JPS62228095A - N6-substituted adenosine - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the present invention are adenosine analogs that have some of the same activities as adenosine. , the core compound has a unique affinity ratio at A1 and A2 receptors,
and has highly desirable central nervous system and cardiovascular activities such as analgesic, antipsychotic, sedative, antihypertensive and antianginal activity.

U.S. Pat. No. 3,590,029 discloses a series of 2-amino-R6-adenosine derivatives including 2-amino-R6-siphenylalkyl acin having circulatory and cardiac activity. There is. West German patent announcement cylinder 2, 4
No. 06,587 is R6- used as a hypolipidemia agent.
Syphenylalkyl adenosine is disclosed which requires the alkyl to be a branched chain. Additionally, U.S. Patent Application Nos. 756,922 and 756,922;
No. 56,004 was found for the novel compounds of the present invention. Alkyladenosines are disclosed.

The present invention relates to compounds having formula (II) and their pharmaceutically acceptable base salts or acid addition salts.

In the above formula, Ar represents (1) phenyl, +211- or 2-naphthalenyl, R3) 2-4 or 6-chenyl, (
4) 2- or 6-furanyl, (group 2-14- or 5
-thiazolo, (6) 2-16-''! or 4-gyrydyl or (7) 2-pyrimidyl, and (1),
(2), (6), (4), (5), (6) Maichiko is (7
) each of argylsulfonyl 4 is substituted by at least one of nitro, where q%q' and q are independently integers from 1 to 4, and n and m are independently te 0~. is an integer of S, with the proviso that A
is a single bond, the total number of n and m is at least 2
or if A is other than a single bond, it must be at least 1, R1 is hydrogen or lower alkyl, and G is hydrogen, lower alkyl, benzyl, lower acyl, benzoyl. , X is an integer of O or 1, and D+'! hydrogen, halogen, amine, acylamino, lower alkylamino or lower cycloalkylamino, E is hydrogen, halogen, amino or hydrazine, Z is (1) -(CH2)-Q [Q is hydrogen, hydroxy, halogen , cyano, azide, amino, lower alkoxy, lower acyloxy, lower thioargyl, lower sulfonylalkyl, (wherein L is 0 to 4, and R6 is hydrogen or R6 if L is 0) may also be the side chain of a naturally occurring amino acid such as pennol as found in the phenylalanine ester or inpropyl as found in the valinyl ester)"!1This is HO2C(CH2)k-C -0- (wherein k is D to 4)], -P (=Y) (OR")2, -
PC=Y) (OR") (○R/// ) and together with R6 (where Y is oxygen or sulfur, and R" and R" are independently hydrogen cylinder or lower alkyl ) or (21TC [wherein J is 01.S, NR7 (wherein R7 is hydrogen,
lower alkyl or 3 to 7 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, etc. or 1- or 2-methylcyclopropyl, 1- or 2-ethylcyclobutyl, etc.), and T
(al NR4R5 (wherein R4 is a linear lower alkyl having 1 to 4 carbon atoms, a hydroxy, lower alkoxy or halogen-substituted linear lower alkyl having 1 to 4 carbon atoms, cyclopropyl, 6-6
secondary alkyl having 6 to 6 carbon atoms, hydroxy having 6 to 6 carbon atoms, lower alkoxy or halogen-substituted secondary argyl, alkenyl having 3 to 6 carbon atoms, 1 to 4 carbon atoms in the alkyl chain. aralkyl having 1 to 4 carbons in the alkyl chain and optionally substituted with hydroxy, halogen, lower alkoxy or lower alkyl groups in the aryl nucleus and optionally heteroaryl is heteroarylalkyl substituted in the nucleus by a hydroxy, halogen, lower alkoxy or lower alkyl group and R5 is hydrogen or a hundred chain lower alkyl having 1 to 4 carbons) or (bl 01R4( R
4 is as described above)], and R2 and R
6 is independently selected from the group consisting of hydrogen, lower alkanoyl, benzoyl, or R2 or R
One of 3 is −PC=Y) (OR”)2 or −P(=
Y) (OR") (OR"') In formula C, R〃 and R'' are the same as above), and R2 and R
3kl- can be taken together to form a lower alkylidene enclosure or where Y and R' are as described above.

In the compound of formula (11), the term ``lower alkyl'' refers to, for example, methyl, ethyl, propyl, isopropyl,
1 such as butyl, sec-butyl, isobutyl, tert-butyl, amyl, isoamyl, neopentyl, hexyl etc.
Straight-chain K having ~6 carbon atoms includes branched alkyl groups.

Monologen especially includes all chlorine, fluorine or bromine.

Lower alkoxy and thioalkoxy are O-alkyl of 1 to 6 carbon atoms as described above for lower alkyl, or S-alkyl.

As mentioned above, lower alkanoyl has 1 to 1 in the alkyl chain.
A straight chain chain having 6 carbon atoms is a branched alkyl group.

As mentioned above, lower acyloxy refers to alkyl- and -0- in which alkyl is a straight or branched chain having 1 to 6 carbon atoms in total.

Lower acyl refers to 1 in a straight or branched alkyl group.
~6 carbon atoms 2.

Lower cycloalkyl is a 6-ring ring consisting of 3 to 7 carbons.
~10 carbons.

The compounds of formula +11 are used in free base form, where possible in the form of base salts and in the form of acid addition salts. Six forms are included within the scope of this invention.

In reality, using the salt form is equivalent to using the base form. Suitable pharmaceutically acceptable salts within the scope of this invention include:
For example, hydrochloride, sulfate, methanesulfonate,
Benzene sulfonate, p-toluene sulfonate etc. are obtained from inorganic acids such as hydrochloric acid and sulfuric acid and organic acids such as methanesulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid etc. One is derived from a suitable organic base and a base such as an inorganic base. Examples of suitable inorganic bases for the formation of salts of the compounds of this invention include hydroxides, carbonates and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc and the like.

The salt can be formed using any suitable organic base. Suitable bases for forming pharmaceutically acceptable base addition salts with compounds of the invention include organic bases that are non-toxic and have sufficient strength to form such salts. . These organic bases are of a range readily understood by those skilled in the art. By way of illustration only, this class includes chemical, tri- and tri-alkylamines such as methylamine, dimethylamine and triethylamine, mono-, tri-hydroxyalkylamines such as mono-, di- and tri-ethanolamine, amino acids such as arginine. and lysine,
These include guanidine, N-methylglucosamine, N-methylglucamine, L-glutamine, N-methylbiperazine, morpholine, ethylenediamine, N-benzylphenethylamine, tris(hydroxymethyl)aminomethane, and the like.

[See, eg, "Pharmaceutical Salts" in J. Pharm, Sci, 66 (11, 1-19 (1977)).

The salts of the above compounds can be prepared by dissolving the free base of the compound of formula (II) in an aqueous or aqueous alcoholic solution or other suitable solvent containing a suitable acid or base and evaporating the solution to form the salt. The free base of the compound (11) is prepared by reacting with an acid in an all-organic solvent, and the compound with an acid group (Ilffi) is prepared by reacting with a base in an organic solvent. In this case, the salt can be separated directly or obtained by concentrating the solution.

The compounds of the present invention are the group R' when R1 is not hydrogen for N of aminoadenosine, and n when n is not equal to m.
The moiety with ↓ and m can have an asymmetric carbon atom at each one of the two carbons to which Ar is attached. The present invention thus encompasses individual stereoisomers as well as mixtures thereof. Individual isomers can be prepared or isolated by methods known in the art. In particular, when Q is 6 and R6 is not hydrogen, the compounds of the present invention include the separated enantiomers and their racemates.

A preferred embodiment of the invention is that G and R1 are hydrogen;
Ar is phenyl, 2-chenyl or 2-furanyl, all of which are substituted or unsubstituted, X is 0, D and E are hydrogen, and Q is hydroxy; 1-12 and R3 are hydrogen, acetyl, benzoyl or taken together to form inzolobylidene, and the total number of 11 and m is not more than 7 (including all compounds of formula 11).

A more preferred embodiment is G, R1 for the preferred embodiment.
, A, r, xXDXE, QXR2 and R3, and further has a definition in which A is a single bond and the total number of n and m is limited to 2 or 3.

In general, the compounds in the formula are advantageously prepared by reacting 111 lopurin riboside having the formula till shown below with the requisite compound having the formula (1)'(r).

(It) (III) (where Ar
,R',GXnz m% A% D% E% Q,,R
3 and R2 are as described above, Hat is halogen, and preferably chlorine and R2 are bromine).

The reaction is carried out in an inert solvent such as an alcohol or in a non-zolotonic solvent such as dimethylformamide.
The reaction is carried out at 5 to about 130°C, conveniently in ethanol under reflux.

It is convenient to add a base, such as triethylamine or calcium carbonate, to neutralize the hydrogen monologonide formed as a by-product of the reaction; ) can be achieved by using an excess of equivalents of the compound. Also, it is convenient to retain the chelate, which is not necessarily required, as a ribofuranose hydroxyl group as an acetate or benzoate ester. If it is desired to produce a compound in which R2 and R5 are hydrogen, then formula +1)
After synthesis of the N6-substituted adenodino compound, these ester protecting groups can be removed with ammonium hydroxide or sodium methoxide.

Compounds of formula tI[l are hydrogen or)~D as logons
and E. Compounds of formula fI), in which D and E are other than hydrogen or halogen, can be replaced by compounds of formula (I), in which D and E are halogen, by substitution with D or E, which is other than hydrogen or halogen. can be manufactured in a stepwise manner from This is carried out using nucleophilic substitution conditions with compounds of formula D-H or E-I (where D or E is other than hydrogen or monohalogen). This can be done before removal.

Compounds of formula (11) where X is 1 can be prepared by peracid oxidation of the corresponding compounds of formula (Il) where X is O using procedures described in the art.

Other variations in the reactions described above are within the skill of the art, and therefore the above description should not be considered limiting.

The compound of formula (1) and its pharmaceutically acceptable acid addition salts have been found to have an affinity for adenosine receptors (referred to for convenience as A1 and A2 receptors). These compounds are active in animal studies that are predictive of neuroleptic activity for the treatment of psychotic disorders such as schizophrenia.

The compounds of the invention also have sedative/hypnotic properties and are useful as such for the treatment of drowsiness. These compounds exhibit unique analgesic properties and are useful in their own right for the treatment of pain.

Additionally, the compounds of the invention are useful as antihypertensive agents in the treatment of hypertension. The compounds also increase coronary blood flow and are useful as such for the treatment of angina and myocardial ischemia.

Adenone receptor binding-A receptor affinity (RB
A, 1) Preparation of membranes Whole brain-cerebellum and brainstem from male Long-Evans rats (150-20C1) were prepared by Plinkman Polytron p
Homogenize in ice-cold 0105M Tris-Hct buffer (PH 7,7) 3 + O volume using T-10 [Setting number 6 for 20 seconds]
) and 20. [lO[]]Xl Solnorol'
Centrifuge in RC-2 for 10 minutes. The supernatant is discarded and the pellet is resuspended and centrifuged as described above. The pellet is resuspended in Tris-Hct a solution 201 containing 2/1 international unit of adenosine deaminase (sigma type 1 from bovine intestinal mucosa) and incubated for 30 minutes at 37°C and then 10 minutes at 0°C. .

The homogenate was centrifuged again and the final pellet was placed in water-cold 0.05 M Tris-'sct buffer (pH 7.7).
) in the original wet tissue type i 20 ray/rn
Resuspend to a concentration of 1 and use immediately.

Test conditions Tissue homogenate (101 w/me)'t, with or without test agent 1. OnM's [JI
-N(1-cyclohexyladenosine (C'n)-cH
A) Q,05M Tris-Hct buffer (p
Incubate for 1 hour at 25°C in triplicate in l(7,7). The incubation volume tht is 21. Unbonded (Sho)-CHA was transferred to Whatman glass fiber (GF
/B) Separation by rapid filtration under reduced pressure through a filter. Cool the filter with water (0.05M)
Rinse six times with cz-grade buffer solution (p?17.7) 5N. Filter Opesokuman Reggie Solf EP (Beckman
Ready-8olv HP) Scintillation Cocktail 10-30 = After shaking for 1F\F or more on a mechanical shaker in N, the radiolabeled ligand retained on the filter was measured by liquid scintillation spectrophotometry. do.

Calculated non-specific binding is defined as the binding that occurs in the presence of 1 mM theophylline. The concentration of test agent that inhibits 50% of specific binding (ICso) is determined by non-linear computer curve fit. ′jk of radioligand binding (pmol/Dulham of tissue)
Scattered plot by linear regression of the line obtained by plotting vs. total (5 catcher dpl
ot).

Since the amount of radioligand bound is a small fraction of the total added, the free radioligand r is defined as the concentration of radioligand added to the incubation mixture (nM). Hill coefficient
t) f, calculated by linear regression of the line obtained by plotting the log of bound radioligand versus log f. Maximum number of binding sites (“max
) e, calculated from the scuttle P plot.

Adenosine receptor binding-A2 receptor affinity (R
BA2) M weave production 200-500? mixed-sex Spragus-Dawley rats
Buy Whole Brain Peruvian Freeze (Lonoyas, Arkansas) from the United States. Male Long-Evans hooded rat, s
) fresh hA (NY% Altamont, Bruce Pruss Farms) gives essentially identical results. The brain is thawed and then kept on ice while the striatum is dissected and removed. The striatum was placed in a water-cooled 50 mM Tris-1-IC1 (pH 7,7,5 at 25°C) for 30 seconds in a Polytron PT-10 (Brinkmann) at a temperature of 5.
Grind in 10 volumes pi-18,26) () at °C. Suspension 'i50. Centrifuge for 10 minutes with DOOXf,
Discard the super-soaking liquid and place the pellets in ice-cold Tris 1 as described above.
Resuspend to 0 volume, recentrifuge, resuspend at 1915 and store in plastic vials at -70°C (stable for at least 6 months). If necessary, the tissue is thawed at room temperature, ground in a polytron, and kept on ice in the used housing.

All incubations were performed on rat striatal membranes of rat weight original tissue type 1Ik5υ9.4BM (3n).
-n-ethyladenosine-5'-carpoxamide ((
3B) -iCA), 50 °C M N6-cyclopentyladenosine (to remove the A luxezoter bond), 1
60 minutes at 25° C. in a 12×75 glass tube containing 1 M Tris with 0 mM MgCl 2 , 0.1 unit/h of adenosine deaminase and 1 g of trimethyl sulfoxide. N6-cyclopentyladenosine is [J,02' dissolved at 10 mM in NHCl and diluted in Tris. Stock solutions and diluted solutions of N6-cyclopentyladenosine can be stored at -20°C for several months. Test compounds are dissolved in 10 ml vol in dimethyl sulfoxide P and diluted in dimethyl sulfoxide to a final culture concentration of 1 oOx on the same day as the experiment. The control culture uses equal volume = uoi] of dimethyl sulfoxide. The resulting concentration of dimethylsulfoxy P has no effect on binding. [5H]-NECA is diluted in Tris at 40°C. Desensitizing solution (5■70.79d
) are sufficient to give a final concentration of 10 and 0.1 units/unit in the incubation, respectively.
2 and adenosine deaminase. For test compounds with IC50 values less than 1M, the order of addition is test compound (107), N6-cyclopentyladenosine (10C1), (jH)NECA (1007).
) and a film (0.79 formation). Inunaruko C from 1M
For test compounds with 5o values and limited water solubility, the order of addition (equal volumes) should be: test compound, membrane
N6-cyclopene f Ruadenosine and C3H) N
It is ECA. After all additions, the tube ranks are swirled and then the tubes are incubated for 60 minutes at 25° C. in a shaking water bath. Swirl the rack of tubes for an additional period of time in between throughout the incubation.

Incubation with 2,4 crIL under reduced pressure
Finishing by passing through a GF/B filter. Pass each tube as follows. Press the contents of the tube onto the filter, add 4N of ice-cold Tris to the tube and press the contents all over the filter and wash the filter twice with 4N of ice-cold Tris. Filtration is completed in approximately 12 seconds. Place the filter in a scintillation vial and
5 ml of Mula 947 syntelesis liquid is added and the vial is left overnight, shaken and counted with a liquid syntelesis counting needle at a efficiency of 40 inches.

Data Analysis Non'W u binding is defined as k 100 y binding in the presence of N6-cyclopentyladenosine and specific binding is defined as total binding minus non-specific binding.

The engineering C5o is a weighted nonlinear least squares curve - fit versus mass -
Effect formula (Weighted nonlinearlea
st 5quares curve-fitting
to the mass-actionequation
n).

where Y is Cpm, T is cpm total binding without drug, S is cpm specific binding without drug, D is the concentration of drug, and K is the IC5Q of the drug.

The weighting factor was calculated under the assumption that the standard deviation is proportional to the expected value of Y. Non-specific binding is treated as infinitesimal (infinite) concentrations of drug in computer analysis.

The IC5o values (nM) for adenosine A1 and A2 receptor affinities =37 are shown in Table 1 below.

3 7.3 &69
5.6 87 Antipsychotic Evaluation The compounds of the present invention are novel chemical entities that are useful as pharmaceuticals for the treatment of psychosis. Antipsychotic activity of representative compounds of the invention is demonstrated by the mouse activity and screen test procedure (MAST) described below.

Animals Nine non-fasted Swiss-Webster male mice weighing 20-30 f are divided equally into 6 groups for each drug dose tested.

That is, the data for each dose are
provided by 6 separate groups of 1 mouse.

Drug minimum 3 doses (1, 0, 30 and 1 o o I
V) are tested for each drug. The processing is
Administer intraperitoneally 1 hour prior to testing.

All used types are calculated as the original compound and 1
Feed 2 volumes to 0 ducks. Compounds are dissolved or suspended in 0.2 methocel. Control animals are injected with methocel.

test Two-part test procedure' (starting after i-1 hour injection.

First, carry out the screen test (ST).
Pharmac, Biochem, Behav,
Please refer to Vol. 6, pp. 351-353 (1977)]
. Briefly, the test consists of placing the mouse all on an individual wire screen and then rotating it 180 degrees at the beginning of a total 60 second observation period. Record the number of mice falling from the inverted screen.

Immediately after this screen test, the final stage test begins by placing each group of six mice into one actophotometer.
es 22, pp. 1067-1076 (1978)].

The actophotometer consists of a cylindrical chamber whose center is occupied by another cylinder containing illumination for six photovoltaic cells located around the periphery of the chamber. Six light flux interruptions are equal to one count. Increase motor activity for 60 minutes 10
Recorded by computer at minute intervals.

Data The data obtained from the screen test is shown as a mouse falling off the screen. The data derived from the locomotor activity of drug-treated mice were compared to the activity of all vehicle-treated animals and are expressed as inhibition of spontaneous locomotion. All chis recorded for locomotor inhibition (LI) are based on 1 hour of accumulated data. Tier the test for both stages. A = 60-100 section, C-61-59
% and N = D ~ 60% 0 Overall Dosage Rating - 41 = Values are obtained by the following criteria.

Motion Blocking Rating + Screen Test Failure Rating = Dose Rating A-N or C=A A-A = CC-N or C=C All other combinations = N LAD achieves A rating It means the lowest dose. Compounds exhibiting an overall dose rating of A at doses of 9 to 100 cm or less are considered to be active. Utilizing this procedure, an overall dose estimate of A is obtained for the compounds in Table 1 at the doses indicated in the table.

The compounds are as shown in the examples.

=42- Table ■ Dose Example of motor activity screen test
(IP) prevent (phrase) prevent failure (
h) 1 0.05 0.3 43 1
11.0 48
05.0 38
03 a03 17
00.1 40
00.3 70
01.0 85
03.0 89
04 (rat po) Dose Locomotor activity screen test example
(IP) Prevention (%) Failure prevention (
%)7 1.0 5
03.0 21 0
10.0 82 010
86 D10
12D Representative Compounds of the Invention (Bottomized in the Examples) Gold and also the following protocol:
IDR or SID5M) f/! : Therefore, it was tested for antipsychotic properties. The compound is ED 5L shown below]
(■/Kg) f and is considered to be active as an antipsychotic in the test procedure.

Manipulated Adult Male Long-Evans Rat (SIDR)
or squirrel monkeys (SIDSM), which are conditioned to press a lever to avoid painful electrical foot shocks.

If the animal fails to press the lever, it receives a shock every 10 seconds until it presses the lever. This 7-yoke can be terminated by pressing the lever. Thereafter, there is no shock as long as the lever is pressed at least once every 20 seconds.

Have each animal behave under self-control.

A period of one week is used to establish baseline behavior and another period after the week is used as the drug period. As soon as one 74 turn of avoidance is established, study the effects of standard and unknown compounds.

When tested according to the procedure described above, the representative compound of Example 1, as shown below, had a 0.55 vvKf in the S than R protocol (rat) as described above and a SID5M as f, - as described above (squirrel monkey). In the following, [152 Juku's EDso is shown.

Response Evaluation All cases are programmed electronically and the responses to these cases are the fee for the program p +
Calculated or used as an a4 tsk.

Antihypertensive Evaluation (AHP3) The usefulness of the compounds of the invention as antihypertensive agents is demonstrated by their efficacy in standard pharmacological test procedures, such as their efficacy in causing a significant decrease in mean arterial blood pressure in conscious rats. . The test procedure is as described below.

Direct Monitoring of Aortic Blood Pressure and Heart Rate from Conscious Rats Continuous monitoring of pulsatile blood pressure (BP) from conscious, unrestrained rats surgically equipped with a polyethylene cannula is demonstrated using a computer-assisted data capture scheme. Achieved by (CADO8). The basic elements of the method are cannulation and CADO8.

Method Cannula insertion procedure: Rats were treated with TeraSeal (1:1 tiletamine HCt and zolazepam HCt) (20-4
Anesthetize with 0 kg/kg, IM) and expose the descending aorta through a midline incision. A cannula made from polyethylene tubing is inserted into the aorta through a small puncture hole below the renal artery. The puncture hole is made with a 23G disposable needle using a section of the aorta that is tightened above and below the puncture site.

PRloo (from O,86wn) maternal and pE5
0 (ID O, 58 ■) A cannula consisting of a tip,
Attach the trocarni, insert through the lumbocnemius muscle and pass subcutaneously along the midline of the back and out between the ears.

Cannula to the lumbar abdominal muscles and scale lae (Scalu)
las) (3 to [] green braided seams) and fix in between. The midline incision is closed in two steps (first muscle, then skin) using continuous overlapping stitches (4-0 stitches). Next, each rat received 30 doses of penicillin.
,000 units (penicillin G procaine sterile solution) is given subcutaneously.

The rat is equipped with a harness-strap device designed to protect the cannula and provide relatively free movement of the rat.

The harness is constructed from hook and loop tape cemented to a metal plate and spring wire (
18-8 stainless steel) with a brass ring attached. Pass each polyethylene cannula through a spring and a pressure transducer (
Mod, el P23Gb) and infusion pump (MA) from Statham Instruments, Hatley, Puerto Rico.
, Sage Mo of Orion Research, Cambridge
del234-7) by PE100 pipe. During the study, rats were given a
4' I) Continuous slow infusion of physiological saline solution (
Approximately 40,011 or 40 to/4' I) per 24 hours
unit). Additionally, if the aortic pulse pressure (systolic-diastolic) is below 25 maHg, the cannula is "flushed" with heparinized saline.
hes).

CADC'S The pulsatile blood pressure and heart rate of each of the 32 rats were
Monitored every minute by an in-laboratory microcomputer directly linked to a data centralization computer. Data is,
The data is carefully stored on central disks and then analyzed and report generated by the main research computer (
transfer to magnetic tape for generation). The entire scheme modulates the main signal from the pressure transducer, systolic, diastolic and mean blood pressure and heart rate by the laboratory microcomputer and storage, analysis and report generation by the main search computer. It consists of generating a main data set of 1 minute values of .

The transducer includes an analog signal conditioning module (analog signal conditioning module).
oningmodules). The module provides a regulated excitation voltage to the transducer, the amplification necessary to interface the microprocessor, and an active low-pass filter to compensate for pressure wave type distortions caused by the flexible liquid-filled narrow cannula. The distortion is 22-26 Hz and this allows reliable estimation of systolic and diastolic blood pressure.

A microcomputer (one for each of the two groups of 16 rats) was connected via a module interface device, an analog-to-digital converter for pressure wave type signals and digital inputs for dose and event marker switches. Connected to the human power component. The microcomputer regulates the sequential acquisition of data from the module interface devices by an internal synchronized timekeeping clock/time pace generator. Using a time pace generator as a reference, blood pressure values and marker switch states for each of the 32 measurement points are extracted every 10 m5ec. The microcomputer processes the received blood pressure samples to provide heart rate and running averages of mean, systolic and diastolic blood pressure.

When tested according to the procedure described above, the example compounds shown in the table produce the changes in MAP (mean arterial pressure) and heart rate shown in the table.

Table 11 16% 623% 1023 Chiro 343% 7 10 32% 9310 Chiro 10 10 10 Chiro 11 10 5% 12 10 23% LAD is the lowest test in which a 10% reduction in blood pressure is achieved for 4 consecutive hours. Means dosing lid.

Accordingly, the present invention also provides psychotic, sleeping sickness, antipsychotic, sedative, analgesic, antihypertensive or antianginal effective amounts of a compound of formula (1) above, together with a pharmaceutically acceptable carrier. Includes pharmaceutical compositions for treating pain, hypertension or angina.

Furthermore, the present invention provides treatment for psychosis, drowsiness, etc. in mammals, which comprises orally or parenterally administering to the mammal a corresponding pharmaceutical composition containing the compound of formula (1) in a suitable dosage form. Includes methods of treating disease, pain, hypertension or angina.

In preparing pharmaceutical compositions from the compounds of the present invention,
Inert, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and wholesomes. A solid carrier can be one or more substances that can also act as a diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, binder or tablet disintegrant. It may also be an encapsulating substance. In powders, the carrier is a finely divided solid that is mixed with the finely divided active compound. In tablets, the active compound is mixed with the carrier having the necessary binding properties in the appropriate proportions and compressed into the desired shape and size. Powders and tablets suitably contain from 5 or 10% to about 70% active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, gum tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term formulation refers to an encapsulating substance such as a carrier and an active ingredient in which the active ingredient (with or without other carriers) is surrounded by the carrier and the result is a capsule in which the carrier is associated with the active ingredient. It is a book designed to contain the formulation of compounds. Similarly, cachets are also included.

Tablets, powders, cachets, and capsules can be used as solid use forms suitable for oral administration.

In the manufacture of full-strength, a mixture of fatty acid glyceryl or a low melting wax such as cocoa butter is first melted and the active ingredient is uniformly dispersed therein, such as by stirring. The molten homogeneous mixture is then poured into conventional sized molds, allowed to cool and thereby solidify.

Liquid form preparations include solutions, suspensions, and emulsions. By way of example, aqueous or water-propylene glycol solutions for parenteral injection may be mentioned. Liquid preparations can also be formulated as solutions in aqueous polyethylene glycol. Aqueous solutions suitable for oral use include:
They can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use include finely divided active ingredients dispersed in water with a viscous substance such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents. It can be manufactured by

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

These particular solid form formulations are also advantageously presented in unit dosage form and used as such to provide a single liquid dosage unit. Alternatively, multiple individual liquid doses may be obtained by measuring the intended volume of the liquid form preparation with a syringe, teaspoon, or other volumetric container after conversion to liquid form. Sufficient amount of solids can be provided so that When producing multiple liquid doses in this way, it is preferred to maintain the unused portion of the liquid dose at a low temperature (eg under refrigeration) in order to retard possible decomposition. Solid form preparations intended for conversion to liquid form are
In addition to the active substances, flavorants, colorants, stabilizers, buffers,
It may contain artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

Liquids utilized for producing liquid form formulations are water, isotonic water, ethanol, glycerin, propylene glycol and mixtures thereof. Typically, the liquid utilized will be chosen with respect to the method of administration. For example, liquid formulations containing large amounts of ethanol are not suitable for parenteral use.

Preferably, the pharmaceutical formulation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, eg, packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number in packaged form.

The amount of active compound in a unit dose of the formulation can be varied or adjusted from 0.01 to 500 kg, preferably from 0.1 to 50 kg, depending on the particular application and the potency of the active ingredient.

The compositions can also contain other compatible therapeutic agents, if desired.

For therapeutic use as described above, the mammalian dosage range for a 70 kg patient is 0.01 per day.
~150 da/kg body weight or preferably 0.
5-50/kg body weight. However, the amount used can vary depending on the needs of the patient, the extent of the disease being treated and the compound used.

Determination of the appropriate amount to use for a particular situation is within the skill of those skilled in the art. Generally, treatment is initiated using small doses of the compound that are less than the optimal dosage. Thereafter, the amount used may be increased in small increments until the optimum effect under the circumstances is reached.

For convenience, the total daily dosage may be divided and administered in portions throughout the day, if desired.

The following examples are presented to illustrate the invention and are not intended to limit the invention to these examples.

Example I N6-((1-phenylcyclopropyl)methyl)adenosine 6-chloropurineribosi)' (8,611!, 30 mmol), (1-phenylcyclozorobyl)methylamine (4,411i, 60 mmol) ) and triethylamine (6,061/, 60 mmol) are refluxed in stirred ethanol (3 ood) under N2 for 20 hours. Cool to Oo to crystallize the product. N6-((1-phenylcyclopropyl)methyl)adenosine (9,24L 79%) as a very pale khaki solid with a melting point of 118-123°C by vacuum filtration and vacuum drying.
).

Calculated value for C2oH2gNs04: C60,459
6, N5.79%, N17.63%. Experimental value: C59,
58%, N5.77%, N17.49.

(1-phenylcyclopropyl)methylamine DMSO
(zomethyl, x, ruho*'/ )' ) (20m)
Phenylacetonitrile (5,8519,50 mmol) in DMS was stirred for 45 min at 25° under N2.
Oil-free NaH(3,0-) in O(100-)
, li', 125 mmol). Heavy gas generation occurs. After another 30 minutes, DMSO (2
1,2-dibromoethane (14,1y,75
(mmol) is added dropwise over the course of 1 hour. The reaction mixture turns purple, is heated to about 500 ℃ and further gas evolution occurs. After an additional hour, the reaction mixture was slowly poured into ice water (
250-) and ether (3X 5 Q+
Extract with aA'). The combined extracts were diluted with water (2 x 100 m
) and saturated salt solution (1ooml) and dried (MgSO4). The solvent is removed under reduced pressure to yield 1-phenylcyclopropanecarbonitrile (6,5Bi, 92%) as a mobile brown oil. NMRδ (CDC
45) 7.25~7.40 (5H, m), 1.6~
1.8.1.2-1.45 (2H and 2H, AA'
BB').

LiA1. H4 (1,81,48 mmol) is added over 5 minutes to a solution of 1-phenylcyclopropanecarbonitrile (658 g, 46 mmol) in ether (200 ml) stirred at 0° under N2. 1 hour later
The reaction mixture was mixed with water (1.8 m), 10 w/v NaOH
Cool by careful addition of solution (1, sd) and water (5,4 rnl). Heavy gas production occurs again.

The mixture was vacuum filtered and the filtrate was diluted with dilute Hcz (o, 2M
, 3X100d). The combined extracts are washed with ether (3×100 WLl) and made basic with NaOH pellets (3.2 g, 80 mmol). Aqueous 1-
is extracted with ether (3x1oowLl). The combined organic phases were diluted with water (2 x 100 Tnl), saturated brine (100 mJ
) and dried (Mgso4).

The solvent was removed under reduced pressure to give (1-phenylcyclopropyl)methylamine (4,98Ii,
74chi). NMRδ(CDCl2)Z1~Z5(
5H, m), 2.77 (2H, s), 1.3 (2
Jbrs), 0.6-0.95 (4H9m).

Example 2 H6-((1-(3-chlorophenyl)cyclopropyl)methyl)adenosine (1-(3-chlorophenyl)cyclozolobyl)methylamine is prepared from (3-chlorophenyl)acetonitrile as described in Example 1. .

The amine as described in Example 1 (1,82,9°10
mmol) and 6-chloropurine riboshir(2,87Li
O mmol) and triethylamine (2.02 g, 2
0 mmol) with an overall yield of 74%, melting point 71~
95° off-white crystalline solid,! : Then H6-((1
-(31'Lolophenyl)cyclopropyl)methyl)adenosine (3,4:1,79%). C20H2
Calculated value for 2N504C1: C55,62, H5,
10, N16.22, Cl3.25%.

Experimental value 2 C55, 30, H5, C15, N 16.50
, C18,15 width.

Example 3 H6-((1-cheno-2-ylcyclozorobyl)methyl)adenosine As described in Example 1, (1-cheno-2-ylcyclopropyl)methylamine was reacted with 2-chenylacetonitrile and 1 , 2-dibromoethane in an overall yield of 57%.

The above amine as described in Example 1 (1,51°10 mmol) and 6-chloropurine riboside (2,871!,1
0 mmol) and triethylamine (2,02L20
reaction with H6-((1-cheno-2-ylcyclozolopyl)methyl)adenosine ((1-cheno-2-ylcyclozolopyl)methyl) as a fluffy off-white solid with a melting point of 136-1385 °C after two crystallizations from ethanol (mmol). 2,9OL71%). Cl8H21N504SKJLj-le calculation value: C
53,60, H5,21, N17.37.5H94%.

Experimental values: C5578, H5,45, N1Z28, 87.
52%.

Example 4 H6-((1-phenylcyclopropyl)methyl)adenosine-N1-oxide m-rioo peroxybenzoic acid (1,8([1,85th, 9 mmol) and BH' in THF (10WLl)
I' stabilizer (0,20 g) was added to N6-((1-phenylcyclopropyl)methyl) in refluxing tetrahyfuran (TPF) (5rnl) over 30 min.
Add to the solution of adenosine (Li9, 9.3 mmol). After a further 30 minutes, the solvent was removed under reduced pressure and the residue was flash chromatographed on silica gel using 15% then 15% CHgOH in CHCLs as eluent and then 10% in CHCLs as eluent.
CH30H of q6 is purified by preparative TLC on silica gel using one use. 1 band R, F, 0.38 CH
Extraction with C2s/CHgOH and rigorous removal of the solvent under reduced pressure yielded N6-((1-phenylcyclopropyl)methyl) as a white solid with a melting point of 105-113°C.
Adenosine-N1-oxy)' (0,48,9,39%
). Calculated value for C20H23N505: C
5B, 11, I (5,57, N16.95%.

Experimental values: C57.01, H5.55, N 16.51
%. lR1647, 1579, 1502, 1214σ
.

Example 55'-deoxy-57-chloro-IL6-((1-
(1-Phenylcyclopropyl)methylamine (0.55 g, 3.75 mmol), 6-chloropurine-57-dioxy-, prepared as in Example 1 in ethanol (4QWLl). 5'-chlororiboside-2', 3'
- A solution of isopropylidene (1,25Ji', 6.6 mmol) and triethylamine (0,75 g, Z55 m9) is refluxed under N2 for 24 hours.

The solvent was removed under reduced pressure and the brown gummy residue was partitioned between ethyl acetate (5C1!A) and water (251R1). The organic phase was decanted and dissolved in water (25WL1), saturated brine (25 -) and dried (MgSO4). The solvent was removed under reduced pressure and the remaining light brown oil was dissolved in aqueous formic acid (50%, 20d) under N2.
Heat for an hour. The solvent was removed under reduced pressure and the remaining light brown oil was dissolved under N2 in aqueous formic acid (50%, 20%
m)) for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (50 ml) and saturated NaHCO3 solution ('15 ml), water (25 d).
, washed with saturated brine (25 ml) and dried (MgSO
a) Do. The solvent was removed under reduced pressure and the remaining brown gummy foam was purified with 10% in CHCLS as eluent.
Separation TL on silica gel using CHs○H once
Purify by C. CHCL upper band R, F, 0.41
Extraction with 3/Me OH and rigorous removal of the solvent under reduced pressure yielded 5'-deoxy-5'-chloro-N6-((1-phenylcyclopropyl ) methyl) adenosine (0,40
g, 27%). Calculated values for C20H22CtN503: C57,76, H5,29, N 16.85
, C18, 54%. Experimental value: C56,74, N5°20
, N16.80, CL 9.13ch.

6-chloropurine-5'-thioxy-5'-10loriboshiP-2',3'-isopropylideneoxyphosphorus chloride (1
2,28,9,80 mmol) inosine-2',3'-isopropylidene (6,16Ii, 20 mmol), tetraethylammonium chloride PC6,6OL (40 mmol) in acetonitrile (40+U) at 25° under N2 , N,N-dimethylaniline (969,80 mmol) and fresh powdered =69-calcium hydride (0,52 g, 20 mmol) over 5 minutes. After a further 5 minutes, the mixture is refluxed for 15 minutes. After cooling, the volatiles are removed under reduced pressure and the residual oil is diluted with CHCl3 (200 g) and pressed into a vigorously stirred mixture of 50% saturated Na2CO3 solution (soomx) and ice (250 g).

The organic phase was separated and the aqueous phase was dissolved in CHCl5 (2X 5
QWLl). The combined organic extracts are washed with saturated sodium carbonate solution (100 rIL6) and dried (Na2sO4). The solvent was removed under reduced pressure and the remaining oil was purified with CHCl3, 2% CH30H in CHCl5 and then 4% CH3 in CHCl3 as eluent.
Purify by chromatography on silica gel using 0H. The solvent was removed under reduced pressure and filtered as an orange-brown gum. -Chloropurine-5'-deoxy-5'-chlororiboside-2',3'-isopropylidene-(2,50,!i') , 66%). NMR (CDC
Z5) δ8.67 (IH, s), 8.25 (IH, s
), 6.15 (I H, a, J=2.5Hz), 5
．． 33, 5.03 (IE (and IH, d ABq, J
,,8=6Hz,J(1=2.5,3H7),4.4
6 (IH, thing d, Jd=3 N7, Jt,=6
Hz), 3.5-5.85 (ABq of 2H, d.

JAB = 12 Hz, J (1 = 6 Hz)
, 1.65 (3H, s), 1.41 (3H, s).

Example 65'-chloro5'-deoxy-N6-(('1-
6-Chloropurine- 5'-deoxy-5'-
Chlorriboside-27,3/-isopropylidene (1,
25 g, 3,6 mmol) (prepared as in Example 5) and triethylamine (0,751!, 1
5 mmol) are reacted together as described in Example 5. Aqueous formic acid hydrolysis produces 5'-chloro-5'-deoxy-N6-((1-cheno-2-ylcyclopropyl)
methyl) adenosif (0,44,9,29%'). Calculated value for C18H20CIN50gS:
C51,25,E(4,74,N 16.61,C1
8°42.87.59%, experimental value: C50,53, H4
,90, N15.90, CL 9.13, S7.22chi.

Example 7 N6-((1-phenylcyclobutyl)methyl)adenosine (1-phenylcyclobutyl)methylamine was reacted with phenylacetonitrile (2,9
3 g, 25 mmol) and 1,3-dibromopropane (757 g, 37.5 mmol) in an overall yield of 62 mmol. The above amine (1,6111,10 mmol) is reacted as described in Example 1 with 6-chloropurine riboshi)' (2,87!7.10 mmol).

Since the compound does not crystallize, the solvent is removed under reduced pressure and the residual gum is dissolved in ethyl acetate (50rnl) and it is dissolved in water (2x2sd) and saturated brine (25d).
By washing and drying (Mgso4) with
Purify the compound. The solvent was removed under reduced pressure and the residual gum was purified with 5% CH30 in C11CLs as eluent.
N6-((1-phenylcyclogutyl)methyl)adenosine (0.24 g, 58%)
is obtained as a white solid foam with a melting point of 95-118°C. C21I (calculated value for 25N504: C611
1, H6,0B, N17.03chi. Experimental value: C61,
21, H6, 23, N17.24%.

Example 8 N6-((1-(3-chlorophenyl)cyclobutyl)methyl)adenosy/ As described in Example 1, (1-(3-lylorophenyl)cyclobutyl)methylamine was reacted with (3-10lophenyl)acetonitrile. (3,79 g, 25 mmol) and 1,6-dipromopronozone (7,57 g, 375
mmol) with an overall yield of 60 mmol.

Ami 7C1,9 as described in Examples 1 and 7
61! , 10 mmol) to 6-chloropurine riboshi)'
(2,87L 10 mmol) and purified. N6-((1-(3-
Chlorophenyl) cyclobutyl) methyl) adenosine (
3,66N, 82%) is obtained. Melting point: 92-98°C.

Calculated value for C21H24C4N604 205 (5,
57, N5.39, N15.71, C1Z97chi. Experimental values: C56.11, H5.33, N 15.4
4.C18,99%.

Example 9 N6-((1-Theen-2-ylcyclozotyl)methyl)adenosine (1-cheno-2-ylcyclobutyl)methylamine was prepared from cheno-2-ylacetonitrile (3,70 ,!i', 60 mmol) and H1
．． Prepared from 3-dizolomopropane (9.01°45 mmol) in an overall yield of 55%.

The above amine (1,6
7L10 mmol) to 6-chloropurine ribbon)'(2
, 87 g, 10 mmol) and purified by column chromatography to give H6-(1-(cheno-2-ylcyclobutyl)methyl)adenosine (3,18II) as a colorless glass with a melting point of 84-92°C. ,
76chi).

Calculated value for C19H23NsO4S: C54,6
B, +(5,52, N111S, 79.87.67%.

Experimental values: C54.88, H5.69, N16.77,
S7.55ch.

Example 1o H6-((1-phenylcyclopentyl)methyl)adenosine Preparation of (1-phenylcyclopentyl)methylamine as the hydrochloride salt at 8 points from 1-phenylcyclopentanecarbonitrile at 185-186°C as described in Example 11. do.

The above amine hydrochloride (5,0
Ii, 24 mmol) to 6-chloropurine ribbon)'(
Column chromatography produced hJ6-((1-phenylcyclopentyl)methyl)methyl)adenosine (3,81', 37%) as a solid white foam with a melting point of 74-78°C. can get. 022F (for 27N504) 1 Calculated value: C6
2,12, E(6,35, N 16.47%.C2
Calculated for 2H2yN5040, 25 CHCl5: C5B, 69, H6,03, N15.38%. Experimental values: C59.02, H5.94, N15.25.

Example 11 H6-((1-phenylcyclohexyl)methyl)adenosine (1-phenylcyclohexyl)methylamine (1,8 (1,8 mmol) and 6
-chloropurine ribbon)' (2.36 g, 8 mmol)
are reacted as described in Example 1. The solvent is removed under reduced pressure and the residue is dissolved in CHCLs and washed with water and dried (ugsoa). The solvent was removed under reduced pressure and the remaining white platform was purified by silica dal chromatography using 1% MeOH in CH2Cl2 as eluent to give a melting point of 87-89°C.
H6-((1-phenylcyclohexyl)methyl)adenosine (1,49Jil, 4
2%). Calculated values for C23H29N504:
C62,87, H6,61, N 15.95%. Experimental values: C62.22, H6.96, N15.70%.

(1-phenylcyclohexyl)methylamine 1-phenylcyclohexane carbonitrile, ammonia 16
Reduction with H2 using a Raney nickel catalyst in methanol containing H2. By stripping off the catalyst and treating with methanolic HCl and isopropyl ether, (1-phenylcyclohexyl)methylamine is precipitated as its hydrochloride salt, melting point 230 DEG-235 DEG C.

Example 12 H6-((1-(4-chlorophenyl)cyclopropyl)methyl)adenosine (1-(4-chlorophenyl)cyclopropyl)methylamine was prepared as described in Example 1 in 4-chlorophenylacetonitrile and ethylenedi 6 from bromide
Produced with an overall yield of 3%.

The above amines prepared as in Examples 1 and 7 (
1,48 g, 8 mmol) and 6-chloropurine ribbon)
' (2,091!, 73 mmol) and triethylamine (1,1A', 8 mmol) with a melting point of 13
A cream-colored solid at 2 to 168°C and N6-
Gives ((1-(4-chlorophenyl)cyclopropyl)methyl)adenosine (1,47L47%). C2o
Calculated value for H22N504 C1: C55,62,
ll-l5.10, N16.22, C1B, 23%.

Experimental values: C56,16, H5,22, N 15.54
, Ct912%.

The following compounds are also prepared by a method similar to Example 1.

Example 13 N6-(1-(4-methoxyphenyl)cyclopropylmethyl)adenosine Melting point 88-91°C Example 14 N6-(1-(3,4-dichlorophenyl)
cyclopropylmethyl)adenosine M point 120-122°C Example 1s N6-(1-(2-methoxyphenyl)cyclopropylmethyl)adenosine Melting point 82-90°C Example 16 N6-(1-then-ro-yl)cyclopropylmethyl) Adenosine MA 122-127°C Example 17 N6-(1-(5-promothien-2-yl)cyclopropylmethyl)adenosine Melting point 112-11
8°C Example 18 N6-(1-naphth-2-ylcyclopropylmethyl)adenosine Melting point 91-95°C Example 19 N6
-(1-naphth-2-ylcyclobutylmethyl)adenosine Melting point 110-118°C Example 20 N6-(1-(2
-chlorophenyl)cyclopropylmethyl)adenosine Melting point 93-101°C Example 21 N6-(1-(2-methylphenyl)cyclopropylmethyl)adenosine Melting point 95-99°C Example 22 N6-(1-(2-furanyl)cyclopropyl Methyl) adenosine melting point 128-130°C Example 23
N6-(1-(5-methylnaen-2-yl)cyclopropylmethyl)adenosine Melting point 103-106°C Example 24 N6-(1-phenylcyclopropylmethyl)adenosine-51-ylhydrozine succinate Melting point 143-145°C Example 25 N6-(1-phenylcyclopropylmethyl)adenosine-51-uronami P melting point 203-205°C

Claims (1)

[Claims] 1) A compound having the formula ▲A mathematical formula, a chemical formula, a table, etc.▼(I), a pharmaceutically acceptable base salt thereof, or a pharmaceutically acceptable acid addition salt thereof. In the above formula, Ar is (1) phenyl, (2) 1- or 2
-naphthalenyl, (3) 2- or 3-thienyl, (4
) 2- or 3-furanyl, (5) 2-, 4- or 5
-thiazolo, (6) 2-, 3- or 4-pyridyl, or (7) 2-pyrimidyl, and (1), (2
), (3), (4), (5), (6) or (7) is unsubstituted or lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, lower acyloxy, amino, N - at least one of lower monoalkyl or N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl or nitro
A is a single bond, O, S, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, q, q′ or q″ are independently integers from 1 to 4), and n and m are independently integers from 0 to 3, provided that if A is a single bond, then the total number of n and m is at least 2. or if A is other than a single bond, it must be at least 1, R^1 is hydrogen or lower alkyl, and G is hydrogen, lower alkyl, benzyl, lower acyl. , benzoyl, x is an integer of 0 or 1, D is hydrogen, halogen, amino, acylamino, lower alkylamino or lower cycloalkylamino, E is hydrogen, halogen, amino or hydrazine, z is (1)-(CH_2)-Q [In the formula, Q is hydrogen, hydroxy, halogen, cyano, azide, amino, lower alkoxy, lower acyloxy, lower thioalkyl, lower sulfonylalkyl, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ where L is 0 to 4 and R_6 is hydrogen or if L is 0, R_6 may be the side chain of a naturally occurring amino acid) or ▲ a mathematical formula, chemical formula, table, etc. (selected from the group consisting of ▼ (in the formula, k is 0 to 4)], −P(=Y)(OR″)_2, −P(=Y)(OR″)
Together with (OR'') and R^3 there are ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (where Y is oxygen or sulfur, and R'' and R
″′ is independently hydrogen or lower alkyl), or (2) ▲ has a mathematical formula, chemical formula, table, etc. ▼ [wherein J is O, S, NR_7 (wherein R_7 is hydrogen,
lower alkyl or cycloalkyl having 3 to 7 carbons) and T is (a) NR_4R_5
(wherein, R_4 is linear lower alkyl having 1 to 4 carbon atoms, hydroxy having 1 to 4 carbon atoms, lower alkoxy or halogen-substituted linear lower alkyl, cyclopropyl, 3 to secondary alkyl with 6 carbon atoms, hydroxy with 3 to 6 carbon atoms,
lower alkoxy or halogen-substituted secondary alkyl, 3-
alkenyl with 6 carbon atoms, 1 in the alkyl chain
aralkyl having ~4 carbons and optionally substituted in the aryl nucleus with hydroxy, halogen, lower alkoxy or lower alkyl groups and having 1 to 4 carbons in the alkyl chain and optionally substituted with hydroxy, halogen, lower alkoxy or lower alkyl groups; and R_5 is hydrogen or straight-chain lower alkyl having 1 to 4 carbons) or ( b
)OR_4, where R_4 is as described above, and R^2 and R^3 are independently selected from the group consisting of hydrogen, lower alkanoyl, benzoyl, or R_2 or R_3 One is -P(=Y)(OR″
)_2 or −P(=Y)(OR″)(OR″′), where R″ and R″′ are as above, and R^2 and R″ together are lower It can form an alkylidene or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein Y and R'' are as described above). 2) The compound according to claim 1, wherein x is 0. 3) Ar is a substituted or unsubstituted group consisting of phenyl, 2-thienyl, or 2-furanyl, and D
and E is hydrogen, Q is hydroxy and R
Said claim 2, wherein ^2 and R^3 are hydrogen.
Compounds described in Section. 4) The compound according to claim 3, wherein A is a single bond and the total number of n and m is 2. 5) The compound according to claim 3, wherein A is a single bond and the total number of n and m is three. 6) The compound according to claim 4, which is N^6-[(1-phenylcyclopropyl)methyl]adenosine. 7) The compound according to claim 4, which is N^6-[[1-(3-chlorophenyl)cyclopropyl]methyl]adenosine. 8) 5'-deoxy-5'-chloro-N^6-[(1-
5. The compound according to claim 4, which is phenylcyclopropyl)methyl]adenosine. 9) The compound according to claim 4, which is N^6-[[1-(4-chlorophenyl)cyclopropyl]methyl]adenosine. 10) The fourth claim which is N^6-[(1-thien-2-ylcyclopropyl)methyl]adenosine
Compounds described in Section. 11) The compound according to claim 5, which is N^6-[(1-phenylcyclobutyl)methyl]adenosine. 12) The compound according to claim 5, which is N^6-[[1-(3-chlorophenyl)cyclobutyl]methyl]adenosine. 13) The compound according to claim 5, which is N^6-[(1-thien-2-ylcyclobutyl)methyl]adenosine. 14) The compound according to claim 5, which is N^6-[(1-phenylcyclopentyl)methyl]adenosine. 15) The compound according to claim 5, which is N^6-[(1-phenylcyclohexyl)methyl]adenosine. 16) The compound according to claim 1, which is N^6-[(1-phenylcyclopropyl)methyl]adenosine-N^1-oxide. 17) The compound according to claim 4, which is N^6-(1-(2-chlorophenyl)cyclopropylmethyl)adenosine. 18) The compound according to claim 4, which is N^6-(1-(2-methylphenyl)cyclopropylmethyl)adenosine. 19) The compound according to claim 4, which is N^6-(1-(2-furanyl)cyclopropylmethyl)adenosine. 20) N^6-(1-(5-methylthien-2-yl)
5. A compound according to claim 4 which is cyclopropylmethyl)adenosine. 21) N^6-(1-phenylcyclopropylmethyl)
5. A compound according to claim 4 which is adenosine-5'-ylhydrozine succinate. 22) N^6-(1-phenylcyclopropylmethyl)
A compound according to claim 4 which is adenosine-5'-uronamide. 23) A pharmaceutical composition containing an effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier. 24) A method of treating psychosis or hypertension in a mammal comprising administering to the mammal an antipsychotic or antihypertensive effective amount of a compound according to claim 1 in unit dosage form. 25) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, E, D, R^2, R^3 and Q are as described above, and Hal is a halogen). A compound is reacted with a compound of formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (wherein Ar, R^1, G, n, m and A are as described above), and when A method for preparing a compound according to claim 1, which optionally comprises further processing of the reaction product to obtain compound (I).