CA1317291C - Antitumor 6-sulfenamide, 6-sulfinamide and 6-sulfonamide purines, purine nucleosides, purine nucleotides and related compounds - Google Patents

Abstract

wherein R1 and R2 independently are H, OH, -O-acyl or O= , or together R1 and R2 are O=

Description

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ANTITUMOR 6-SULFENAMIDE, 6-S~LFINAMIDE AND
6-SULFONAMIDE PURINES, PURINE NUCLEOSIDES, PURINE NUCLEOTIDES AND RELATED COMPOUNDS

TECHNICAh FIELD

This invPntion is directed to certain 6-sulfenamide, 6 sulfinamide, and 6-sulfonamide purines, purine nucleosides and purir,e nucleotides including 3-deaza, 7-deaza and 8-aza derivatives thereof, to their preparation and to using these compounds to treat malignant tumors ln v1vo.

BACKGROUND ART

Certain antimetabolites are known useful cancer chemo-therapeutic agents. One such antimetabolite chemothera-peutic agent is 6-mercaptopurine. 6-Mercaptopurine was initially found to be highly active against adenocarcinoma and currently 6-mercaptopurine is utilized as a drug of choice in the treatment of leukemia Its use in the treat-ment of leukemia led to dramatic increases in controlling this disease. Other useful antimetabolites are 6-thio~
guanine and 5-bromouracil. Nucleoside and nucleotide analogs of these and other purines and pyrimidines had been synthesized and tested as antitumor agents.
Purine and pyrimidine nucleosides and nucleotides are ubiquitous throughout biological systems. It further appears that most of the analogs of purines and pyrimidines exert their biological activity only after conversion to a corresponding nucleotide. In view of this, a number of purine and pyrimidine nucleosides and nucleotides have been synthesized and screened for their antitumor propertiesA
To be an effective chemotherapeutic agent a compound must possess a number of desirable properties. First of 3~ all, it must, of course, be an active antitumor agent.
Coupled with this, it must not exhibit too great a host toxicity or must exhibit reversible toxicity such that the host is capable of surviving the chemotherapeutic treatment ., .

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regimen. optimally the chemotherapeutic agent shoul~ not induce the development of drug resistant cell lines. The in~lucement of drug resistant cell line occurs with certain kno~-n chemotherapeutic agents, as for instance, 6-mercaptopurine and cytosine arabinoside.
Further, effective chemotherapeutic agents need totransport to the site in the body inflicted with the neoplastic condition~ Thus depending upon the type of tumor, this requires thak chemotherapeutic agents be capable of reaching tumor containing organs. This includ~s being able to effectively penetrate the central nervous system by crossing the blood brain barrier. As i9 evident by the sparsity of clinically efective chemotherapeutic agents, very few compounds possess a sufficient nu~ber of these capabilities to be clinically useful.
Many effective chemotherapeutic agents require repeated dosing in order to progressively diminish and kill the neoplastic cell populations affecting the host. During these repeated administrations of the chemotherapeutic agent it is further advantageous for the agent to not develop resistant cell lines. Because of the development of resistant cells by certain drugs presently used in the treatment of many neoplastic disease states, combinations o~
drugs are usually utilized. Thus, as resistant cells develop to a first drug, treatment with a second or further druy is often made in an attempt to effecti~ely treat the drug resistant neoplastic cells.
We have found that certain 6-sulfenamide, 6-sulfinamide and 6 sulfonamide purines, purine nucleosides and purine nucleotides and related analogs exhibit one or more of the properties discussed above, and further exhibit significant antitumor activity so as to be useful as antitumor agents in :: ~rivo.

DISCLOSURE OF THE INVENTION

The present inventior~ relates to a novel class of 6-sulfenamide, 6-sulfinamide and 6-sulfonamide purines, purine 3 L31 7 2-9 ~
nucleosides, purine nucleotides and 3 and 7 deaza and 8 aza derivative6 thereof and to their preparation and use as : antitumor agents.
In accordance with the invention, disclosed are compounds of the formula:
X

N ~ ~T
lo Z ~ G N
.
wherein Z is H or -NH2;
o O
ll ll X i5 -S-NH2, -S-NH2 or -S-NH2;

; G, T and Q are C-H or N;
Y is H or an ~-pentofuranose or ~-pentofuranose of the formula:

R2 ~p Rl R3 wherein Rl and R2 independently are Hl OH, -O-acyl or 3s 4 ~ 3 OH f-O=P-O- , or together R1 and R2 are O=P-O-OH OH
and R3 and R4 are H or one of R3 or R~ is OH and the other is H; provided that when Y is H, Z is -NH2; and pharmaceutically acceptable salts thereof.
These compounds are useful as antitumor agents or they are intermediates for compoullds which have these properties.
They can be used to treat an affscted host as~ for example a mammalian host (i.e. a warm blooded host~ by serving as the active ingredients of suitable pharmaceutical ccmpositions.
Additionally, in accordance to the invention, an antitumor composition for the treatment o~ tumors in vivo contains as its active ingredient a therapeutic effective amount of a compound of the above formula.
Further, in accordance with the invention/ tumors in warm blooded animals are treated by adm.inistering to the animal in need thereof, a pharmaceutical compositi.on containing as the active component therein a therapeutically : effect amount of a compound of the above formula.
The method of the invention and khe antitumor composition of the invention used therain, are effective in bringing about regression, palliation, inhibition vf growth, i 25 and remission of tumors.
Particularly useful are compound of the above ~ormula wherein Y is a ~-pentofuranosa of the formula:

Rl R3 Included in this group a.re 2-amirlo-9~-D~ribo~uranosyl-9H-purine-6-sulfenamide (see compound 18), 2-amino-9-~-D-ribofuranosyl-9H-purine-~-sulfinamide (see compound 19~, 2-amino-9-9-D-ribofuranosyl-9H-purine-6-sulfonamide (see com-~c~ 3 pound 20) and 2-amino-9 (2~-deoxy~ -er~thro-pentofUrano-syl)-gH-purine-6-sulfinamide (see compound 23).
Exhibiting particularly useful antitumor properties is the above 2-amino-9-~-D-ribofuranosyl-9H-purine-6-sulfin-amide. This compound exhibits a particularly us~fulcombination of solubility, activity and the lack of generating resistant cell lines as well as being able to penetrate the central nervous system and b~ active in both an oral and an injectable form.
For use in pharmaceutical compositions of the invention, a pharmaceutical carrier would be utilized.
Preferably, the pharmaceutical carrier would be chosen to allow for administration of a suitable concentration of the active compounds of the invention either by oral administration, ophthalmic administration, topical administration, suppository administration or by suitable injection as a solution or suspension into the effected host. The dose and choice of administration of the active compounds of the invention would depend upon the host harboring the malignant tumor, the type of tumor, and the tumor site. For injection, the active compounds of the invention could he administered intravenously, intramuscularly, intracerebrally, subcutaneously, or intraperitoneally.
The compounds of the invention are especially useful in treating carcinomas, sarcomas and leukemias. Included in such a class are mammary, colon, bladder, lung, prostate, stomach and pancreas carcinomas and lymphoblastic and myeloid leukemias.
Other compounds of the invention are useful as intermediates for the preparation of the active antitumor compounds of the invention. Further certain of the compounds of the invention are useful as prodrugs for other active antitumor compounds of the invention.

BEST MODE FOR CARRYING OUT THE INVENTION

A group of 6-sulfenamide, 6-sulfinamide and 6-sul~onamide purines, purine nucleosides and purlne nucleotides and related analogs have been found to have antitumor properties or be intermediates for compounds having such antitumor properties. Included in this group of compounds are purin~s which have been substituted on the purine ring at the 2 position with an amino group and various nucleosides and nucleotides as well as modification of the purine ring at the 3, 7, and 8 positions forming deaza and aza purines. Included in this group are the ribo~uranosyl, the deoxyribofuranosyl and the arabino-fuxanosyl nucleosides, the monophosphates of these nucleo-sides and the 3',5'-cyclic phosphates of these nucleosides and derivatives thereof. Included in the deaza and aza purine compounds are the 3-deaza and the 7-deaza purine as well as the 8-aza-7-deaza purine.
One particular compound, 2-amin~-9-~-D-ribofuranosyl 9H-purine-6-sulfinamide, has exhibited good ln vivo activity coupled with an excellent dos~ response per~ormance while penetrating the central nervous system and exhibiting a lack of resistance cell generation. This compound is water soluble and orally active. Further, it has demonstrated activity against cells which have become resistant to other chemotherapeutic agents.
The 6-sul~onamide analog of this compound exhibits many of the properties o~ the 6-sul~inamide with the exception of lack of oral actlvity and CNS penetration. The deoxy derivative o~ this compound, i.e. the 2-deoxy-~-D-~y~h~-pento~uranosyl derivative, also exhibits good activity with increased water solubility.
While we do not wish to be bound by theory, it is bel ieved that many purines, pyrimidines, and purine and pyrimidine nucleosides exhibit their antitumor activity by being enzymatically phosphorylated in situ to their 5' phosphate derivative. Other enzyme systems are known which convert the 5'-phosphate to a 3',5'-cyclic phosphate.

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Additionally, ~sterases are known which cleave phosphates and/or cyclic phosphates. In any event, activity has been shown for compounds o~ the invention as bokh nucleosides and nucleotides.
In addition to phosphate or cyclic phosphate derivatives (phosphoryl ester prodrugs) the compounds o the inventions can also be administer~d as acyl ester prodrugs which are then also cleaved in vlvo to the parent compound.
Suitable acyl derivatives can be selected as, for example, from formyl, acetyl, propionyl, butyryl, isobutyryl, hexanoyl and benzoyl. Preferably acetyl is utilized. One or more hydroxyl group on the nucleosides o~ the invention can be suitable reacted to yield such a Cl-C8 acyl prodrug.
In performing the invention, a compound of the invention or a selected derivative thereof, is appropriately admixed with a suitable pharmaceutical carrier which may ~e as simple as sterilized water or could be a complex carrier having appropriate agents to suitably mimic certaill biological environmental, i.e., pH or salt adjustment for solution suitable for intravenous, intramuscular or other injections, or other appropriate carrier manipulation for different routes of administration of the compounds o~ the invention.
In selecting a suitable pharmaceutical carrier, consideration of the type o~ tumor, the site of the tumor and the health and age of the host would be given.
Additionally, if a derivatized form of a compound o~ the - invention i~ used, consideration of the chamical reactivity of the derivative would also be given. Thus, if a phosphate form o~ a compound of the invention is used in practicing the invention, it might be used in the presence of a suitable buffer or an acceptable pharmacelltical salt thereof.
Acceptable salts of the phosphate moiety can be selected from, but not necessarily limited to the group consisting of alkali and alkaline earths, e.g. sodium, potassium, calcium, magnesium, lithium, or ammonium and substituted ammonium, trialklyammonium, dialkylammonium, ~ 3 ~ r7 ~

alklyammonium, e.g. triethylammonium, trimethylammonium, diethylammonium, octylammonium, cetyltrimethylammonium and cetylpyridium.
Since the compounds of the invention are water soluble they could suitably be given to a host as a solution in a suitable carrier. Alternately, however~ suspensions, emulsions, or other formulations o~ the compounds of the invention could be used where indicated. The pharmaceutical carrier, in addition to having a solubilizing or suspending agent therein, might include suitable diluents, ~uffers, surface active agents or other similar agents as are typically used in pharmaceutical carriers. However, the total composition of the pharmaceutical carrier would be chosen to be compatible with the site of the delivery, the mode of delive~y, the concentration of the active ingredient and other parameters as are standard in the pharmaceutical arts.
The compounds of the invention would be suitably admixed with the pharmaceutical carrier such that they would be present in a composition of at least 0.1 percent Dy weight of the total composition. Pre~erably, the compounds of the invention would be present in a pharmaceutical carrier at a concentration of about 10% to about 90% by weight o~ the total composition.
A therapeutic effective amount of the compounds of the invention, as will be evident from the biological responses and solubilities given below, would be utilized in treatiny an affec-ted host animal taking into consideration certain parameters such as the type of tumor, the tumor site, the form of administration of the compound, and the physical size and condition of the host. In any event, the actual amount should be sufficient to provide a chemotherapeutically effective amount of the agent in the host in a convenient carrier. This will be readily within the ability of those skilled in the Art given the disclosure herein.
The compounds of the invention can be given as single doses or as multiple doses divided into sub-doses given ~ 3 .~ 7 i~
g daily or over a period of days. As will be evident from th~
examples below, compounds of the invention exhibit certain dose response curves and, as such, optimization o~ a dosage schedule is well within the skill of the Art given the disclosure herein.
; In novel processes of the invention, generally 6-mercaptopurine derivatives as the purine base, nucleoside or nucleotide are treated with chloramine to prepare the corresponding 6-sulfenamides. The chloramine can be prepared in situ by reacting ammonium hydroxide with sodium hypochlorite. The 6-sulfenamides are then selectively oxidized either to the 6-sulfinamide or fully oxidized to the 6-sulfonamide compounds. Generally for selective oxidation to the 6-sulfinamide, 1 eq. of an oxidizing agent is utilized~ For full oxidation to the 6-sulfonamide, further equivalents o~ the oxidizing agent are utilized.
Preferred as an oxidizing agent for process of the invention is m-chloroperoxybenzoic acid.
j The above processes have been found useful for both preparing free purines, purine nucleosides and purine nucleotides of the invention. Typically, the 6-sulfinamide is prepared utilizing 1 eq. of the above referred to _-chloroperoxybenzoic acid, and the 6-sulfonamide is prepared utilizing 4 eq. of m-chloroperoxybenzoic acid. It is evident that 6-sulfonamide compounds can be prepared directly ~rom the corre~ponding 6-sulfenamide compounds or could be prepared via the 6-sulfinamide compounds as an intermediate.
Schemes I and II illustrate the general reaction schemes for pxeparation of compounds o~ the inventlon from starting 6-mercaptopurine precursors. In scheme I, the heterocycle utilized is a purine, whereas in scheme II
various deaza and aza heterocycles are depicted. In cross reference between the schemes and the illustrative examples which follow, the numbers in the parentheses following the names that app~ar after each example refer to the compound numbers and structures that appear in schemes I and II.

1 0 ~ J e~
SCHEME I

l H2 I Hz l H2 S S S=O O~S=O
HN ~N~ N ~ N~N

Y r Y Y

Z = -NH2 Y = -H
COMPOUND , COMPOUND --~ COMPOUND --~ COMPOUND

Z = -H
Y = -~-D~ribofuranosyl COMPOUND ~ COMPOUND i COMPOUND i COMPOUND

Z = -H
Y = -~-D-arabinofuranosyl COMPOUND ~ COMPOUND --~ COMPOUND --~ COMPOUND

. Z = -H
Y = -2-deoxy-~D-,erythro-pentofuranosyl 30COMPOUND --~ COMPOUND --~ COMPOUND --~ COMPOUND
. 13 ~4 ~5 16 .

, r~

Z = -NH2 Y = -~-D-ribofuranosyl COMPOUND --~ COMPOUND --~ COMPOUND --~ COMPOUND
5~7 18 19 29 Z = -NH
Y = -2-~eoxy-~-D-erythro-pentofuranosyl 10COMPoUND , CoMPOUND , COMPOUND --~ COMPOUND

Z = -NH2 Y = -~-D~ribofuranosyl 5'-phosphate COMPOUND --~ COMPOUND , COMPOUND

Z = NH2 Y = -~-D-ri~ofuranosyl 3',5'-cyclic phosphate COMPOUND --~ COMPOUND --~ COMPOUND
28 ~9 30 Z = -NH
Y = -5-~eoxy-~-D-ribofurano~yl COMPOUND --~ COMPOUND , COMPOUND --~ COMPOUND
~0 ~1 42 ~3 z = -NH
3 0 y a -2-~eoxy-~D-erythro-pentofuranosyl COMPOUND --~ COMPOUND --~ COMPOUND ~-~ COMPOUND
~ 45 ~6 ~7 ' ~ ~ 1 7 ~

Z = -NH
Y = -~-D-arabino~uranosyl COMPOUND , COMPOUND --~ COMPOUND ~-~ COMPOUND
4~ 4g 50 51 Z = NH2 Y = 2,3,5-tri-O-acetyl-~-~-ribo~uranosyl , 10 - COMPOUND

"
., : SCHEME II

7 I H2 yH, . s s s=o o=s=o --~T --> N ~ ~ N ~a,.~, ~Q
. 25 zJ~G il zJ~G N ZJ~ H ZJ~C' N
j r Y r r .
..
G = N
:~ T = N
.~ Q = CH
,, Z = -NH2 Y = -~-D-ribo~uranosyl COMPOUND --~ COMPOUND --~ COMPOUND
31 3z 33 : ' "' 11 3~ t~3, G = CH
T = CH
Q = N
Z = -NH2 Y = -~-D-ribofuranosyl COMPOUND --~ COMPOUND --~ COM.POUND

lo G - N
Q = CH
Z = -NX~
Y = -2-aeoxy-,B-D-exythro-pentofuranosyl COMPOUND --~ COMPOUND ~ COMPOUND
37 3~ 3g G = N
T = CH
Q = CH
Z = H
Y = -2-deoxy-~-D-erythro-pentofuranosyl COMPOUND --~ COMPOUND - ~ COMPOUND --~ CO~POUND
52 53 s~ 55 G = N
T = N
Q = CH
Z = H
Y = -~-D-ribo~uranosyl COMPOUND ~COMPOUND
~6 57 .

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The following illustrative examples are given ~or the preparation of compounds of the invention. Unless otherwise indicated, the various startiny 6-mercaptopurine -ompounds or other compounds utilized for the staxting materials were obtained from suitable commercial sources. In these illustrative examples, the preparation of the compounds of the invention is accomplished utilizing the processes of the invention.

1o EXAMPLE 1 2-Aminopurine-6-sulfenamide ~2).
To an ice-cold 5.25% sodium hypochlorite solution (33.8 mL) was added 7N NH40H (17.8 mL) and stirred for 10 minutes~
A solution of 2-aminopurine-6-thione 1, see A.G. Beaman and 15 R.K. Robins, J. Am. Chem. Soc., 83, 4038, (1961), (1.67 g, 22 mmol~ in 2N KOH (11 mL) was added and continued stirring for 25 min at 0C. The mixture was allowed to stand at 0C
without stirring for 1.5 h. The precipitate was collected by filtration and washed with small amount of water and EtO~
20 to obtain 1.45 g (36%) of the title compound, mp >250C: UV.
~max (pH 1) 325 nm (~ 6,400), 2~0 nm (sh): ~max (pH 7) 310 nm (~ 5,900), 237 nm (~ 6,800): ~max (pH 11) 312 nm (~
5,900): lH NMR (DMSO-d6): ~ 5.78 (br s, ~, NH2, exchangeable in D2O), 7.73 ~s, 1, C8H): Anal. Calcd for C~H6N6S.1/2 H2O
25 (191.1~: C, 31.41: H, 3.27: N, 43.98: S, 16.79. Found: C, 31.89: H, 3.~7: N, 43.33: S, 17.19.

EXAMPhE 2 2-Aminopurin -6-sulfinamide (3)~
2-Aminopurine-6-suffenamide 2 (182 mg, 1 mmol) was suspended in EtOH (lO0 mL) and cooled to 0C. m-Chloroperoxybenzoic acid (~5%, 20~ mg, 1 mmol) was added portionwise during 1 h with stirring, and stirring continued ~`
for additional 30 min. After filtration, the filtrate was concentrated to half the volume in vacuo. Ethyl ether (50 mL) was added and allowed to stand in a refrigerator overnight. The precipitate was collected by filtration and washed with ether to obtain 115 mg (58%) of the d~sired .

15 13.~7,^?~3.
compound, mp. >250C, : UV ~max (pH 1) 332 nm (~ 4,600~ 240 nm (sh): ~max (pH 7) 326 nm (~ 4~500) ~max (pH 11) 326 nm (~ 4,200), 283 nm (~ 2,800): IR(KBr): 1140 (SO) cm 1 1H NMR
; (DMSO-d~ 6.59 (br s, 2,-SONH2, exchangeable in D2O), 6.57 (~r s, 2, NH2, exchangeable in D2O), 8.12 (s, 1, C8H), 12.50 (br 5, 1, NH, exchangeable in D2O). Anal. Calcd for C5H6N6OS (198.21): Cl 30.30: H, 3.05: N, 42.40: S, 16.18.
Found: Cl 30.02: H, 2.82: Nl 42.64: S, 15.97.

2-Aminopurine-6-sulfonamide (4) To a suspension of 2-aminopurine-6-sul~enamide 2 (500 mg, 2.7 mmol) in EtOH (250 mL) was added m-chloroperoxybenzoic acid (85%, 2.25 g, 11 mmol) and stirred for 1.5 h at room temperature. After filtrationl the filtrate was evaporated to dryness. The residue was triturated with ether and then purified on a silica gel column using ethyl acetate : (EtOAc:H~O:l~PrOH, 4:2:1, upper ; phase) (90:10, v/v) as eluent. The precipitation from EtOH-ether gave 162 mg (28%) of the title compound, mp >250C: UV
~max (pH 1) 338 nm ~ 4,200): ~max (P~ 7~ 329 nm (~ 4,000):
~max (pH 11) 325 nm (~ 4,100), 285 (2,800): IR (KBr) 1150 (S=O), 1320 tSO2) cm 1 lH NMR (DMSO-d6): ~ 6.67 (br s, 2, NH2, exchangeable in D2O), 7.61 (br s, SO2NH2, exc:hangeable in D2O), 8.29 (s, 1, C8H), 12.75 (br s, 1, NH, exchangeable in D2O): Anal Calcd for C5H6N6O2S (214.21): C, 28.03: H, 2.82: N, 39.24: S, 14.97. Found: C, 2~.20: H, 2.72: N, 38.98: S, 15.03.

9-B-D~Ribofuranosy~-gH-purine-6-sulfenamlde ~6) Commercial 0.77M sodium hypochlorite (5.25%, 15 mL) was cooled to ~0C and added with stirring to similarly cooled 0.77M ammonium hydroxide (29%, 3.7 mL diluted to 40 mL with H2O). The resulting solution of chloramine was mixed with a solution of 9-~D-ribofuranosyl-9H-purine-6-thione 5 (2.84 g, 10 mmol) in 2M potas~ium hydroxide (5 mL) at <0C. The mixture was stirred for 40 min until it had warmed to room 16 ~3~7~
temperature and the solvents were evaporated. The residue was dissolved in MeOH (50 mL) and adsorbed onto silica gel (2 g). The excess solvent was evaporated under reduced pressure and the residue was loaded onto a silica gel column ( 3 x 40 cm) packed in CH2C12. The column was eluted ~ith CH2C12:MeOH (8:2, 7:3, v/v). The appropriate homogeneous fractions were combined and the solvents evaporated to give 6 as a foam (1.5 g, 50% yield): m.p. 100C: UV: ~max (pH 1) 301 nm (~ 11,100): ~max (pH 7) 288 nm (~ 8,700): ~ma~ (pH
lo 11) 288 nm (~ 9,500): 1H NMR (DMsO-d6): ~ 4.15 (s, 2, S-NH2, exchanged with D2O), 6.00 (d, 1, J = 5.73 Hz, C1,H), 8.70 (s, 1, C2H), 8.77 (s, 1, C8H), and other sugar protons.
Anal- Calcd for Cl0H13N54S (299.3): C, 40-13- H, 4-38 N, 23.40: S, 10.71. Found: C, 40.29: H, 4.46: N, 23.10: S, 10.45.

9-~-D-Ribofuranosyl-9H-purine-6-sulfinamide (7).
To an ice-cooled stirred solution of 6 (0.299 g, mmol) in ethanol (30 mL), a solution of _-chloroperoxybenzoic acid (0.2 g, 1 mmol) in ethanol (10 mL) was added dropwise during 10 min. After 40 min the solvent was evaporated, the residue was disso~ved in MeOH (30 m~) and adsorbed onto silica gel (10 g). The excess solvent was evaporated under reduced pressure and the dry residue was loaded onto a flash silica gel column (2 x 40 cm) packed in CH2C12. The column was ~luted with CH2C12:MeOH (8.2 and then 7:3, v/v). ~he appropriate homogeneous fractions were combined and the solvents were evaporated to ~ive 7 as a foam, m.p. 80C, (0.21 g, 67% yield). IR (KBr~: 1050 (vs, S=O), 1330 (s, S=O), 3000~3600 (OH, NH2)cm 1 UV: ~max (pH
1) 272 nm (~ 3,600): ~max (pH 7) 273 nm ~f 4,100): ~m~x (pH
11) 273 nm (f 3,200): lH NMR (DMSO-d6): ~ 6.08 (d, 1, J =
5.4 Hz, C1,H), 6.6~ (s, 2, SONH2, exchanged with D2O), 9.00 (s, 1, C2H), 9.08 (~, 1, C8H), and other sugar protons.
Anal. Calcd ~or CloH13N5O5S.1/2 H2O (324.3): C~ 37.04: H, 4.32: N, 21.60: S, 9.88. Found: C, 37.43- H~ 4.53: N, 21.36: S, 9O97.

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9-~-D-Ribo~uranosyl-9H-purine-6-slllfonamide (8).
To a solution of 6 (0.299 g, 1 mmol) in ethanol (35 mL) at room temperature, a solution of m-chloroperoxybenzoic : acid (0.8 g, 4 eq.) in ethanol (20 mL) was added, with stirring. After 30 min the ~eaction mixture was evaporated and the residue was purified by flash column chromatography and treated in the same way as described for 7, -to gi~e 8 as a foam, (0.11 g, 33~ yield): IR (KBr): 1060, 1080 (s, S=O), 1340 (vs~ b, S02), 3000-3600 (OH, NH2)cm : ~V. ~max (pH 1) 275 nm (~ 14~000) ~max (pH 7) 275 nm (~ 12,900) ~max (pH
11) 272 nm (~ 17,800): lH NMR (DMSO-d6): ~ 6,10 (d, 1, ~ =
5.4 Hz, Cl,H), 7.80 (br s, 2, SO2NH2, exchanged with D2O), 9.04 (s, 1, C2H), 9.10 (s, 1, C8H) and other sugar protons.
Anal. CalCd for C10H13N56S-C2H5QH-1/2 2 ( C, 37.28: H, 5.18: N, 18.12: S, 8.28, Found: C, 37.24: H, 4.51: N, 18.26: S, 8.13.

9-~-D-Arabinofuranosyl-9H-purine-6-sulfenamide (10).
Commercial 0.77M sodium hypochlorite (5.25%, 46 mL) was cooled to <0C and added with stirring to similarly cool~d 0.77M ammonium hydroxide (29%, 11.1 mL diluteA to 120 mL
with H2O) The resulting solution of chloramine was mixed with a solution o~ 9~-D-arabinofuranosyl-9H-purine-6-thione 9 (8.52 g, 30 mmol) in 2M pota~ium hydroxide (15 mL) at <OC. The mixture was stirred until it had warmed to room .' temperature (40 min~. After 1 h the product that crystallized out was filtered, washed with ethanol, dried at room temperature and recrystallized from ethanol to give (5 g, 56% yield) of 10. m.p. 176-178C (dec.): W : ~max (pH 1) 295 nm ~ 6,000)~ ~ma~ (pH 7) 285 nm ~ 5,800~: ~max (P~ 11) 285 nm (~ 5,500) lH N~R lDMSO-d6): ~4.15 (s, 2, S-NH2, excha~ged with D2O), 6.37 (d, 1, J = 5.19 Hz, C1,H), 8.50 (s, 1, C2H), 8071 (s, 1, C8H), and other sugar protons.
cd for Cl0H13Ns4S (299-3~: C, 40.13- H, 4,38 N
23.40: S, 10.71. Found: C, 39.94: H, 4.38: N, 22.90: 5, , ".

., 18 ~3172~1 11. 00.

9 ~ D-Arabinofuranosyl-9H-purine-6-sulfinamide (11).
To an ice cooled stirred solution of 10 (1.5 g, 5 mmol) in ethanol:H2O (525 mL, 20:1, v/v), _-chloroperoxybenzoic acid (1 g, 1 eq.) in ethanol (50 mL) was added dropwise during 20 min. After 4 h the separated crystals were filtered off, the filtrate was evaporated to dryness, triturated with methanol, filtered, washed with methanol and dried at room temperature to yield 11, (0.5 g, ~1% yield), m.p. > 120C. The filtrate was evaporated and puri~ied by chromatography as described for 6 to yiPld another crop of 11, (0.25 g, 15%: overall yield 46%). IR (KBr): 1060 (vs, br, S = O), 1330 (s, S = O), 3000-3600 (NH2, OH) cm 1 W :
ax (pH 1) 272 nm (~ 3~000): ~max (pH
~max (pH 11) 272 nm (~ 1,700): lH NMR (DMSO-d6): ~ 6.46 (d, 1, J = 5.16 Hz, C1,H), 6.71 (s, 2, SONH2, exchanged with D2O), 8.83 (s, 1, C2H), 9.06 (s, 1, C8~), and other sugar protons. Anal. Calcd for CloH13N5O5S 0.3H2O (321-32): C, 37.38: H, 4.24: N, 21,80: S, 9.97. Found: C, 37.03: H, 4.19: N, 21.42: S, 10.37.

9-~-D-Arabinofuranos~9H~purine-6-sulfonamide (12).
To a solution of 10 (3.6 g, 12 mmol) in ~thanol (1200 mL) and water (80 mL) at room temperature was added m-chloroperoxybenzoic acid (8.8 g, 4 eg.) with stirring. The reaction mixture was left overnight at room temperaturec The pr~cipitatPd product (12) was ~iltered, washed well with ethanol to yield 3 g (75%) of 12. The filtrate was concentrated to get another crop of (12), 0.3 g (6%) over-all yield (81%): m~p. 160C (dec.): IR (KBr)- 1050 (s, S =
O), 1340 (V5, br, SO2), 3000-3600 (OH, NH2~cm 1 UV: ~max (pH 1) 275 nm (~ 5,600): ~max (pH 7) 276 nm ~ 6,500): ~max ~pH 11) 274 nm (~ 6,900): 1H NMR (DMSU-d6): ~ 6~70 (d, 1, J
= 5.28 Hz, Cl,H), 7.85 (s, 2, SO2NH2; exchanged with D2O), 8.a8 (s, 1, C~N), 9.08 (s, 1, C8~), and other sugar protons.

19 ~3~72~
Anal. Calcd ~or CloH13N56S 1/2H20 (3 4.12: N, 20.5~: S, 9.41. Found: C, 35.63: H, 4.07: N, 20.27: S, 8097.

9-~2-Deoxy-~-D-erythro-pentofuranosyl)-9H-Purine-6-sulfenamide (14~
Commercial 0.77M sodium hypochlorite (5.25~, 15 mL) was cooled to <0C and added with stirring to similarly cooled 0.77M ammonium hydroxide (29%, 3.7 mL diluted to 40 mL with ~2) The resulting solution of chloramine was mixed with a solution of 9-(2-deoxy-~-D-~ythro-pentofuranosyl)-9H-purine-6-thione 13 (2.68 g, 10 mmol) in 2M potassium - hydroxide ~5 mL) at <0~C. The mixture was stirred until it had warmed to room temperature (50 min). The solvent~ were evaporated and the residue was purified by ~lash chromatography as described for 6 to give 14 as a foam (2.1 g~ 71% yield)- UV: ~max (pH 1) 300 nm (~,): ~max (pH
7) 288 nm (~8,200) ~ma~ (pH 11) 288 nm (~10,300~ 1H NMR
(DMSO-d~ 3.87 (s, 2, SNH2, exchanged with D2O), 6.43 (t, 1, J = 3.54 Hz, Cl,H), 8.75 (s, 1, C2H), 8-84 (s, 1, C8H), and other sugar protons. Anal. Calcd for CloH13N5O3S
(283.3): C, 42.39: H, ~.62: N, 24.72: S, 11.32. Found: C, 42.12: H, 4.85: N, 24.48: S, 11.51.

~ =1_ Deoxy-~-D-erythro-pentofuranosy~l) 9_ pu_ ne 6-sulfinamide ~15).
To an ice-cooied stirred solu~ion of 14 (0.368 g, 1.3 mmol) in ethanol (20 mL), _-chloroperoxybenzoic acid ~0.26 g, 1 eq.~ in ethanol (10 mL) was added dropwise during 10 min. The mixture was warmed to room temperature (90 min).
The product which crystalli~ed out was filtered, washed with ethanol, dried at room temperature to yield 15 (0.18 g, 46%
yield), m.p. 120C: IR (KBr~O 1060 (vs, S=O), 1360 ~S=o), 3000-3500 (NH2, OH)cm 1 UV: ~max (pH 1) 272 nm (~7,400):
~max (pH 7) 273 nm (~8,600~: ~max (pH 11) 274 nm (~9,100)-H NMR (DMSO-d6): ~ 6.50 (t, 1, J = 6.60 Hz, Cl,H), 6.68 , ~. 3.~7,~
(s, 2, SONH2, exchanged with D2O), 8.94 (s, 1, C2H), g.06 (s, 1, C8H~, and other sugar protons. Anal. Calcd ~or CloH13N5O4S (299.3): C, 40.13: H, 4.38: N, 23.40: S, 10.71.
Found: C, 40.39: H, 4.40: N, 23.32: S, 10.51.

9~ Deoxy-~-D~erythro-pentofuranosyl)-9H-purine-6-sulfonamide (16).
To a ~tirred solution of 14 ~1.3 g, 4.6 mmol) in ethanol (120 mL) was added a solution o~ m--chloroperoxybenzoic acid (3 g, 4 eq.) in ethanol t50 mL) at room temperature. After 1 h the reaction mixture was evaporated and the residue was purified by flash column chromatography as described for 8 to yield 16, (0.6 g, 41%) as a ~oam. IR (KBr): 1140 (s, S=O)~ 1320 (vs, SO2), 2800-3500 (NH2, OH)cm 1 UV: ~ma~ (pH 1) 275 nm (~5,800)o ~m~ ~pH 7) 275 nm (~7,600): ~max (pH 11) 273 nm (~7,900):
H NMR (DMSO-d6): ~ 6.53 (t, 1, J = 6.45 Hz, C1, H), 7.85 (s, 2, SO2NH2, exchanged with D2O), 9.00 (s, 1, C2H), 9.08 (s, 1, C8H), and other sugar protons. Anal. Calcd ~or C1oH13N5O5S.lf2H2O (324.3): C, 37.03: H, 4.32: N, 21.60: S, .88. Found: C, 36.67: H, 4.1~: ~, 22.01: S, 10.26.

, EXAMPLE '13 252-Amino-9-~-D-ribofuranosyl-9H-purine-6-sul~enamide ,' (1~)-Sodium hypochlorite, 0.77M (76 mL, 0.532 mmol, ~reshly opened bottle of commercial bleach) was placed in a stoppered 1 L flask and the ~lask was submerged in an ice 30bath. Ammonium hydxoxide, 0.77M (20~ mL, 1.4 mmol) was similarly cooled in an ice bath. Acetone was added to the ice haths to obtain a temperature of <0C in both solutions.
The ammonia solution was then added rapidly to the bleach solution and the flask was immediately stoppered. The mixture was stirred in the cold (O to -5C) ~or approx. 15 min and then a suspension of thioguanosine 17 (15 g, 0.0501 mmol ~ in 2 N KOH was added quickly and rinsed into the chloramine mixture with a small amount o~ water. The flask ."

.

21 ~3~
was immediately stoppered. The reaction mixture was initially a clear yellow solution but after a few minutes a white solid began separating. The reaction mixture was stirred in the cold (0 to -5C) for 30 min and then the solid was collected and washed with ethanol (50 mL). The solid was further washed by suspension in ethanol (3 x 50 mL) and air dried to yield 11.7 g, (0.0372 mmol, 74%) of 18, m.p. lg6-198C dec.: UV: ~max (pH 1) 332 nm (~3,000): ~max ~pH 7) 311 nm (~3,53: ~max ~pH 11) 311 nm (~3,500): 1H NMR
10 (DMS0-d6): ~ 3.91 (s, 2, SNH2, exchanged with D~0), 5.80 (d, 1, J = 5.97 Hz, C1'~), 6.50 (s, 2, NH2, exchanged with D20), 8.18 (s, 1, C8H), and other sugar protons. Anal.
Calcd~ for CloH14N64S (314 ) C, 38.21: H, 4.49: N, 26.74: S, 10.20. Found: C, 38.16: H, 4.68: N, 26.49: S, 15 10.49.

2-Amino-9 ~-D-rlbofuranosyl-9H-purlne-6-sulfinamide (19) -A mixture of 2-amino-9-~-D-ribofurano~yl-9H-purine~6-sulfenamide (18) tl-57 g, 0.005 mol), ethanol (700 mI,) and water (50 mL) was vigorously stirred and cooled in an ice bath. After the temperature o~ the suspension had decreased to <10C, acetone was added to the ice bath to obtain a temperature of <O~C. With continual stirring a solution of commercially available (Aldrich Chem Co.) 3-chloroperoxybenzoic ~cid (80-85%, 1.0 g, 0.0046-0.0049 mol) in ethanol (40 mL) was added dropwise o~er a period o~
approx. 15 min. The reaotion flask was stoppered, the mi~ture was allowed to stir and w~rm as th2 ice melted, and then stirred at ambient temperature for a total reaction time of 19 hr. The reaction mixture was filtered (Whatman GF/A glass microfiber filter) to remove a trace o~
undissolved solid and then the filtrate was evaporated in vacuo and ~t a temperature of <25~C to near dryness. The product was washed ~rom the evaporation flask with acetone (50-100 m~) and the solid was collected by filtration, suspended in diethyl ether (50 mL), refiltered, dried under 22 ~ 3~72)~
vacuum at ambient temperature: (1.3 g, 0.0042 mol, 85%), m.p. 183-1~5C dec. with prior sintering and darkening. IR
(KBr): 1040 (vs, S=O), 3000-3600 (NH2, OH)cm ~: UV: ~max (pH 1) 333 nm (~2,900): ~max (pH 7) 326 nm (~10,700): ~max ~pH 11) 325 nm (~8,700): 1H NMR (DMSO-d6)~ ~ 5.85 ~d, 1, J
= 5.52 Hz, Cl,H), 6.49 (5, 2, SONH2, exchanged with D2O), 6.98 (s, 2, NH2, exchanged with D2O), 8.45 ts, 1, C8H), and other sugar protons. Anal. Calcd. for Cl0Hl4N6o5s.l/2c2H5oH
(353.32): C, 37.39: H, ~.82: N, 23.80: S, 9 07. Found: C, lV 37.29: H, 4.56: N, 23.78: S, 8.92.

2-Amino-9-~-D-ribofuranosyl-9H-purine-6-sulfonamide (20).
To a stirred suspension of 18 (3.14 g, 10 mmol) in EtOH:CH2C12 (800 mL, 3:1, v/v) at room temperature was added a solution of m-chloroperoxybenzoic acid ~8 g, 4 eq.) in ethanol (60 mL). After 4 hl the separated crystals were filtered, washed with ethanol to get 2.55 g (74%) of a 20 mixture of 19 and 20. By fractional crystallization from methanol, 20 (2 g, 64%) was obtained. Recrystalliæation of 20 from H2O-MeOH (100 mL, 8:2, v/v) gave colorless crystals (1 g, 34%), m.p. 210C (dec.)- IR (KBr): 1320 (vs, SO2), 3000-3600 ~NH2, OH)cm 1 UV: ~max (pH 1) 332 nm (~7 700): ~ x tPH 7) 328 nm (~8,600): ~max (pH 11) (~12,700): 1H NMR (DMSO-d6): ~ 5.85 (d, 1, J = 5.85 Hz, C1,H), 6.99 (s, 2, SO2NH2, exchanged with D2O), 7.52 (s, 2, NH2, exchanged with D2O), 8.48 (s, 1, C3H), and other sugar protons. Anal. Calcd. ~or C1oH14N6O6S (346.32): C, 34.68:
H, 4O07 N, 24.27: S, 9.26. Found: C, 34.49: H, 4.18: N, 24.09: S, 9.51.

2-Amino-9-(2-deoxy-~-D-erythro-pentofuranosyl ? -9H-purine-6-sulfenamide (22).
Commercial 0.77M sodium hypochlorite (5025%, lS mL) was cooled to <0C and added with stirring to similarly cooled 0.77M ammonium hydroxide (29~, 3.7 mL diluted to 40 mL with ' ., ~3~2~

H20). The resulting solution of chloramine was mixed with a solution of 2-amino-9-(2-deoxy-~-D-erythro-pentofuran~syl)-9-H-purine-6-thione 21, prepared as per K. Ramasamy et al., J. Heterocycl. Chem, (in press), (2.83 g, lo mmol) in 2M
potassium hydroxide (5 mL3 at 0C. After ~0 min the solvents were evaporated and the residue was dissolved in MeOH (50 mL) and adsorbed onto silica gel (1 g). The excess solvent was evaporated under reduced pressura and the residue was loaded onto a silica gel column (4 x 15 cm) packed in CH2Cl2. The column was eluted with CH2Cl2 MeOH
(8:2, 7:3, v/v). The appropriate homogeneous fractions were combined and the solvents evaporated to yield 22 (2.6 g, 86%), m.p. 130C (dec~): UV: Xmax (pH 1) 328 nm (~11,700):
~max tPH 7) 309 nm (~10,600): ~max (pH 11) 309 nm (~10,900):
1H NMR (DMSO-d6): ~ 3.90 (s, 2, SNH2, exchanged with D20), 6.23 (t, 1, J = 6.60 Hz, C1,H), 6.50 (s, 2, NH2, exchanged with D20), ~.16 (s, 1, C8~), and other sugar protons. Anal.
Calcd. for CloH14N603S (298-32): C, 40.27: H, 4.70: N, 28.19: S, 10.74. Found: C, 40.10: H, 4.40: N, 27089: S
10.53.

2~Amino-9-(2-deoxy-~-D-erythro~pento~ur3nosylL~H-; purine-6-sulfinamide (23).
To an ice-cooled stirred suspension of 22 (0.298 g, 1 mmol) in ethanol (200 mL) and CH2C12 (50 mL), m-chloroperoxybenzoic acid (0.5 g, 1 eq.) in ekhanol (30 mL) was added dropwise during 15 min. A~ter 80 min the clear solution of the reaction mixture was adsorbed onto silica gel (1 g) and the excess solvent was evaporated under reduced pressure and the residue loaded onto a silica gel column (2.5 x 15 cm) packed in CH~Cl2. The column was eluted with CH2C12:MeO~ (802, 75:25, v/v). The appropriate homogeneous fractions were comhined and the solvent evaporated to yield 23 (0.65 g, 69%), m.p. 80C (dec.): IR
(~Br): 1050 (vs, S=O), 3000-3600 (NH2, OH3cm l UV
(pH l) 339 n~ (~4,300) ~max (P~ 7) ~x ~pH 1l~ 326 n: (~6,000): 1H NNR (DMSO-d6~- ~ 6.27 (t, 24 ~s~
1, J = 6~75 Hz, C1IH), 6.51 (s, 2, SONH2, exchanged with D2O), 6.g8 (s, 2, NH2, exchanged with D2O), B.43 (s, 1, C8H), and other sugar protons. Anal. Calcd. ~or C1oHl~N6O~S
(314.32): C, 38.21: H, 4.49: N, 26.74: S, 10.20. Found.
C, 38.48: H, 4.83: N, 26.75: S, 10.21.

2-Amino~9-t2-deoxy-~-D-erythro-pentofuranosyl)-gH~
purine-6-sulfonamide (24).
To a stirred suspension of 22 (0.895 g, 3 mmol) in ethanol (250 rnL) at room temperature was added m-chloroperoxybenzoic acid (2.4 g, 4 eq.). After 6 h the clear solution of the reaction mixture was evaporated to dryness. The residue dissolved in EtOH (10 mL) and adsorbed onto silica gel (1 g.). The excess solvent was evaporated und2r reduced pressure and loaded onto a silica gel column (2.5 x 15 cm) packed in CH2C12. The column was eluted with CH2C12:MeOH (85:15, 8:2, v/v). The appropriate homogeneous fractions were combined and the solvent evaporated to yield 24 (0.25 g, 25%) as semisolid: IR (KBr): 1350 (s, SO2), 3000-3600 (NH2, OH)cm 1 UV ~max (pH 1) 332 nm (~4,300) ~max (p~I 7} 329 nm (~5,200): ~max (pH 11) 320 nm (~6,500):
H NMR ~DMSO-d6): ~ 6.28 (t, 1, J = 6.75 Hz, C1lH~, 6~99 (s, 2, SO2NH2, exchanged with D2O), 7.52 (s, 2, NH~, exchanged with D2O), 8.46 (s, 1, C8H), and other sugar prvtons. Anal. Calcd. for C1oH14N6sS H2~1/2C2H5H
(330.32): C, 35.58: H, 5.12: N, 22.64: S, 8.63. Found: C', 35.49: H, 5.33: N, 22.57: S, 8.43.

2~Amino-9-~-D-ribofuranosylpurine-6-sul1nam de 5'~
Monophosphate Potassium Salt (27).
To an ice-cold 5.25% sodium hypochlorite solution (2.3 mL) was added 4N NH40H ~2 mL) and stirred for 10 min. 2-Amino-9~~-D-ribo~uranosylpurine-6-thione 5'-Monophosphate 25, prepared as per M. Saneyoshi, Chem. Pharm. Bull!, 19, 493 (1971), ~569 mg, 1.5 mmol) in 2N KOH (0.75 mL) was added and stirring continued for 2 h at 0C. The mixture was ~3~
evaporated to dryne~s and the residue was applied on XAD~4 column and eluted with water. The ~ractions containiny desired compound were combined and evaporated to dryness to obtain 420 mg of the sulfenamide dipotassium salt 26. The white powder 26 (378 mg) was dissolved in 20 mL of water and cooled to 0CO m-Chloroperoxybenzoic acid ~85~, 250 mg, 1.2 mmol) in MeOH tl0 mL) was added and stirred for 40 min.
After the filtration, the filtrate was concentrated to 3 mL
in vacuo and purified on XAD-~ column using water as eluent to provide 145 mg of the titie hygroscopic compound 27:
m-p- >250~C UV ~max (pH 1) 332 nm: ~max (pH 7) 2 ~max (pH 11) 320 nm: IR (KBr) 1045 (S=O) cm 1 lH NMR (DMSO-d~ 5.88 (d, 1, C1,H, J = 6.0H~), 6.73 (br s, 2, NH2, ' exchangeable in D2O), 8.50 (s, 1, C8H) : FA~-MS (on glycerol) ~/z 449 [M~H]+: 411 [M-K+H]~: (NaCl addition) /z 494 EM+2Na]+, 472 [M+Na+H~+.

~ EXAMPLE 20 `, 2-Amino-9-~-D-ribofuranosylpurine_6-sulfenamlde 3'.5'-cyclic ~hosphate (29).
Commercial 0.77M sodium hypochlorite (5.25%, 1.2 mL) ,was cooled to <0C and added with stirring to similarly cooled 0.77M ammonium hydroxide (29%, 0.3 mL diluted to 3 mL
, with H2O). The resulting solution of chloramine was mixed ,;25 with a solution of 2-amino~9-~-D-ribofuranoSylpUrine-6-9-~
thione 3',5'-cyclic phosphate 28, prepared as per RoBo Meyer et al, J. ~Y~l~ Nucleotide Res., 11 159 (1975), (0.3 g, 0083 mmol) in 2M potassium hydroxid~ (0.37 mL) at ~0C.
~The mixture was stirred for 1 h and the ~olvents were ,'30 evaporated. The residue was dissolved in MeOH and adsorbed onto silica gel (1 g). The excess solvent was evaporated under reduced pressure and the solids were loaded onto a silica gel column (1.5 x 15 cm) packsd in CH2C12. The column was eluted with CH2C12:MeOH (8:2, 4:6, v/v). The ~,35 appropriate homogeneous fractions were combined and the 'solvents evaporated to give the ~itle compound 29 (0O25 g, ,,~0%): m.p. Z65C (dec): UV. ~max (pH 1) 329 nm (c10,400):
~max (pH 7) 309 nm (~9,000)~ ~max (pH 11) 309 nm (~8~800)o .
':

26 ~ 3~7~
lH NMR (DMSO-d6): ~ 3.93 (s, 2, S-NH2, exchanged with D2O), 5.82 (s, 1, C1~H), 6,58 (s, 2, NH2, exchanged with D2O), ~.08 (s, 1, C8H), and other sugar protons.

2-Amino-9-~-D-ribofuranosylpurine-6-sulfinamide 3',5'-cyclic phosphate (30).
To an ice-cooled stirred suspension of 29 (0.13 g, 0.35 ; mmol) in ethanol (20 mL), _-chloroperoxybenzoic acid (0.07 g, 1 eq.) in ethanol (5 mL) was added dropwise during 10 min. The reaction mixture was stirred for 5 h. The precipitated product was filtered, washed with ethanol, dried to yield the title compound 30, (0.1 g, 72%): IR
(KBr): 1030 (s, S=O), 1360 (~, SO2), 3000-3600 (OH, NH2)cm UV: ~max (pH 1) 330 nm (9~000) ~max (pH 7) 325 nm (~4,500): ~max (pH 11~ 324 nm (~4,700): 1H NMR (DMSO-d6):
5.88 (s, 1, C1lH), 6.60 (s, 2, SONH2, exchanged with D2O~, 7.13 (s, 2, NH2, exchanged with D2O), 8.36 (s, 1, C8H), and other sugar protons.

6-Amino-1-(2,3,5-tri-O-acetyl ~-D-ribofuranosyl)-yrazolor3,4-dlpyrimidin-4-one.
A solution of acetic anhydride ~60 m1) and 4-dimethylaminopyridine (300 mg) in dry dimethyl~ormamide (300 mL) was cooled below 10C. 6-Amino~ D-ribo~uranosyl-pyrazolo[3,4-d]pyrimidill-4-one, prepared as per H.B. Cottam et al, Nucleic Acid Research, ~1, 871 882 (1983), (6.0 g, 21 mmol) was added and stirred for 3 h below 10C. Methanol (150 mL) was added and stood for 30 min at 0C. After the removal of solvent ln vacuo, the residue was dissolved in EtOAc (500 mL) and filtrated. The filtrate was wash~d with water, dried over anhydrous Na2SO4, and evaporated to dryness. The mixture was purified on silica gel column with CH2Cl2:MeOH (97:3, v/v) as the solvent to yield 302 g (37%) of title compound. The analytical sample was obtained by crystallization from acetone-hexane : mp 191<193C: UV: ~max ~MeOH) 253 nm (:16,700): lH NM~ (DMSO-d6) ~2 00, 2.07 and ,.~

:

27 13~72~
2.09 ~3s, 9H, 3-CH3 of Ac), 6.10 (d, 1~, ~=3.6 Hz, C1,H), 6.81 (br s, 2, -NH2, exchangeable in D2O) 7.94(s, 1, C3H), 10.73(s, 1, NH) : Anal. Calcd for C16H1gN5O8 (409-35): C, 46.94: H, 4.68: N, 17.11. Found C, 47.03: H, 4.67: N, 16.90.

6-Amino-1-(2~3,5-tr~-o-acetyl-~-D-ribofuranos~~LL=
pyrazolo[3 4-d]pyrimidine-4-thlone.
6 Amino-1-(2,3,5-tri-O-~cetyl-~-D-ribo~uranosly)pyrazo-1O-[3,4-d]pyrimidin-4-one (5.0 g, 12.2 mmol) and phosphorus pentasulfide (3.5 g, 15.7 mmol) in anhydrous pyridine was refluxed for 5 h. After removal of half volume of solvent ln vacuo, the mixture was poured into 600 mL of water and then extracted with CH2Cl2 (200 mL, 6 times). The combined extract were washed with water, dried over anhydrous Na2SO~, evaporated to dryness. The residue was purified on silica gel column with CH2C12:MeOH (98:2, v/v) as solvent to yield 3.0 g (58%) of desired compound. mp 230<232C: UV ~max (MeOH) 336 nm (~21,700), 272 nm (~10,700): lH NMR (DMSO-d6) ~2.00, 207, and 2.09 ~3s, 9H, 3-CH3 of Ac), 6.08 ~d, 1, J=3.6 Hz, C1,H), 7.09 (br s, 2, NH2), 8.07 (s, 1, C3H), 12.16 (br s, 1, NH): Anal. Calcd for C16H19O7N5S (425.41):
C, 45.17: H, 4.50: N, 16.46: S, 7.54. Found: C, 45.23: H, 4.50: N, 16.30: S, 7.46.

256-Amino~ D-ribofuranosylpyr _o~l~LI~t~ ~y ~i ine-4-thione. (31) 6-Amino-1-(2,3,5-tri-O-acetyl-~D-ribofuranosyl)pyrazo~
1O[3,4-~]pyrimidine-4-thione (2.4g, 5.6 mmol) was suspended in MeOH (150 mL) and lN NaOMa was added to pH 10. The mixture was refluxed for 8 h and maintained at pH 10 by addition of lN NaOMe. A~ter cooled to room temperature, the mixture was neutralized with Dowex 50[H+] resin and the solvent was evaporated. The residue was purified on silica gel column with CH2Cl2:MeOH (9:1, v/v) to yield 1.2 g (71%) of the title compound. mp 222-224C: W ~max (pH 1) 328 nm (5,900), 268 nm (~2,300), 237 nm ~6,300). ~max (pH 7)328 nm (~5,900), 268 nm (~2,6003, 237 nm (~6,700): ~max (P~ 11) 319 nm (~4,800), 276 nm (2,400), 236 nm (~6,100): 1H N~R

:

~ 3~7~ ~
(~MSO~d6) ~5.85 td, lH, J=4.5 Hz, C1,H), 7.01 (br s, 2, NH2~
exchangeable in D20), 7.~9 (g, 1, C3H), ~2.07 (s, 1, NH, exchangeable in D20). Anal. Calcd for CloH13N504S (299.30):
C, 40.13: H, 4.38: N, 23.40: S, 10.71. Found: C, 39.88: H, 4.37: N, 23.12: S, 10.49.

6-Amino~ -D-ribofuranosylpyrazolo r 3,4-dlpyrimidine-4-sulfenamide (32).
_ To aqueous 5.25% sodium hypochlorite solution (4.6 mL) cooled to 0C was added 1.4N NH40H (12 mL~ and stirred ~or 10 min. 6 Amino-l-~-D-ribofuranosylpyrazolo[3,4-d]pyrimi-dine-4-thione 31 (sOO mg, 3 mmol) in 2N KOH (1.5 mL) was added and allowed to stand for 2 h at 0C. EtOH (15 mL) was added to dissolve the gelatinous reaction mixture and filtered. The filtrate was evaporated to dryness with a small amount of silica gel. Purification of the residue on silica gel with CH2Cl2:MeOH (6:~, v/v) gave 144 mg (15%) of the title compound 32 : m.p. 145-150C (dec): W : ~m~x (pH 1) 327 nm (~6,300): 253 nm (5,200), 236 nm (10,600):
~max ~pH 7) 303 nm (~6,500): 273 nm (5,500) 232 nm tl7,700):
~max tPH 11) 303 nm (~6,100): 274 nm (S,OOO), 232 nm (16,000): lH NMR tDMSO-d6): ~4.74 ts, 2, SNH2, exchangeable in D20), 5.99 (d, 1, J = 4.5 Hz, Cl,H)), 6.81 (s, 2, NH2, exchangeable in D20) 8.~ ts, 1, C3H): Anal.
Calcd ~or CloHl4N6o~s.l/4H2o- t318 N, 26.36: S, 10.06. Found: C, 37.88: H, 4.58: N, 25.95: S, g.67.

EX~MPLE 23 6-Amino~ -D-ribofuranosylpyrazolor3,4 d]pyrimidine-4-sulfinamlde t33)-; A solution of 6 amino-1-~-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-4-sulfenamide t32) (100 mg, 0.32 mmol) in ~tOH
(40 mL) was cooled to 0C and m-chloroperoxybenzoic acid (85%, 70 mg, 0.3~ mmol) in EtO~ t20 mL) was added dropwise during 20 min. The mixture was concentrated to 5 mL in vacuo below 10C, and then ether (30 mL) was added to yield 73 mg (69%) of desired compound 3~ : m.p. 158 162C tdec):

~ 3 ~
UV: ~max (pH 1) 327 nm (~3,500): 233 (13,000): ~max (pH 7 and 11) 323 nm (~4,700): 232 (~7,000): IR (K~r) 1065 (S=O) cm 1 lH N~R ~DMSO-d~ 6.06 (d, 1, J = 5.0 Hz, Cl,H) 6.77 (s, 2, SONH2, exchangeable in D2O), 7.34 (br s, 2, NH2, exchangeable in D2O), 8.27 (d, 1, C3H): Anal. Calcd for CloHl4N6oss-l/3H2o (336-32) C, 35.71: H 4 39: N
24.99: S, 9.53. Found: C, 35.95: H, 4.21: N, 24.86: S, 8.93.

6-Amino~ -D-ribofuranosylimidazor4 5-c~pyridine-4-sulfenamide (35).
~ queous sodium hypochlorite (5.25~, 4.6 mL, 3.2 mmol) was cooled to 0C. Twelve mL of 1.4N ammonium hydroxide was added and stirred for 10 min at 0C. A suspension of 6-amino-l-~-D-ribofuranosylimidazo[4,5-c]pyridine-4(5H)-thione 34, prepared as per P.D. Cook and R. K. Robins, J. Orq.
Chem., 43, 189 ~197B), (900 mg, 3 mmol) in 2N potassium hydroxide (1.5 mL) was added and stirred for 1.5 h at 0C.
The precipitate was collec~ed by filtration, washed with water, EtOH, and acetone and dried at room temperature over P2O5 to yield 660 mg of desired compound 35: m.p. 134 137C
(dec): UV: ~max (pH 1) 374 nm (~7,000): 26~ (5,400), 230 (21,400) : ~max (pH 7) 322 nm (~5,500), 261 (5,800) 223 25 (24,000) ~max (pH 11) 319 nm (~8,500), 223 (24,100) lH
NMR (DMSO-d6): ~3.70 (5, 2, exchangeable in D2O, SNH2), 5.61 (d, 1, J = 6.4 Hz, Cl,H), 5.63 (s, 2, exchangeable in D2O, NH2), 6.25 (s, 1, C7H), 8.12 ~s, 1, C2H). Anal. Calcd for CllH15N5O45.1/2H2O: C, 40.99. H, 5.00 N, 21.73: S, 30 9.95. Found: C, 41.12: H, 4.81: N, 21.43^ S, 10.23.

6-Amino-l-~-D-ribofuranosylimidazo[4~cJpyridin~ 4 sulfinamide (36).
To a solution of 6-amino~ D-ribofuranosylimida zo[4,5-c]pyridine-4-sulfenamide 35 (~50 mg, 0.48 mmol) in EtOH (60 mL) was added _-chloroperoxybenzoic acid (85~, 95 mg, 0.48 mmol) portionwise during 40 min at 0DC. After ~3~7~
stirring for an additional 10 min, the mixture was ~iltered.
The filtrate was concentrated to 10 mL and poured into ethyl ether (40 mL). The title compound was obtained as precipitate which was collected by filtration, washed wi~h ethyl ether and dried at room temperature over P2O5 ln vacuo to yield 105 mg (67%) : m.p. 171-176C: UV: ~max (pH 1) 344 nm (~3,400), 263 (3,150), 230 (19,900) ~max (pH 7) 317 nm (~3,100), 259 (2,g00) 225 (19,700): ~max (pH 11) 318 nm (~3,200), 258 (3,000), 225 (19,900): IR (KBr): 1045 (S=O) 10 cm 1 1H NMR (DMSO-d6)o ~5.71 (d, 1, J = 6.1 Hz, Cl,H), 6.03 (s, 2, SONH2, exchangeable in D2O)~ ~6.33 (s, 2, NH2, exchangeable in D2O), ~6.68 (s, lH, C7H), 8.36 (s, 1, C2H).
d for CllHl5N5Oss-l/2H2o (338-34) C~ 39O05 H
4.77: N, 20.69: S, 9.48. Found: C, 39.43: H, 4.56: N, 15 20.29: S, 9.43.

2-Amino-7-(2-deoxy-~-D-ervthro-pentofuranosyl)Pyrrolo-[2,3 d~pyrimidine-4-sulfenamide (38).
Four mL of 5.25% aqueous sodium hypochlorite (2.8 mmol~
was cooled and added to 10 mL of 1.4N ammonium hydroxide.
After stirring for 30 min at 0C, 2-amino-7-(2-deoxy-~-D-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine-4~thione 37 (0.78 g, 2.8 mmol) in 1.3 mL of 2N potassium hydroxide was added and stirred for 1 h at 0C. The precipitate was collected by ~iltration, washed wlth EtOH and dried at 25C
over P2O5 in vacuo to obtain 670 mg (81%) of the title compound 38. m.p; 162-l64oc (dec): UV ~max (pH 1~
nm (~28,500~: 347 (5,600): ~max (pH 7) 234 nm (~35,400), 317 ~10~400) ~max (P~ 11) 234 nm (~30,900), 318 (10,300). 1H
NMR (DMSO-d6): ~4.11 (s, 2, exchangeable in D2O, SNH2), 6.18 (s, 2, exchan~eable in D2OI NH2), 6.44 (dd, 1, J = 8.3 and 5.9 Hz, Cl,H), 6.61 (d, 1, J = 3.8 Hz, C5H), 6.18 ~d, 1, J = 3.8 Hz, C H). Anal. Calcd for C11H15N$O3S.1/4H2O:

35 (301.83): C, 43.77: H, 5.17: N, 23 20: S, 10.62. Found-C~ 43.5g~ H, 4.95: N, 23.13: S, 10O32.

EXaNPLE 27 ' ~3~7~ ~
?-Amino-7-(2-deoxy-~-D-erythro-pentofuranosyl)pyrrolo~
[2,3-d~pyrimidine-4-sulfinamide (39).
2-Amino-7-(2-deoxy-~-D-erythro-pentofuranosyl)pyrrolo-[2,3-d]pyrimidine-4-sul~enamide 33 (300 mg, 1 mmol) was suspended in EtOH (120 mL) and cooled to 0C. m-Chloroperoxybenzoic acid (~5%, 100 mg, 1 mmol) in EkOH (30 mL) was added dropwise during 1.5 h. After stirring for an additional 30 min at 0C, the mixture was concentrated to 10 mL in vacuo below 25C. Ethyl ether (lU0 mL) was added to the concentrate solution and allowed to stand in khe refrigerator overnight. The precipitate was collected by filtration, washed with ethyl ether and dried at 25C under reduced pressure to yield 110 mg (35~) o~ desired compound 39: m.p. 122C (dec~: W: ~max (pH 1) 352 nm (~3,100):
- 15 272 (3,100), 240 (21,100): ~max (pH 7) 336 nm (~4,800), 239 ~ max (pH 11) 337 nm (~4,600), 239 (20 500) IR
(KBr) 1060 (S=O) cm 1 1H NMR (DMSO-d6): ~6.45 (s, 2, exchangeable in D2O, SONH2), 6.49, (dd, 1, J = 8.3 and 5.9 Hz, Cl~H)~ 6.62 (s, 2, exchangeable in D2O, NH2), 6.73 ; 20 (d, 1, J = 3.8 Hz, C5H), 7.38 (d, 1, J = 3-8 Hz, C6H).
Anal- Calcd for CllH15Ns4S: C, 42.16: H, 4.82 N, 22.35 S, 10.23. Found: C, 41.91: H, 4.86: N, 22.07: S, 9.91.
.
EX~MPLE 28 2-Amino-9-(5-deoxy-~ D-ribo~uranosyl!-9H-pur -6-sulfenamide (41).
Commercial 0.77M sodium hypochlorite (5~25%, 3.2 mL~
was cooled to < 0C in an ice-salt bath and added with stirring to similarly cooled 1.4~ ammonium hydroxide (29~, 0.8 mL diluted to 8 mL with water). The resulting solution of the chloramine was mixed with a solution of 2~amino-9-(5--deoxy-~-D-ribofuranosyl)~9H-6-thiopurine [E.J. Reist, P.~.
Hart, L~ Goodman and B.R. Baker, J. ~Eg~ Chem.~ 2~, 1557 (1961), 40, 0.56 g, 2 mmol] in 2M potassium hydroxide solution (1 mL) at 0C. The mixture was stirred until it had warmed to room temperature (~ 2 h~. After 3 h of stirring, the clear reastion mixture was evaporated to dryness. The residue was dissolved in methanol (20 mL), -32 ~33 7~3~
adsorbed onto silica gel (~ 2 g) and the excess solvent evaporated under reduced pressure. The dry residue was loaded onto a silica gel column (1.5 x 20 cm) packed in dichloromethane. The column was eluted with 5 dichloromethane:methanol (85:15, 8:2, v/v). The appropriate homogeneous ~ractions were pooled and the ~olvent evaporated to yield 0.52 g (87%) of 41, mp 160-162C (dec.): UV ~ ma~
(p~ 1) 328 nm (~ 10,800): ~max (pH 7) 306 nm (~ 9~500): ~max (pH 11) 308 nm (~ 10,300): 1H NMR (DMSO-d6): ~ 1.28 (d, 3, lO CH3), 3.89 (s, 2, SN~12, exchanged with D2O), 5.74 td, 1, J =
5.22 Hz, C1,H), 6.51 (s, 2, NH2, exchanged with D2O), 8.12 (s, 1, C8H), and other sugar protons. Anal. Calcd. for CloH14N6O3S (298.32): C, 40.26; H, 4.73; N, 28.17; S, 10.75.
Found: C, 40.49; H, 5.01; N, 27.85; S, 10.56.

2-Amino-9-(5-deoxy-~-D-ribofuranosvl)-9H-purine-6-sulfinamide (42).
A solution of m-chloroperoxybenzoic acid (0.10 g, 0.5 20 mmo]) in ethanol (10 mL) was added dropwise to an ice-cooled stirred solution of 41 (0.15 g, 0.5 mmol) in ethanol (25 mL), during 15 min. The reaction mixture was allowed to stand at 0C overnight and then evap~rated to dryness under reduced pressure. The residue was triturated with a mixture 25 of ethanol (2 mL) and ethyl ether (30 mL). The precipikated crystalline product was collected by filtration and dried at 80C for 3 h to yield 70 ~Ig (45%) of the title compound, mp > 100C (dec.)~ IR (KBr): 1050 (vs, s, S=O), 3100-3600 (NH2~ OH)cm : ~V: ~max (pH 1) 330 nm (~ 3~00): ~max (P~ 7) ( ~400) ~m~x ~pH 11) 321 nm (~ 4,300): lH N~R
(~SO-d6): ~ 1.30 (d, 3, C~3), 5.80 (d, 1, J = 5 25 Hæ, C1,H), 6.51 (s, 2, SONH2, exchang~d with D2O), 6.98 (s, 2, NH2, exchanged with D2O), 8.40 (s, l, C8H), and other sugar protons. Anal. Calcd. for CloH14N~O4S (314.32): C, 38.21;
35 H, 4.49; N, 26.74; S, 10.20. Found: C, 37.98, H, 4.41; N, 26.51; S, 9.91.

EXA~P~E 30 33 ~3~7~
2-Amino-9-(5-deox~ D-ribofuranosyl~9H-purine-6-sulfonamide ~43).
To a stirred solution of ~1 (0.30 g, 1 mmol) in ethanol (35 mL) at room temperature was added _-chloroperoxybenzoic acid (0.80 g, 4 mmol) and the mixture was allowed to stand overnight. The reaction mixture was evaporated to dryness and the residue was triturated with a mixture o~ ethanol (2 mL) and ethyl ~ther (20 mL)O After storing in the refrigerator (~ 4C) overnight, the precipitated crystalline product was collected by filtration and dried at 80C for several hours to yield 0.17 g (52%) o~ the title compound, mp > 90C. IR (XBr): 1160 ~s, S=Q), 1350 (vs, b, SO2), 3000-3600 (NH2, OH)cm 1; UV: ~max (pH 1) 331 nm (~ 5,400):
~max (pH 7) 326 nm (~ 5~500) ~max (pH 11) 318 (~ 6,500): H
; 15 NMR (DMSO-d6): ~ 1.30 (d, 3, CH3), 5.80 (d, 1, J = 5.13 Hz, C1,H), 6.99 (s, 2, SO2NH2, exchanged with D2O), 7.54 (s, 2, NH2, exchanged with D2O), 8.44 (s, 1, C8H), and other sugar protons. Anal. Calcd. for CloH14N6O5S (330.32): C, 36.36;
H, 4.27; N, 25.45; S, 9.71. Found: C, 36.41; H, 4.55; N, 20 25.38; S, 10.08.

EXAMPLh 31 2-Amino-9-(2-deoxy-a-D-erythro-pentofuranosyl)-9H-; purine-6-sulfenamide (45).
Commercial 0.77M sodium hypochlorite (5.25%, 15 mL) was cooled to < 0C in an ice-salt bath and added with ~tirring to similarly cooled 1.4M ammonium hydroxide (29%, 3.7 mL
diluted to 40 mL wlth water). The resulting solution of the chloramine was mixed with a solution o~ 2-amino-9-(2-deoxy-~-D-erythro--pentofuranosyl)-9H 6 thiopurine ~R.H. Iwamoto, E.M. Acton an~ L. Goodman, J. ~ed. Chem., 6, ~8~ (lg63), 44, 2.83 g~ 10 mmol] in 2M potassium hydroxide solution (5 mL) at 0C. The reaction mixture was stirred until it had warmed to room temperature (about an hour)O The crystalline material that deposited was collected by ~iltration, washed with cold water (2 x 5 mL), followed by ethanol (10 mh~ and air-dried to yiald 2.5 g (84%) o~ the title compound, mp 163 C (dec-): UV: ~max (pH 1) 328 nm (~ 9~700): ~max (pH 7) 34 :~3172~

t ,900): )~max (pH 11) 308 nm (~ 12,400): lH NMR
(DMSO-d6): ~ 3.98 (5, 2, SNH2, exchanged with D2O), 6.2ï
(dd, 1, J = 5.10 Hz, Cl,H), 6.49 (s, 2, NH2, exchanged with D2O), 8.19 (5, 1, C8H), and other sugar protons. Anal.
Eor ClOH14N603S (298.32) C, 40.27; H, 4 70; M
28.19; S, 10.74. Found: C, 39.98; H, 4.70; N, 28.01; S, 10.79.

?-Amino-9-L2-deoxy-~-D-erythrO-pent purine-6-sulfinamide (_).
A solution of m-chloroperoxybenzoic acid (0.50 g, 2.5 mmol) in ethanol (50 mL) was added dropwise to an ice-cooled (0-5C), stirred solution of 45 (0.75 g, 2.5 mmol) in 15 ethanol (150 mL), during 15 min. The reaction mixture was allowed to stand at room temperature overnight and the crystalline product tl~at deposited was collected by filtration. The product was washed with ethanol (2 x 15 mL) and air-dried to yield 0.24 g (31%) of 4fi, mp 178C (dec.).
20 IR (~Br): 1040, 1300 (s, S=O), 3100-3600 (NH2, OH)cm l; UV:
~max (pH 1) 329 nm (~ 3,800): 3~max (1?H 7) 323 nm (~ 5,B00):
)~max (pH 11) 323 nm (~ 3,700)~ lH NMR ~DMSO-d6): ~ 6.27 (dd, 1~ J = 5-5 Hz, Cl~a), 6-50 (s, 2, SONH2, exchanged with D2O), 6.94 (s, 2, NH2, exchanged with D20), 8O43 (s, 1, 25 C8H), and other sugar protons. Anal. Calcd. for CLoHl,~,N604S
(314.32): C, 38.21; H, 4.49; N, 26.74; S, lQ.20. Found: C, 38.34; H, 4.59; N, 26.47; S, 10.17.

,.

- 30 2 Amino-9-(2~deoxy-~-D-erythro-pentofuranosyl)-9H
purine 6-sulfonamide ~47).
~ o a stirred solution of 45 (0.75 g, 2.5 mmol~ in ethanol (lS0 mL) at room temperature was added m-chloroperoxybenzoic acid ~2.0 g, 10 mmol) and the mixture 35 was stirred for 3 h. Silica gel (~ 2 g) was added to the clear reaction mixture and the excess solvent was evapora~ed.
under reduced pressure. The dry residue was loaded onto a silica gel colu=n (1.5 x 20 cm) packed in dichloromethane.

.

The column was eluted with dichloromethane:methanol t85:15, 8:2, v/v). The appropriat2 homogeneous fractions were pooled and the solvent evaporated to dryness. The residue was crystallized from aqueous ethanol to yield 0.30 g (36~) ; 5 of the title compound, mp > lOODC. IR (KBr)~ 0, 1340 (vs SO2), 3000-3600 (NH2, OH)cm : UV: ~max (pH 1) 3 (~ 5~00) ~max (pH 7) 327 nm (~ 9,800): ~max (pH 11) 319 nm (~ 10,500): lH NMR (DMSO-d6): ~ 6.27 (dd, 1, J = 5.37 Hz, C1~H), 6.96 ~s, 2, SO2NH2, exchanged with D2O), 7.51 (5, 2, NH2, exchanged with D2O), 8.4~ ts, 1, C8H), and other sugar protons. Anal. Calcd. for CloH14N6O5S (330.32): C, 36.36;
H, 4.27; N, 25.45; S, 9.71. Found: C, 36.11, H, 4.25; N, 25.31; S, 10.08.

2-Amino-9-~-D~arabinofuranosyl-9H-purina-6-sul~enamide (49)-To an ice-cold solution of ammonium hydroxide (1.4N, 20 mL) was added 0.77M sodium hypochlorite solution (5.25~, 7.5 mL, 5.25 mmol) in one lot. The mixture was stirred at 0C
for 10 min. A solution o~ 2-amino-9-~-D-arabinofuranosyl-9H purine-6-thione [W.W. Lee, A.P. Martinez, R.W. Blackford, V.J. Bartuska, E.J. Reist and L. Goodman, J. Med~ Chem., 1~, 819 (1971), 48, 1.49 g, 5 mmol] in lN pota~sium hydroxide solution (5 mL, 5 mmol) was added in one lot, and the reaction mixture was stirred at 0C for 1 h. After allowing the reaction mixture to warm up to 15C during 1 h, the ~lear solution was evaporated to dryne~s under reduced pressure. The residue was purified by flash chromatography over silica gel using dichloromethane -~ methanol gradient.
The homogeneou~ fractions were pooled and evaporated to dryness. The residue was crystallized from a mixture of dichloromethane and methanol to give 0.85 g (54%) o~ the title compound, mp 190-192C. IR (KBr): 3200-3400 (NH2, OH)cm 1 UV: ~max (pH 1) 227 nm (~ 26,400), 25~ (10,600), 328 (19,400): ~max (pH 7) ~22 nm ( 22,~00), 243 ~13,70~), ( 3~200) ~max (pH 11) 221 nm (~ 22,200), 243 (13 500) 308 (13,200): ld NMR (~MSO-d~ 4.09 (-, Z, SNd ., , .
,j 36 ~ 2~1 exchanged with D2O), 6~13 (d, 1, J = 4.0 Hz, C1,H), 6.50 (g, 2, NH2, Pxchanged with D2O), 7.99 (s, l/ C8H), an~ other sugar protons. Anal. Calcd. for C1oH14N6O4S ~314.32) C, 38.21; H, 4.49; ~, 26.74; S, 10.20. Found: C, 38.40; H, 4.47; N, 26.53; S, 10.29.

2-Amino-9-~-D-axabln fu anosyl-9H-purine-6-sulfinamide (50)-A solution of ~9 (1.5 g, 4 7 mmol) in ethanol (350 m~
and water (50 mL) was cooled to 0C. To this cold solution was added m chloroperoxybenzoic acid (80%, 0.90 g, 4.45 mmol) in ethanol (5Q mL) during 1.5 h. After th addition, the reaction mixture was stirred at ice-bath temperature for 1O5 h. The solven~ was evaporated under reduced pressure and the residue was dissolved in methanol (50 mL). Silica gel (~ 5 g) was added and evaporated to dryness. The dried silica gel was placed on top of a flash silica gel column and the column was aluted with ethyl acetate -~ methanol gradient. The pure compound crystallized out after concentration of the homogeneous fractions. The product was collected by filtration and dried to give 0.95 g (60%) of the title compound, mp > 200~C (dec.): IR (KBr): 1120 (S=O), 3100-3600 (NH2, OH)cm 1 UV: ~max (pH 1) 220 nm t~
17,900~, 249 (7,600), 330 (5~10~) ~max (pH 7) ~25 nm (~
24,100), 248 (sh) (6,100), 323 (8,000): ~ma~ (p~l ~1) 224 nm (~ 21,000), 244 (sh) (6,600), 322 (6,600): lH NMR (DMSO-d6):
~ 6.17 (d, l, J = 4.03 Hz, Cl,H), 6.50 (s, 2, SONH2, exchanged with D2O), 6.97 (s, 2, NH2, exchanyed with D2O), 8.25 (s, l, C8H), and other sugar protons. Anal. Calcd. ~or C1oH14N6O5S (330.32): C, 36.36; H, 4.27; N, 25.44; S, 9.71.
Found: C, 3~.65; H, 4.09; N, 25.19; S, 9.~6.

2-Amino-s-~-D arabinofuranosyl-9H~purine~6~sulfonamid (51)-To a stirred solution of 49 (0.46 g, 1.46 mmol) in ethanol (250 mL) and water ~50 mL) was added m-37 ~3~2~
chloroperoxybenzoic acid (1.0 g, 5.84 mmol) in ethanol (50 mL) dropwise during 1 h at room temperature. A~ter the addition, the reaction mixture was stirred at room temperature for 6 h and evaporated to dryness under reduced 5 pressure. The residue was purified by flash silica gel chromatography using ethyl acetate -~ methanol as the gradient. The homogeneous fractions were pooled and evaporated to dryness to give 0.30 g (59~) of the title compound, mp > 193C. IR (~Br): 1170 (S=O~, 1340 (SO2), 3100-3600 (NH2~ OH)cm 1 UV ~max (pH 1) 222 nm (~ 16,900), ( ~200)D ~max (pH 7) 225 nm (~ 17,300) 326 (4 goo) ~max (pH 11) 223 nm (~ 17,200), 320 (5,600): lH NMR (DMSO
d6): ~ 6.18 (d, 1, J = 4.3 Hz, Cl,H), 6.95 (s, 2, SO2NH?, exchanged with D2O), 7.48 (br s, 2, NH2, exchanged with D20), 8.27 (s, 1, C8H), and other sugar protons. Anal.
Calcd. for CloH~4N606S 1/2Et0A~ (390.37): C, 36.92; H, 4.65;
N, 21.52: S, 8.20. Found: C, 37.04; H, 4.32; N, 21.50; S, 8.41.

7-(2-De.oxy-B-D-erythro-~entofuranosyl)pyrrolo r 2,3-dl-pyrimidine-4-sulfenamide (53).
To an ice-cold solution of ammonium hydroxide (1.4N, 8 mL) was added 0.77M sodium hypochlorite solution (5.25~, 3 mL, 2.1 mmol) in one lot. The mixture was stirred at 0~C
for 10 min. A solution o~ 7-(2 deoxy-~-D~erythro~
pentofuranosyl)pyrrolo[2,3-d]pyrimidine-4-thione [H.B.
Cottam, Z. Kazimierczuk, S. Geary, P.A~ McKernan, G.R.
Revankar and R.K. Robins, J. Med. Chem., 2B, 1461 (1985), 52, 0.53 g, 2 mmol] in lN potassium hydroxide solution t2 mL, 2 mmol) was added in one lot, and the reaction mixture was stirred at 0C for 1 h. After allowing the reaction mixture to warm up to 15C during 1 h, the clear solution was evaporated to dryness under reduced pressure. The residue was purified by flash chromatography over silica gel using dichloromethane:methanol (95:5, v/v) as the elu~nt.
The homogeneous fractions were pooled and evaporated to dryness. The residue was crystallized from s mixture of "

38 ~3~7t~
methanol and dichloromethane to give 0.31 g (55~) o~ the title compound, mp 153-155C. IR (KBr): 3200-3450 (NH~, OH)cm 1 UV: ~max (pH 1~ Z66 nm (~ 9,900), 321 (22,900):
~ (pH 7) 295 nm (~ 11,200): ~max (pH 1 ) 17,100): 1H NMR (DMSO-d6): ~ 4.29 (s, 2, SNH2, exchanged with D2O), 6.62 (t, 1, J = 6.7 Hz, C1lH), ~.85 (d, 1, C5H), 7.71 (d, 1, C6H), 8.54 (s, 1, C2H), and other sugar protons.
Anal. Calcd. for CllH14N4O3S (282.28) C, 46-80; H, 4.99; N, 19.84; S, 11.34. Found: C, 47.01; H, 4.63; N, 19.63; S, 11.52.

7-(2 Deoxy-~-D-erythro-pento~uranosyl)pyrrolo[2,3-dl-pyrlmidine-4-sulfinamide (54).
To a solution of 53 (1.41 g, 5 mmol) in ethanol:water (190:10, v/v), cooled to 0C in an ice bath was added m-chloroperoxybenzoic acid (80%, 1.01 g, 5 mmol) in ethanol (50 mL), dropwise during 1.5 h. The reaction mixture was stirred at 0C for 1~5 h before the solvent was evaporated under reduced pressure. The residue was dissolvsd in ethanol (25 mL) and diluted with ethyl ether (150 mL) and stored in the refrigerator ovarnight. The precipitated solid was collected by filtration and drled to yield 1.0 g (67~) of the title compound, mp 170-172C. IR(KBr): 1100 ~S=O), 3200-3400 (NH2, OH)cm 1; UV: ~max (P~ 1) 231 nm (~
, (6~200)~ ~max (pH 7): 227 nm (~ 28,300), 285 (6,200), 302 (sh) (5,400): ~max (P~ 224 nm (~ 22,800~, 273 ~5,900), 301 (sh) (3,200): 1H NMR (DMSO-d6~: ~ 6.66 (s, 2, SONH~, exchanged with D2O), ~.71 (t, ~, J = 6.8 Hz, Cl,H), 7.06 (d, 1, C5H), 7.97 (d~ 1, C6H)~ 8-86 (s, 1, ~2H)~
and other sugar protons. Anal. Calcd. for CllH14N~O4S
~298.28): C, 44.2g; H, 4.73; N, 18.77; S, 10.73. Found: C, 44.30; H, 4.49; N, 48O48; S, 10O91.

7-(2-Deoxy~-D~erythro-pentofuranosyl)pyrrolo r 2,3-dL-pyrimidine~4-sulfonamide (55).
To a stirred solution of 53 (1.41 g, 5 mmol) in a - .

3 9 :~ 3 ~ 7 ~ eJ ~
mixture of ethanol:water (300:50, v/v) was added m-chloroperoxybenzoic acid (3.44 g, 20 mmol) in ethanol (50 mL) dropwise during 1.5 h at room temperature. A~ter the addition, the reaction mixture was stirred ak room 5 temperature for 12 h and evaporated to dryness under reduced pressure. The residue was dissolved in ethanol (50 mL), mixed with silica gel (~ 5 g) and again evaporated to dryness 1n va~uo. The dry residue was placed on top of a flash silica gel column (5 x 30 cm). The column was eluted successively with dichloromethane (1 L), dichloromethane:acetone (1:1, 500 mL) and then dichloromethane -~ methanol gradient. The appropriate - homogeneous fractions were pooled and concentrated to about 50 mL, and stored in the refrigerator overnight. The product that crystallized out was collect~d by filtration and dried to yield 1.10 g (71%), mp 175-177C. IR (KBr):
1150 (S=O), 1350 (SO2), 3100-3600 (NH2, OH~cm 1 UV: ~max (pH 1) 228 nm (~ 27,700), 284 (5,100), 310 (sh) (3~800):
~max (pH 7) 228 nm (~ 27,400), 285 (4,900), 308 (sh) (3,800): ~max (P~ ll) 22~ nm (~ 25,800), ~84 (5,700): lH NMR
i~ (DMSO~d6): ~ 6.72 (t, 1, J = 7.2 Hz, C1,H), 6.92 (d, l, C5H), 7.82 (br s, 2, SO2NH2, exchanged with D2O), 8.08 (d, 1, C6H), 8.9S (s, l, C2H), and other sugar protons. Anal.
~- for CllHl4N4sS (314-22): C, 42.04; H, 4.49; N
17.82; S, 10.18. Found: C, 42.07; H, 4.~6; N, 17.62; S, 10.15.
, l=~ D Ribofuranosylpyrazolo~3 ~-d]pyrimidine-4 sulfen-amide (57).
Commercial 0.77M sodium hypochlorite (5.25%, 8 mL) was cooled to c 0C in an ice-salt bath and added with stirring - to a similarly cooled 0.7M ammonium hydroxide (29%, 2 mL
diluted to 20 mL with water). The resulting solution of chloramine was mixed with a solution of l-~-D~
ribofuranosylpyrazolo[3,4-d]pyrimidine-4(5H)-thione ~J~LoG~
Montero, G.A. Bhat, R.P. Panzica and L.B. Townsend, J.
Heterocycl. ChemO, 14, 483 (1977), 56, 1.42 g, 5 mmol] in 2M

,,, . .

13:1 r~2~
potassium hydroxide solution (2.5 m~,) at 0C. The reaction mixture was stirred until it had warmed to room temperature (about an hour), and allowed to stand for 2 more hours. The product that crystallized out was collected by ~iltration, washed with cold ethanol (2 x 10 mL) and dried at room temperature to yield 0.61 g (41%) of the title compound.
Recrystallization from ethanol:water (3:1) gave analytically pure material of mp 166-169C- UV: ~max (P~ 1) 295 nm (~
28 000): ~ (pH 7) 293 nm (~ 24,000): ~max (pH 11) ( 21,000): 1H NMR (DMSO~d6): ~ 4.70 (s, 2, SNH2, exchanged with D20), 6.24 (d, 1, J = 4.53 Hz, C1,H), 8.67 (s, 1, C3H), 8.75 (s, 1, C6H), and other sugar protons. Anal. Calcd. for C1oH13N5O4S (299.3): C, 40.13; H, 4.3%; N, 23.40; S, 10.71.
Found: C, 40.35; H, 4~34; N, 23.2%; S, 10.79.

2-Amino-9-(2,3,5-tri~O-acetyl-~-D-ribofuranosyl)-9H-urine-6-sulfinamide (58).
A mixture of dimethylaminopyridine (10 mg) and acetic anhydride (1 mL) in anhydrous N,N-dimethylformamide (2 mL) was cooled to -15C. 2-Amino-9-~-D-ribofuranosyl-9H-purine-6 sulfinamide (19, 0.10 g, 0.3 mmol) was added and the mixture was stirred for 40 min at -15C. The reaction was quenched by the addition o~ methanol (4 mL) and the ~s resulting solution was stirred at 10C for 20 min and then evaporated to dryness. The resi~ue was tritura~ed with ethyl ether (10 mL) and the product was precipitated by the addition of hexane to yield 0.102 g (75%) of the title compound as amorphous solid. IR (KBr): 1050, 1095 (s, S=O), 1745 (vs, C=O), 3200-3500 (NH2)cm 1 W : ~max (pH 1) ( 6~100) ~max (pH 7) 328 nm ( 6,700) ~m (pH 11) 321 nm (~ 7,000): 1H NMR (DMSO-d6): ~ 2.03-2.13 (3s, 9, 3COCH3), 6.15 ~d, 1, J = 3.5 Hz, Cl,H~, 6-51 (s, 2, SONH2, exchanged with D2O), 7 . 07 ~S, 2, NH2, exchanged with D20~, %.44 (s, 1, C8H), and other sugar protons. Anal. Calcd. for C16H20N6O8S (456.43): C, 42,10; H, 4.42; N, 18.41; S, 7.03.
Found: C, 41.99, H, 4.47; N, 18.19; S, 6.79.

41 ~3~
As illustrative examples of use of the compounds of the invention the followiny examples are given. In these examples the efficacy of the compounds of the invention are demonstrated using standard tests against certain malignant tumors. These standard tests utilize protocols developed under the auspices of the Developmental Therapeutics Program, Division of Cancer Treatment, Mational Cancer ~nstitute, Bethesda, Maryland, U.S.A~ Except as otherwise indicated the tests conform to thase protocols and are evaluated utilizing criteria defined by the protocols.
For the purposes of these examples certain of standard abbreviations are utilized as follows: ip intraperitoneal: qd - Once a Day: bid - Twice a Day: tid -Three Times a Day- qid - Four Times a Day: %T/C Percent Treated Divided by Control: %I~S - Percent Increased Life Span: inj - Injection.
For those tests whose results are indicated as % T/C
generally using NCI protocols for the L1210 tumor cell line, a value greater than 125~ is considered as having activity.
For those tests expressed as a percent of the ori~inal inoculum, values above 100 are considered inactive while those below 100 are viewed as active. Values below 25% are considered capable of producing effective therapy, those below 10% are considered ~ood and those below 5% are considered very good. This expresses the percent of the cells which sur~ived treatment based upon the original cells in the inoculum. Those tests expressed as increases in life span (% ILS) indicate the increased life span of the drug ~reated group compared to a control group.
THERAPEUTIC EX~MPLE A
As an indicator of reproducible activity, compounds of the invention and other known cancer chemotherapeutic agents were screened against L1210 lymphoid leukemia in vivo utilizing the mouse as a test species. Normal NCI protocols for this test require 105 seed cells of the L1210 cell linP.
However for the purposes of tests with the L1210 cell line in testing the compounds of the invention for antitumor 42 ~3~7~
activity, a log greater, i~e. 106 cells were utilized.
Table 1 demonstrates the results of inoculating mice with 106 Ll210 seed cells and the spread of this tumor cell line throughout the body to multiple organ systems in the test species. As is indicative of Ta~le 1, at day 7 the L1210 cellular population in multiple organ systems greatly axceeded 105 cells in each of the organs assayed. It is thus evident from Table 1 that if a chemotherapeutic agent is to be effective against the ~1210 tumor line seeded at 106 i~ must reach all of the organ systems of the animal in : view of spread of this neoplastic disease to all these organ systems.

. 20 .
.

,~

~ , ,:

3 ~ 3 ~

AFTER
INTRAPERITONEAL INOCULATION ON DAY ol TISSUE POST INOCULATION DAY

BRAIN <100 >400,000 LUNG <100 >600,000 SPLE~N >6,000 <4,000,000 LIVER ~64,000 >120,000,000 BLOOD NONE >300~000 MARR0W NONE >500,000 1. Inoculated IP on day 0 with 1o6 L1210 cells.
THERAPEUTIC EXAMPLE B
Ta~les 2-a and 2-b illustrate a dose response for Compound 19 against L1210 inoculated mice expressed as both increased life span compared to control and as the number of cells o~ the original inoculum surviving drug treatment. As is evident from the various regimens of drug treatment shown in Tables 2-a and 2-b, effective therapeutlc e~ects are noted and a dose response to Compound 19 is evident. The ef~icacy for Compound 19 seen in Tables 2-a and 2-b is similar to that æeen Por Cytosine Arabinoside with the exception that to see e~fects with CytosinQ Arabinoside like those in Tables 2 a and 2-b for compound 19, Cytosine Arabinoside must be given every three hours. Test results are given utilizing standard protocols based on mean survival time and are expressed as T/C percentages ~treated animals/control animals).

' '14 ~3~72~
TABLE 2-a LIFE SPAN (g6T/C OF L1210 INOCULATEDl ~qICE T:REATED2 WITH

(mg/kg/inj) (qd days indicated) (bid days indicated) 1,4,71,3,5,7 1-7 1,4,7 1,3,5,7 1-7 22 161~93 ~0 173 269 2~g _ _ 1. BDF1 female mice were inoculated ip on day O with 106 L1210 cells~
2 ~ Drug was delivered l~y the ip route.
3. Treatment group included 2 long term survivors which ~: were not included in the calculation of life span.
4. Treatment group included 1 long term survivor which was not included in the calculation of life span.
5. Treatment group included 1 mouse which died from drug toxicity and was not included in the calculation o~ life span.

., ~.

TABLE 2-b (expressed as % of original inoculum) DOSAGE DRUG DELIVERED DRUG DELIVERED
5 (mg/kg) (qd days .indicated~ (bid days indicated) 1,4,7 1,3,5,7 1-71,4,7 1,3,5,7 1-7 62 594 50 13 5.6 0.3 2/5 104 29 17 1~5Cl l/5T2 173 1.1 0.2 _ _ ____ -1. Data expressed as number of long term survivors (Cures) per the number of animals in test group.
2. Data expressed as number of toxic deaths (Toxic Doses) per the number of animals in test group.

2~

~. 3 ~ 9 ~

'~HERAPEUTIC EXAMPLE C
In Example C the oral efficacy of Compound 19 was compared to that for the dru~ when given intraperitoneally.

RESPONSES OF L1210-INOCULATED BDFl MICE TO COMPOUND 19 GIVEN ORALLY AND INTRAPERITONEALLY

. ~ ~
DRUG INCREASED LIFE SPAN PRODUCED

~MG/KG/INJ) ORALLYINTRAPERITONEALLY

104 38 ~30 Mice were inoculated intraperitoneally on day 0 with a million cells of murine leukemia Ll210. Drug was given qd days 1, 4 and 7. Increased life span is the mean increase in the treated group presented as a percentage of the mean life span of control mice.

~ S~ 7~ ~
~7 THERAPEUTIC EX~MPLE D
In Example D Compound 19 is compared with 6-Thioguanosine. As per the oral treatment of Compound 19 seen in Table 3, in Table 4 it is evident that Thioguanosine has a flat dose response whereas Compound 19 shows a dose response curve when injected intraperitoneally.

RESPONSES OF L1210-INOCULAT~D BDFl MI OE TO

DRUG INCREASED LIFE SPAN PRODUCED BY
DOSAGE
(MG/KG/INJ) 6-THIOGUANOSINE COMPOUND 19 8.1 48 NR

173 52 (toxic) 189 2 5 _ __ _ NR = Not Run Mice were inoculated intraperitoneally on day 0 with a million cells of murine leukemia L1210. ~rugs were given qd days 1, 3, 5 ~and 7. Increased life span is presented 30 as a percentage o~ the mean life span of control mice.

, ~

., 48 1 ~ 7,~
THERAPEUTIC EXAMPLE E
Further elucidation of the dose response of Compound 19 is shown in Table 5. A dose of 288 mg per kg represents the maximum solubility of Compound 19 in water which was utilized as the drug vehicle for this test. As is evident from Table 5, Compound 19 shows an excellent dose response curve when delivered only once on day 1 with significant activity indicated at or above 37 mg per kg.

RESPONSE OF MICEl INOCULATED WITH L1210 CELLS2 SCHEDULE OFDOSAGE T/C
DELIVERY (mg/kg) (%) - -qd: day 1 2884 TOX

104 15~

bid: day 1 62 184 tid: day 1 62 133 qid: day 1 62 194 ---~
1. Each treatment yroup consisted of 3 female E3DF1 mice.
2. Mice were inoculated i.p. with L1210 cells (106 per mouse) on day 0.
3. Dru~ delivery ~as by the i.p. route.
4. Maximum solubility.

; 35 49 :~3~
THERAPEUTIC EXAMPLE F
In Example F Compound 19 and other known cancer chemotherapeutic agents were bioassayed for activity against neoplastic cells in the brain utilizing the L1210 cell line injected intracranially into test animals. In Tahle 6-a Compound 19 is compared to a control and in Table 6-b Compound 19 is compared to other known cancer chemotherapeutic agents. ~5 iS evident from Table 6-a there is a significant reduction in the number of neoplastic cells in the brain of the test animal after i.p. infection with Compound 19. This is indicative of both activity of Compound 19 and the ability of Compound 19 to cross the blood brain barrier. As is indicative of Table 6-b, Compound l9 shows an excellent therapeutic effeet when compared to known chemotherapeutic agents evaluated by this test procedure. Only three known chemotherapeutic agents out of the seven tested showed results approximately equal to or better than those for Compound 19.
,, TABLE 6-a BDF1 mice were inoculated intracranially on day 0 with lx105 L1210 cells. 24 hr later, on day 1, the mice were 25 injected ip with Compound 19 or 0.9~ NaCl. 2~ hr a~ter drug ` delivery the brains were collected, homogenized, and injected ip into untreated mice. Each mouse received the equivalent of half a brain. Thereafter, li~e span was monitored and, using inoculum-response data as a base o~
comparison, estima~es were made oP the numbers of viable i cells in trea~ed and control brains.
~ 30 _____________________.________.__________~__________________ cell/half brain day 2 change due to drug logl0 cell number logl0cells Compound 173 mg/kg 5.42 ~61016 -~.10 -92.08%

Control6.52 3295013 ______________________________________________________________ .

TABLE 6-b VIABLE L1210 CELLS IN MOUSE BRAIN 24-HR AFTER A SINGLE I.P.
TREATMENT WITH VARIOUS ANTICANCER DRUGS
DRU~ DOSAGE RESIDUAL CELLS
: 5 (mg/kg) (% o~ control brain) Methotrexate 12 97 Adriamycin 3 89.5 6-Mercaptopurine160 37 Cytosine Arabinoside 1200 15 Cyclophosphamide140 11.5 Compound 19 173 7.9 Tiazofurin 1~00 2.9 BCNU 20 1.6 _ _ __ _ In Examples G through K Compound 19 was tested against L1210 cell lines which had developed resistance to other :known cancer chemotherapeutic agents. Depending upon th0 r~sistant cell line which was being tested and the mode o~
25 administration and/or treatment regimen, Compollnd 19 shQwed activity against various cell lines which are resistant to .other known chemotherapeutic agents.
" ~

,, .

,.............................. .

51 1~3~72~
THERAPEUTIC EXAMPLE G
In Example G Compound 19 was tested against both L1210 calls and L1210 cells which were resistant to 6-Mercaptopurine, 6-Thioguanine and 6-Thioguanosine. As i5 evident from the different drug regimens shown, Compound 19 exhibited activity against the drug resistant cells. As was note~ above, drugs in the 6-Mercaptopurine ~amily are presently among the drugs of choice for treatment of leukemia. It is thus avident from Table 7-a that Compound 19 is active against cells which have become resistant to these drugs.

TABLE 7-a 15 L1210 AND L1210/6MP, 6TG CELLSl SURVIVING

(schedule indicated) (mg/kg/inj) L1210 L1210/6MP,6TG3 ~0 qd: dayl 173 1.4 4.6 10~ 5.4 54.5 62 0.8 15.9 bid: day 1 62 0.8 15.9 tid: day 1 62 0.4 15.9 1. Expressed as % of day zero, intraperitoneal inoculum of 1x106 cells.
2. Drug delivery was by the intraperitoneal route.
3. 6MP = 6 Mercaptopurineo 6TG = 6-Thioguanine:
6TGR = 6-Thioguanosine.
.~

' 52 ~3~7 ~
Table 7-b shows the activity of Compound 19 against cells resistant to the 6-Mercaptopurine ~amily of drugs expressed as increased life span. ~s is eviden~ ~rom Table 7-b Compound 19 shows efficacy against these resistant cells 5 when the affected animal was treated intraperitoneally.

TABLE 7-b ACTIVITY OF COMPOUND 19 AGAINST L1210 AND L1210/6MP,6TG
WHEN
DELIVERED ORALLY OR INTRAPERITONEALLY

Drug Tumor Dosage Schedule Route L1210 L1210/6MP,6TG
mg/kg/in;
%ILS1 Rcp2 ILS RCP
,~

37bid 1,3,5,7 ip 79 (.32) 66 (~28) oral 49 (3.73) 0 . 62bid 1,4,7 ip 88 (.14) 75 (.09) oral 40 (8.48) 1. % Increase Life Span.
2. Residual C~ll Population.

..

.

,, 53 :~ 3 ~ 3 THERAPEUTIC EXAMPLE H
In Example H, the results o~ which are shown in Table 8, Cytosine Arabinoside resistant L1210 cells were treated with Compound 19. As is evident ~rom Table 8, Compound 19 5 showed greater efficacy against this resistant cell line than it did to the parent non-drug resistant L1210 ce'ls.
This is indicative cf 'collateral activity' of compounds of the invention against resistant cells.

L1210 AND L1210/AR~-C CELLS1 SURVIVING

(qd days indicated) (mg/kg/inj) L1210 Ll210/ARA-C

1 173 1.4 o.o23 l, 4, 7 173 l.1 0.6 1, 4, 7 104 29.0 1.7 : 25 .. . .
1. ~xpressed as % o~ day zero, intraperitoneal inoculum of lx106 cells.
2. Drug delivery was by the intraperitoneal route.
3. Indicative of 'collateral activity'.

1 ~ 11. Pl ~ p~l ,~,, THERAPEUTIC' EXAMPLE I
In Exam]ple I Compound 19 was tested against M~thotrexat2 resistant L1210 cells. Depending upon the dose level and the dose regimen, activity can be seen against these Methotrexate resistant cells.

L1210 AND L1210/MTX CELLSl SURVIVING TREATMENT
WITH COMPO~ND 19 15 (qd days indicated) (mg/kg/day) L1210 Ll210/MTX

1 1731.4 1.6 1, 4, 7 1731.1 33~8 l, 4, 7 10429.0 238.4 l. Expressed as ~ of day zerQ, intraperitoneal inoculum o~
lx106 cells.
2. Drug delivery was by intraperitoneal route.
3. MTX - Methokrexate.

~ 3 ~ 7 ~
THERAPEUTIC EX~MPLE J
In Example J, the results of which are shown in TahlP
10 below, Compound 19 was tested against 5-~luorouracil resistant cells. Large dosages of Cvmpound 19 were highly active against these resistant cells.

L1210 AND L1210/5FU4 CELLSl SURVIVING TREATMENT

15(qd days indicated)(mg/ky/day) L1210 L1210/FU

1-7 104 0.043 3 1, 3, 5, 7 173 0.213 1, 3, 5, 7 104 17 525 1. Expressed as % of day zero, intraperitoneal inoculum o~
lx106 cells.
2. Drug delivery was by intraperitoneal route.
3. Treatment group included 1 long term survivor which was 30 not included in the calculation of lifa span.
4. 5FU = 5-Fluorouracil.

Compound 19 has not been found to generate resistant cell lines as per the other known cancer chemotherapeutic agents listed in Tables 7 through 10 above. However, Compound l8 does generate drug resistant cell lines.

..

56 .~ 3 ~ P~
THERAPEUTIC EXAMPLE K
In Example K, the results of which are shown in Table 11 below, Compound lg was tested against drug resistant cell lines developed against Comp~und 18. As is evident from the results shown in Table 11, Compound 19 differs from Compound 18 only by the state of oxidation between the sulfenamide o~
Compound 18 and the sulfinamide of Compound 19. As is evident from Table 11 Compound 19 .is e~fective against those L1210 cell lines which have developed resistance against Compound 18. Thus, while Compound l8 may mimic 6-Thioguanosine in that it generates drug resistant cells, themode of action of Compound 19 is bel.ieved to be completely different as is expressed by its activity seen in Example G
against 6-Thioguanosine resistant cell lines and its activity in Example K against Compound 18 resistant cell lines.

TABLE ll 20L1210 AND L1210/DRUG RESISTANT CELLSl SURVIVING TREATMENT

(qd days indicated) (mg/kg/day) L1210 L1210/COMPOUND 18 25qd: day 1 173 1.4 7~5 104 5.4 17.9 62 8.5 100.0 bid: day 1 62 0.8 27.4 1. Expressed as % of day zero, intraperitoneal inoculum of 1x106 cells.
2. Drug delivery was by intraperitoneal route A

5'7 ~ 3 1 ~2~:3.
THERAPEUTIC EXAMPLE L
In this Example Compounds 1~ and 19 were tes~ed singularly and then in combination first given bokh toyether and then given in different orders. As is evident from the 5 result tabulated in Table 12 both Compounds 18 and 19 induced increases in life span in 'he test animals with the activity of the compounds given simultaneously or sequentially being similar or even inferior to that seen for - Compound 19 by itself.

15 COMBINED DRUG TREATMENT OF L1210: COMPOUND 19 AND COMPOUND 18 Schedule of Delivery1 %ILS2 Day 1 Day 2 ; 20 Compound 19 88 Compound 18 51 Compound 19 and 58 Compound 18 Compound 19 Compound 18 91 Compound 18 Compound 19 84 ,~

35 1. Dosages: Compound 19 173 mg/kg Compound 18 22 mg/kg.
2. ~ Increase Life Span.

, 58 13~7~
THERAPEUTIC EXAMPLE M
In Example M a further example was run similar to that of Exhibit L except that Compound 19 was utilized in conjunction with the known chemotherapeutic agent Tiazofurin. As is evident ~`rQm the results tabulated in Table 13 increased activity i5 seen when Compound 19 and Tiazofurin are given sequentially. Sequence dependency was also observed with the best result being produced when Compound 19 preceded Tiazofurin.

COMBINED DRUG TREATMENT QF Ll210: COMPOUND 19 AND TIAZOFURIN
Schedule of Delivery1 %ILS2 Day 1 Day 2 _ Compound 19 81 Tiazofurin 44 Compound 19 and 69 Tiazofurin Tiazofurin Compound 19 100 Compound 19 Tiazofurin 150 1. Dosages: Compound 19 173 mg/kg Tiazo~urin 22 mg/ky 2. Increase Life Span s THERAPEUTIC EXAMPLE N
In Example N other compounds of the invention were tested against L1210 cells. All of the compounds listed in Table 14 exhibit activity. Further, Table 14 shows thP
maximum solubility (in water unless otherwise indicated) and the maximum tolerated dose. Activity in Table 14 a is tabulated as both increases in life span and as cells surviving treatment and that in table 14-b as T/C.

59 ~3~7~
TABLE 14-a R~SPONSE OF L1210 INOCULATED BDF1 MICE
TO COMPOUNDS OF THE INVENTION
COMPOUND MAX. SO~. MAX. TOLERATED ~ILS CELLS
# DOSAGE DOSAGE SURVIVING
( MG/ XG ) t MG/ ~G ) TREATMENT
(% OF DAY 0 INNOC.) 8 480 173 43 6.4 22 173 173 47 6.0 29 480 480 59 1.7 23 4~0 173 59 2.0 288 288 59 1.7 2 104(NaOH) 104 63 2.0 2 62(DMSO) 37 66 0.8 14 800 288 66 1.0 6 480 480 67 2.8 16 800 173 69 1.0 18 2~ 22 85 0.3 1. Ahove data resulted ~rom single QD day 1 treatment of BDF1 mice on day 0 with 1o6 cell L~210. Both cell inoculation and treatment were IP.
2. In water unless otherwise indicated.
` :

~3~
TABLE 14-b RESPONSE OF L1210 INOCULATED BDFl MICE
TO COMPOUNDS OF THE INVENTION
COMPOUND MAX. S~I,. T/C
# DOSAGE
( MG/ KG ) 42 104(NaOH~ 172 43 480 ~.30 10 ~5 480 172 1. Above data resulted from single QD day 1 treatment of BDFl mice on day 0 with 106 cell L1210. Both cell inoculation and treatment were IP.
2. In water unless otherwise indicated.

Compound 19 was also tested against a variety of solid tumors. No activity was noted against B-16 melanoma, Lewis lung carcinoma or human lung carcinoma LX-1. Activity, however, was noted in a variety of other solid tumors as per examples 0 through S below.

THERAPEUTIC EXAMPLE O
In this exa~ple Compound 19 was tested against reticulum cell sarcoma ~5076. For this and certain other tests below, test results are shown as ~T/~C. Utilizing this protocol the difference in tumor weight be~or ,~ treatment and after treatment of the treated animals compared to the control animals is determined. As is seen in Table 15, Compound 19 exhibited activity against this cell line and shows a dose response for this aotivity.

61 ~3~

SCHEDULE OF DOSAGETUMOR WT3 (Mean + lSD5 ~T/~C
5 DELIVERY2 ~mg/kg/inj) staging4evaluation (qd days indicated) day day 1,3,5,7,9,11 173.0 35~ + 81 409 + 385 5.0 138.4 355 + 79855 + 325 45.4 110.8 396 + 1161121 + 343 65.8 0 396 + 104149~3 + 438 _ 1. C57B1/6 female mice (7/group) were inoculated s.c~ with 1x106 M5076 cells on day 0.
2. Drug was delivered by the i.p. route.
3. Tumor weight was estimated from caliper measurements using the formula: tumor wt. ~mg) = w21/4. 45.
4. Treatment was initiated on staging day (day 15 post inoculation).
5. Day 12 post initiation of treatment.

62 ~ 3 .~ 7 ~
THERAPEUTIC EXAMPLE P
In Example P Compound 19 was tested against human mammary carcinoma MX-l. As per the results tabulated in Table 16, Compound 19 exhibited a dose response against this solid tumor.

RESPONSE OF HUMAN MAMMARY CARCINOMA MX
TO TREATMENT WITH COMPOUND 1~

SCHEDULE OF DOSAGE TUMOR WT3 (Mean + lSD) ~T/~C4 DELIVERY2 (mg/kg/inj) staging5 evaluation6 lS (qd days day day indicated) :
1,3,5,7,9,11 ~73.0 323 + 127 489 + 104 17.6 138.4 330 + 11~ 884 + 415 58.9 110.8 321 + 132 ~43 + 2g7 66.1 o 325 + 112 1266 ~ 695 1. CD-l nu/nu female mice (7 per group) were implanted s.c.
with fragments (<25 mg ea.) of MX-1 carcinoma on day o.
2. Drug delivery was by the i.p. route.
3. Tumor weight was estimated from caliper measurements using the formula: tumor wt (mg) = w21/4.45.
4. NCI guidelines suggest a ~T/~C < 20% for demonstration of moderate activity.
5. Treatment was initiated on staging day (day 17 post implant).
6. Day 15 post initiation of treatment.

.
;

.

~3~7,~ ~
THERAPEUTIC EXAMPLE Q
In Example Q Compound 19 was tested against Colon 26 Adenocarcinoma. Except when given once a day in the regimen on days 1, 4 and 7, for the other dosages and test regimens Compound 19 exhibited acti~ity against this tumor.

RESPONSE OF MICEl BEARING COLON 26 ADENOCARCINOMA2 DELIVERY3 (mg/kg/inj) ~days post inoculation) (%) 15 qd: day5 1, 4, 7 173 31 135 qd: days 1,3,5,7 173 42 183 20 qd: days 1-7 104 38 165 bid: days 1,4,7 104 175 bid: days 1,4,7 62 45 196 1. Each treatment yroup consisted of 11 female C'DF1 mice.
2. 3X106 cells of Colon 26 Adenocarcinoma were implanted i.p. on day 0.
3. Drug delivery was by the i.p. route.
4. NCI guidelines suggest a T/C > 150% for demonstration of significant activity.
5. Treatment group included 6 toxic deaths.

64 3 3~.72~:~
THERAPEUTIC EXAMPLE R
Compound 19 was ~urther tested against Human Colon Adenocarcinoma CX-1. For comparison purposes the activity of other clinically active antitumor agents is shown in Table 18-a. Activity ayainst this tumor system is indicated at a ST/~C value of less than 20.

TABLE 18-a NSC DRUG ACTIVITY ~ATING
# ~T/ISC2 740 Methotrexate 66 752 6-Thioguanine 81 15 755 6-Mercaptopurine 9g 3053 Actinomycin D 73 3088 Chlorambucil 60 8806 Melphalan 101 13875 Hexamethylmelamine 85 19893 5-Fluorouracil 88 26271 Cyclophosphamide 113 26980 Mitomycin C 62 49842 Vinblastine 119 63878 Cytosine arabinoside 73 67574 Vincristine 89 77213 Procarbazine 60 95441 Methyl CCNU 83 119875 Cis-Platinum 66 123127 Adriamycin 72 125066 Bleomycin 51 178248 Chlorozo~ocin 75 .
1. Data taken ~rom~: Ao Goldin, et al, Current Results O~
30 The Screening Program Of The Division O~ Cancer Tr~atment, National Cancer Institute, Euro~ J. Cancer, Vol. 17, 129-142, (1981).
2. Activity indicated at ~T/~C < 20.
`:

In a like manner Compound 19 was tested against this tumor system with the results shown in Tabl~ 18-b. As is shown, at the i73 mg level when drug was glven on ~sys .
., ~3~
1,4,7,10 and ~3, activity against this tumor sy~tem is demonstrated.

` TABLE 18-b RESPONSE OF HUMAN COLON ADENOCARCINOMA CS-l SCHEDULE ~F DOSAGE TUMOR W~3 (mean + lSD~
DELIVERY mg/kg~in;) staging evaluation ~T/~C4 (qd days indicated) day day lo 1,3,5,7,9 173.0 22g + 141 364 ~ 254 (16) 39.9 1,4,7,10,13173.0 226 + 125 279 + 121 (17) 15.8 1,3,5,7 173.0 222 + 79 302 + 1~4 (12) 38.5 1,4,7,10 173.0 226 + 103 402 + 187 (16) 52.1 1,3,5,7,9,11138.4 220 ~ 80 358 + ~25 (15) 46~6 1,4,7,10,13,16 138.4 215 + 81296 + 186 (12) 38.9 1,3,5,7,9 138.4 226 + 120 27~ + 114 (12~ 25.0 1,4,7,10,13138.4 225 + 104 375 + 155 (15) 50.7 ~0 0 218 + 81 426 + 195 (12) _ _ 0 218 + 81 514 + 252 (15) _ _ 0 218 + 81 556 + ~38 (16) _ _ 0 218 + 81 553 + 231 (17) 1. CD-1 nu/nu female mice (6 per group) were lmplanted s.c.
with fragments (<25 mg ea.) of CX-1 adenocarcinoma on day 0.
2. Drug delivery was by the i.p. route.
3. Tumor weight was estimated from caliper measurements using the formula: tumor wt (mg)=w21/4.45.
4. NCI guidelines suggest a T/C < 20% for demonstration of moderate activity.
5. Treatment was initiated on staging day (day 33 post implant).
6. The day of occurxence (shown in parenthesis~ of optimum ~/~ % between day 12 and day 21 post initiation of treatment.

., , 66 ~3~7~

It is indicative that activity against this tumor system is possible utiliæing optimum dose scheduling o~
Compound 19 against this tumor system.

THERAPEUTIC EXAMPLE S
Compound 19 was also tested against Murine Glioma 261.
In this test activity is indicated at levels of T/C below 42%. As is shown in Table 19, Compound 19 is active at various doses against this tumor system.

RESPONSE OF MURINE GLIOMA 261l TO TREATMENT

DELIVERY2(mg/kg/inj)(mg) (~) qd: days 1-9 104 5 + 54 1.4 62 137 + 12~ 39.3 37 119 + 105 34.1 22 80 + 130 22.9 O 349 + 139 1. C57B1/6 male mice (6/group) were implanted s.c. with ~ra~nents (<25 Tng/ea) of Glioma 261 on day 0.
2. Drug was delivered by the i.p. routeO
3. On day lO post implant, tumor sizes were estimated from caliper measUrementS USing the ~ormula: tumor wt(mg) =
w21/4.45.
4. Mean + lSD.
j 5. Activity indicated at or below T/C of 42%~

, 67 ~ 3~7,~
THERAPEUTIC EXAMPLE T
As an example of activity among the dif~erent members of the oxidation series repre~ented by sulfenamides, : sulfinamides and sulfonamides comparison of activity of Compounds 18, 19, and 20 is shown in Table l9-a and is summarized in Table 19-b. As is evident from the summaries in Table l9-bo Compounds 18 and 19 effectively cross the blood brain barrier and thus are active intracranially whereas at the high oxidation state of Compound 20 no intracranial activity i5 seen. Oral activity is seen for both Compounds 18 and 19 but not present in Compound 20O
Contrasted to this is activity against resistant cells wherein Compounds 19 and 20 are active but Compound 18 in ; fact shows no activity. As was shown in Example K, Table 11 above, Compound 19 in fact was active against cells which developed resistance to Compound 18.

.

., ~.
. 30 '', ' '.' 1 ~l 7~
6~
TABLE 19-a Activity against ~ctivity against Activity against I. c. I.P. L1210 cellsI.P. L1210 cells L1210 cells with oral drugresistant to administration 6MP, 6TG, 6TGR

I.~ Cell Dosage Kill Schedule Dosage T/C Schedule Dosage T/C
~mg/kg) (x) (mg/kg) (%) (mg/kg) (%) _______________________________________________________________ Compound 18 22 57.3qd:dl 22 153.0 qd:dl 22 93~8 13 1~7.0 8 14~.0 Compound 19 173 92.1gd:dl,4,7 173 138.5qd:dl 173 144.5 104 13~.5 104 122.2 62 144.6 62 127.3 37 144.6 bid:dl 104 150.0 bid:dl,3,5,7 37 148.6 62 133.3 bid:dl,4,7 62 140.0tid:dl 62 133.3 - bid:dl,3,5,7 37 165.6 0 bid:l,4,7 62 175.0 Compound 20 62 0.0 bid:dl,4,762 103.3bid:dl,4,7 62 163.3 37 103.3 37 130.0 22 103.3 22 ~06.7 The different compounds of the sulfinamide, sulfenamide and sulfcnamide series ~s is demonstrated by Compound 18, 19 and 20 show various advantages and disadvantages with the sulfinamide Compound 19 having optimization o~ certain properties. Compound lg shares the best properties of both Compounds 18 and 20 ~3~72~.

TABLE l9-b ACTIVITY VS. ORAL ACTIVITYACTIVITY VS.
Io~ CE~LS ~1210/6MP:6TG:6TGR

Compound 18 + +
Compound 19 ~ + +
10 Compound 20 - - +

Compound 19 exists as two enantiomers. The above test results for Compound 19 were done on the racemic mixture of these enantiomers. Further, separation of these enantiomers to a high degree of (but not absolute) puriky has been effected. The separate enantiomers have been independently tested and further tested as contrived mixtures of known amounts of the enantiomers. Of the two purified enantiomers, enantiomer B shows a higher solubility than enantiomer A and the racemic mixture exhibits solubility characteristics of enantiomer B exhibiting solubility ak about 17.3 mg per ml~ In contrast to this enantiomer A
exhibits solubility of about 3.7 mg per ml. The two enantiomers present comparable activity, however, because of the solubility of enantiomer A is less than enantiomer B, tests with enanti~mer A have been done at a much lower dosage level.

., ., "

.

, 7o 131 J ~ 9 ~
THERAPEUTIC EXAMPLE U
In this example the enantiomers of Compound 19 labeled enantiomer A and enantiomer B were tested independent of one another. The results o~ these tests are indicated utilizing two different protocols as are shown in Tables 20-a and 20-b. Enantiomer A shows greater ackivity with respect to enantiomer B because of solubility differences.

TABLE 20-a LIFE SPAN (%T/C) OF L1210 INOCULATEDl MICE TREATED2 WITH COMPOUND 19 ENANTIO~ER A OR ENANTIOMER B
DRUG DOSAGE T/C
(mg/kg) ~%) Compound 19 Enantiomer A 37 108.7 Enantiomer B 173 144.9 1~ BDF1 female mice were inoculated i.p. on day 0 with 106 L1210 cells.
2.Drug was administered i.p. dq:day 1.

TABLE 20-b Ll210 CELLS1 SURVIVING TREATMENT2 WITH

~RUG DOSAGE % OF ORIGINAL
(mg/kg) YNOCULUM
- - _ _ Compound 19 Enantiomer A 37 182.8 Enantiomer B 173 7.5 1. BDF1 female mice were inoculated i.p. on day O with 106 L1210 cells.
2. Drug was administered i.p. dq:day l.

71 13~7~ ~

THERAPEUTIC EXAMPLE V
In this example different regimens of dosages ~or enantiomer A of Compound 19 were utilized and the results were tabulated in Table 21. The percent of contamination o~
enantiomer A with enantiomer B and with a ~urther contaminate comprising Guanosine and Compound 20 was tested using HPLC. As is evident from ~able 21, when the dosage of enantiomer A was divided into multiple dose regimens effective therapy was indicated.

TABI,E 21 EFFECT OF COMPOUND 19 ENANTIOMER-A ON T~E MEANS LIFE SPAN OF
BDFl MICE INOCULATED I.P. WITH lX10 CELLS OF L1210 Drug ScheduleTotal Drug % ILS Cells Delivered of (mg/kg) Surviving (mg/kg/inj) Delivery Delivered as Treatment A B Contam- (% o~
inant original inoc.) 37qd, day 1 35.47 0.63 0.9022 64 37bid, day 1 70O94 1.26 1.8044 10 25 37tid, day 1 106.41 1.89 2.7072 37qid, day 1 14~.88 2.52 3.6072 37qid, day 1 177.35 3.15 4.50 0 tox As shown, all injections were made on day lo For mice treated more than once, treatment was completed within 20 minutes. Enzntiomer A was 35.~7% A and 1.71% B: thus, these two enantiomers comprised 97.58% of the material delivered.
The A-B ratio was 95.87:1.71. There were 3 mice in each treatment group.

THERAPEUTIC EXAMPLE W
In this example, concocted mixtures of enantiomers A
and B were made. In addition, these mixtures were contaminated with small amount of contaminant~ comprising 5 Guanosine and Compound 20. As is indicative from the results shown in Table 22, activity does not reside with only one or the other of the two enantiomers but is apparently optimized in mixtures of the enantiome.rs. It is presently believed a 50/50 mixture of the enantiomers of 10 compound 19 is suggested for use in antitumor compositions of this compound.

EFFECTS OF VARIOUS RATIOS OF COMPOUND l9-ENANTIOMERS A AND B
15 ON THE MEAN LIFE SPAN ~F BDFl MICE INOCULATED I.P. WITH
lX10 CELLS OF L1210 Drug A/B Ratio Total Drug (mg/kg) g6 lLS Cells Delivered Delivered as Surviving (mg/kg/inj) A B Contam- Treatment inant (% of original inoc.) 62 90/1055.586. 42 1.74 14 ~0 104 70/3073.5331.13 3.50 20 58 25 173 50/5087.1785.83 5.09 57 (2 tox) 2 173 30/7059. 03113. 97 6.3:L 31 19 173 10/9019.0~153.92 4.14 37 11 173 90/10156.9116.09 ~.88 62 (2 tox) 173 70/30121.2651.74 5.83 43 (4 tox) 7 173 50/5087.6985.48 5.10 62 ~2 ~ox~ 1 173 30/705~ .74118. 26 3. 29 40 8 173 10/9019. 36153.6d, 3.44 29 25 A11 treatments were made qd, day 1. Each trPatment group consisted of 5 mice: the postinoculation li~e span of these treated mice was compared w.ith that OI 9 control mice that were injected with a 0.9% solution of NaCl.

73 ~ 7~

For delivery to a host inflicted with a neoplastic disease compounds of the invention can be ~ormulated in various formulations to prepare pharmaceutical compositions containing the compounds o~ the invention as active ingredients. The following illustrative examples are given fcr the formulations of such pharmaceutical compositions utilizing Compound 19 as the illustrative compound. In these examples, Pharmaceutical Preparative Example illustrates the use of the compounds of the invention in injectables suitable for intravenous or other types of injection into the host animal. Pharmaceutical Preparative Example 2 is directed to an oral syrup preparation, Pharmaceutical Preparative Examples 3 to an oral capsule preparation and Pharmaceutical Preparative Example 4 to oral tablets. Pharmaceutical Preparative Example 5 is directed to use of the compounds of the invention in suitable suppositories. For Pharmaceutical Preparative Examples 1 through 5, the ingredients are listed followed by the method~ of preparing the compositionO

INJECTABLES
.
Compound 19 250 mg - 1000 mg Water for Injectio~ USP q.s.
- - -Compound 19 is dissolved in the water and passed through a 0.22; filter. The filtered so~ution is added to ampoules or vials, sealed and sterilized.

;

-~ 3 ~l 7 ~

SYRUP
250 mg Active ingredient/5 ml syrup ~

Compound 19 50.0 g Purified Water USP q.s. or 200 ml Cherry Syrup q.s. ad 1000 ml _ , Compound 19 is dissolved in the water and to thissolution the syrup is added with mild stirring.

CAPSULES
100 mg 250 mg or 500 mg Compound 19 500 g A~ ~ Lactose WSP, Anhydrous q.s. or 200 g -' Sterotex Powder HM 5 g Combine compound 19 and the Lactose in a twin-shell blender equipped with an int~nsifier bar. Tumble blend Eor two minutes, followed by blending for one minute wikh the intensifier bar and then tumble blend again for one minute.
A portion of the blend is then mixed with the Sterotex Powder, passed throuyh a #30 screen and added back to the remainder o~ the blend. The mixed ingredients are then blended for one minute, blended for the intensifier bar for thirty seconds and tumble blended for an additional minute.
Appropriate sized capsules are filled with 141 mg, 352.5 mg or 705 mg of the blend, respectively, for the 100 mg, 260 mg and 500 mg containing capsules.

.
~ ~ fr~ de r~r ~

~3~ 3 TABLETS
100 mg, 200mg or 500 mg Compound 19 500 g Corn Starch NF 200.0 g Cellulose Micxocrystalline 46.0 g 10 Sterotex Powder HM 4-0 g Purified Water q.s. or 300.0 ml Combine the corn starch, the cellulose and Compound 19 together in a planetary mixer and mix for two minutes. Add the water to this cor~bination and mix for one minute. The resulting mix is spread on trays and dried in a hot air oven at 50 C. until a moisture level of 1 to 2 percent is obtained. The dried mix is then milled with a Fitzmill through a #RH2B screen at medium speed. Th~ Sterotex Powder is added to a portion of the mix and passed through a #30 screen and added back to the milled mixture and the total blended for five minutes by drum rolling. Compressed tables of 150 mg, 375 mg and 750 mg respectively, of the total mix are formed with appropriate sized punches ~or the 100 my, 25 250 mg or 500 mg containing tables.

PHA~U~ACEUTICAL PREPARATIVE EXAMPLE 5 SUPPOSITORIES
250 mg, 500 mg or 1000 mg per 3 g __ _ _ Compound 19 250 mg 500 mg 1000 mg Polyethylene Glycol 1540 1925 mg 1750 mg 1400 mg 35 Polyethylene Glycol 8000 825 mg 750 mg ~00 mg :
Melt the Polyethylene Glycol 1540 and the Polyethylene Glycol 8000 together at 60C. and dissolve Compollnd 19 into ~3~72~

the melt. Mold thi~ total at 25 C. into appropriate suppositories .

~5

Claims (35)

1. A compound of the structure:

wherein Z is H or -NH2;

X is -S-NH2, -?-NH2 or -?-NH2;

G, T and Q are C-H or N;
Y is H or an .alpha.-pentofuranose or .beta.-pentofuranose of the formula:

wherein R1 and R2 independently are H, OH, -O-acyl or O= , or together R1 and R2 are O= , and R3 and R4 are H or one of R3 or R4 is OH and the other is H; provided that when Y is H, Z is -NH2; and pharmaceutically acceptable salts thereof.

2. A compound of claim 1 wherein:
Z is -NH2.

3. The compound of claim 1 wherein:
T is C-H; and G and Q are N.

4. A compound of claim 1 wherein:
X is -?-NH2.

5. A compound of claim 1 wherein: Y is a .beta.-pentofuranose of the formula wherein R1, R2, R3 and R4 are are defined in claim 1.

6. A compound of claim 5 wherein:
R3 is OH and R4 is H.

7. A compound of claim 5 wherein:
X is -?-NH2 or -?-NH2.

8. A compound of claim 5 wherein:
R1 and R2 are OH.

9. A compound of claim 5 wherein:
Z is -NH2.

10. A compound of claim 7 wherein:
X is -?-NH2.

11. A compound of claim 6 wherein:
wherein R1 and R2 independently are OH or O= or together R1 and R2 are O=, and pharmaceutically acceptable salts thereof.

12. 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfenamide.

13. 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfinamide.

14. 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfonamide.

15. 2-Amino-9-(2-deoxy-.beta.-D-erythro-pentofuranosyl)-9H-purine-6-sulfinamide.

16. 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfin-amide 3',5'-cyclic phosphate.

17. 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfin-amide 5'-monophosphate.

18. Use of a therapeutically effective amount of a compound of the structure:

wherein Z is H or -NH2;
X is -S-NH2, -?-NH2 or -?-NH2;

G, T and Q are C-H or N;
Y is H or an .alpha.-pentofuranose or .beta.-pentofuranose of the formula:

wherein R1 and R2 independently are H, OH, -O-acyl or O=, or together R1 and R2 are O=, and R3 and R4 are H or one of R3 or R4 is OH and the other is H; provided that when Y is H, Z is -NH2; or pharmaceutically acceptable salt thereof to treat a tumor in a warm-blooded animal.

19. Use of claim 18 wherein:

Z is -NH2;
T is C-H: and G and Q are N: and Y is a .beta.-pentofuranose of the formula:

wherein R1, R2, R3 and R4 are as defined in claim 18.

20. Use of claim 19 wherein:
R3 and R4 are H or R3 is OH and R4 is H.

21. Use of claim 19 wherein:
X is -?-NH2.

22. Use of a therapeutically effective amount of a compound selected from the group consisting of:
2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfenamide, 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfinamide, 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfonamide, 2-Amino-9-(2-deoxy-.beta.-D-erythro-pentofuranosyl)-9H-purine-6-sulfinamide, 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfinamide 3',5'-cyclic phosphate, and 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfinamide 5'-monophosphate to treat a tumor in a warm-blooded animal.

23. Use of claim 22 wherein said compound is 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfinamide.

24. Use of claim 22 wherein: said compound is in association with a pharmaceutically acceptable diluent or carrier as a pharmaceutical composition suitable for oral or injected administration.

25. An antitumor composition for the treatment of tumors in vivo containing as its active ingredient an effective amount of a compound selected from compounds of the structure:
wherein Z is H or -NH2;
X 18 -S-NH2, -?-NH2 or -?-NH2;
G, T and Q are C-H or N;
Y is H or an .alpha.-pentofuranose or .beta.-pentofuranose of the formula:
wherein R1 and R2 independently are H, OH, -O-acyl or O= or together R1 and R2 are O=, and R3 and R4 are H or one of R3 or R4 is OH and the other is H; provided that when Y is H, Z is -NH2; and pharmaceutically acceptable salts thereof; in an inert carrier thereof.

26. A composition of claim 25 wherein:
Z is -NH2;
T is C-H; and G and Q are N; and Y is a .beta.-pentofuranose of the formula:
wherein R1, R2, R3 and R4 are as defined in claim 25.

27. A composition of claim 26 wherein:
R3 and R4 are H or R3 is OH and R4 is H.

28. A composition of claim 26 wherein:
X is -?-NH2.

29. An antitumor composition for the treatment of tumors in vivo containing as its active ingredient an effective amount of a compound selected from the group consisting of:
2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfenamide, 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfinamide, 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfonamide, 2-Amino-9-(2-deoxy-.beta.-D-erythro-pentofuranosyl)-9H-purine-6-sulfinamide, 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfinamide 3',5'-cyclic phosphate, and 2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfinamide 5'-monophosphate;
in an inert carrier thereof.

30. A composition of claim 29 wherein said compound is:
2-Amino-9-.beta.-D-ribofuranosyl-9H-purine-6-sulfinamide.

31. A process for preparing a compound of the structure wherein Z is H or -NH2;
X is -S-NH2, -?-NH2 or -?-NH2;

G, T and Q are C-H or N;
Y is H or an .alpha.-pentofuranose or .beta.-pentofuranose of the formula:

wherein R1 and R2 independently are H, OH, -O-acyl or O= or together R1 and R2 are O=, and R3 and R4 are H or one of R3 or R4 is OH and the other is H; provided that when Y is H, Z is -NH2;
comprising the steps of:
treating a compound of said structure wherein X is =S
with chloramine to form a compound of said structure wherein X is -S-NH2 ;
isolating said compound.

32. The process of claim 31 further including:
treating a compound of said structure wherein X = -S-NH2 with an oxidizing agent to form a compound of said structure wherein X is -?-NH2 or -?-NH2 ;

isolating said compound.

33. The process of claim 31 further including:
treating said compound of said structure wherein X
is -S-NH2 with one equivalent of said oxidizing agent to form a compound of said structure wherein X is -?-NH2 ;
isolating said compound.

34. The process of claim 31 further including:
treating said compound of said structure wherein X is -S-NH2 with an excess of said oxidizing agent to form a compound of said structure wherein X is -?-NH2 ;

isolating said compound.

35. The process of claim 32 including:
selecting m-chloroperoxybenzoic acid as said oxidizing agent.