AU608258B2 - N9-cyclopentyl-substituted adenine derivatives - Google Patents

Description

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I To: i QC258 Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE

SPECIFICATION

(ORIG INAL)I Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: a

S

Related Art: 0 a.

a

S.

This document contains the amendments made under Section 49 and is correct for printing, Name of Applicant: SAjldress of Applicant: *Actual inventor: *A dress for Service: CIBA-GEIGY AG 141 Klybeckstrasse, 4002 Basile, Switzerland JEN CHEN and ALAN J. HUTCHISON -RW-.W-A-T-hRS-&-S0N-S- -6-U,--STRETFMFLOR.4AU--ALArOO Complete Specification for the invention entitled: N 9 CYCLOPENTYL-SUBSTITUTED ADENINE DERIVATIVES The following statement is a full description of this invention, including the best method of performing it known to 11s UU>-DLO J3, i JOI yiDk-cfl. 3

L

To: The Commissioner of Patents 9.79 521 a 1 4-16170/+/CGC 1233 N9-Cyclopentyl-substituted adenine derivatives The instant invention is directed to certain functionalized N9-cyclopentyl-substituted adenine derivatives as adenosine receptor ligands, to pharmaceutical compositions thereof, to methods for their preparation, and to their use in mammals as therapeutically effective adenosine receptor agonists.

.The compunds of the invention are effective as adenosine, particularly adenosine-2 receptor ligands which are useful in mammals as adenosine receptor agonists, particularly as adenosine-2 receptor agonists.

10 Said advantageous properties render the compounds of the invention useful for the treatment of conditions in mammals responsive to 0* c* selective adenosine receptor stimulation, particularly to adenosine-2 receptor stimulation, e.g. cardiovascular conditions such as hypertension, thrombosis and atherosclerosis, also central nervous system conditions comprising psychotic conditions such as schizo- 15 phrenia, and convulsive disorders such as epilepsy.

The compounds of the invention are structurally related to the natural product aristeromycin which is cited, e.g. in J. Org.

Chem. 51, 1287-1293 (1986) and publications referred to therein, and which is characterized in the literature as a carbocyclic analog of adenosine.

More specifically, the instant invention is directed to the compoundo of the formula I EL1; A r 2

NH-R

1 R (I) N

R

R'4 Ne R3 R wherein R, R 3 nd RS independently represent hydrogen or hydroxy provided that at least one of R, R 3 and R 5 represents hydroxy; RI represents hydrogen, lower alkyl, C3-C 7 alkenyl, hydroxy-lower alkyl,

C

3 -C6cycloalkyl, C 3 -Cscycloalkyl-lower alkyl, 2-norbornyl, 2-norbornyl-lower alkyl, aryl, aryl-lower alkyl, aryl-Ca-C6cycloalkyl, 9-fluorenyl or 9-fluorenyl-lower alkyl; or R I represents a bicyclic benzo-fused 5 or 6-membered saturated carbocyclic radical or a benzo-fused 5 or 6-membered saturated heterocyclic radical containing a heteroatom selected from oxygen and sulfur directly attached to the fused benzene ring, any said bicyclic radicals being optionally substituted on the benzo portion by lower alkyl, lower alkoxy or halogen; R 2 represents hydrogen, halogen, -SR' or

-N(R

9

)R

1 in each of which R 1 has meaning as defined hereinbefore provided that RI in -SR I does not represent hydrogen; R 9 represents hydrogen or lower alkyl; RI represents hydroxymethyl provided that

R

2 does not represent either hydrogen or -NHR' in which R 1 represents either hydrogen or lower alkyl; or R4 represents lower alkoxymethyl, lower alkylthiomethyl or -CONHR 6 in which R 6 represents lower alkyl, aryl-lower alkyl, C 3

-C

6 cycloalkyl or hydroxy-lower alkyl; pharmaceutically acceptable ester derivatives thereof in which free hydroxy groups are esterified in form of a pharmaceutically acceptable ester; and salts thereof.

The invention is even directed to the compounds of formula I wherein all substituents have the meaning given hereinbefore except that R' is different from C3-C 7 alkenyl and hydroxy-lower alkyl and wherein

R

9 denotes exclusively hydrogen.

i ir L i~l( ni 'inru~ l~~uri~;i~ IA 1 i 3 Preferred are the compounds of formula I wherein R and R 3 represent hydrogen or hydroxy; R 5 represents hydroxy; R 1 represents hydrogen or lower alkyl; or RI represents aryl or aryl-lower alkyl wherein aryl represents thienyl, pyridyl, naphthyl, phenyl or phenyl substituted by halogen, trifluoromethyl, lower alkoxy, lower alkyl or by a substituent -W-Z in which W represents a direct bond, lower alkylene, or oxy-lower alkylene, and Z represents cyano, carboxy, carboxy derivatized in the form of a pharmaceutically acceptable ester or carboxy derivatized in the form of a pharmaceutically acceptable amide; or R 1 represents a substituent of the formula B

S

54

I

4

S

*5 .54 .4

I

I

\2) S in which A represents methylene, oxygen or sulfur, m represents zero or one, and R a represents hydrogen, lower alkyl, lower alkoxy or halogen; R 2 represents hydrogen, halogen, -SR I or -N(R 9

)R

L in which R' has meaning as defined hereinbefore except that R I in SR I does not represent hydrogen; R 9 represents hydrogen or lower alkyl; R 4 represents hydroxymethyl provided that R 2 does not represent either S hydrogen or -NHR I in which RI represents hydrogen or lower alkyl; or R. represents lower alkoxymethyl, lower alkylthiomethyl, or -CONHR 6 20 in which R 6 represents lower alkyl, aryl-lower alkyl, C 3

-C

6 cycloalkyl or hydroxy-lower alkyl; pharmaceutically acceptable ester derivatives thereof in which one or more free hydroxy groups are esterified in form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof.

The invention is even directed to those compounds of formula I wherein all substituents have the meaning given hereinbefore as being preferred except that R I is different from aryl and wherein R 9 denotes exclusively hydrogen.

i 4- A particular embodiment of the invention relates to the compounds of formula I cited hereinabove wherein R represents -CONHR 6 and R,

R

1

R

2

R

3

R

5

R

6 R m and R a have meaning as defined above; pharmaceutically acceptable ester derivatives thereof as defined above; and pharmaceutically acceptable salts thereof.

Another particular embodiment relates to the compounds of formula I wherein R4 represents hydroxymethyl with the proviso for R 2 given hereinbefore.

Preferred are the compounds of formula II SH2 0 R6-

_R/

R

3

OH

wherein R 2 represents hydrogen, halogen, SR I or N(R 9

)R

I

R

I

represents aryl or aryl-lower alkyl in which aryl represents thienyl, pyridyl, phenyl or phenyl substituted by halogen, trifluoromethyl, lower alkoxy, lower alkyl or by a substituent -W-Z in which W represents a direct bond, lower alkylene or oxy-lower alkylene, and Z represents cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; or R' represents a substituent of the formula B' /A II in which A represents a direct bond, methylene, oxygen or sulfur, and R a represents hydrogen, lower alkyl, lower alkoxy or halogen; R 3 represents hydrogen or hydroxy; and R 6 represents lower alkyl, Ca-C6cycloalkyl or hydroxy-lower alkyl; R 9 represents hydrogen or L-21---

I~

5 lower alkyl; pharmaceutically acceptable prodrug ester derivatives thereof in which free hydroxy groups are esterified in form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof.

The invention is even directed to those compounds of formula II wherein all substituents have the meaning given hereinbefore as being preferred except that RI is different from aryl and wherein

R

9 denotes exculsively hydrogen.

Preferred are the compounds of formula II wherein R 2 represents hydrogen, chloro or N(R 9 )RI; Ra represents hydrogen; R 3 represents hydroxy; R 6 represents lower alkyl, C 3

-C

6 cycloalkyl or hydroxy-lower S alkyl; and RL, R 9 and A have meaning as defined above; pharmaceutically acceptable prodrug ester derivatives thereof in which free hydroxy groups are esterified in form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof.

Further preferred are the compounds of formula IIa n H2

N

1, 2 or 3, represents Ci-C 3 alkyl, and Ar represents 3- or 4-pyridyl, phenyl or phenyl substituted by halogen, trifluoromethyl, lower alkoxy, lower alkyl or by a substituent -W-Z in which W represents a direct bond, straight chain Cl-C~alkylene or oxy-CI-C3- E 1 OR OR akyene and Z represents hydrogen, chloro, lower alkoxycarb Ccyclocarbamoyl, N or -N(R)-(CHN,N-di-ower akycarb represents zero or the integer -Calk, 2 or 3, yl repropylesents Cor -Calkydroxy--, and Ar represents 3- or 4-pyridyl, phenyl or phenyl substituted by halogen, trifluoromethyl, lower alkoxy, lower alkyl or by a substituent -W-Z in which W represents a direct bond, straight chain Ci-Clalkylene or oxy-CI-C3alkylene and Z represents cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; R 6 represents Ci-Cqalkyl, cyclopropyl or hydroxy-Cz-C4alkyl; R 7 and R 8 represent i_ ii 6 hydrogen, lower alkanoyl, lower alkoxy-lower alkanoyl, aroyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; and pharmaceutically acceptable salts thereof.

The invention is even directed to those compounds of formula IIa wherein R 2 represents hydrogen, chloro or NH(CH 2 -Ar in which n represents the integer 1, 2 or 3, and Ar, R 6

R

7 and R 8 have meaning as defined hereinbefore as being further preferred.

Particularly preferred are said compounds of formula IIa wherein R 2 represents hydrogen, chloro, NH-CH 2

CH

2 -cyclohexyl, N(CH 3

)-CH

2

CH

2 cyclohexyl, N(CH 3

)-CH

2

CH

2 -Ar or -NH-CH 2

CH

2 -Ar in which Ar represents 2- or 3-pyridyl, phenyl or phenyl monosubstituted by a substituent

-CH

2

CH

2 -Z in which Z represents cyano, carboxy, lower alkoxycarboo nyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; R 6 represents ethyl or hydroxyethyl; R 7 and R 8 represent hydrogen, lower alkanoyl or lower alkoxy-C 2 -Cialkanoyl; and pharmaceutically acceptable salts thereof.

The invention is even directed to those compounds of formula IIa wherein R 2 represents hydrogen, chloro or NHCH 2

CH

2 Ar in which Ar,

R

6

R

7 and R 8 have meaning as defined hereinbefore as being particularly preferred.

Most preferred are the compounds of formula IIa wherein R 2 represents hydrogen, 2-phenylethylamino, 2-(p-carboxyethylphenyl)ethylamino or 2-(2-pyridyl)ethylamino; R 6 represents ethyl; R 7 and R 8 represent hydrogen; and pharmaceutically acceptable salts thereof.

A particular preferred embodiment of the invention is also represented by the compounds of formula IIb 7- TH2 SIjHH

R

S.

N

I(lib)

C

OR

7

OR

8 wherein R 6 represents ethyl; R 7 and R 8 represent hydrogen or lower alkanoyl; R 9 represents hydrogen or methyl; RI 0 represents hydrogen or methyl; R 11 represents cyclohexyl, pyridyl, phenyl, or phenyl monosubstituted by halogen, lower alkoxy or -CH 2

CH

2 -Z in which Z represents carboxy or lower alkoxycarbonyl; and pharmaceutically acceptable salts thereof.

The general definitions used herein have the following meaning within the scope of the present invention.

The term "lower" referred to above and hereinafter in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up to and including 4 and advantageously one or two carbon atoms.

S

Lower alkyl is straight chain or branched and preferably contains 1 to 4 carbon atoms, and represents for example ethyl, propyl, butyl, and advantageously methyl.

Lower alkoxy is straight chain or branched and preferably contains 1 to 4 carbon atoms, and represents for example methoxy, ethoxy, propoxy.

Lower alkylene is straight chain or branched and preferably contains 1 to 4 carbon atoms, and represents for example methylene or ethylene.

Lower alkenyl represents Ca-Cyalkenyl, advantageously allyl.

:I -8- Halogen is preferably chloro, but may also be fluoro, bromo or iodo.

Cycloalkyl represents preferably 3 to 6 ring membered cycloalkyl, i.e. C 3

-C

6 cycloalkyl. C 3 -CsCycloalkyl re-resents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl in the group R 6 Cycloalkyl-lower alkyl represents preferably (cyclopentyl or cyclohexyl)-Cl-Ci 4 alkyl, advantageously 1- or 2 -(cyclopentyl or cyclohexyl)-ethyl, -propyl or -butyl.

egs Aryl is an optionally substituted carbocyclic or heterocyclic aromatic radical, being preferably phenyl, 1- or 2-naphthyl, or aphenyl substituted by one to three of lower alkyl, lower alkoxy, halogen or trifluoromethyl, or phenyl substituted by a substituent -W-Z in which W represents a direct bond, lower alkylene or oxy-lower alkylene and Z represents cyano, carboxy or carboxy derivatized in the form of a pharmaceutically acceptable ester or

S.

emide; or pyridyl; or thienyl; or pyrrolyl; or indolyl.

*S

a.

Aryl-lower alkyl represents preferably aryl-Cl-Calkyl, e.g. benzyl or 1- or 2-phenyl-(ethyl, propyl or butyl) each unsubstituted or substituted on the phenyl ring as defined under aryl above; or 2-, 3- or 4-pyridylmethyl or 3- or 4-pyridyl)-(ethyl, propyl or butyl); or 1- or 2-naphthylmethyl or or 2-naphthyl)-(ethyl, propyl or butyl).

Hydroxy-lower alkyl represents preferably 3- or 4-hydroxy-C 2

-C

4 alkyl, advantageously hydroxyethyl.

Pyridyl represents 3- or 4-pyridyl, advantageously 2- or 3-pyridyl. Thienyl represents 2- or 3-thienyl. Pyrrolyl represents preferably N-pyrrolyl. Aryl-cycloalkyl represents for example 2-phenylcyclohexyl, 2-phenylcyclopropyl or 2-N-pyrrolyl-cyclohexyl.

g M I 1i1 116 W W_ -9- A bicyclic benzo-fused 5 or 6-membered saturated carbocyclic radical represents preferably 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl, each optionally substituted on benzo portion as indicated above for phenyl under aryl.

A bicyclic benzo-fused 5 or 6-membered saturated heterocyclic radical represents preferably 2,3-dihydro-3-benzofuranyl, 2,3-dihydro-3-benzothiofuranyl, 3,4-dihydro-2H-[11 ]--3-benzopyranyl or 3,4-dihydro-2H-[1J-3-benzothiopyranyl, each optionally substituted on benzo portion as indicated above for phenyl under aryl.

Lower alkoxycarbonyl preferably contains 1-4 carbon atoms in the alkoxy portion and represents for example methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or advantageously ethoxycarbonyl.

4e* Lower alkanoyl represents preferably straight chain or branched

S.

Ci-Cqalkanoyl, e.g. acetyl, isobutyryl, or pivaloyl.

Lower alkoxy-lower alkanoyl represents preferably lower alkoxy-C 2 C4alkancyl, e.g. methoxyacetyl, or 3-ethoxy-propionyl.

Aroyl represents preferably benzoyl, benzoyl substituted by one to 406004 three of lower alkyl, lower alkoxy, halogen or trifluoromethyl; 2-, 3- or 4-pyridylcarbonyl; or 2- or 3-thienylcarbonyl.

N-Mono- and N,N-di-lower alkylcarbamoyl represents for example N-methyl-, N-ethyl-, N,N-dimethyl- and N,N-diethylcarbamoyl.

Carboxy esterified in form of a pharmaceutically acceptable ester represents advantageously esterified carboxy that may be convertible by solvolysis or under physiological conditions to free carboxy, e.g. lower alkoxycarbonyl; (amino, mono- or di-lower alkylamino)substituted lower alkoxycarbonyl; carboxy substituted lower alkoxycarbonyl, e.g. alpha-carboxy-substituted lower alkoxycarbonyl; lower alkoxycarbonyl-substituted lower alkoxycarbonyl, e.g. alpha-lower alkoxycarbonyl-substituted lower alkoxycarbonyl; aryl-substituted 3 1 i

I

10 lower alkoxycarbonyl, e.g. optionally substituted benzyloxy carbonyl or pyridylmethoxycarbonyl; (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxy carbonyl, e.g. pivaloyloxymethoxycarbonyl; (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxymethoxycarbonyl; bicycloalkoxycarbonyl-substituted lower alkoxycarbonyl, e.g. bicyclo[2,2,1]heptyloxycarbonyl-substituted lower alkoxycarbonyl, especially bicyclo[2,2,l]heptyloxycarbonylsubstituted methoxycarbonyl such as bornyloxycarbonylmethoxycarbonyl; 3-phthalidoxycarbonyl; (lower alkyl, lower alkoxy, halo)-substituted 3-phthalidoxycarbonyl; lower alkoxycarbonyloxy-lower alkoxy-carbonyl, e.g. l-(methoxy- or ethoxycarbonyloxy)-ethoxycarbonyl; aryloxycarbonyl, e.g. phenoxycarbonyl or phenoxycarbonyl advantageously substituted at the ortho position by carboxy or S+ lower alkoxycarbonyl.

a Carboxy derivatized in form of a pharmaceutically acceptable amide represents preferably carbamoyl, N-mono-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl.

The pharmaceutically acceptable ester derivatives in which one or a moie free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester are particularly prodrug esters that may be convertible by solvolysis under physiological conditions to the compounds of formula I having free hydroxy groups.

S

Preferred as said prodrug pharmaceutically acceptable esters are straight chain or branched lower alkanoic acid esters, the acetic, isobutyric, pivaloic acid esters; lower alkoxy-lower alkanoic acid esters, the methoxyacetic, 3-ethoxypropionic acid esters; arylcarboxylic acid esters, the benzoic, nicotinic acid esters; carbamic and N-mono or N,N-di-lower alkylcarbamic acid esters (carbamates), e.g. the N-mono- or N,N-di-ethylcarbamic or N-mono- or N,N-di-methylcarbamic acid esters. Most preferred are the lower alkanoic acid and lower alkoxyalkanoic acid esters.

i

OWN

1. I 11 Pharmaceutically acceptable salts are generally acid addition salts, which are preferably such of therapeutically acceptable inorganic or organic acids, such as strong mineral acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, gluconic, citric, maleic, fumaric, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic, cyclohexylsulfamic acid; or a* ascorbic acid. For compounds having a free carboxy group, salts are also derived from bases, e.g. the alkali metal salts such as the sodium salt.

1I 0 The novel compounds of the invention are active in state of the art in vitro and in vivo test systems, indicative of adenosine receptor

S**

agonist activity in mammals.

The adenosine receptor agonists of the invention are useful in mammals including man for the treatment of central nervous system disorders, particularly psychoses such as schizophrenia, and of cardiovascular disorders, particularly hypertension and thrombosis.

The above-cited properties are demonstrable in in vitro and in vivo a tests, using advantageously mammals, e.g. rats, dogs, monkeys or isolated organs, tissues and preparations thereof. Said compounds can be applied in vitro in the form of solutions, e.g. preferably aqueous solutions, and in vivo either enterally or parenterally advantageously orally or intravenously, e.g. .thin gelatin capsules, as starch suspensions or in aqueous solutions. The dosage in vitro may range between about 10 5 molar and 10 9 molar concentrations. The dosage in vivo may range between about 0.001 and 25 mg/kg/day, preferably between about 0.0025 and 10 mg/kg/day depending on the compound and the route of administration.

a uLum seieccea trom oxygen and sulfur directly attached to the fused benzene ring, any said bicyclic radicals being optionally substituted on the benzo portion by lower alkyl, lower alkoxy or S./2

I.

:i 12 Adenosine-2 receptor binding properties, indicative of the adenosine-2 receptor agonist activity of the compounds of the invention are determined in vitro by determining their ability to inhibit the specific binding of 3 3 H-NECA), e.g. essentially as described by R.F. Bruns et al., Mol. Pharmacol. 29, 331 (1986), in striatal membrane preparations from corpus striatum of male Sprague-Dawley rats. The concentration of a particular compound required to displace the specific binding of 4 nM 3 H-NECA is determined in the presence of 50 nM cyclopentyladenosine.

S* Adenosine 1 receptor binding properties of the compounds of the invention indicative of adenosine-l-receptor agonist activity are determined, essentially according to R.F. Bruns et al. in Proc. Natl. Acad. Sci. U.S.A 77, 5547 (1980), by determining their ability to inhibit the specific binding of 3 H-cyclohexyladenosine 3 H-CHA) in rat brain membrane preparations from male Sprague-Dawley rats. The concentration of a particular compound required to displace the specific binding of 1 nM 3 H-CHA is determined.

Selectivity for the adenosine-2 (A2) receptor can be ascertained by comparing the relative potency in the two adenosine receptor assays.

ge*@ Indicative of in vivo adenosine receptor agonist activity, the hypotensive activity of the compounds of the invention as well as their effect on heart rate can be measured in normotensive or spontaneous hypertensive rats on intravenous or oral administration.

Typically, the blood pressure lowering effect in inormotensive rats can be determined as follows: Adult male rats weighing 300-400 g are anesthetized using Inactin (100 mg/kg, A femoral artery and contralateral vein are cannulated for direct blood pressure measurement and i.v. drug administration, respectively. Animals are allowed a 15 minute equilibration period before testing. Vehicle 1 ml/kg, is administered over "I I 13 a 30 second period followed by a 0.3 ml saline flush administered over a 30 second period. Changes in diastolic blood pressure are recorded using a Beckman polygraph while heart rate is recorded as a derivative of the blood pressure pulse. The test compound is administered in the same manner as vehicle and a dose response curve is established. Percent changes in heart rate and blood pressure are recorded.

The blood pressure lowering effect in the spontaneous hypertensive rat is determined on oral administration.

The compounds of the invention which are selective as adenosine-2 receptor agonists effectively lower blood pressure without any S ,significant effect on the heart rate.

A

S* Antipsychotic activity can be demonstrated e.g. by measuring the inhibition of one-way conditioned avoidance or Sidman avoidance in the rat, or by measuring the antagonism of the behavioral stimulant effects of apomorphine.

*o Antithrombotic activity can be demonstrated by measuring the inhibition of collagen induced platelet aggregation.

Illustrative compounds of the invention display ICso values in the -6 adenosine-2-receptor binding assay in the range of about 5 x 10 to *O-8 S* 2 x 10 M; the compounds also display hypotensive activity in the anesthesized normotensive rat at a dose of about 0.0025 to 0.035 mg/kg i.v. and in the spontaneous hypertensive rat at a dose of about 3 to 10 mg/kg p.o.

The compounds of the invention of formula I and herein-cited derivatives thereof can be prepared using processes which comprise: a) for compounds of formula I wherein R, R 2

R

3 RI and R 5 have meaning as defined hereinabove provided that one of R and R represents hydroxy, condensing a compound of the formula III i 'i I. I: t-- 14

IH-R'

N-*

NI (III) H \N \R wherein R I and R 2 have meaning as defined above, with a compound of the formula IV R

(IV)

IIIII i 0iniI wherein R 3 and R' have meaning as defined above, in the presence of a strong base, and separating any resulting isomers if so required; b) for compounds of formula I wherein R, R 1

R

2

R

3

R

4 and R 5 have meaning as defined hereinabove, condensing a compound of the formula V x

N

R

3

R

wherein X represents a leaving group; R, R 2

R

3

R

4 and R 5 have meaning as just defined above, with a compound of the formula VIa

R'-NH

2 (Via) in which R 1 has meaning as defined above; ii i ii i ii L_ I. 15 c) for compounds of formula I wherein R 2 represents -SR' or

-N(R

9

)R

I

condensing a compound of the formula VII

TH-R

I

-N-9

S(VII)

1

R

3

R

wherein R, R 1

R

3 R and R 5 have meaning as defined above, and X represents a leaving group, with either a compound of the for- •wherein R I has meaning as defined above; or with a compound of the R'-SH (VIb) or a reactive alkali metal salt derivative thereof wherein R 1 has meaning as defined above; or with a compound of the formula VIc

RI-N(R

9 (VIc) wherein R 1 and R 9 have meaning as defined above; d) for compounds of formula I wherein R represents -CONHR 6 as defined hereinabove, oxidizing a corresponding compound of the formula I wherein R represents hydroxymethyl and wherein other hydroxy groups are in protected form, and derivatizing the so obtained carboxylic acid to a compound of formula I wherein R 4 represents -CONHR 6

I.I

16 e) for compounds of formula I wherein R 4 represents lower alkylthiomethyl condensing a compound of formula I wherein R 4 represents hydroxymethyl with a di-lower alkyl disulfide in the presence of a tri-lower alkylphosphine or converting a compound of formula I wherein RI reprasents hydroxymethyl to a reactive esterified derivative thereof and reacting same with a lower alkylmercaptan or a reactive alkali metal salt derivative thereof; f) for compounds of formula I wherein R 2 represents -SR

I

reacting a compound of the formula VII wherein X represents -SH and wherein R,

R

1

R

3

R

4 and R 5 have meaning as defined above with an electroo* philic reagent corresponding to the radical RI; and, as further required in any of the above-cited processes, temporarily protecting any interfering reactive group(s) in the starting materials and then subsequently removing the protecting groups to yield a resulting *compound of formula I; and, if desired, converting a resulting compound of formula I into another compound of the invention, and if desired, converting a resulting free compound into a salt or a resulting salt into a free compound or into another salt, and if required, separating any mixture of isomers or racemates obtained into the single isomers or racemates, and if required, resolving a racemate into the optical antipodes.

A leaving group in the above processes respresents especially halo, for example chloro, bromo or iodo, aliphatically or aromatically substituted sulfonyloxy, for example methylsulfonyloxy or 4-methylphenylsulfonyloxy (tosyloxy), or aliphatically substituted thio, for example lower alkylthio such as methylthio.

In starting compounds and intermediates which are converted to the compounds of the invention in a manner described herein, functional groups present, such as amino and hydroxy, are optionally protected by conventional protecting groups that are common in preparative organic chemistry. Protected amino and hydroxy groups are those that 17 can be converted under mild conditions into free amino and hydroxy groups without the molecular framework being destroyed or undesired side reactions taking place.

Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, T.W. Greene, and "Protective Groups in Organic Synthesis", Wiley, New York 1984.

For example, a hydroxy group may be protected in the form of esters, e.g. as acyl derivatives such as the lower alkanoyl, benzyloxycarbonyl or lower alkoxycarbonyl esters, or such hydroxy group may be protected in the form of ethers, e.g. as the 2-tetrahydropyranyl, Strityl or benzyl ethers.

Hydroxy groups on adjacent carbon atoms can also be protected e.g.

in the form of ketals or acetals, such as isopropylidene or benzylidene derivatives.

In a resulting protected compound of formula I or intermediate, in which one or more of the functional groups are protected, the S* protected functional groups, e.g. hydroxy groups, can be liberated in a manner known per se, e.g. by means of solvolysis, especially hydrolysis with acid, or by hydrogenolysis.

The preparation of the compounds of the invention according to process a) which involves opening of an epoxide ring is preferably carried out in a polar solvent such as dimethylformamide and at an elevated temperature, advantageously at a temperature ranging from to 125°C. The reactive organometallic derivative, e.g. the lithium, sodium or potassium derivative of the starting material of formula III is preferably first prepared in situ by reacting a compound of the formula III with a corresponding strong base such as 1 1 [^ft- .m ti.- 1 1 1 18 sodium, potassium or lithium hydride or amide in a polar anhydrous solvent such as dimethylformamide, advantageously at room temperature.

Process a) is preferred for compounds of formula I wherein R 2 represents hydrogen or halogen.

Starting materials of formula III (adenine and derivatives thereof) can be prepared according to methods known in the art for the synthesis and derivatization of purines, e.g. as illustrated in Barton and Ellis, Comprehensive Organic Chemistry Vol. 4, pp. 499-518.

0 Starting materials of formula IV are either known in the art or are preferably prepared as illustrated below. A more specific embodiment relates to the compounds of formula IVa, particularly the compounds of formula IVa wherein R represents -CONHR 6 as defined herein.

S. iV ii R R R- i uo OH OH (VIII) (IX) (IVa) 0 selenium dioxide ii): m-chloroperbenzoic acid A cyclopentene derivative VIII wherein R 4 has meaning as defined herein can be hydroxylated, e.g. with selenium dioxide in organic solvents such as tetrahydrofuran and dimethoxyethane, preferably at reflux temperature to give the hydroxy substituted cyclopentene derivative of formula IX. Epoxidation of the cyclopentene derivatives of either formula VIII or IX, e.g. with m-chloroperbenzoic acid in a solvent such as dichloromethane at room temperature, yields a corresponding epoxide of formula IV wherein R 3 represents hydrogen or wherein R 3 represents hydroxy (of formula IVa above), respectively.

Ii 19 The epoxidation of the cyclopentene derivatives can also be carried out under Sharpless epoxidation conditions with t-butyl hydroperoxide, preferably in the presence of vanadium or titanium catalysts such as vanadyl acetylacetonate or titanium tetraisopropoxide.

Asymmetric epoxidation for kinetic resolution of the epoxides into the optically active isomers can be similarly carried out in the presence of e.g. a diester of d- or X-tartaric acid, as described in Pure and Applied Chemistry 55, 589 (1983).

The preparation of the compounds of the invention according to !process b) which involves the displacement of a leaving group X chloro) in a compound of the formula V by an amine of the *S 0 formula VIa is preferably carried out at elevated temperature, e.g.

at a temperature ranging from 75 to 150 0 C, with an excess of the amine, in the absence or presence of a solvent, particularly a polar solvent such as methanol or dimethylformamide, or under elevated pressure, or in the presence of a base such as triethylamine.

The starting materials of formula V wherein R 2 represents hydrogen or halogen can advantageously be prepared by condensing a compound of the formula X De

HN

R II R*tf*"'k2t

(X)

6

R

3

R

wherein X, R and R 2

-R

5 have meaning as defined for compounds of formula V, optionally in partially protected form, with formic acid or a mixture of formic acid and acetic anhydride, with a lower alkylcarboxylic acid ester of a di-lower alkoxymethanol or with a tri-lower alkyl orthoformate, and as required, liberating any protected hydroxy groups.

1 I a 20 The condensation is preferably carried out by reacting a compound of formula X with a tri-lower alkyl orthoformate, such as triethyl orthoformate in a polar solvent such as dimethylacetamide in the presence of an acid such as concentrated hydrochloric acid, preferably at room temperature.

The intermediates of formula X can be prepared by condensing e.g. a compound of the formula XI y 1

(XI)

S0 wherein R 2 has meaning as defined for formula V, with a compound of the formula XII

R

R

NH

2 S* (XII) *5

R

3

R

wherein R, R 3 R and R 5 have meaning as defined above, e.g.

according to general procedures described in J. Am. Chem. Soc. 91, 3075 (1969) and J. Org. Chem. 45, 531 (1980), preferably in the S* presence of a base such as triethylamine.

The compounds of formula XI and XII can in turn be prepared according to procedures known in the art, e.g. the compounds of formula XII can be prepared according to Tetrahedron Letters 22, 2331 (1981) or J. Org. Chem. 45, 531 (1980).

.L ii~ i I 21 The starting materials of formula V wherein R 2 represents -SRi or

-N(R

9 and X represents a leaving group, can be prepared e.g. by reacting a compound of formula V wherein X represents hydroxy (or as the oxo tautomer thereof) which a halogenating agent such as phosphorus oxychloride.

The intermediates of formula V wherein X represents hydroxy can in turn be prepared oy first converting a compound of formula V, or a protected derivative thereof, wherein X and R 2 both represent chloro R to a compound of formula V wherein X represents hydroxy and R 2 represents chloro by hydrolysis with acid and subsequently converting said intermediate, using methodology as described e.g.

I *for process and to a compound of formula V wherein X represents hydroxy and R 2 represents -SR 1 or -N(R)RI.

The preparation of the compounds of the invention according to process c) which involves the displacement of the leaving group X chloro) in a compound of formula VII by an amine of the formula VIa or VIc is carried out essentially as described above under process The displacement by a mercaptan of the formula VIb is carried out preferably in the presence of a strong base e.g. an .lkali metal hydroxide such as sodium hydroxide.

The starting materials of formula VIa, VIb and VIc are either known or are prepared using methods known in the art, and as described herein.

The starting materials of formula VII can be prepared e.g. essentially as described under process by reacting the correspondingly substituted purine derivatives with an epoxide of the formula IV.

The preparation of compounds of the invention wherein R 4 represents

-CONHR

6 according to process d) can be carried out by oxidzing the corresponding compounds wherein R 4 represents hydroxymethyl, the other hydroxy groups in the molecule being in a protected form, with i- i I 22 e.g. potassium permanganate, and converting the so obtained carboxylic acid to a reactive derivative, e.g. the acid chloride, and condensing said 'arboxylic acid chloride with an amine of the formula R 6 -NHa, under conditions well known in the art.

The preparation of compounds of the invention wherein R4 represents lower alkylthiomethyl according to process e) can be carried out by converting the corresponding compounds wherein R 4 represents hydroxymethyl, the other hydroxy groups being preferably in a protected form, to e.g. the chloro derivative by treatment with e.g.

thionyl chloride in hexamethylphosphorus triamide (HMPT) and reacting said chloro derivative with e.g. the lithium salt of a es:. lower alkyl mercaptan, for example lithium methylmercaptide, in a polar solvent such as tetrahydrofuran.

Alternately, a compound wherein R 4 is hydroxymethyl is treated with a di-lower alkyl disulfide in the presence of e.g. tributylphosphine at elevated temperature in a polar solvent such as dimethylformamide.

The starting compounds for processes d) and e) can be prepared e.g.

as described in process a).

The preparation according to process of compounds of the invention wherein R 2 represents -SR' is carried out according to procedures well-known in the art, e.g. by displacement of a leaving group.

The starting materials of formula VII wherein X represents -SH can be prepared e.g. by reacting a compound of formula VII wherein X represents a leaving group, e.g. chloro, with an alkali metal hydrogen sulfide such as sodium hydrogen sulfide.

4lii A, I- a 23 The compounds of the invention or intermediates leading thereto can be converted into other compounds of the invention or corresponding intermediates using chemical methodology known in the art and as illustrated herein.

The compounds of formula I wherein R 2 represents halogen, e.g.

chloro, can be converted according to process c) as described above to compounds of formula I wherein R 2 represents -NHR'.

The conversion of compounds of formula I containing free hydroxy groups to ester derivatives thereof may be carried out by condensation with a corresponding carboxylic acid, advantageously as a 008 reactive functional derivative thereof, according to acylation (esterification) procedures well-known in the art.

The compounds of formula I wherein R 4 represents hydroxymethyl SS* (amino and any other hydroxy groups in the molecule being in protected form) can be converted to compounds of formula I wherein R represents lower alkoxymethyl by condensation with an equivalent amount of e.g. a lower alkyl halide such as a lower alkyl iodide in the presence of an equivalent amount of a strong base, such as sodium hydride in a non-aqueous solvent, such as dimethylformamide.

A compound of formula I containing a primary amino group (e.g.

wherein NHR' is NH 2 may be converted to a compound of formula I wherein NHR' represents a secondary amine, e.g. wherein R 1 represents lower alkyl, by treatment with a reactive derivative of the alcohol corresponding to R I e.g. with a lower alkyl halide such as a lower alkyl iodide, according to methodology well-known in the art for alkylation of amines.

A compound of formula I containing a lower alkoxycarbonyl group, e.g. a compound of formula I wherein the substituent Z represents lower alkoxycarbonyl, can be converted to the corresponding i 24 carboxylic acid by hydrolysis of the ester, e.g. with aqueous base, such as sodium hydroxide or potassium hydroxide solution or with dilute mineral acid, e.g. hydrohalic acid.

A compound of the invention wherein Z represents carboxy can be converted to the corresponding compounds wherein Z represents lower alkoxycarbonyl according to known esterification procedures, e.g. by treatment as a reactive functional derivative, such as an acyl halide or a mixed anhydride e.g. derived from a lower alkyl halocarbonate such as ethyl chloroformate, with the appropriate alcohol.

The above-mentioned reactions are carried out according to standard 4 A methods, in the presence or absence of diluents, preferably such as 4o 9are inert to the reagents and are solvents thereof, of catalysts, A0r*** condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures preferably near the boiling point of the solvents used, at atmospheric or superatmospheric pressure.

The invention further includes any variant of the present processes, «in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed under the reaction conditions, or in w'iich the reaction components are used in the form of their salts or optically pure antipodes. Whenever desirable, the S" above processes are carried out after first suitably protecting any potentially interfering reactive functional groups, e.g. as illustrated herein.

Advantageously, those starting materials should be used in said reactions that lead to the formation of those compounds indicated above as being preferred.

The invention also relates to novel starting materials and processes for their manufacture.

i iiY 1 c I I 25 Depending on the choice of starting materials and methods, the new compounds may be in the form of one of the possible isomers, for example, as diastereomers, as optical isomers (antipodes), as racemates, or as mixtures thereof.

In case diastereomeric mixtures of the above compounds or intermediates are obtained, these can be separated into the single racemic or optically active isomers by methods in themselves known, e.g. by fractional distillation, crystallization or chromatography.

The racemic products of formula I or basic intermediates can be *o resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, by the fractional crystallization of d- or X-(tartrate, dibenzoyltartrate, mandelate or camphorsulfonate) salts.

Advantageously, the more active of the antipodes of the compounds of 4* this invention is isolated.

Finally, the compounds of the invention are either obtained in the free form, or as a salt thereof. For example, any resulting free base can be converted into a corresponding acid addition salt, preferably with the use of a pharmaceutically acceptable acid or anion exchange preparation, or resulting salts can be converted into the corresponding free bases, for example, with the use of a S* stronger base, such as a metal or ammonium hydroxide, or any basic salt, an alkali metal hydroxide or carbonate, or a cation exchange preparation. These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are then first converted into salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

26 The compounds, including their salts, may also be obtained in the form of their hydrates, or include other solvents used for the crystallization.

The present invention also relates to the use of the compounds of the invention for the preparation of pharmaceutical compositions, especially pharmaceutical compositions having selective adenosine (particularly adenosine-2) receptor stimulating activity which can be used for the treatment of e.g. psychotic conditions, such as schizophrenia, and cardiovascular conditions, such as hypertension, thrombosis and atherosclerosis.

I* The pharmaceutical compositions according to the invention are those a suitable for ente.ral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, for the treatment of diseases responsive to adenosine (particularly adenosine-2) receptor stimulation as given above, such as hypertension, comprising an effective adenosine-2 receptor stimulating amount of a compound of the invention, alone or in combination with one or more 0.

*0 pharmaceutically acceptable carriers.

Go The pharmacologically active compounds of the invention are incor- *porated into pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.

0

U

Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salts and/or polyethylene glycol; for tablets also c) binders, e.g.

magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulore and/or polyvinylpyrrolidone; if desired, d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable L- 4~ ii i 1' L I- 27 compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, the compositions may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75 preferably about 1 to 50 of the active ingridient.

Suitable formulations for transdermal application include an effective amount of a compound of the invention with carrier.

*0 Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.

Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound, optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and I predetermined rate over a prolonged period of time, and means to secure the device to the skin.

.fee** 6 The present invention also relates to the use of compounds of the 0 invention having adenosine receptor stimulating properties and pharmaceutical compositions comprising said compounds for the treatment in mammals of disorders responsive to selective adenosine receptor stimulation, particularly psychotic conditions (e.g.

schizophrenia) and cardiovascular conditions hypertension and thrombosis).

One aspect relates advantageously to the method of treatment of cardiovascular disorders in mammals, e.g. such responsive to adenosine (particularly adenosine-2) receptor stimulation, for example hypertension, using an effective amount of a compound of the invention, preferably in the form of above-cited pharmaceutical compositions. _l fi whr dmadiw-' l I 28 The dosage of active compound administered is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, and on the form of administration.

A unit dosage for a mammal of about 50 to 70 kg may contain between about 1 and 50 mg of the active ingredient.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 2 and 13 kPa. The structure of final products, intermediates and starting materials is confirmed by analytical methods, e.g. microanalysis and spectroscopic characteristics MS, IR, NMR).

The numbering of the positions of the adenine and or purine rings is as conventionally used in the art Merck Index, tenth edition).

Unless otherwise indicated the final products are preferably isolated as the free base by crystallization from a mixture of an Salcohol (methanol, ethanol or isopropanol) and ethyl ether.

Example 1: To a suspension of 1.2 g sodium hydride (60 washed S* with dry ether) in 20 ml of dry dimethylformamide is added 2.58 g adenine. After 10 minutes stirring at room temperature the resulting mixture is treated with a solution of 4.9 g 2-alpha-hydroxy-3alpha-4-alpha-epoxy-cyclopentane-l-8-N-ethylcarboxamide in 30 ml of dry dimethylformamide, heated at 105 0 C for 18 hours, then cooled to room temperature. The reaction mixture is quenched with water and concentrated under vacuo. The crude product is purified by reverse phase chromatography using 120 g of reverse phase octadecylsilane

(C

8 l)-bonded silica gel to yield a) 2-alpha-4-alpha-dihydroxy-38- (9-adenyl)-cyclopentane-18-N-ethylcarboxamide, m.p. 250-253 0 C, and b) 2-alpha-3-alpha-dihydroxy-4-B-(9-adenyl)-cyclopentane-1-8-N- -29ethylcarboxamide (the compound of formula Ha wherein R 2

R

7 and R are hydrogen and R 6 is ethyl) which is recrystallized from methanol, m.p. 208.5-209'C; NMR(CD 3 OD): 8.36 8.18 4.5 (1H,dd); 4.28 (lH,dd).

The starting material is prepa.red as follows: To a mixture of 750 ml of dry tetrahydrofuran and 375. ml of dry dimethoxyethane is added g 3-cyclopentene-l-N-ethylcarboxamide, followed by 12 g selenium dioxide at room temperature. After the reaction is heated to with mechanical stirring overnight and cooled to room temperature, the resulting solution is filtered through CeliteO. The filtrate is concentrated under vacuo and the residue is chromatographed on 400 g silica gel using 4 methanol in ethyl acetate as eluent to give 2-alpha-hydroxy-3--cyclopentene-l- -N-ethylcarboxamide, m.p. 48-50 0

C.

0 A solution of 4.6 g 2-alpha-hydroxy-3-cyclopentene-1-0-N-ethylcarboxamide, 10.23 g m-chloroperbenzoic acid and 70 ml of dichloromethane is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is partitioned between ether and water. The aqueous layer is concentrated in vacuo to obtain 2 -alpha-hydroxy-3-alpha-4-alpha-epoxy-cyclopentane-l-R- N-ethylcarboxamide, m.p. 83-850C.

Similarly prepared are: 0 c) 2 -alpha- 3 -alpha-dihydroxy-4-I3-[9-(2-chloroadenyl) ]-cyclopentane- Vee: l-B-N-ethylcarboxamide, m.p. 233-237 0 C; NMR(CD 3 OD); 8.34 (1H,s); 4.43 (lH,dd); 4.25 (lH,t); d) 3-alpha-hydroxy-4-0-( 9-adenyl)-cyclopentane-1-0-N-ethylcarboxamide, m.p. 282-285OC; NMR(CD 3 0D): 8.17 8.15 (lH,s); 4.7 (1H,s); e) 2 -alpha-3--alpha-dihydroxy-4-0-( 9-adenyl)-cyclopentane-1-0-Ncyclopropylcarboxamide, m~p 218-.220OC; NNR(CD 3 OD): 8.20 (lH,s); 4.47 (1H,dd); 4.25 (1H,t);

V

I~ 30 f) 2-alpha-4-alpha-dihydroxy-3-g-( 9 cyclopropylcarboxamide, m.p. above 250*C; g) 3-alpha--hydroxy-4-0--(9-(2-chloroadenyl) 1-cyclopentane-1-0-Nethylcarboxamide, m.p. 197-~200OC; NMR(CD 3 OD): 8.1 (1H,s); 4.13 (lH,q).

The starting material for compounds c and d, trans-3,4-epoxy-cyclopentane-l--N-ethylcarboxanide, is prepared by epoxidation of 3-cyclopentene-1--N-ethylcarboxamide with m-chloroperbenzoic acid followed by chromatographic purification on silica gel (using 2 methanol in ethyl acetate as eluent).

Example 2: a) A stirred mixture of 58 mg of 2-alpha-3-alpha-dihydroxy-4-0-[9- (2-chloroadenyl)].-cyclopentane--l-B-N-ethylcarboxamide and 1.5 ml of freshly distilled 2-phenylethylamine is heated to 130%C for 14 hours and cooled to room temperature. Excess 2-phenylethylamine is removed under vacuo and the residue is triturated with ether. The solid 0 0: which is obtained after filtration is recrystallized from methanol to give 2-alpha-3-alpha-dihydroxy-4-0-[ 2 -(2-phenylethylamino)-9adenyl]-cyclopentane-1-0-N-ethylcarboxamide, the compound of formula Ha wherein RI is 2-phenylethylamino, RI is ethyl, R 7 and R 8 *are hydrogen; m.p. 234-236'C; NI4R(CD3OD): 7.9 4.46 (lH,t); 4.33 (1H,t).

Similarly prepared are: b) 3-alpha-hydroxy-4-0-[ 2-phenylethylamino)-9-adenylj cyclom.p. 220-224 0 C; NMR(CD3OD): 7.73 3.22 2.91 2.48 (2H,t); c) 2-alpha-4-alpha-dihydroxy-3-$-[ 2 -phenylethylamino)-9-adenyl]m.p. 224-226 0 C; NMR(CD 3

OD):

7.8 4.25 (1H,dd); 31 d) 2-alpha-3-alpha-dihydroxy-4-B-[2-(2-pyridylethylamino)-9-adenyl]-

NMR(CD

3 0D): 7.93 4.47 4.37 (1H,t).

Example 3: To a suspension of 241 mg sodium hydride (60 washed with dry ether) in 8 ml dry dimethylformamide is added 932 mg of 2-chloroadenine. After 10 minutes stirring at room temperature, the resulting mixture is treated with 800 mg of 1-0-hydroxymethyl-2alpha-hydroxy-3-alpha-4-alpha-epoxycyclopentane in 5 ml dry dimethylformamide and heated at 105 0 C for 18 hours, then cooled to room temperature. The reaction mixture is quenched with water and r* *concentrated under vacuo. The crude product is chromatographed on 100 g reverse phase octadecylsilane (Cas)-bonded silica gel (eluent, 5 methanol in water) to give a) 2-alpha-4-alpha-dihydroxy-1-Bhydroxymethyl-3--[9-(2-chloroadenyl)]-cyclopentane, m.p. 252-254 0

C,

and b) 2-alpha-3-alpha-dihydroxy-1-B-hydroxymethyl-4-3-[9-(2-chloroadenyl)]-cyclopentane, m.p. 236-2380C; NMR(CD 3 0D): 8.17 (1H,s); (1H,dd); 4.04 (1H,dd).

The starting material is prepared as follows: A solution of 4.15 g of 1-hydroxymethyl-3-cyclopentene in 500 ml of dry tetrahydrofuran and 250 ml of dimethoxyethane is treated with 4.15 g selenium dioxide at room temperature. The resulting mixture is heated at 70 0

C

for 18 hours, then cooled to room temperature and filtered through CeliteO. The filtrate is concentrated under vacuo and the residue is chromatographed on 100 g of silica gel (eluent, 4 methanol in ethyl acetate) to give trans-1-hydroxymethyl-2-hydroxy-3-cyclopentene.

A solution of 818 mg trans-1-hydroxymethyl-2-hydroxy-3-cyclopentene, 2.2 g m-chloroperbenzoic acid and 40 ml of dichloromethane is stirred at room temperature for 80 minutes. The solvent is removed unter reduced pressure and residue is partitioned between ether and 0 0e 0 *C 0 0 0* 0 p 0 32 water. The aqueous layer is concentrated in vacuo to obtain 1-8-hydroxymethyl-2-alpha-hydroxy-3-alpha-4-alpha-epoxy-cyclopentane.

Example 4: A suspension of 40 mg of sodium hydride (60 washed with ether) in 3 ml of dimethylformamide is treated with 200 mg of 2-(2-phenylethylamino)adenine at room temperature. Stirring is continued at room temperature until the reaction mixture becomes homogeneous. The reaction mixture is then treated with 160 mg 2-alpha-hydroxy-3-alpha-4-alpha-epoxy-cyclopentane-1-8-N-ethylcarboxamide. The resulting solution is heated at 100 0 C for 14 hours. The reaction mixture is then cooled to room temperature quenched with water and the solvent is removed under vacuum. The crude product mixture is first chromatographed in silica gel eluting with 10 Me0H/CH2Cl 2 to 15 MeOH/CH 2 Cl 2 The resulting product is then chromatographed on reverse phase octadecylsilane (C 18 )-bonded silica gel eluting with up to 50 methanol in water; a mixture of isomers, 2-alpha-3-alpha-dihydroxy-4-8-[2-(2-phenylethylamino)- 9-adenyl]-cyclopentane-1-0-N-ethylcarboxamide of example 2a and 2-alpha-4-alpha-dihydroxy-3-8-[2-(2-phenylethylamino)-9-adenyl]cyclopentane-1-8-N-ethylcarboxamide is obtained.

The starting material 2-(2-phenylethylamino)adenine is prepared by reacting 2-chloroadenine with excess 2-phenylethylamine at about 140 0 c0.

Example 5: To a stirring solution of 2.7 g of 4-8-(5-amino-6-chloro- 4-pyrimidinylamino)-2-alpha-3-alpha-dimethylmethylenedioxy-cyclopentane-1-B-N-ethylcarboxamide in 40 ml of triethyl orthoformate is added 0.7 ml of concentrated hydrochloric acid. The solution is stirred at room temperature for 24 hours. After removal of the solvent, 4-8-(6-chloro-9-purinyl)-2-alpha-3-alpha-dimethylmethylenedioxy-cyclopentane-1-8-N-ethylcarboxamide is obtained as an oil, which is used in the next step without further purification.

-33 A solution of 2.2 g of 4 6 -chloropurin-9-yl)-2-alpha-3--alpha-diin 30 ml of saturated methanolic ammonia is heated overnight in a sealed tube.

After removing the solvent, the residue is heated at 55 0 C in 15 ml IN hydrochloric acid for 1.75 hours. The solvent is removed under vacuum to give an amorphous solid.

Chromatography on a flash silica gel column eluting using a methanol/dichloromethane gradient gives 9 -adenyl)-2-alpha- 3-alpha-dihydroxycylopentane-1-03-N-ethylcarboxamide, identical to the compound of example 1b.

The starting material is prepared as follows: A mixture of 10.5 g of 5,6-dimethylmethylenedioxy-2-azabicyclo[ 2.2.1 ]heptan-3-one and 50 ml of ethylamine is heated at 140'C in a steel bomb overnight. After removal of the solvent, the residue is purified by column 0* **chromatography (silica gel) using a gradient of dichloromethane/methanol as eluent to give 4-0-amino-2-alpha-3-alphao To a solution of 5.3 g of 4 -B--amino-2--alpha-3-alpha--dimethylmethyin 70 ml of n-butanol is added 7.5 g of 5-amino-4,6-dichloropyrimidine followed by 9.2 ml of triethylamine. After the reaction is heated for 24 hours at 150'C, the solvent is removed in vacuo. The residue is partitioned between ethyl acetate and a saturated sodium bicarbonate solution.

*Vs* The organic layer is dried over sodium sulfate and concentrated to dryness. The crude solid is chromatographed on a silica gel column eluting using a hexane/ethyl acetate gradient to yield 4-0-(5-amino- 6 -chloro-4-pyrimidinylamino) -2-alpha-3-alpha-dimethylmethylenedioxycyclopentane-1-8-N-ethylcarboxamide.

b) Similarly prepared is 2-alpha-3-alpha-dihydroxy-4-0-[ 9-(2-chloroadenyl) I-cyclopentane-1-0-N-ethylcarboxamide, the compound of example ic.

i 34 The starting material is prepared as follows: To a solution of 614 mg 5-amnino-2,4,6-trichloropyrimidine and 813 mg 4-8-amino- 2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1-8-N-ethylcarboxamide in 15 ml of n-butanol is added 1 ml of dry triethylamine; the resulting mixture is heated at reflux for 15 hours and cooled to room temperature. All the volatiles are evaporated and the residue is partitioned between.dichloromethane and water. The organic layer is dried over magnesium sulfate and concentrated to an oil. The crude product is chromatographed on 100 g silica gel using 1:1 hexane and ethyl acetate as eluent to give 4 -8-(5-amino-2,6dichloro-4-pyrimidinylamino)-2-alpha-3-alpha-dimethylmethylenedioxy-cyclopentane-1-8-N-ethylcarboxamide as an amorphous solid.

S C* S Example 6: A stirred mixture of 26 mg 2-alpha-3-alpha-dihydroxy-1-8-

S

hydroxymethyl-4-0-[9-(2-chloroadenyl)J-cyclopentane and 0.3 ml freshly distilled 2-phenylethylamine is heated at 130 0 C for 14 hours and cooled to room temperature. Excess 2-phenylethylamine is removed under vacuo and the residue is triturated with ether. The solid which is obtained after filtration is purified by flash column chromatography using a reverse phase octadecylsilane (C, 8 )-bonded

C*

**silica gel packing and eluting with mathanol/water (5:3 to The resulting product is then crystallized from ethanol/ether to give 2-alpha-3-alpha-dihydroxy-1-8-hydroxymethyl-4-8-(2-(2-phenylethylamino)-9-adenyl]-cyclopentane, m.p. 118-120*C; NMR(CD 3 0D): 7.73 7.18 2.85 (2H,t).

Example 7: The following compounds of formula II wherein R 3 represents hydroxy can be prepared substantially according to the general procedures previously described herein.

I 35 Compound es es 0 0 0e 0*

S

0S 0000

S

S

S

OS

S 0

S.

0@ *00

SS

S S

S.

S

S

S

0

S.

0 0 00SS0*

S

NH(OH2) a-p-C6lIi-CH2CH2COOH NH(CH2) 2 -p-C 6 Hz 4 -OCHzCOOH 3, 4-dihydro-.5-methoxy-2H[ 1 lbenzothiopyran-3-ylamino 2-indanyla-mino 1,2, 3,4-tetrahydro-2-naphthylamino 3,4-dihydro-2H-[1 I-benzopyran---ylamino

H

SCH2CH2C6!1 5 NH(CH2) 2 -P-C6,z-OCH2CH2 0001 2-cyclohexylethylamino 1 -naphthylmethylamino N-methyl-2-phene thylamino 2-p-methoxyphenyl-l-methyl-ethylamino 2-ph eny ipropylamino NH(CH2) 2 -P-0 6

H

4 -CH2COOH NH(OHZ) a-P-C 6 Hi.-CH2CON(CH 3 a NH(CH2) 2 -p-C 6 Hi.Cl

NHCH

2

CH

2 CH20H CH2 CII 3 CHz OH 3 CH2CH 3

OH

2

OH

3 CHa CH 3

OH

2

CH

3

OH

2

OH

2

OH

OH2C H 3

OH

2

OH

3 CHa OH 3 OHaOH3

OH

2

OH

3 OHZa H 3 OH2 013 CHaOH 3 OH2a H 3 C2 OH 3 OH2OH3 235-2370C 2 28-2 320C 223-225oC 194-1960C 210-2120C 17 3-1 7600 Compound can be advantageously prepared as follows: p-Bromophenylacetonitrile is first condensed with t-butyl acrylate under conditions of the palladium acetate catalyzed Heck reaction. The resulting acrylate is hydrogenated with palladium on charcoal catalyst followed by reduction (of the cyano group) with sodium borohydride in the presence of cobalt(II) chloride to yield t-butyl p-(2-aminoethyl)phenylpropionate. Condensation with 2-alpha-3-alpha-dihiydroxy-4-0-[ 9- (2-chloroadenyl) ]-cyclopentane-1-0-N-ethylcarboxamide yields the t-butyl ester of compound which is hydrolyzed to compound with aqueous hydrochloric acid.

36 Compound b) is similarly prepared. The starting material for condensation with the 9-(2-chloroadenyl)cyclopentane derivative is prepared by condensation of p-hydroxyphenylacetonitriie with t-butyl bromoacetate in the presence of potassium carbonate.

The starting material for compound is prepared as follows: To a cooled mixture of 30.6 g of m-methoxybenzenethiol, 54.4 g of 45 potassium hydroxide in 100 ml of dimethylsulfoxide is added 36.0 g of alpha(bromomethyl)acrylic acid in 25 ml of dimethylsulfoxide at such a rate as to maintain the reaction temperature at 50-55 0

C.

After 1 hour the reaction mixture is diluted with water and washed S* with ether. After acidification, the product is extracted with ether, the organic layer is dried over magnesium sulfate and the solvent is removed in vacuo to afford alpha-(3-methoxybenzenethiomethyl)acrylic acid. This material is dissolved in 570 ml of o-dichlorobenzene and 7.2 g of triethylamine and heated to 200°C for 5 hours. After cooling, the products are extracted with sodium bicarbonate solution, the aqueous layer is acidified and the products extracted with ether. After drying over magnesium sulfate, the solvent is removed in vacuo to afford a mixture of 3,4-dihydro- 5-methoxy-2H-[l]-benzothiopyran-3-carboxylic acid and 3,4-dihydro- 7-methoxy-2H-[1]-benzothiopyran-3-carboxylic acid.

This mixture of acids is dissolved in 500 ml of t-butyl alcohol and treated with 17 g of triethylamine and 36 ml of diphenylphosphoryl azide. After 5 hours reflux, the solvent is removed in vacuo and the residue is dissolved in ether and washed with IN sodium hydroxide and IN hydrochloric acid. After drying over magnesium sulfate, the solvent is removed in vacuo and the residue is chromatographed on silica gel (1 kg) with ether/hexane as the eluent to afford in succession N-t-butoxycarbonyl-3,4-dihydro-5-methoxy-2H-[l]-benzothiopyran-3-amine and N-t-butoxycarbonyl-3,4-dihydro-7-methoxy-2H- [1]-benzothiopyran-3-amine.

I I I 37 A solution of 10 g of N-t-butoxycarbonyl-3,4-dihydro-5-methoxy-2H- [l]-benzothiopyran-3-amine in 30 ml of trifluoroacetic acid is kept at room temperature for 1 hour. The solvent is removed in vacuo, the residue is treated with IN sodium hydroxide and the product is extracted with ether. After drying over magnesium sulfate, the solvent is removed in vacuo to afford 3,4-dihydro-5-methoxy-2H-[1]benzothiopyran-3-amine as an oil.

The starting material for compound is prepared as follows: A mixture of 20 g of p-bromophenylacetic acid, 30 ml of ether, 1 ml of sulfuric acid and 35 ml of isobutylene is shaken in a sealed bottle for 24 hours. The reaction mixture is diluted with ether and washed with sodium hydroxide solution. After drying over magnesium sulfate the ether is removed in vacuo to afford the t-butyl ester as an oil. A mixture of 9.6 g of this material is refluxed with a mixture of 6.1 g of N-vinylphthalimide, 160 mg of palladium acetate, 800 mg of tri-o-tolylphosphine, 10 ml of acetonitrile and 8 ml diisopropylethylamine for 24 hours. The reaction is diluted with water, the resulting precipitate is collected and recrystallized from methanol/dichloromethane. The resulting solid is hydrogenated at 400 kPa pressure over 2 g of 10 palladium on carbon catalyst in 100 ml of ethanol and 100 ml of tetrahydrofuran for 16 hours at room temperature. After removal of the solvent in vacuo the residue is heated at reflux with 10 ml of hydrazine hydrate and 20 ml of ethanol S. for 2 hours. The reaction is diluted with ether and washed with 5 potassium hydroxide solution. The ether is dried over magnesium •sulfate solution and the solvent is removed in vacuo. The residue is chromatographed on silica gel with 5 ammonia saturated methanol in dichloromethane as the eluent, to afford p-(t-butoxycarbonylmethyl)- 2-phenethylamine as an oil.

The starting material for compound is prepared as follows: A mixture of 6 g of p-bromophenylacetic acid in 100 ml of dichloromethane and 5 ml of oxalyl chloride is stirred at room temperature for 16 hours. After removal of the solvent in vacuo the residue is dissolved in dichloromethane and treated with excess dimethylamine at ii -ii i I I 38 room temperature. After 1 hour the reaction mixture is washed with water, the organic layer is dried over magnesium sulfate and the solvent is removed in vacuo to afford p-bromo-N,N-dimethyl-phenylacetamide as an oil, which is converted to p-(dimethylaminocarbonylmethyl)-2-phenethylamine as described for the starting material above.

Example 8: 2-alpha-3-alpha-dihydroxy-1-B-hydroxymethyl-4-B-(5-amino- 2,6-dichloro-4-pyrimidinylamino)-cyclopentane (480 mg) is treated with ml triethyl orthoformate and 0.1 ml concentrated HC1, and the reaction mixture is stirred at room temperature for one hour. The reaction mixture is then concentrated under vacuum and the residual S* oil is dissolved in 20 ml of saturated methanolic ammonia, the solution is placed in a sealed tube and heated at 60°C for 12-16 hours. The solvent is r;noved under vacuum and the residue heated with 30 ml IN HC1 at 60°C for 2 hours. The solvent is removed under vacuum and the crude product is separated by flash chromatography on a reverse phase octadecylsilane (Csi)-bonded silica gel packing, eluting first with water, followed by 5 10 and 20 methanol in water to yield 2-alpha-3-alpha-dihydroxy-l-8-hydroxy- S methyl-4-B-(2-chloro-9-adenyl)-cyclopentane (see example NMR (CD30D): 8.2 4.50 (1H,dd); 4.03 (1H,dd); 3.70 (2H,m); 2.46 2.25 1.90 (1H,m).

The starting material is prepared as follows: A mixture of 5.2 g of methyl 4-B-amino-2-alpha-3-alpha-dihydroxycyclopentane-1-B-carboxylate (Tetrahedron Letters 1981, 2331), 3.4 g of 5-amino-2,4,6-trichloropyrimidine and 5.2 ml of triethylamine in 60 ml n-butanol is heated to reflux under nitrogen atmosphere for 16 hours. The reaction mixture is cooled to room temperature and the solvent removed under vacuum. The residue is partitioned between ethyl acetate and water. The organic solution is extracted with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The crude product is purified by flash column chromatography on silica gel, eluting with ethyl acetate and then 10 methanol/ethyl acetate to yield methyl 2-alpha-3-alpha-dihydroxy-4--(5-amino-2,6-dichloro-4-pyrimidinyl- -39as a white solid. NMR-(CD 3 0D)-, 4.43 4.25 3.95 3.72 2.94 (1H,m); 2.60 1.70 (1H,m).

Calcium chloride (466 mg) and sodium borohydride (320 mg) are combined in 30 ml tetrahydrofuran at room temperature. The reaction mixture is stirred at room temperature for one hour, then 700 mg of methyl 2-alpha- 3-alpha-dihydroxy-4-0-( 5-amino-2 ,6-dichloro-4-pyrimidinylin 30 ml tetrahydrofuran is added.

The reaction mixture is stirred at room temperature for two days. The reaction mixture is treated with 14 ml acetic acid at room temperature and stirring is continued for two hours. The solvent is removed under vacuum to afford an amorphous solid. The crude product mixture is separated by flash column chromatography on reverse phase octadecyl- 1 silane (C,8)-bonded silica packing, eluting with methanol/water (first 1:9, then 2:8, then 3:7) to yield 2-alpha-3-alpha-dihydroxy-1-0hydroxymethyl-4-0-(5-amino-2 ,6-dichiloro-4-pyrimidinylamino)-cyclopentane; NXR (CD 3 0D): 4.40 3.9 (2H,dd); 3.6 (2H,dd); 2.4 2.15 1.28 (1H,rn).

Example 9: 2-alpha-3-alpha-dihydroxy-l-B-ydroxymethyl-4-0--( 2-chloro- 9-adenyl)-cyclopentane (150 mg) is treated with 3.0 ml phenethylamine and the mixture is heated at 13000 for 5.5 hours. The residue is 4 *9triturated with an ethyl ether/water mixture. The layers are sep-rated and the aqueous layer is combined with the insoluble material and concentrated to an oil. The crude product mixture is separated by flash column chromatography on reverse phase Cia-octadecylsilane

(C

18 )-bonded silica gel packing, eluting first with water, followed by 30 50 methanol in water to yield 2-alpha-3-alphadihydroxy-1-3-hydroxymethyl-4--I2-( 2-phenylethylamino)-9-adenyl cyclopentane as a white solid; m.p. 149-150'C; NMR (d 6 -DbfSO): 7.75 7.28 6.7 (2H,bs); 6.22 5.00 (1H,d); 4.69 4.53 (211,m); 4.37 3.84 (1H,m).

Example a) To 2.5 g of (+)-4-R-(5-amino-2,6-dichloro-4-pyrimidinyl-amino)- 2-alpha-3-alpha-dimethylme thylenedioxy-cyclopentane-l-R-N-ethylcarboxamide is added 40 ml triethyl orthoformate and 0.5 ml of concentrated hydrochloric acid at room temperature. After stirring at room temperature for three hours the reaction mixture is concentrated under high vacuum to afford a yellow oil. The oil is dissolved in 100 ml of a saturated solution of ammonia in methanol, and heated at 65-70%C in a 3teel pressure reactor overnight. The reaction mixture is cooled to room temperature and solvent removed under vacuum to al.Jord crude product. Chromatography on silica gel, eluting with dichloromethane followed by dichioromethane containing up to 10 of methanol, gives (+)-2-alpha-3-alpha-dimethylmethylenedioxy-4-Q-(2-chloro-9adenyl)-cyclopentane-l- 3-N-ethylcarboxamide as a white amorphous solid; at 25 +2.800 methanol); NMR (CD 3 OD): 8.25 (lH,s);

SBUS..D

5.05 3.23 (211,q); 2.94 2.54 1.58 (3H,s); a 1.31 1.12 (31,t).

A mixture of 1.8 g of (+)-2-alpha-3-alpha-dimethylmethylenedioxy- 2-chloro-9-adenyl) -cyclopentane-l-R-N-ethylcarboxamide and 40 ml U a. of 1N hydrochloric acid is heated at 60'C for 3 hours. The solvent is removed under vacuum and the residue triturated with methanol and 9 a ether, then collected and dried under vacuum to give (-)-2-alpha- 3-alpha-dihydroxy-4-3-(2-chloro-9-adenyl)-cyclopentane---N-ethylcarboxamide hydrochloride; m.p. 190%C uj 2 5 -8.70' (c=0.77,

D

methanol); NMR (CD 3 OD): 9.29 4.48 (1H,dt); 4.23 (1H,dt); 2.90 (11H,m); 2.70 2.24 1.16 (3H,t).

b) Similarly prepared is (+)-2-alpha-3-alpha-dihydroxy-4-0-(2-chloro- 9-adenyl)-cyclopentane-1-B-N-ethylcarboxamide.

The optically acitve starting materials are prepared as follows: Racemic 4-0-amino-2-alpha-3-alpha-dimethylmethylenedioxycyclo- (example 5, 5.4 g) is combined with 8.90 g of (-)-dibenzoyl-L-tartaric acid monohydrate in 100 ml boiling compositions.

41 ethanol and allowed to cool slowly to room temperature. The crystals which form are collected, washed with cold ethanol and dried under vacuum to yield colorless needles; a 25 -66.690 (c=1.09, methanol).

The (-)-4-8-amino-2-alpha-3-alpha-dimethylmethylenedioxy-cyclopentanel-B1-N-ethylcarboxamide dibenzoyl-L-tartrate salt is dissolved in water, the solution is treated with excess sodium bicarbonate and the solvent is removed under vacuum. The filtrate is triturated with ethyl acetate. The solids are filtered off and the filtrate is concentrated under vacuum to give (-)-4-8-amino-2-alpha-3-alpha-dimethylmethylenedioxy-cyclopentane-1-B-N-ethylcarboxamide as a yellow oil; U 5 -31.150 (c=2.27, methanol); NMR (CDC13): 4.81 (1H,dd);

D

4.39 3.26 1.80 (1H,dt).

a* The filtrate from the crystallization of the levorotatory salt is concentrated under vacuum and the residue treated with excess aqueous S* sodium bicarbonate. The solvent is removed under vacu!u and the residue is triturated with ethyl acetate. The insoluble material is collected and the filtrate concentrated under vacuum to give a yellow oil. The oil is combined with 4.00 g (+)-dibenzoyl-D-tartaric acid S* monohydrate in 90 ml boiling ethanol and allowed to cool slowly to 54 *.'room temperature. The resulting crystals are collected, washed with cold ethanol and dried under vacuum to yield the dextrorotatory salt as colorless plates; 2 5= +68.410 (c=1.1 4

CD

3 OD); NMR (CDCl 3 6.55 4.81 (2H,dd); 4.4 3.5 3.29 (2H,q); 2.77 2.4 1.8 1.48 1.29 (3H,s); r •1.13 (3H,t).

(+)-4-B-Amino-2-alpha-3-alpha-dimethylmethylenedioxy-cyclopentane- 1-B-N-ethylcarboxamide dibenzoyl-D-tartrate (7.04 g) is dissolved in water and treated with excess NaHCO 3 The solvent is removed under vacuum and the residue is triturated with ethyl acetate. The solids are filtered off and the filtrate concentrated under vacuum to afford (+)-4-B-amino-2-alpha-3-alpha-dimethylmethylenedioxy-cyclopentane- 1-8-N-ethylcarboxamide as a yellow oil; a 2 +32.260 (c=1.52, methanol); NMR (CDC3): 4.81 (1H,dd); 4.41 3.29 (2H,m); 1.84 (iH,dt).

uj 4-a.Lpna-i-alpha-dihydroxy-4-0-( 9 -adenyl)-cyclopentane-1-8-N- -42 To a solution of 2.016 g of 5-amino-2,4,6-trichloropyrimidine and 2. 32 g of (+)-4-0--amino-2-alpha-3-alpha-dimethylmethylenedioxy-cyclopentane-l-0-N-ethylcarboxamide in 40 ml n-butanol is added 2.8 ml of triethylamine and the resulting mixture is heated at reflux under nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature and the solvent removed under vacuum. The residue is partitioned between ethyl acetate and water. The ethyl acetate solution is extracted with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness to yield a dark amorphous solid. The crude product is chromatographed on silica gel eluting with ethyl acetate, hexane (1:2 to 4:1) to give a 5-amino-2 ,6-dichloro-4-pyrimidinylamino) -2-alpha&-3-alpha-dimethylmethylenedioxy-cyclopentane-1-a-N-ethylcarboxamide, as a white amorphous solid; u25= +27.360 methanol); NNR (CDCla): 5.95 (1H,bs); 4.72 4.51 3.31 2.84 (1H,d); 2.55 1.93 1.49 (311,s); 1.29 (M3H8); 1.18 (3H,t).

Similarly, condensation of 5-amino-2,4,6-trichloropyrimidine with the levorotatory amine yields the corresponding levorotatory intermediate.

0 000 Example 11: 0 a) t-Butyl p-(2--aminoethyl)-phenylpropionate (3.12 g) is combined neat a with 500 mg of (-)-2-alpha-3-alpha-dihydroxy-4-0-(2-chloro-9-adenyl)-

U~

25 -8.70' (c=0.77, methanol), 0

D

:%eeand heated at 12000 under nitrogen atmosphere for five hours. The 0 reaction mixture is cooled to room temperature and triturated with ether. The insoluble material is filtered off and dried under vacuum.

The solid obtained is triturated with water and the insoluble material is collected and dried under vacuum to yield 2-alpha-3-alpha-di- 2-(p-(2-t-butoxycarbonylethyl)-phenethyl-amino)-9as an off-white solid; m.p. 215%C NMR (CDCl 3 7.9 7.13 4.68 (lH,q); 4.47 4.32 3.58 3.23 2.82 (411,m); 1.4 1.14 such being an optical antipode of Ut,dct); 4.25 (1H,t); 43 the compound of formula IIa wherein R 2 represents p-(t-butoxycarbonylethyl)-phenethylamino, R 7 and R 8 represent hydrogen and R 6 represents ethyl.

b) Similarly prepared is the optical antipode derived from the corresponding dextrorotatory starting material.

c) Similarly prepared is the racemic 2 -alpha-3-alpha-dihydroxy- 4-8-[2-[p-(t-butoxycarbonylethyl)-phenethylamino]-9-adenyl]-cyclopentane-1-8-N-ethylcarboxamide, m.p. 206-208 0 C, using the racemic starting material.

t-Butyl p-(2-aminoethyl)-phenylpropionate is prepared as follows: p-Bromophenylacetonitrile (50 t-butyl acrylate (46 ml), palladium (II) acetate (575 mg) and tri-o-tolylphosphine (3.1 g) are combined with 125 ml triethylamine in a steel pressure reactor and heated at 140 0 C for 16 hours. The reaction mixture is cooled to room temperature and poured into 500 ml 3N hydrochloric acid at 0 C. The solids are extracted into ethyl acetate and the ethyl acetate solution is extracted with saturated sodium chloride solution and dried over 9 magnesium sulfate. The crude product is triturated with 9ether/hexane filtered and dried under vacuum to yield t-butyl p-(cyanomethyl)-phenyl-acrylate; m.p. 80-82 0 C; NMR (CDCl 3 7.5 7.32 6.39 3.78 1.52 (9H,s).

t-Butyl p-(cyanomethyl)-phenylacrylate (6.0 g) is combined with 600 mg 10 palladium on carbon in 80 ml isopropanol and 24 ml IN hydrochloric acid and treated with hydrogen at room temperature. After 8 hours at 300 kPa pressure, the catalyst is filtered off and the filtrate concentrated under vacuum. The residue is triturated with ether, filtered and dried under vacuum to afford t-butyl p-(2-aminoethyl)-phenylpropionate hydrochloride as a white solid. The hydrochloride salt is partitioned between ethyl acetate and IN sodium hydroxide. The ethyl acetate extract is washed with a saturated sodium chloride solution and dried over magnesium sulfate. Filtration and concentration of the filtrate affords t-butyl p-(2-aminoethyl)- 7.8 4.25 (lH,dd); 44 phenyipropionate as a yellow oil; NMR (CDCl 3 7.1 (4H,s); 2.98 2.89 2.73 2.5 2.02 (2H,s); 1.42 (9H,s).

Example 12: a) Optically active 2-alpha-3-alpha-dihydroxy-4-P-[ t-butoxycarbonylethyl)-phenethylaminolL:-9-adenyl ]-cyclopentane-l-a-N-ethylcarboxamide of example Ila (160 mg) is treated with 20 ml of IN hydrochloric acid and heated at 60'C for one hour. The solvent is removed under vacuum and the residue triturated with ethanol, filtered off and dried under vacuum to give (-)-2-alpha-3-alpha-dihydroxy- 4-B-[2-(p-(2-carboxyethyl)-phenethylamino)-9-adenyl]-cyclopentanel-0-N-ethylcarboxamide hydrochloride as a white solid; m.p. 243-245'C; *01 4* (c=0.99, DMS0); N14R (CD 3 0D): 8.11 7.18 (4H,q);

D

4.76 4.5 4.28 3.75 (2H,dt); 3.24 (2H,q); 2.94 2.85 2.44 2.3 1.16 (3H,t); representing the levorotatory antipode of the compound of formula Ha wherein R 2 represents p-(carboxyethyl)-phenethylamino, R 7 and R8 represent hydrogen and R 6 represents ethyl.

b) Similarly prepared is the corresponding dextrorotatory antipode, 242-245*C, u2 5 +3.480 (DMS0).

D

S c) Similarly prepared is also the 'racemic compound (example 7a), m.p. 235-237-C.

Example 13: Treatment of (-)-2-alpha-3-alpha-dihydroxy-4--[2-(p-2carboxyethyl)-phenethylamino)-9--adenyl]-cyclopentane-1-0-N-ethylcarboxamide hydrochloride with ethanol and conc. sulfuric acid as catalyst under reflux overnight gives after workup (-)-2-.alpha-3- 2-(p-2-ethoxycarbonylethyl-phenethylamino)- 9-adenyl]-cyclopentane-1-.R-N-ethylcarboxamide; NNR (CD3OD): 4.05 1.29 (t,3H).

45 Example 14: A mixture of 18 mg of 2-alpha-3-alpha-dihydroxy-l-0hydroxymethyl-4-p-(2-chloro-9-adenyl)-cyclopentane (example 3), 100 mg of sodium hydrogen sulfide, and 0.5 ml of N,N-dimethylfornamide is stirred at 1400C overnight. The reaction mixture is cooled to room temperature, neutralized with 0.1N hydrochloric acid to pH 6, then concentrated under reduced pressure to give crude 2-alpha-3-alphadihydroxy-1-0-hydroxymethyl-4-0-( thio-9-adenyl) -cyclopentane. The crude product is dissolved in a mixture of 3 ml ethanol, 1 ml 0.25N sodium hydroxide, 0.5 ml allyl bromide ard the mixture is stirred at room temperature for 20 hours. The reaction mixture is poured into water, neutralized with 0.1N hydrochloric acid to pH 7, then concentrated under reduced pressure to yield an amorphous solid. Flash chromatography of the crude product on a reverse phase C 1 8-column, eluting with water/methanol affords 2-alpha-3-alpha-dihydroxy- *1-0-hydroxymethyl-4-0-( 2-allylthio-9-adenyl)-cyclopentane, m.p. 126-1280C, NMR (CD 3 OD): 8.2 6.0 5.3 (1H,dd); 5.1 O1HMd); 4.75 4.58 4.05 (1H,dd); 3.8 (1H,xn); *3.67 2.4 2.24 2.02 (1H,m).

Example 15: Treatment of 2-alpha-3-alpha-diacetoxy-4-0-I2-( 2-phenylethylamino)-6-chloro-9-purinylI-cyclopentane-1-0-N-ethylcarboxamide with saturated nethanolic ammonia at 100'C in a sealed tube yields 2-alpha-3-alpha-dihydroxy-4--[2-(2-phenylethylamino)-9-adenyljof example 2a.

The starting material is prepared as follows: To a solution of 740 mg of 2-alpha-3-alpha-dimethylmethylenedioxy-4-0-( 5-amino-2 ,6-dichloro- 4-pyrimidinylamino)-cyclopentane-1-8-N-ethylcarboxamide in 10 ml triethyl orthofornate is added 0.15 ml concentrated hydrochloric acid at room temperature. The reaction mixture is stirred for 18 hours, then concentrated under reduced pressure to give an oil. A solution of the oil in n-butanol is then heated at reflux for 4 hours and cooled.

All the volatiles are evaporated to yield crude product which is then purified by flash chromatography on silica gel. Eluting with 4 -46methanol in dichioromethane gives 2-alpha-3-alpha-dimethylmethylenedioxy-4-0-(2 ,6-dichloro-9-purinyl)-cyclopentane-1-0-N-ethylcarboxamide; NMR (CD 3 OD/CDCl 3 8.2 2.1-2.9 (3H,m).

A solution of 60 mg of 2-alpha-3-alpha-dimethylmethylenedioxy-4-0- (2 ,6-dichloro-9-purinyl)-cyclopentane-l-8-N-ethylcarboxamide in 5 ml 1 N hydrochloric acid is heated to reflux for 5 hours and cooled. The reaction mixture is concentrated under reduced pressure to give crude product. The crude product is dissolved in 3 ml of methanol, 0.1 ml of phenylethylamine is added and the solution is heated under ref lux for hours. After the reaction is complete, all the volatiles are evaporated. The resulting crude solid is purified by chromatography on a reverse phase C-18 packing, eluting with water/methanol (8:1 to 5:1) to give 2-alpha-3-alpha-dihydroxy-4-8-[2-(2-phenylethylamino)-6hydroxy-9-purinylI-cyclopentane-1-03-N-ethylcarboxamide; NMR (CD 3 0D): 8.3 7.2-7.4 (511,m); 4.85 4.45 (1H,dd); 4.3 (lH,dd); 3.15 2.95 2.84 2.62 2.2 (1H,m).

Selective acetylation using a procedure as illustrated for a similar transformation in Can. J. Chem. 59, 2601 (1981) yields 2-alpha-3- 2-(2-phenylethylamino)-.6-hydroxy-9-purinylj- Chlorination with phosphorous oybrieand diethylaniline yields 2calpbna-3-lh-dia-etoy-4a [2(2-henletylaino-6-chloro-9purinyll-cyclopentane-1-3-N-ethylcarboxamide.

Example 16: The following compounds are prepared substantially according to procedures described in the previous examples: a) 2-alpha-3-alpha-diydroxy-4-03-[ 2-chloro-N6-( 2-N-pyrrolylcyclohexyl)-9-adenyl]-cyclopentane-1-0-N-ethylcarboxamide, m.p.

above 150%C (dec.); b) 3-alpha-hydroxy-4-0-f 3-phenylpropylamino)-9-adenyl]-cyclopentane-1-13-N-ethylcarboxamide, m.p. 185-186'C; 47 c) 3-alpha-hydroxy-1--ydroxymethyl-4-03-[2-( 2-phenyipropylanino)- 9-adenyl I-cyclopentane.

d) 2-alpha-3-alpha-dihydroxy-4-3-[I2-anilino-9-adenyl] -cyclopentane-1-IR-N-ethylcarboxamide; e) 2-alpha-3-alpha-dihydroxy-1-03-hydroxymethyl-4-$-[ 2-phenethylthio)-9-adenyllcyclopentane; f) 2-alpba-3--alpha-dihydroxy-1- -hydroxymethyl-4-0--[ 2-lip-(2-carboxyethyl) -phenethylamino] -9-adenyl] -cyclopentane; g) 2-alpha-3-alpha-dihydroxy-1-03-hydroxymethyl-4-3-I2-anilino-9adenyl]-cyclopentane.

Example 17: a) Preparation of 10,000 tablets each containing 10 mg of the active ingredient: Formula: .b 0** 9 5*

S.

5* ft~~5* .5.

S

S. .5

S

S

2-alpha-3-alpha-dihydroxy-4-3-( 9-adenyl)cyclopentane-l-a-N-e thylcarboxamide Lactose Corn starch Polyethylene glycol 6,000 Magnesium stearate Purified water 100.00 g 2,400.00 g 125.00 g 150.00 g 40.00 g q. s.

Procedure: All the powders are passed through a screen with openings of 0.6 mm.

Then the drug substance, lactose, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml of water and the) suspension added to the 9 .9 9 9 *9 9 9 9 9 9 48 boiling solution of the polyethylene glycol in 260 ml of water. The paste formed is added to the powders, which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35°C, broken on a screen with 1.2 mm openings and compressed into tablets, using concave punches upper bisected.

b) Preparation of 1,000 capsules each containing 10 mg of the active ingredient: Formula: 2-alpha-3-alpha-dihydroxy-4-B-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane-l-B-Ncarboxamide 10.00 g Lactose 207.00 g Modified starch 80.00 g Magnesium stearate 3.00 g Procedure: All the powders are passed through a screen with openings of 0.6 mm.

Then the drug substance is placed in a suitable mixer and mixed first with the magnesium stearate, then with the lactose and starch until homogeneous. No. 2 hard gelatin capsules are filled with 300 mg of said mixture each, using a capsule filling machine.

c) Similarly prepared are capsules and tablets of the other compounds disclosed herein, e.g. of 2-alpha-3-alpha-dihydroxy-4-8-[2-(p-carboxyethyl-phenethylamino)-9-adenyl]-cyclopentane-1-B-N-ethylcarboxamide hydrochloride.

i,

Claims (25)

1. A compound of the formula I NH-R t N N R n2 R 3 R wherein R, R 3 nd R 5 independently represent hydrogen or hydroxy provided that at least one of R, R 3 and R 5 represents hydroxy; R 1 represents hydrogen, lower alkyl, C 3 -C 7 alkenyl, hydroxy-lower alkyl, C3-C 6 cycloalkyl, Ca-Cecycloalkyl-lower alkyl, 2-norbornyl, 2-nor- bornyl-lower alkyl, aryl, aryl-lower alkyl, aryl-C3-C6cycloalkyl,

9-fluorenyl or 9-fluorenyl-lower alkyl; or R I represents a bicyclic benzo-fused 5 or 6-membered saturated carbocyclic radical or a benzo-fused 5 or 6-membered saturated heterocyclic radical containing a heteroatom selected from oxygen and sulfur directly attached to the fused benzene ring, any said bicyclic radicals being optionally substituted on the benzo portion by lower alkyl, lower alkoxy or halogen; R 2 represents hydrogen, halogen, -SR I or -N(R 9 )R 1 in each of S, which R' has meaning as defined hereinbefore provided that R' in -SR' does not represent hydrogen; R 9 represents hydrogen or lower alkyl; R4 S" represents hydroxymethyl provided that R 2 does not represent either hydrogen or -NHR I in which R I represents either hydrogen or lower alkyl; or R 4 represents lower alkoxymethyl, lower alkylthiomethyl or -CONHR 6 in which R 6 represents lower alkyl, aryl-lower alkyl, C3-Cscycloalkyl or hydroxy-lower alkyl; pharmaceutically acceptable ester derivatives thereof in which free hydroxy groups are esterified in form of a pharmaceutically acceptable ester; and salts thereof. r 50 2. A compound according to claim 1 of formula I wherein R and R 3 represent hydrogen or hydroxy; R 5 represents hydroxy; R 1 represents hydrogen or lower alkyl; or R' represents aryl or aryl-lower alkyl wherein aryl represents thienyl, pyridyl, naphthyl, phenyl or phenyl substituted by halogen, trifluoromethyl, lower alkoxy, lower alkyl or by a substituent -W-Z in which W represents a direct bond, lower alkylene, or oxy-lower alkylene, and Z represents cyano, carboxy, carboxy derivatized in the form of a pharmaceutically acceptable ester or carboxy derivatized in the form of a pharmaceutically accoptable amide; or R I represents a substituent of the formula B I 4 R a (B) in which A represents methylene, oxygen or sulfur, m represents zero or one, and Ra represents hydrogen, lower alkyl, lower alkoxy or halogen; R 2 represents hydrogen, halogen, -SRI or -N(R 9 )RI in which R L has meaning as defined hereinbefore except that R I in SR I does not S.g represent hydrogen; R 9 represents hydrogen or lower alkyl; R 4 represents hydroxymethyl provided that R 2 does not represent either hydrogen or -NHR 1 in which RI represents hydrogen or lower alkyl; or R4 represents lower alkoxymethyl, lower alkylthiomethyl, or -CONHR 6 in which R 6 represents lower alkyl, aryl-lower alkyl, C3-C6cycloalkyl or hydroxy-lower alkyl; pharmaceutically acceptable ester derivatives thereof in which one or more free hydroxy groups are esterified in S* form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof. 3. A compound according to claim 1 wherein R4 represents -CONHR 6 4. A compound according to claim 1 wherein R 4 represents hydroxymethyl. A compound according to claim 1 of formula II 1 H2 R 6 N 1 R 3 OH wherein R 2 represents hydrogen, halogen, SR 1 or N(R 9 R I represents aryl or aryl-lower alkyl in which aryl represents thienyl, pyridyl, phenyl or phenyl substituted by halogen, trifluoromethyl, lower alkoxy, lower alkyl or by a substituent -W-Z i which W represents a direct bond, lower alkylene or oxy-lower alkylene, and Z represents cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; or R' represents a substituent of the 9 formula B' *9 I r in which A represents a direct bond, methylene, oxygen or sulfur, and R a represents hydrogen, lower alkyl, lower alkoxy or halogen; R 3 represents hydrogen or hydroxy; and R 6 represents lower alkyl, C-C6cycloalkyl or hydroxy-lower alkyl; R 9 represents hydrogen or lower alkyl; pharmaceutically acceptable prodrug ester derivatives thereof in which free hydroxy groups are esterified in form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof. 6. A compound according to claim 5 wherein R 2 represents hydrogen, chloro or N(R 9 )RI; R a represents hydrogen; R 3 represents hydroxy; R 6 represents lower alkyl, C 3 -C6cycloalkyl or hydroxy-lower alkyl; and R 9 and A have meaning as in claim 5; pharmaceutically 52 acceptable prodrug ester derivatives thereof in which free hydroxy groups are esterified in form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof. 7. A compound according to claim 5 of formula IIa OR 7 OR 8 wherein R 2 represents hydrogen, chloro, N(R 9 )-(CH 2 -Cs or CGcyclo- alkyl, or -N(R 9 )-(CH 2 )n-Ar in which n represents zero or the integer 1, 2 or 3, R 9 represents Ci-C 3 alkyl, and Ar represents 3- or 4-pyridyl, phenyl or phenyl substituted by halogen, trifluoromethyl, lower alkoxy, lower alkyl or by a substituent -W-Z in which W represents a direct bond, straight chain Ci-C4alkylene or oxy-C1-C3- alkylene and Z represents cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; R 6 represents Cl-C4alkyl, cyclopropyl or hydroxy-C2-Calkyl; R 7 and R 8 represent hydrogen, lower alkanoyl, lower alkoxy-lower alkanoyl, aroyl, Scarbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; and pharmaceuti- cally acceptable salts thereof. 8. A compound according to claim 7 wherein R 2 represents hydrogen, chloro, NH-CH2CH 2 -cyclohexyl, N(CH 3 )-CHaCH 2 -cyclohexyl, N(CH 3 CH 2 CH 2 -Ar or -NH-CH 2 CH 2 -Ar in which Ar represents 2- or 3-pyridyl, phenyl or phenyl monosubstituted by a substituent -CH 2 CH 2 -Z in which Z represents cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; R 6 represents ethyl or hydroxyethyl; R 7 and R 8 represent hydrogen, lower alkanoyl or lower alkoxy- C2-C4alkanoyl; and pharmaceutically acceptable salts thereof. (example 5, 5.4 g) is combined with 8.90 g of (-)-dibenzoyl-L--tartaric acid monohydrate in 100 ml boiling -53 9. A compound according to claim 7wherein R 2 represents hydrogen, 2-phenylethylamino, 2-(p-carboxyethylphenyl)-ethylamino or 2-(2-pyridyl)ethylamino; R 6 represents ethyl; R 7 and R 8 represent hydrogen; and pharmaceutically acceptable salts thereof. A compound according to claim 5 of formula I~b T2 N- (Ib) R 6 2-N- RI\ .OR 7 OR' wherein R 6 represents ethyl; R 7 and R 8 represent hydrogen or lower alkanoyl; RI represents hydrogen or methyl; RIO represents hydrogen or methyl; R' 1 represents cyclohexyl, pyridy], phenyl, or phenyl mono-. substituted by halogen, lower alkoxy or -GH 2 CH 2 -Z in which Z represei 1 ts carboxy or lower alkoxycarbonyl; and pharmaceutically acceptable salts thereof. *II. A compound according to claim 1 being 2-alpha-3--alpha-dihydroxy- 4-0-(9-adenyl)-cyclopentane-1-03-N-ethylcarboxamide or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 being 2-alpha-3-alpha--dihydroxy- 2-(p-(2-carboxyethyl)-phenethylamino)-9-adenyl 1-cyclopentane- or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 being 2-alpha-3-alpha-dihydroxy- 4-0-[I2-(2-phenylethylamino)-9-adenyl1-cyclopentane-1-0.-N-ethyl- carboxamide or a pharmaceutically acceptable salt thereof. methanol); NMR (CDCla): 4.81 (1H,dd); 4.41 3.29 (2H,m); 1.84 (1H,dt). I 54

14. A compound according to claim 1 being 2-alpha-3-alpha-dihydroxy- l-8-hydroxymethyl-4-B-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane or a pharmaceutically acceptable salt thereof. A compound according to claim 1 being 2-alpha-3-alpha-dihydroxy- 4-0-[2-(2-cyclohexylethylamino)-9-adenyl]-cyclopentane-l-B-N-ethyl- carboxamide or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 1 wherein all symbols have meaning as defined in said claim except that R' is different C3-C 7 alkenyl and hydroxy-lower alkyl and wherein R 9 denotes exclusively hydrogen. 0 SO C O C C og 0 COO O a O 0 0 0

17. A compound according to claim 2 wherein all meaning as defined in said claim except that R I and wherein R 9 denotes exclusively hydrogen.

18. A compound according to claim 5 wherein all meaning as defined in said claim except that R' and wherein R 9 denotes exclusively hydrogen,

19. A compound according to claim 7 wherein all meaning as defined in said claim except that R 2 chloro or NH(CH 2 -Ar in which n represents the A compound according to claim 8 wherein all meaning as defined in said claim except that R 2 chloro or NHCHaCH 2 Ar. symbols hae'a is different symbols have is different the from the from aryl the from aryl symbols have the represents hydrogen, integer 1, 2 or 3. symbols have the represents hydrogen,

21. A pharmaceutical composition comprising a compound claimed in any one of claims 1-12.

22. A pharmaceutical composition comprising a compound claimed in any one of claims 13-20. I 55

23. A pharmaceutical composition comprising a compound claimed in any one of claims 1-12, in admixture or conjunction with one or more pharmaceutically suitable carriers.

24. A pharmaceutical composition comprising a compound claimed in any one of claims 13-20, in admixture or conjunction with one or more pharmaceutically suitable carriers. A compound elaimcd in any one of iI-ims 1-12 for uc in a therapeutic method of treating humans and animals.

26. A compound claimed in any one of claims 13-20 for use in a therapeutic method of treating humans and animals.

27. A compound claimed in any one of claims 1-12 as a enosine receptor agonist.

28. A compound claimed in any one of claims 3-20 as adenosine receptor agonist.

29. Use of a compound claimed in ay one of claims 1-12 for the manufacture of a pharmaceutical/composition.

30. Use .pound cl med in any one of claims 13-20 for the manufactu a phar ceutical composition. S" 31. Use of a co ound claimed in any one of claims 1-12 for the manufacture a pharmaceutical composition for application as adenosine receptor agonist. 32 Isc2 of a compound claimed in any one of claims 13-20 for the anufacture of a pharmaceutical composition for application as 1 56 Process for the manufacture of a pharmaceutical composition, wherein a compound claimed in any one of claims 1-12 is worked up with a pharmaceutical carrier. 2. Process for the manufacture of a pharmaceutical composition, wherein a compound claimed in any one of claims 13-20 is worked up with a pharmaceutical carrier. 27. Process for the manufacture of a compound of formula I shown in claim 1, in which formula all symbols have the meanings given in claim 1, or a salt thereof, which consists in I a) for compounds of formula I wherein R, R R, R 3 R4 and R 5 have meaning as defined hereinabove provided that one of R and R represents hydroxy, condensing a compound of the formula III N* V. H I (II) H 0 wherein R 3 and R 2 have meaning as defined above, in the presence of a strong base, and separating any resulting isomers if so required; or b) for compounds of formula I wherein R, R1, R2, R 3 R and RI have meaning as defined hereinabove, condensing a compound of the formula V Imeaning as defined hereinabove, condensing a compound of the formula V I?_i~iiiiil IlilC-. I r 57 N-* R 3 R wherein X represents a leaving group; R, R 2 R 3 R' and R s have meaning as just defined above, with a compound of the formula VIa R 1 -NH2 (VIa) in which R I has meaning as defined above; or c) for compounds of formula I wherein R 2 represents -SRI or -N(R 9 )R 1 condensing a compound of the formula VII 9H-R I R N- (VII) R 3 R a a wherein R, R I R 3 R 4 and R 5 have meaning as defined above, and X represents a leaving group, with either a compound of the formula VIa R1-NH 2 (Via) wherein R 1 has meaning as defined above; or with a compound of the formula VIb R'-SH (VIb) I i -58 or a reactive alkali metal salt derivative thereof wherein RI has meaning as defined above; or with a compound of the formula VIc R'-N(R (VIc) wherein R I and R 9 have meaning as defined above; or d) for compounds of formula I wherein R 4 represents -CONHR 6 as defined hereinabove, oxidizing a corresponding compound of the formula I wherein R 4 represents hydroxymethyl and wherein other hydroxy groups are in protected form, and derivatizing the so obtained carboxylic acid to a compound of formula I wherein R represents -CONHR 6 or e) for compounds of formula I wherein R* represents lower alkylthio- methyl condensing a compound of formula I wherein R4 represents hydroxymethyl with a di-lower alkyl disulfide in the presence of a tri-lower alkylphosphine or converting a compound of formula I wherein R 4 represents hydroxymethyl to a reactive esterified derivative thereof and reacting same with a lower alkylmercaptan or a reactive alkali metal salt derivative thereof; or f) for compounds of formula I wherein R 2 represents -SR I reacting a compound of the formula VII wherein X represents -SH and wherein R, R 3 R4 and R 5 have meaning as defined above with an electrophilic S* reagent corresponding to the radical R and, as further required in *1 6Ju any of the above-cited processes, temporarily protecting any inter- fering reactive group(s) in the starting materials and then sub- S* sequently removing the protecting groups to yield a resulting compound of formula I; and, if desired, converting a resulting compound of formula I into another compound of the invention, and if desired, converting a resulting free compound into a salt or a resulting salt into a free compound or into another salt, and if required, separating any mixture of isomers or racemates obtained into the single isomers or racemates, and if required, resolving a racemate into the optical antipodes. b) 3-alpha-hydroxy-4-B-[2-(3-phenylpropylamino)-9-adenyl]-cyclo- pentane-1-B-N-ethylcarboxamide, m.p. 185-186 0 C; t 00 0 *o o 00 S *0 00000 o* 0 0* g 0 .0 0.; r 59 28. A compound whenever prepared according to the process of claim 27. 29. A process according to claim 27 wherein a compound obtained by one of the processes a) to f) is converted into another compound according to the invention, by including esterifying free carboxy Z, or by converting'esterified carboxy Z into fee carboxy, and/or a resulting salt is converted into the free compound or into another salt and/or a resulting free compound having a salt forming group is converted into a salt. A method of treating an animal, including a human, for a condition responsive to adenosine receptor stimulation, which comprises administering to said animal an effective amount of a compound according to any one of claims 1 to 12.

31. A method of treating an animal, including a human, for a condition responsive to adenosine receptor stimuiation, which comprises administering to said animal an effective amount of a compound according to any one of claims 13 to

32. The method of claim 30 or 31 wherein said condition is a psychotic condition.

33. The method of claim 32 wherein said psychotic condition is schizophrenia.

34. The method of claim 30 or 31 wherein said condition is a cardiovascular condition. The method of claim 33, wherein said cardiovascular condition is hypertension, thrombosis or atherosclerosis.

36. A compound of formula I as shown in claim 1, said compound substantially herein described with reference to any one of Examples 1 to 16. starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml of water and the suspension added to the

37. A pharmaceutical composition substantially as herein described with reference to Example 17. DATED this 24th day of December, 1990. CIBA-GEIGY AG By Their Patent Attorneys ARTHUR S. CAVE CO. S. 56 S. S S S .i S. S S S 0 55 5 S S S.

55.. S S. 55 S S *SS* 55 S S S S S* S *S S