AU637015B2

AU637015B2 - Dideoxydidehydrocarbocyclic pyrimidines

Info

Publication number: AU637015B2
Application number: AU10180/92A
Authority: AU
Inventors: Mei Hua; Peter Leslie Myers; Richard Storer; Robert Vince
Original assignee: University of Minnesota System
Current assignee: University of Minnesota System
Priority date: 1988-01-20
Filing date: 1992-01-13
Publication date: 1993-05-13
Anticipated expiration: 2009-01-20
Also published as: HUT48887A; KR890011902A; IL88999A; BE1003815A4; JPH02196788A; PL277261A1; SE8900192L; PT89482A; RU2114846C1; FI890286L; GB2217320B; NO890253L; PL163814B1; SE505213C2; PT89482B; ATA10689A; JP2793825B2; AU626278B2; DE3901502A1; CA1339896C

Description

I

637015 Regulation 3.2

AUSTRALIA

Patents Act 1952 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

S..

0

S..

S.

S 0

S.

S

*~SS

S

650S59

S

00 S S .55 S. 0S .5 09 S *55 50

S

Name of Applicant: REGENTS OF THE UNIVERSITY OF MINNESOTA Actual Inventor(s): Robert Vince Mei Hua Petei' Leslie Myers Ric 'Storer Address for Service, DAVIES COLLISON CAVE, Patent Attorneys, Level 10, 10 Barrack Street, New South Wales, Australia *0 SS S S

S

,J OS S S Inve~ttion Title: DIDEOXYDIDEHYDROCARBOCYCLIC

PYRIMIDINES

The following statement is a full description of this invention, including the best method of performing it known to us: 1- -1A- 53623/000.535 DIDEOXYDIDEHYDROCARBOCYCLIC PYRIMIDINES The present invention relates to intermediates useful in the synthesis of dideoxycarbocyclic nucleoside analogues, in particular carbocyclic 3'-dideoxy- 2',3'-didehydro purine nucleoside analogues.

In view of the similarity between viral and host cellular functions it is difficult to selectively attack a virus while leaving the host cell intact. Thus, there are relatively few agents effective against viruses per se and it is difficult to find antiviral agents having an acceptable therapeutic index, i.e. agents which have 15 a meaningful antiviral effect at a dose level at which the agent has an acceptable toxicity, or side effect, profile.

SOne group of viruses which have recently assumed major significance are the retroviruses responsible for 20 the human acquired immunodeficiency syndrome (AIDS).

Such viruses have previously been referred to by various terminologies but are now generally referred to as human immunodeficiency viruses (HIV's); two such viruses, HIV- .I and HIV-II, have been reproducibly isolated from 25 patients suffering from AIDS and related conditions such as AIDS related complex (ARC) and persistent generalised lymphadenopathy.

Although a number of nucleosides have been taught as useful in the treatment of conditions associated with 30 HIV infections, only zidovudine (AZT, Retrovir) has received regulatory approval for the treatment of such conditions. However, it is known that zidovudine has severe side effects, causing suppression of the bone marrow leading to a drop in the white blood cell count with consequent pronounced anaemia, and there is a need for effective agents which are less cytotoxic.

Our copending application no. 28671/89 claims a 2 novel class of nucleoside analogues having antiviral activity. The compounds are of formula (I)

X

Z N N HO-CH2\ (I) wherein X is hydrogen, NRR 1 SR, OR or halogen; Z is hydrogen, OR 2 or NRR 1 R, R 1 and R 2 may be the same or different and are 15 selected from hydrogen, C 1 4 alkyl and aryl; and pharmaceutically acceptable derivatives thereof.

The compounds of formula are cis compounds and the cyclopentene rings of the compounds of formula (I) **go contain two chiral centres (shown in formula by 20 and may thus exist in the form of two optical isomers enantiomers) and mixtures thereof including racemic mixtures. Thus in the compounds of formula (I) either the chiral centre to which the base is attached is in the R configuration and the chiral centre to which S 25 the CH 2 0H moiety is attached is in the S configuration (hereinafter the D isomer) or the chiral centre to which the base is attached is in the S configuration and that to which the CH 2 0H moiety is attached is in the R configuration (hereinafter the L isomer). Conveniently 30 the compounds are in the form of either a racemic mixture or substantially as the pure D isomer. The D isomers may be represented by the formula (Ia) 3

X

I\N

Z N

N

HO- (Ia) where X and Z are as defined for formula The term halogen refers to fluorine, chlorine, bromine and iodine; when X is halogen it is preferably chlorine.

The term C,.

4 alkyl refers to a straight or branched chain alkyl group for example methyl, ethyl, n-propyl, o* 15 iso-propyl, n-butyl, sec-Dutyl and t-butyl.

Conveniently C 1 .4alkyl is methyl.

The term aryl refers to any mono- or polycyclic aromatic moiety and includes unsubstituted and ego* substituted aryl (such as phenyl, tolyl, xylyl, anisyl) 20 and unsubstituted and substituted aralkyl including ar(C 1 4 )-alkyl such as phen(C 1 4 )alkyl for example benzyl or phenethyl.

In the compounds of formula Z is preferably amino.

25 In one preferred class of compounds of formula (I) X is OR, in particular OH.

In a further preferred class of compounds of formula X is NRR in particular NH 2 or hydrogen.

Particularly preferred compounds of formula are 30 those wherein Z is NH 2 and X is H, NH 2 or, especially, OH. Such compounds in particular have especially desirably therapeutic indices as antiviral agents.

By "a pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of formula or any other compound which, upon administration to the recipient, is capable of providing (directly or 4 indirectly) a compound of formula or an antivirally active metabolite or residue thereof.

Preferred esters of the compounds of formula (I) include carboxylic acid esters in which the non-carbonyl moiety of the ester grouping is selected from hydrogen, straight or branched chain alkyl methyl, ethyl, npropyl, t-butyl, n-butyl), alkoxyalkyl (e.g.

methoxymethyl), aralkyl benzyl), aryloxyalkyl phenoxymethyl), aryl phenyl optionally substituted by halogen, C1.4 alkyl or C14 alkoxy); sulphonate esters such as alkyl- or aralkylsuphonyl methanesulphonyl,; amino acid esters L-valyl or L-isoleucyl) and mono-, di- or tri-phosphate esters.

With regard to the above described esters any alkyl 15 moiety present advantageously contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.

Pharmaceutically acceptable salts of the compounds 20 of formula include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, 25 lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalen-2-sulphonic and benzenesulphonic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may S* 30 be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal sodium), alkaline earth metal (e.g.

magnesium), ammonium and NR 4 4 (where R is C,- 4 alkyl) salts.

5 The compounds either themselves possess antiviral activity and/or are metabolizable to such compounds. In particular the compounds are effective in inhibiting the replication of retroviruses, including human .retroviruses such as human immunodeficiency viruses (HIV's), the causative agents of AIDS.

Certain compounds in particular those wherein Z is H also possess anticancer activity.

Our copending application 28671/89 also discloses processes for preparing compounds of formula (I) including reacting a compound of formula (II) x NH2 S NH z N NH (II)

Y-CH*

(wherein X and Z are substituents having the meaning of formula or are protected forms thereof and Y is OH or a protected form thereof) or a pharmaceutically acceptable derivative thereof with a reagent selected 25 from formic acid and reactive derivatives thereof, followed where necessary by removal of unwanted groups introduced by said reagent and/or by removal of any protecting groups present.

The p'sent invention now provides compound of 30 formula (I11 as defined above and pharmaceutically acceptable derivatives thereof.

In the compounds of formula (II) Z is preferably amino.

In one preferred class of compounds of formula (II) X is OR, in particular OH.

In a further preferred class of compounds of formula (II) X is NRR 1 in particular NH 2 or hydrogen.

6 Particularly preferred compounds of formula (II) are those wherein Z is NH 2 and X is H, NH 2 or, especially, OH.

Suitable methods for preparing compounds of formula (II) are described below. It will be appreciated that the following reactions may require the use of, or conveniently may be applied to, starting materials having protected functional groups, and deprotection might thus be required as an intermediate or final step to yield the desired compound. Protection and deprotection of functional groups may be effected using conventional means. Thus, for example, amino groups may be protected by a group selected from aralkyl (e.g.

benzyl), acyl or aryl 2,4-dinitrophenyl); 15 subsequent removal of the protecting group being effected when desired by hydrolysis or hydrogenolysis as appropriate using standard conditions. Hydroxyl groups S may be protected using any conventional hydroxyl protecting groups, for example, as descried in 'Protective Groups in Organic Chemistry', Ed. J.FoW.

McOmie (Plenum Press, 1973) or 'Protective Groups in Organic Synthesis' by Theodora W. Greene (John Wiley and Sons, 1981). Examples of suitable hydroxyl protecting S. groups include groups selected from alkyl methyl, 25 t-butyl or methoxymethyl), aralkyl benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups "t such as tetrahydropyranyl, acyl acetyl or benzoyl) and silyl groups such as trialkylsilyl tbutyldimethylsilyl), The hydroxyl protecting groups may 30 be removed by conventional techniques. Thus, for example, alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g. by hydrolysis under acidic or basic conditions. Aralkyl groups such as triphenylmethyl may similarly be removed by solvolysis, e.g. by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved by hydrogenolysis in the presence of a noble metal catalyst such as 7 palladium-on-charcoal. Silyl groups may also conveniently be removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.

The comLounds of formula (II) in which Z represents hydrogen or hydroxyl may be prepared directly from the compound 2a I I 2a by reaction with an excess of a pyrimidine of formula oo** 15 (III)

X

I

Ao (II<

N

20 (wherein Y is a halogen aton, e.g. chlorine and Z is hydrogen or hydroxyl) in the presence of an amine base 25 such as triethylamine and in an alcoholic solvent (e.g.

n-butanol), conveniently at reflux.

Compounds of formula (II) in which Z represents NH 2 may be prepared using the compound of formula 2a by reaction with an excess of a pyrimidine of formula (IV)

X

(IV)

HNN H 2N N 1 \y 8 (wherein Y is as defined in formula (III) above) under similar conditions to those described just above for the preparation of compounds of formula (II) in which Z represents hydrogen or hydroxyl to give a compound of formula (V)

X

N

I I (V)

H

2 N N H

HO-CH

2 r .ees which may be diazotized using a diazonium salt ArN+E' S(wherein Ar represents an aromatic group, e.g. p- *chlorophenyl, and E' represents an anion, e.g. a halide such as chloride) in a solvent such as water, an organic 20 acid such as acetic acid or a mixture thereof, conveniently at about ambient temperature to give a compound of formula (VI)

X

I

N=N-Ar 25*

SHO-CH

2 S* (wherein Ar is as defined just above) which may be converted to the desired compound of formula (II) by reduction using for example a reducing metal such as zinc in the presence of an acid, e.g. acetic acid. It will be appreciated that the choice of reducing agent 9 will depend on the nature of the group X.

The compound 2a may be prepared from the versatile precursor, la-acetylamino-4a-acetoxy-mathylcyclopent-2ene (la) by hydrolysis in the presence of a mild base, such as an alkaline earth metal hydroxide.

The compound la is a known compound described in US Patent No. 4,138,562.

Resolution of a compound of formula (II) or an intermediate or starting material therefore may be effected by any suitable method known in the art see for example 'Stereochemistry of Carbon Compounds' by E.L. Eliel (McGraw Hill, 1962) and 'Tables of Resolving Agents' by S.H. Wilen.

The invention will be further described by 15 reference to the following detailed examples wherein elemental analyses were performed by M-H-W-Laboratories, Phoenix, AZ. Melting points were determined on a Mel- Temp apparatus and are corrected. IR spectra were determined as KBr pellets with a Nicollet 50XC FT-IR 20 spectrometer. Mass spectra were obtained with an AEI Scientific Apparatus Limited MS-30 mass spectrometer.

All chemicals and solvents are reagent grade unless otherwise specified.

e g **So 1.0 Example 1 )-4-[(5-Amino-6-chloro--4-pyrimidinyl)-aminol-2cyclopentenylcarbinol (3a) A mixture of lca-acetylamino-4a-acetoxymethyl cyclopent-2-ene (la) 15 rnmol) and aqueous barium hydroxide (0.5N, 300m1) was refluxed overnight. After cooling, it was neutralized with dry ice.

The precipitate was filtered out, and the aqueous solution wros concentrated to dryness. The residue was extracted with absolute ethanol and concentrated again to yield 2a as a colourless syrup 1.6g (14mmol).

To this syrup, 5-amino-4,6-di4chloropyrimidine (4.59g 28 mmol), triethylamine (4.2g, 42 mmol), and n-butanol (50ml) were added and the mixture mzru refluxed for 24 hr. The volatile solvents were removed, the residue was absorbed on silica gel packed in a flash column x 12cm) and eluted with CHCl 3 -Me0H. (20:1) to yield 2.69g of compound 3a; m.p. 130-1.32 0 C. An analytical sample was obtained by ~recrystallisation from ethyl acetate (EtOAc), m.p. 134-135 O, MS 6655ev, 200 0 m/e 240 and 242 and 209 144 IR: 3600-2600 1620, 1580 Anal. (C uH 13

CIN

4 C, H, N.

Example 2 (±Soa4 )S4 2Aio6 hlr--yrmdn )-aio 2 *0 cyclopentenylcarbinol (4s) To 14 mmol of crude 2a (Example 1) 2-amino-4,6-dichloro- 6 pyrimidine (3.74g, 22.8 mmol), triethylamine (15m1) and n-butanol *5956(75m1) were added and the mixture was refluxed for 48 hr. The volatile solvents were removed, residue was treated with methanol to separate the undissolved by- product (the double pyrimidine £nucleoside). The methanol solution was absorbed on silica gel (8g) packed into a column (4.0 x 14cm) and eluted with CHCI 3 -MeOH (40:1) to yield 1.52g of crude 4a. The product was recrystallised from ethyl eratate to yield 4a; m.p. 132-1340C, MS (30 ev, 200 0 m/e 240 and 242 and 209 144 IR: 3600-3000 (NH2, OH), 1620,1580 C=N); AMal. (C 10

H

13

CN

4 C,H, N.

11 Example 3 (+)..(ia,4c)-4-([(2-Amino-6-chloro-5-(4-chlorophenyl)-azo]-4pyrimidinyl-amnino)-2-.cyclopentenylcarbinol A cold diazonium salt solution was, prepared from p-chloroaniline (1.47g, 11.5 mmol) in 3N HCl (25rn1) and sodium nitrite (870mg, 12.5 mmol) in water (10ml). rhis solution was added to a mixture of 4a (2.40g, 10 mmol), acetic acid (50m1), water (50m1) and sodium acetate tzihydrate (20g). The reaction mixture was stirred overnight at room temperature. The yellow precipitate was filtered and washed with cold water until neutral, then it was air-dried in the fujnehood to yield 3.66iq of 5a, m.p. 2290C (dec). The analytical sample was obtained from acetone-methanol m.p. 241-243 0 C (dec). MS 2600C): m/e 378 and 380 and M+ 282 iik: 3600-3000 (NH 2 OH), 1620, 1580 Anal. (C1 6 HI.Cl 2

N

6 0) C, H, N.

b 0,1 Example 4 cyclopentenylcarbinol (6a) A mixture of 5a (379mg, 1 mmol), zinc dust (0.65g, 10 mmol), *acetic acid (0.32 ml), water (15m1) and ethanol (15m1) was refluxed under nitrogen for 3 hr. The zinc was removed and the solvents were evaporated. The residue was absorbed on silice gel packed into *w a column (2.0 x 18cm), and eluted with CHC1 3 -MeOH A pink 400" syrup was obtained. Further purification from methanol-ethe,2 yielded 6a as pink crystals, 170mg m.p. 168-170 0 C, MS (30 ev, 2200C); m/e 255 and 257 and M+ 224 159 IR: 3600-3000

(NH

2 OH) 1620,1580 Anal. (CjaH 1 4~ClNb) C, H, N.

Claims

12- The claims defining the invention are as follows: 1 A compound of the formula (II) N Y-CH, .NH 2 S S 3 S S S *9 S 55 S wherein X is hydrogen, NRR 1 SR, OR, is halogen or protected forms thereof; Y is OH or a protected form thereof; Z is hydrogen, OR 2 NRR', or protected forms thereof; R, RI, R 2 are the same or different, and are selected from hydrogen, C.-1 4 alkyl, aryl, substituted aryl, aralkyl or substituted alkyl; and pharmaceutically acceptable salts, esters, and salts of such esters, thereof. A compound of formula (II) according to claim 1 and pharmaceutically acceptable salts thereof. A compound according to claim 1 or claim 2 wherein Z is H, OH or NH 2 A compound according to any of claims 1 to 3 wherein Z is NH 2 A compound according to any one of claims 1 to 4 wherein X is hydrogen, chloro, NH 2 SH or OH. A compound accordingly to claims 1 to 5 wherein X ib OH. 13 7 A compound according to any one of claims 1 to 5 wherein X is H or NI,. 8 A compound according to anyone of claims 1 to 7, wherein Y is a mono-, di-, or tri- phosphate ester. 9 A compound according to any one of claims 1 to 8 in the form of substantially a recemic mixture. A compound according to any one of claims 1 to 8 consisting substantilly of an optical isomer. 11 A compound according to any one of claims 1 to 8 consisting substantially of the D isomer. 12 A compound of the formula (II) as described in claim 1, said compound substantially as herein described with reference to any one of the Examples. DATED this 19th day of February 1993. THE REGENTS OF THE UNIVERSITY OF MINNESOTA By their Patent Attorneys DAVIES COLLISON CAVE 0* *e ABSTRACT Disclosed are compounds of the formula x N NH 2 Y-CH 2 whiere X is hydrogen, NRR', SR, OR, halogen or protected forms thereof; Y is OH or a protected form thereof; Z is hydrogen, OR 2 NRR 1 or protected forms thereof: R, RI, RI are the same or different, and are selected from hydrogen, C 1 -4 alkyl; optionally substituted mono-, or polycylicaryl, and optionally substituted aralkyl, (where the meaning of the aryl and alkyl portions of aralcyl are as described previously); and pharmaceutically acceptable derivatives thereof. *Voo: as 6 .0. t o S