SI8211200A8 - Process for obtaining of 9-(2-hydroxy-ethoxymethyl) guanine derivatives of purine - Google Patents

Description

Tech Area "

The invention relates to a process for the preparation of novel substituents of purine compounds 1 of their pharmaceutically acceptable salts, and in particular to a process for the preparation of 9- (2-hydroxylethoxymethyl) guanine derivatives of purline. These are pharmacological, especially antiviral personal features.

Technical problem

The invention solves the problem of obtaining new 9- (2-hydroxylethoxylmethyl) purl derivatives, by ammonolz of a suitably selected derivative, in order to obtain the product of the desired pharmacological action and to avoid the negative side of similar known antiviral products.

The state of the art

In 1971, Schaeffer, et al. (J. Med. Chem, 14,367 (1971)) Discussed the synthesis of several purine acyclic nucleosides in a study of adenosine deaminase enzyme-substrate interaction. In particular, 9- (2-hydroxylethoxymethyl) adenyl I was specifically treated here. Its substrate activity with adenosine deaminase was measured.

Known antiviral agents include Idoxurldin (Prusoff, Blochem Blophys Acta, 32 295 (1959) and trlflurldln, i.e., 5-trifluoromethyl 2'-dlocellurldin (Kaufman I Heldelberger, Science, 145, 585 (1964)) and the use of surface treatment for herpes infection. ARA, that is, 9-beta-Darablnofuranosyl-adenine, which is also used for systemic treatment of herpes encephalitis has also been proposed. These antiviral agents are, however, relatively indiscriminate in their actuarial action, that is, they not only destroy the virus, also the host cells that contain the virus, which actually means that they are relatively toxic.

Description of a solution to a technical problem with an example

The process of the invention now provides purl derivatives that are highly selective in the therapeutic sense, destroying only unwanted viruses and not the host cells.

Thus, it has been found that the substituent purines of formula (I)

in which X is a kionic or sulfur, and R ¹ , R ² , R ² R ⁴ , R ⁵ IR® are various substituents, having antifoural activity against different classes of DNA and RNA viruses both in vitro and in Jfl vlvg experiments. The compounds are particularly active against dtomegatovirus, adenovlrus, adenovlrus 5 in particular, rhino virus, Mengo virus and Slndbls virus. They are particularly active against vacdnia-1 herpes viruses, including the fl slmplex, zoster and varlcella, in mammals, which cause diseases such as herpetlo keratltls in rabbits and herpetlo encephalltla in mites. In addition, they can be used in the treatment of Infectious mononucleosis.

According to the invention, there is provided a compound of formula (I) wherein X is sulfur III xylene, R ¹ is hydrogen, halogen, hydroxy, alkoxy, azl, H, alkyl, amino, alkylamino III dlalkylamphene; R ² is hydrogen, halogen, amino or azld; R ³ is hydrogen, straight, branched lyl cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl); R ⁴ is hydrogen, hydroxy III alkyl; R ³ is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzyloxyl, benzyloxyloxy, benzolloxylalkyl, sulfamoyloxyl, phosphate, carboxypropionyloxyl, acetoxyl, or a substituted carbamoll group of formula NH.CO-Z wherein Z is alkyl, aryl or alkyl; more sulfonyl, amino, carbamoll Ul halogen group; R ⁶ is hydrogen lyl alkyl, provided 9 3 4 6 1 with the proviso that when X is xylene and Fr, R, R IR are hydrogen, R is not amino or methylamino, when R ^{5 is} hydrogen, hydroxy or benzyloxy; also provided that when R ^{2 is} hydrogen, R ^{1 is} not 3 4 5 being chlorine; I, with the proviso that the bath is X klseonik, Pr, R, R and R mean hydrogen and R ⁸ is methyl, R ¹ is not Buddha etllamino Ul amino yl and their salts, both in its naročlto farmaceutskl prlhvatljlvih salts.

Compounds of formula (I), wherein X is sulfur or xylene; R ¹ is hydrogen, halogen, hydroxy, alkoxy, azld, thio, aiklitlo, amino, alkilamlno yl dlalkllamlno; R ^{2 is} hydrogen, halogen, amino lyl azld; R ³ is hydrogen, straight, branched or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl; R ⁴ is hydrogen, hydroxy or alkyl; R ³ is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzoitoxyl, benzoyloxymethyl, benzyloxyl, sulfamoyloxyl, phosphate, carboxylpropionylloxyl, acetoxy lyl substituted carbamolyl group of formula NH.CO-Z wherein Z is alkyl, aryl. or aralkyl optionally substituted by One or more sulfonyl, amino, carbamoll, halogen; R ³ is hydrogen, an III alkyl group; as the above conditions, or salts thereof, especially in the form of pharmaceutically acceptable salts, are preferred compounds.

With the above conditions, the compounds of formula (I) as defined above, in which X is a xylene, are particularly preferred; R ¹ is hydrogen, halogen, hydroxy, alkoxy, soil, alkyl, amino, alkylamino, dlalkylamino III azld; R ² is hydrogen, halogen, amino or azld; R ³ is hydrogen, straight III branched lyl cyclic alkyl, hydroxyalkyl III phenyl; R ⁴ is hydrogen or hydroxy; R ³ is hydrogen, hydroxy, benzyloxyl, hydroxyalkyl, amino, carboxypropionylloxyl, acetoxyl, benzyloxyl, benzoic acidmethyl, phosphate, sulfamoyloxyl, substituted carbamoll group of the formula HH.C & Z, where Z is alkyl, M 1 III sulfonyl, or amino substituted, , carbamoll groups, halogen; R ⁶ is hydrogen, ill alkyl, with the proviso that R ³ is hydroxy only when r is ¹ amino, hydroxy, alkilamlno, aiklitlo, lil dlalkllamlno a R ² s amines I FR vedonlki h ⁸ yes hidroksialkll only bath ja R hidreksli R ⁸ ja vedonlk only k & da i R ¹ hydroxy lil halogen; when R ^{8 is a} benscycloel R ² is not halogen; R ³ Is acetoxyl only when f? I Fr both amino or both halogen! R * is a substituted carbamoll of the formula NH.C & 2 wherein I 2 is a group CHHNHjjCHjdgHg only when R ^{1 is} dlaikiiamino; III theirs

40078 salts, in particular in the form of pharmaceutically acceptable salts.

It is also found that the particularly high active compounds of formula (I), as defined above, in which X is X chloeonyl, R ^{1 is} halogen, amino, hydroxy III alkylthio; R4 is amino; R ⁵ is hydroxy, benzyloxy, carboxylpropionyloxy, acetoxyl or hydroxyalkyl 1 R ³ , 4 6 5

RIRs are hydrogen, provided that R is hydroxyalkyl only 15 and when R is hydroxy and R is acetoxyl only when Jo is R amino. Compounds in which X is sulfur, R ¹ halogen, amino III alkylammonium IR ² , R, R ⁴ , R® IR® are hydrogen, also have very high activity.

A preferred halogen substituent is chlorine. The term alkyl used herein means this group of 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms.

Salts that are specifically suited for therapeutic use are salts of pharmaceutically acceptable organic acids such as lactic, acetic, malaric, III p-toluenesulfonic acid, and salts of pharmaceutically acceptable mineral acids such as hydrochloric III sulfuric acid.

The present invention provides a process for the preparation of substituted purines of formula (I) or their acid addition salts, wherein the Compound of Formula (HI), wherein one or both of M and G is hydrogen lyl halogen, III amino, hydroxy, azido , arachoxy, mercapto III hldrazine group

(III) is converted to the compound of formula (I), and then, when the product is base, if necessary, the compound of formula (I) is converted to its pharmaceutically acceptable acid addition salt, or when the product is a salt of the compound of formula (I), this salt translates lil to its desired salt as needed.

The conversion of the compound of formula (III) to the compound of formula (I) is performed by converting one or both of groups G and M by halogenation to a halogen atom; to the hydroxyl group by hydroroll; to soil III alkylthio group aulfuradjorn; to the hydrogen atom by the reduction of III desulfurate; III pruning azld. Conversion is also carried out using an enzyme, an example of adenyl deamylase, whereby the compound of the compound is translated into a double R = OH, R ² = Nrig, U Aqueous) and an initial pH of about 7.0CI initial pH of about 7.0.

The invention particularly relates, as mentioned above, to the process for the preparation of 9- (2-hydroxyethocalmethyl) guanine, and comprises the ammonolysis of 24-chloro-9 ^ 2-hydroxyethylhexyl triethyl) hydroxybenzoxycarbonyl; methanol, at elevated temperature, especially at about 125 ^ΰ 0.

According to a further aspect of the invention, a fermacetsuccal preparation comprising a Compound of Formula (l) is provided wherein X, h, ή ² , R ³ , R ⁴ , R® IR® have the aforementioned suffocation when j is an R® alkyl group.

it has from 1 to 8 carbon atoms and in all other cases, when the substituents have an alkyl nucleus, it has from 1 to 4 carbon atoms; III its pharmaceutically acceptable salt; together with a pharmaceutically acceptable carrier. In a particular aspect of the invention, the pharmaceutical composition comprises a compound of formula (I) in the form of an effective Dosage Form.

The term effective single dose or effective single dose used herein means a predetermined antiviral amount sufficient to effect an in vivo oral administration. Pharmaceutically acceptable carriers are drug delivery materials, and may be solid, liquid III gaseous materials, which are inert and medically acceptable and agree with the active ingredient.

Ovl pharmaceutical preparations may be administered parenterally, orally, as suppositories, III uterine insert, superficial in the form of ointments, creams, aerosols, powders, lil in the form of nasal drops or eyes, etc., depending on the use of the II ae preparation for treatment internal lil external viral infections.

For internal infections, the preparations are administered orally or parenterally at a dose, calculated from the free base, from about 0.1 to 250 mg per kg, preferably 1.0 to 50 mg per kg, of body weight of the mammal, and is used in humans as a single dose. given several times daily in an amount of 1 to 250 mg per dose.

For oral administration, fine powdered lil granules may contain diluents, dispersing ll or surfactants, and may be in the form of a beverage, in water or in syrup; in capsules III bags in dry form III in the form of a non-aqueous solution of lil suspensions, suspensions may also include suspending agents; in tablet form, which may include binders and lubricants; Or in suspension in water lit syrup. When desired, lil is necessary, it may include flavoring, protecting, suspending, thickening, or emulsifying agents.

Preferred forms are tablets and granules, and these may be outweighed.

For parenteral administration or capillary administration, such as for ocular infections, the compounds may be presented as aqueous solutions at a concentration of about 0.1 to 10%, preferably 0.1 to 7%, preferably 0.2% w / v. The solution may contain antioxidants, buffers and the like.

Alternatively for Irtfekdju eyes, Or for other external tissues e.g. mouth and skin, the preparations are preferably applied to the Infected part of the body as a surface cream III ointment. The mole preparation should be in the form of an ointment, for example with a water-soluble oily base, III cream, e.g. with water-kram oil at a concentration of about 0.1 to 10%, preferably 0.1 to 7%, most preferably 1% w / v.

The compounds of the formula (l) 9 * (24ildfocalmethyl, guanine (R ¹ - OH, R ² * NH _g ) and 2 <amln »4- (24tldfokdetoketmetlt} Mkdenln are the wettest, especially because of their very high activity of herpes vlfiis, In addition , 2-amino-4-fluoro-O ((2-benzenethoxyethoxy) methyl) purine, 9 (S-benzenyloxylethoxymethyl) guanine, thi * (1-Wildfoxypropoxyethyl) ethyl, 24Wily ^ mother (tit »* ^ (2 · hydrokeletoxymethyl) coffeeboxlpinnextlethysomethmethylgvanlh, *>(&

eeefokeietekslmetii) * 2,4dlamlh6 pufsln, 8-chloro- ^ ethylthiomethyl purirt, β-ethyltiometlladenln, D-ethyltlometll-8-methylamino-puri also show wax activity against the herpes virus l vacelnlae.

40073

Another aspect of the invention provides a method of separating a viral infection in a mammal comprising administering an effective antiviral amount, as defined herein, of a substituted purine of formula (I), or a pharmaceutically acceptable salt thereof. The administration is preferably carried out by surface application or oral lil parenteral route.

The invention will now be illustrated by the following example.

Example: 9- (2-Hydroxylethoxymethyl) guanyl I: R ¹ = OH; R ² = nh ₂ .

Solid sodium nitrite (0.97 g) was added at room temperature with stirring for 1 h in a solution of 2-chloro-9- (2 · chloroxethoxylmethyl) adsinine (0.5 g) in glacial hydrochloric acid (10 ml). The reaction mixture was stirred for a further 4 1/2 h. The white solid was removed by filtration, (washed with cold acetic acid and then well triturated with cold water to remove the concentrated sodium acetate. The solid product was preserved. The combined filtrate) acetic acids and from the wash were evaporated at reduced pressure and at bath temperature. 40 ° CI the residual oil was triturated with cold water. The resulting solid was combined with a previously isolated solid and the combined solid was dried and crystallized from ethanol to give 2-chloro-9- (2-hydroxylethoxymethyl) hypoxanthine (0.25 g), m.p. 310 ° C. Elemental analysis The NMR spectrum is in agreement with this structure.

A mixture of 2-chloro - N - (2-hydroxylethoxymethyl) chlopoxanthane (0.375 g) and methanol (80 ml) sealed with anhydrous ammonia was heated in a bomb at 125 ° C for 5 h. The bomb was cooled in an ice bath and the reaction mixture was removed. The solvent and excess ammonia were removed under reduced pressure at 50θ0. After triturating the residue with cold water to remove the formed ammonium chloride, the residual solid was dried and then recrystallized from methanol to give pure 9- (2h! Droxlethoxymethyl) guanine (0.24 g), mp 258.5 - 257 ° C.

is preserved. Combined acetic acid I filtrate (the washes were evaporated under reduced pressure and at a bath temperature of 40 C and the residual oil was triturated with cold water. The resulting solid was combined with the previously isolated solid and the combined substance was dried and recrystallized from ethanol to give 2 <chloro * 9- (2 * hydroxymethyl) chlopoxanthine (0.25 g), mp 310 [deg.] C. Elemental analysis The NMR spectrum was consistent with this structure.

A mixture of 2-chloro-9- (2-hydroxylethoxymethyl) chlopoxanthane (0.375 g) and methanol (80 ml) sealed with anhydrous ammonia was heated in a bomb at 125 ° C for 5 h. The bomb was cooled in an ice bath and the reaction mixture was removed. The solvent and ammonia residue were removed under reduced pressure at 50 ° C. After trituration of the residue with cold water to remove the formed ammonium chloride, the residual solid was dried and then recrystallized from methanol to give pure 9- (2-hydroxylethoxymethyl) guinol (0.24 g), m.p. 256.5 - 257 ° C.

Claims (1)

A process for the preparation of 9- (2-hydroxyethoxymethyl) guanine purine derivatives of formula (I): CH ₂ 0CH ₂ CH ₂ 0H is indicated t I I, STB 2-chloro-9- (2hidroksletokslmetll) hlpoksantin formula (II) Preparation of 9- (2-Hydroxylethenylmethyl) guinea solid sodium nitrate (0.97 g) was added at room temperature with stirring for 1 h to a solution of 2-chloro-9- (2hydroxyethoxystyreneGin (0.5 g) in glacial acetic acid ( The reaction mixture was stirred for a further 4 1/2 hours. The white solid was removed by filtration, washed with cold acetic acid and then well triturated with cold water to remove the sodium acetate present, a solid product. CK ₂ OCH ₂ CH ₂ OH is heated to 125 ° C in methanol saturated with ammonia. Published and printed by the Federal Patent Office, Belgrade, Uzun Mirkova 1