SI8412049A8 - Process for obtaining 5'-deoxy-5-fluoro(cytidine or uridine) as well as their phisiologic bearable additional salts with acids - Google Patents

Description

PROCEDURE FOR OBTAINING 5 '' - DEOXI-5-FLUOR (GlTIDINE OR URIDIN)

1. TECHNICAL FIELD

The present invention relates to the field of organic chemistry and pharmaceutical chemistry.

2. TECHNICAL PROBLEM

The invention includes a process for the preparation of novel pyrimidine nucleosides that can be used as anti-tumor agents, in particular a process for the preparation of 5'-deoxy-5fluorocytidine and 5'-deoxy-5-fluorouridine, as well as their physiologically tolerable acid addition salts.

3. BACKGROUND OF THE INVENTION

The introduction of the 5'-deoxy substituent into pyrimidine nucleosides was described previously. Thus, v / empen et al., J .Amer. Chem. Soc. 82, 1624 (1960) described the synthesis of 5'-deoxy-uridine, 5'-deoxy5'-fluoro-cytidine, and 5'-deoxy-5'-fluoro-uridine. Japanese Pat. 49-116081 describes the preparation of 5'-deoxy-cytidine by reduction of the corresponding 5'-halo (Br or I) or 5'-methyl or benzylmercaptan. No anti-tumor activity has been attributed to any of the aforementioned final products.

2-.

Palco and ^ οχ, J. Med, Chem. 11,148 (1968) describe the synthesis of 1- (5 '-deoxy- [beta] -D-arabinofuranosyl) cytosine. This compound was found to be inactive against L 1210 leukemia and Burkitt cell cultures, probably because such compound could not form a 5'-phosphorylated derivative.

Hein et al., Nucleic Acids Research 3, 1125 (1976) also obtained 5 '-deoxyuridine and 2', 5'-dideoxyuridine by alternating reduction by the methods. No biological activity was attributed to the products obtained.

Japanese patent No. 51-086481 describes the preparation of 2 ', 5'-dideoxy-5-fluorouridine from the corresponding 25'-dideoxy-5-iodo compound. The product has been shown to be an anti-cancer agent that inhibits the growth of sarcoma fossils.

U.S. Patent No. No. 3,687,931 describes the preparation of 5'-deoxy5'-chloro or bromo nucleosides using triphenylphosphine using carbon monoxide or carbon tetrabromide. The compounds have been found to have antibiotic, antimetabolic and enzymatic inhibitory activity.

Compounds of 5 '-deoxyuridine and 2', 5'-dideoxy-5-fluorouridine are described in C.A. 76 (1972) 154079p and in Japanese Pat. 76-86481.

-34. DESCRIPTION OF THE SOLUTION

The compounds of the invention are readily obtainable from

Of 5-gluorcytidine or. fluororidine and indeed by analogous methods for the preparation of 5 '-deoxycytidine or 5'-deoxyuridine from cytidine, resp. uridine. Thus, for example, starting nucleosides are iodinated in a known manner in the 5'-position either directly or, more preferably, after prior protection of both hydroxy groups in the 2'- and 3'-position to form a single ketal. The 5'-iodo compound obtained is then reduced to the corresponding 5'-deoxy compound either by catalytic hydrogenation or by a reducing agent such as complex metal hydrides. In the case of a non-ketalized iodine compound, the desired product is obtained directly. Finally, 5'-deoxy5-fluorocytidine and 5'-deoxy-5-fluoro uridine can, if desired, be converted in a known manner to physiologically acceptable acid addition salts by treatment with physiologically acceptable acids.

The process according to the invention is characterized in that 5'-deoxy-5-iodo-5-fluorocytidine or The 5'-deoxy-5-iodo-5fluorouridine in the 5'-position reduces and optionally treats the resulting 5'-deoxy-5-fluorocytidine or 5'-deoxy-5-fluorouridine with physiologically acceptable acids.

The term "physiologically tolerable salts" includes non-toxic salts which form 5'-deoxy-5-fluorocytidine and -uridine with inorganic mineral acids or organic acids, e.g. hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, acetates, formates, maleates, fumarates or benzoates

The introduction of the iodine atom into the 5'-position can be carried out either in 5-fluorocytidine or · 5-fluororidine, or in fact primarily in one 2 ', 3'-ketal. For example, the introduction of iodine can be done by treatment with a single iodizing agent such as methyltriphenoxyphosphonium iodide (MTPI) in one polar

A -4-proton organic solvent, such as dimethylformamide (DMP), at a temperature between 0 and 100 ° C, preferably at room temperature.

Conversion of the 5'-iodine compound to the corresponding 5 deoxy compounds can be easily accomplished by catalytic hydrogenation in a protic polar solvent such as one alcohol, preferably methanol, using a precious metal catalyst such as palladium, optionally one an inert carrier such as coal or barium sulfate, or in the presence of nickel. Hydrogenation can be carried out at a temperature between 0 and 60 ° C, preferably at room temperature, and under a pressure of from 1 to 5 atmospheres, preferably at normal pressure, in the presence of an organic base, preferably a tri-lower alkyl amine such as triethylamine .

5 * -deoxy-5-fluorocytidine and S ^ -deoxy-S-fluorourldine as well as their physiologically tolerable acid addition salts act against Brichle's carcinoma and earkor 160 in aiVes within the Wide Dosage Area, oral and parenteral.

These compounds are therefore valuable precursors to the thyroid 1 foot to be adapted as arches in the form of pharaaoeut preparations with diroctnia or to slow down the release of the active substance. Suitable for non-toxic, inert, carrier or heavy carriers such as water, gelatin, gualarabic, alder Seder, starch, inclining etherate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. which are suitable for enteral (for example oral) IU paronteral application. The pharmaceutical preparations may be in Svratoa form, for example as tablets, dyes, suppositories, capsules, or in t {8noa form, for example as solutions, suspensions or emulsions.

- 5 V Cases are sterilized, that is, they contain other excipients such as preservative, stubble, filler or oleaginous agents, aids for »taste enhancement, salts for average osmotic pressure or poorer» a way that is routine with every expert *

Anti-tumor tests! I

For the administration of 2 animals of compounds au dissolved in water.

18-20 g of tofikin belin oiBevisa and a container of trocar small parts have been planted! tuaora (20-30 rugs) subcutaneously in the right groin area * Tuar parts were made by animals wearing tuaors implanted 7-10 days earlier »Treatment with sapoScto on Implant Day 1 continued one day a day for 8 days Lives were killed 8 days after implantation and tumor! were extracted and moraines * IsraBuaea then the ratio of the tumor's tumor weight to the untreated control group (C) to the taurus weight of the treated group (T) · The tumor growth inhibition was given as a percentage (CT) · 100 / C «One compound ee so tral active» with some dosage if another growth rate of 50 or more prooents was still present, the solid form of this tumor was obtained by subcutaneous implantation of 0.5 but one suspension divides the aooltic toilet by diluting 1-10 square inches of the kitchen counter. g heavy white alpha, koac is 7-10 days early wounded tumor. Treatment 1 presenting the results was returned as described above.

The compounds obtained on the compounds of the invention described herein and with the two compounds of international practice will be summarized in Tables 11 2.

Table 1t Action plridia-2aakl © asl <M against Saxony 180 code -alšisva e

©

tn «h

ΙΛ \ O (!>

tO tO tS tO ® &

<h

Fig 3 R

V «\ O ΙΛ to * ·» * <«<*» Φ »« 0 a g <* (S tn m t * t—

T · O tA «A tnintotototointo®

S0M> S0M> S9S0lAS0 <D a s g s g s * <w tO A V tO and m h <»**« - 1- * »CJ

<0

M

ά

8 5 * W «~

SIA W and v »• ΙΛ N to

A and n «· sn

8 8 S S a *

In Al «·

-8gsfoolagt The effect of pinUdin-aukloosids against Erlih's carotenoid in draws

Jodinjonjo Dose χ 8 / sag / W Tested animal jo Survivor Growth growth »/ $ / 5 ** Deok3l-5 * fluo3> 400 I.p. 15 14 91 cytidine 200 24 23 72 100 16 16 65 50 24 23 57 25 15 15 45 000 p.o. 8 8 99 400 16 16 95 200 24 24 80 100 24 24 71 50 16 16 58 25 16 16 57 5 '~ Des & ai ~ 5 ~ fluo2> 400 i.p. 16 14 98 uriain 200 24 22 86 100 24 20 71 50 24 25 59 25 24 22 45 800 p.o. 8 8 99 400 16 16 98 200 16 16 90 100 15 15 70 50 8 8 56 25 8 8 27 5 * -Detethelpyridine 200 i.p. 8 8 9 100 8 8 41 2 ', 5' - »l (lookai-5- 400 l * p. 16 14 81 fiU <MPU3? idia 200 16 14 68 100 16 16 yi 200 p.o. 8 8 54

-9—

Priaer ι

5 * -deokai-5 *-iodo-5-fluoroitidine (1.5 g) in methanol (30 ml) and trleth-aatl (1 al) hyarogenic acid with constant aol for 90 hours at room temperature 1 under normal pressure in the presence of charcoal (0.75 g, W). Separated catalyst, washed with notanol, filtrate evaporated to a vapor 1, uncovered, saturated, in water (100 al) · The aqueous solution was propubated over Dowex 50

2.3 x> 0 m) · The first is © luireno with water (1 1) and the aatla of watering aaonljum ^ fcldroksldota (28, 2 1). The ammonium apple elaatl was evaporated to dryness 1 the residue was extracted twice and 200 ml each was dissolved * 1 was dissolved in 1, finally, recrystallized from ethanol «0.68 $ g (69 $) 5 ^, -deokai-5- was obtained fliioreltidine mp 207-208 ° C. The substance obtained was obtained in both ways described below in a manner known as "

8a a solution of 5-fluoroltldln (2.61 g) in HOMi ($ 0 melt) acted ea Μ2ΡΧ ($, 42 g) at $ gases at the same temperature. · Once again! ® (5.42 g) · After 90 alnuts, 10 al aethanOl 1 was added after 1 minute, the solution was evaporated to oily consistency. The residue was dissolved in oaeftl etH * acetate / methanol (1t1. saproolaSkL ratio, 30 ml) 1 transferred to an olUkagel column (600 g) · The stem was aulane using aaede etU-acetate / methanol (10i1, saprealnskl ratio) · W 10 ** per 20 al fractions were collected «Fraction 1 <XW80 eu combined, evaporated and the boiling residue was taken up in water (30 ml). Dowex 50® aqueous solution of water (H ** obWaa 2.3 r 40 oa) · First eluted the fruit with a, aatim, of 2 K anoaiyuz hydride. The eluate was evaporated to a crystalline weight of 200 ag (5.4 &lt; + >). ) 87 ~ 189 ° G.

sSsaaeaiMaaa

Raetvor 5 • -deoxy · # * - iodine * 2 *, 3 '-Ο-ΙπορτορϋΙύοη-ί -fluoroitidine (20 g) in sraeSi trfllu <n> -3dietene kieelines and water (9 * 1, sapreoine moieties, 100 al) The mixture was kept at room temperature for 70 minutes and the sat was washed to dry. · The residue was dissolved twice in 200 g of ethanol and the solution was evaporated each time and the residue was finally dissolved in til-acstat (200 ml). In addition, after crystallization of trlethylrouin, crystalline precipitate was condensed after standing over barrel. Yield M β (93%).

A solution of S ^ dooedO-S ^ jo ^^ fluorouridiiia (291 ag) in notsnol (10 al) and trietH-enine (0.5 acre) was hydrogenated at room temperature and under noreal pressure in the presence of a Southern coal strike (5%). 145 ag) 1 1/2 hours. The catalyst was purified, the filtrate was evaporated to dryness and the residue was dissolved in an ainiza- tive amount of hot ethyl acetate. On the course of composing sparks * triethyl-eaonium * iodide was added which was removed by precipitation »The filtrate was evaporated to dryness and covered with ethanol · 130 ag (68 £) 5 * -de <^ oi * 5-fluororidine was obtained.

The foil supotsao was obtained in both of the following ways *

-11 ») tejfeaBaartžžna

A solution of 5-ilorurldln (2.62 g) in MB (50 was aliquoted with H2PI (5.42 g) 1 1/5 gas at 3 rpm ·> 0 min. oily residue dissolved in ethyl aootate (50 ol4 1 transferred to an oligagel scavenger (500 g). 3tubes of eluted otil-aoetato at 5 [mu] m were extracted with 20 ol fractions each. the residue was dissolved in Brudeoil-aoetate (50 tol} · After the addition of hSkean (10 al), a crystalline substance was obtained «After crystallization at room temperature, crystalline precipitate was washed with hokeanoa 1 oeu * Boa under aaan jonia pressure. 1 oatlBnl lye was obtained A total of 1.15 g (W) of 5'-doo3cel-5 * -iodine-5-fluox * urtilnft t. «174.5-175.5 ° C.

b) le S ^l -daok3j-5'-jo ^ -4'.3'-G-laaarOBmdaTt-S-nw> rnrtiUT ₁ ft g 5Wo <^ l ^ ^# -jod ^% 5 ^l -0-lsopxoplllden-5 -iluapurldls trotlrano still at ambient temperature for 15 minutes with trifluoro-airdic acid 1 water (<bi, sapraine portions, al} · The solution was boiled to dryness, 100 al ethanol 1 was added twice and the residue was further procrictollean and ethyl ^ acetate «Bring on 1,865g (88lbs).

Dos. 9047/168-Div.I

P- <230.XI.1984

BEST SUBMISSION? APPLICATIONS A KIND OF WAY FOR BUSINESS

USING THE RECORDED FINDING

5 * »deok8i» 5 * »iodine» 5 »Fluorocytidine (1.5 g) in methanol (30 ml) 1 triethyl amine (1 ml) was hydrogenated with constant stirring. Dreams for 90 minutes at normal temperature and at normal by pressing in the presence of palladium on charcoal (0.75 g, 10%), the catalyst was diluted with straining, washed with methanol, the filtrate was evaporated to dryness and dissolved, then, in water (W0 sl) · The aqueous solution was passed through a Dowex- a 50 ^ (H * —shape,

2.5 x 50 em) »First eluted with water (1 l) and then with aqueous ammonium sulphide (2N, 2 1) · Ammonium eluates were evaporated to dryness and the residue was extracted twice with 200 ol of ethane each» la 1 was evaporated and finally crystallized from ethanol, 0.685 g (69%) of 5Weoxy * 5 * fluorocytidine were obtained.

207 * 208 ° C. The starting material was obtained in both of the following ways:

*) that

A solution of 5 flu fluoroitldine (2.61 g) in 2MP (50 µl) was treated with HEBI (5.42 g) for 5 sachets at room temperature, since the formation of thin layer chromatography could be carried out in the reaction mixture. MSFI (5.42 g) was added once after 90 minutes. After 10 minutes, 10 ml of methanol was added and after 15 minutes the solution was evaporated to an oily oil. The residue was dissolved in ethyl acetate / methanol ( 1: 1, volume ratio, 30 ml) 1 transferred to a column of si »ligel (600 g), the column is elulane by birth emefie ethyl * acetate / methanol (10: 1, volume ratio) * Collect yen fractions of ~ 42> ρο 20 ml. Fracoij © 190-280 cu coupled, retained Solid ootetole jraatvoron in water (30 al). The aqueous solution was applied to Dowex 50® (H * -obIi] aa 2.3 π 40 oa). The first is olulcon with water a »catim, assisted by 2 H ononium hydrocoids. Eluate 3 Evaporated to crystalline wet weight 200 mg (5.4%). Decrystallisation of ethanol gave 3θ Ciota supatnn tt 187-109 ° ® · _; b) ia 5A-dQom ^? - 3od-X », 3» -O ^ jco ^ gmilijign

-5-fluoroitidine #

A solution of 5 * -do? Xai-5 '-iodine-2 ·, 3 M5-iaopropllidone ~ £ -fluorocytldine (20 g) in a mixture of trifluoroacetic kioolino and' · Λ 'water (9i1 _f sapreminok dolov, 100 ml) is at room temperature for 70 minutes and the aatia 3o is evaporated to dryness. The residue is dissolved twice in 200 ml of ethanol each and the solution is evaporated each time and the residue is dissolved in otll-aootate (200 ml). He was neutralized, d at In, by the face of the trlethlin and began to stand overnight crystalline precipitate jo oouiSen. Prinoo »16, ββ (93%).

Claims (2)

PATENT REQUIREMENTS 1. A process for producing a 5'-deoxy-5-fluorcitidina, ie 5 ¹ -deoxy-5-fluoruridina Kao and their physiologically tolerable adicionih.soli with acid, is indicated time, a hundred, the 5'-deoxy-5'-iodo-5 -fluorocytidine, resp 5'-deoxy-5'-iodo-5-fluorouridine by catalytic hydrogenation in a protic solvent, at a temperature between 0 and 6C, under a pressure of 101,325 to 506,625 kPa, in the presence of an organic base, is reduced in the 5'-position and if If desired, the resulting 5'deoxy-5-fluorocytidine and 5'-deoxy - N - fluororidine are treated with physiologically acceptable acid. 2. The process of claim 1, wherein the reduction is carried out by catalytic hydrogenation in methanol in the presence of palladium on charcoal and triethylamine at room temperature.