include a regulated excitation voltage to the transducer, amplification necessary to interface with the microprocessor, and a flexible, fluid-filled active tube to correct pressure waveform distortions caused by the cramped cannula. - Equipped with a low pass filter. The strain was 22-26 Hz, which provided reliable estimates of both systolic and diastolic blood pressure.

The microcomputer (one for each of two groups of 16 animals) is connected to a module interface unit, an AD converter for pressure waveform signals, and digital inputs for dose and event marker switches. Connected input component &C through. The microcomputer has an internally synchronized time/time reference generator that runs throughout the monoule φ.
A companion that controls data acquisition from the interface unit. Blood pressure values and marker switch status were sampled every 10 milliseconds for each of the 32 terminals using the time base generator. Microcomputer f.

- The data processor processes each blood pressure sample it receives and calculates the "running aperture" of Ju heart rate.
age ) J values, and mean systolic and diastolic blood pressure values were given.

When tested according to the above procedure, the following MAP and heart rate were obtained with the compounds of the examples.

Example 1 10 MAP ↓22% 117%
117% 115% ↓17chi I (El ↑3chi
↑16chi ↑19chi ↑17chi ↑9chi30 MAP
↓50To ↓20chi ↓26chi ↓29% ↓29
Chi H'B ↑6 chi ↑15 chi 725% ↑24 chi
↑19chi Example 2 10 MAP 148% ↓3
0chi 126% ↓20chi ↓21chi H1'l O
CH ↑10 CH ↑12 CH ↑19 CH ↑14 CH Example 3
10 MAP ↓27chi 115% ↓14chi 1
17% ↓16CH HEI ↑4CH 119% 120
% 711% N5% Coronary Blood Flow Evaluation The usefulness of the compounds of the present invention as effective agents for the treatment of angina is demonstrated by standard pharmacological test methods, such as the effect of producing a significant increase in coronary blood flow in rats. This test method is described below.

Method: (400-600P) iNa Heparin 20
00 units and anesthetized with fr-Na bendoparbital (9 in 50 η/) administered intraperitoneally. Once anesthetized, the rat heart is quickly dissected and the ascending aorta is fitted into an aortic perfusion cannula and secured with ligating means. The coronary arteries are first perfused for 2-3 minutes at a rate of approximately 15 m11 min and then at a constant pressure of 70 mm Hg and a temperature of 67°C. An electrocardiogram (ECG) is recorded using two platinum electrodes located at the base and apex of the left ventricle. A second heart is excised, cannulated and perfused in the same manner as above. Base both hearts in parallel.

Standard physiological salt solution (pss) has the following composition (concentration in mM)' (modified Krebs-Han
seleit bicarbonate buffer. That is, NaC
t, 127; NaHCO3, 25; Dextrose, 5
．． 5 S Na pyruhate, l O: KO2,4,7
; Mg5Oa, 1.1; KH2PO4,1,2;
Ca(/2 ・2H20,2,5: CaNa2ED'
l'A1 [105° Observe a 50 minute stabilization time before starting the test glotcol.

Microprocessor Controlled Coronary Perfusion and Medication System This microprocessor controlled system controls the
pp) and drug concentration can be maintained constant independent of upstream flow rate changes. The maintained levels of CPP and drug concentrations can be varied by commands communicated through the microprocessor keyset. Concentrated Drug Solution (DC) - Total Coronary Blood Flow (CF)
Complete drug dose-response curves are constructed by perfusing at a rate proportional to T). Drug concentration is increased by appropriate increases in the DC injection rate to the CFT across the microprocessor keyboard. The proportional flow rate of DC:CFT is approximately 0.0002:1 at the lower end of the dose-response curve and Q,02:i at its upper end. Dose-response curves covering at least two logarithms are created by preparing two DCs with a concentration difference of 1:100. After an initial dose range of two log doses, DC'i switching, appropriate pumping rate? Adjust and continue dose-response curve construction for another two log doses. A standard dose-response curve is constructed starting at a subthreshold dose and increasing in 1/2 log dose increments until ending at a dose that produces a near-maximal active total response. Standard standardized hardware is 10-9 to 10
-'Test over a range of M.

measurement
Heart rate (HE) and coronary blood flow (cF) are measured.

In the case of HI'l, the unit is the number of beats per minute (bpm),
In the case of CF, it is 7 minutes per milliliter (1 nl/min).

HF1t'; calculated from gcG strip chart recordings and CF calculated by recording analog outputs from pumps 1 and 2. The output from Ponbuna 1 is C
FT, and the output from pump ◆2 (CF of heart B (CFB). Calculate the CF (CFA) of heart A (CFT-CFB=CFA).

The effects of the compounds of Examples 1 and 2 and 3 obtained using the above method are as follows, and it can be seen that the compound of Example 6 is preferable for increasing coronary blood flow.

Example 1 Example 2 Example 3 Chi↑ Chi↓ Chi↑ Chi↓ Chi↑ Chi↓ Dose (
Molar concentration) CF HFI CF HFI
CF HFl3x10-' NT
NT 7 -I NT NTlxlo-
801371412 3x10-87 0 48 4 49 81x1
0-' 27 2 NT NT 58 3
63x10-'40'2 60 25 67 4
41x10-' 44 5 62 30 62
653X10-' 49 8 NT NT
67 68*NT means no test has been conducted.

The present invention further provides for administering orally or parenterally to a mammal suffering from hypertension or angina a corresponding pharmaceutical composition containing a compound of formula (1) according to the above definition in a suitable unit dosage form. Also encompassed is a method of treating hypertension or angina in such a mammal.

Inert, pharmaceutically acceptable carriers for preparing pharmaceutical compositions from the compounds of this invention can be either solid or liquid. Solid forms include powders, tablets, dispersible pellets, capsules, cashews and herbal medicines. A solid carrier can be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, or tablet disintegrant. It may also be an encapsulating material. In the case of powders, the carrier is a finely divided solid in admixture with the finely divided active compound. In the case of tablets, the active compound is mixed with a carrier having the necessary binding properties in suitable proportions and compacted to the desired shape and size. Powders and tablets preferably contain from 10 to about 70 grams of active ingredient per serving. Suitable solid carriers include magnesium carbonate, magnesium stearate, Merck, sugar, lactose, pectin, starch, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa milk fat, and the like.

The term "formulation" encompasses the active ingredient (with or without other carriers) and thus includes the carrier together with the active ingredient.

Includes formulations of the active compound and encapsulating material as a carrier to give capsules. Similarly, cachet is also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

For the advancement of herbal medicines, a low-melting wax such as a mixture of fatty acid glycerides or cocoa milk fat is first melted and the active ingredient is homogeneously dispersed therein, for example by stirring. The molten homogeneous mixture is then poured into conveniently sized molds and allowed to cool and thereby solidify.

Liquid formulations include solutions, suspensions and emulsions. - By way of example, water or water-propylene glycol baths may be mentioned for parenteral injection. Liquid preparations can also be formulated as solutions in aqueous polyethylene glycol solutions. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and optionally adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions suitable for oral use consist of the finely divided active ingredient dispersed in water with the viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. It can be prepared by

Also included are solid formulations which are intended to be converted to liquid formulations before use I for oral or parenteral administration. Such liquid dosage forms include baths, suspensions and emulsions. These particular solid formulations are most conveniently presented in unit dosage form and are used as such to form a single liquid dosage unit. Alternatively, after conversion to a liquid dosage form, multiple individual liquid doses can be obtained by measuring a predetermined volume of the liquid dosage form with a syringe, teaspoon or other volumetric container, etc. , may provide sufficient solids. If multi-dose liquid doses are prepared in such a way, is there any expected decomposition of said liquid doses in unused portions? Preferably it is maintained at low temperatures (ie under refrigeration).

Solid preparations intended to be converted into liquid dosage forms contain, in addition to the active substance, flavoring agents, colorants, stabilizers, buffers,
Artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc. may also be included. The liquid used to prepare the liquid formulation may be water, isotonic water, ethanol, glycerin, propylene glycol, etc., and mixtures thereof. Of course, the liquid used and the route of administration? Liquid formulations containing large amounts of ethanol are not suitable for parenteral use.

Preferably, the pharmaceutical formulation is in unit dosage form. In such dosage form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Unit dosage forms are also capsules,
Can it be the cachet or the pill itself, or is it any of these? It may be packaged in an appropriate number.

The amount of active compound in a unit dosage formulation may vary or be adjusted over a range of 1 to 500, preferably 5 to 100, depending on the application and the effectiveness of the active ingredient. Optionally, the composition may include other compatible therapeutic agents. It can also be included.

In therapeutic applications such as those mentioned above, the dosage range for supplementary animals for treatment targets of 70F is 0.1 to 150 μ/kli.
'body weight/day or preferably 1-50 η/kg body weight/day. However, the dosage may vary depending on the requirements of the patient, the severity of the condition being treated and the compound used.

Determination of the appropriate dosage for a particular condition is within the skill of those skilled in the art. In general, treatment involves administering smaller doses of the compound than the optimal dose! It starts with the amount. Thereafter, the dosage is increased in small increments until the optimum effect under the conditions is achieved. For convenience, if desired, the total daily dosage may be divided and administered in portions during the day.

The present invention will be illustrated by the following examples, but the invention is not limited thereto.

Example 1 N6-acenaphthyladetsucin 6-chloropurine conjugate (2,85', 10 mmol) was converted into 1-aminoacenaphthene.HCt (2,1?, 1
0 mmol) and triethylamine (2,5f, 25
It was added all at once to the solution in 150 ml of mol. This solution was stirred under reflux overnight.

The solution was cooled to room temperature 1-1 and then cooled to 8°C to precipitate. The mixture was dried overnight at 65°C under X-nitrogen. Yield 1.8t (43%): mp 146.5~
150℃. Elemental analysis (C22H21N5048 calculated value:
C=6500, H=5.05, N=16.70: Actual value: C=62.95, H=5.12, N=1 &70.

The synthesis of the starting compound amine from a known ketone is as follows.

The ketone j (4,
61,27,5 mmol) of ethanol (1 oad) was added to the bath solution. The new solution was stirred at reflux for 4 hours, then cooled to room temperature and left overnight. The solution is evaporated to dryness in vacuo and the residue is stirred into water (200 ag). The precipitate kW is collected and dried under vacuum at 45°C for 7 hours.

Yield 4.8? (96%); mp 174-178°
;1H6 elemental analysis (C12H9NO・0.15H20)
, Calculated values: C=77.55, H=4.96, N=S5
6: Actual value: C=77.60, H=5.32, N=
7.56.

IH; E13.164: r Elsevier'
s Encyclopedia" The oxime (4
,88? , 26 mmol) dissolved in saturated (room temperature) methanol (100 i1) and Raney nickel (
1,5M) e-added.

The bath solution was pressurized with H2 for 6a5 minutes at room temperature, and then
Warmed to 40°C for 18 & 5 minutes. The mixture was cooled to room temperature and the pressure was released. Is the mixture k filtered and catalyzed? The catalyst was removed and washed with catalyst 1T) IF (100d). The combined organic layers were evaporated in vacuo and the residue was added to isopropanol/HCL (saturated at room temperature). The bath solution was cooled to 8°C and precipitated. Collect solid tP and 4
It was vacuum dried at 5°C for 5 hours. Yield 3.5 M' (74 inches); mp>290°C. Elemental analysis (C+2H11N-HC
A) , Calculated value 2 C, = 70.07, H = 5.88, N
=6.81, cz-=17.23; Actual value: C=71.
59,)! =5.95, N=6.20, ct-=17.
26°H' NMR (D6-DM80, 200mH
z) :δ533(d of d, J=18Hz 2
Hz, IH), δ3.82 (d of a, J=8
Hz, 18Hz, IH), δ5.22(n, IH
), δ 7.38 to s 89 (n, 6H), δ & 76 (s
, 3H).

Example 2 N6-(1-acenaphthylenylmethyl)adenosine 6-
Chlorogrin lyseside (1,15?, 4 mmol), triethylamine (1, Of, 10 mmol) combined
N-((1-acenaphthylenyl)methylcyamine, A, (1, Or, 4.6 mmol) prepared in Example A below.
The mixture was stirred under reflux in 100ml ethanol (100ml) overnight. The solution was cooled to room temperature and filtered through PI to precipitate ? Removed. The solid N-(
1-acenaphthylenylmethyl)adenosine was obtained. Elemental analysis (C25H21Nso4・Q, 25EtOH), calculated values: C=6572, H=5.12, N=15.81:
Actual measurements: C=6449, H=4.99, N=15.7
8゜Example 3 N6- ((1,2-dihydro-1-acenaphthylenyl)methyl]adenosine 6-chloropurine lyseside (1,7f, 6 mmol),
triethylamine (1,5f, 15 mmol) and fcN-((C2-dihydro-1
-acenaphthylenyl) methylcyamine, B (1,4?
, 6.4 mmol) tethanol (100 mA)
The mixture was stirred under reflux overnight. That melt? It was cooled to room temperature and filtered to remove all solids. The solution was washed with ethanol (50mt) and vacuum dried at 65°C for 4 hours to yield 2.21 (85m) of white solid (mp17
3-175°C).

Elemental analysis (C23H2sNsO4), calculated value: C=65
．． 75, H=5.35, N=16.16; Actual value: C=
63.55, H=5.49, N=16. OO.

Example A N-((i-acenaphthylenyl)methyl, methyl)amineacenaphthanone (a4f, 50 mmol) and zinc iodide (■) (~15~) were combined with trimethylsilyl cyanide (5,
5r, 55 mmol) and stirred overnight at room temperature in the absence of solvent. The reaction mixture was diluted with dry THF (15
od) and lithium aluminum hydride (LAH) (2, IP, 55 mmol) in THF.
(150d) was added dropwise to the slurry in (150d). that new 5t
LW was slowly (2 hours) warmed to reflux and stirred for 4 hours. The reaction was cooled to room temperature and added with water (100g).
It was carefully quenched. That sura IJ-'(I N N
Treated with aOH (50m7) and filtered to remove solids. The solid content was washed with kTHF (200d),
And P-liquid? THF was removed by evaporation, the aqueous bath was extracted with ether (3 x 200 g), and the organic bath liquid f IN NaOH (I D 0 m7), water (1
Washed once with 100 rn and saturated brine solution (100 d). The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was stirred into SCt saturated ethanol (15ON) and heated to 50 °C for 2.5 min.
Warmed for hours. Ethanol was evaporated in vacuo to t˜50d and cooled to 8°C. The precipitated solid 'tF was collected and 65
It was dried under vacuum for 6 hours at °C to obtain a 3.2F (1%) white hydrochloride (mp method 245 °C). Elemental analysis (C15H11
N-HCt): Calculated value: C=71.72, H=5.5
6, N=6.44, cl'=16.28; Actual value: C=
71.69, H=5.67, N=6.35, Cf)=1
6.00゜Example B N-((1,2-dihydro-1-acenaphthylenyl)methyl)amine N-((1-acenaphthylenyl)methyl)amine hydrochloride prepared in Example A above, A, (1, El, a33m9
)? Dissolved in methanol (1 ood) and 5% Pd
/C(a,2r)'r: Added. The mixture was stirred for 2.5 h at room temperature under 51 psi hydrogen and fc (hydrogen absorption: AJ' = 6.8 psi, calculated 7.1
).

Claims (1)

[Claims] 1) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, ■ is a double bond or a single bond depending on the case; n = 0 to 4; X, X', Y , Y' are each independently H, OH, halogen, amino, nitro, lower alkyl, trifluoromethyl, or lower alkoxy; R_1 is H, alkyl, OH, or lower alkoxy; R_2 is H or halogen; can be:
R_2', R_3' and R_5' are each independently hydrogen, alkanoyl, benzoyl, or benzoyl substituted with lower alkyl, lower alkoxy, halogen or trifluoromethyl, or R_2
' and R_3' may both be 2',3'-isopropylidene) or a pharmaceutically acceptable acid addition salt thereof. 2) The compound according to claim 1, wherein X, X', Y and Y' are hydrogen. 3) The compound according to claim 2, wherein R_1 is hydrogen and n is 0. 4) The compound according to claim 2, wherein R_1 is hydrogen and n is 1. 5) The compound according to claim 3, wherein R_2 is hydrogen. 6) The compound according to claim 5, wherein R_2', R_3' and R_5' are each independently hydrogen, acetyl or benzoyl, or R_2' and R_3' together represent isopropylidene. 7) The compound according to claim 6, which is N^6-(acenaphthyl)adenosine. 8) The compound according to claim 4, wherein R_2', R_3' and R_5' are each independently hydrogen, acetyl or benzoyl, or R_2' and R_3' together represent isopropylidene. 9) The compound according to claim 8, which is N^6-(1-acenaphthylenylmethyl)adenosine. 10) Claim 9 which is N^6-[(1,2-dihydro-1-acenaphthylenyl)methyl]adenosine
Compounds described in Section. 11) 6-halopurine riboside represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Hal is a halogen) About 2
5 to about 130°C for about 1 to 48 hours. Method. 12) A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 13) A method for treating hypertension in a mammal suffering from hypertension, comprising administering to the mammal a compound according to claim 1 in unit dosage form. 14) A method for treating angina in a mammal suffering from angina, comprising administering to the mammal a compound according to claim 1 in unit dosage form.