JPH05504551A - Inhibitors of purine nucleoside phosphorylases - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Inhibitors of brine nucleoside phosphorylase The present invention relates to 2-amino-3H,5H- Viroro C3.2-d] Pyrimidin-4-one derivatives and 4-oxo 3 The present invention relates to derivatives of H,5H-pyrrolo(3.2-f)pyrimidine. Moreover, the present invention is 4-oxo38.5H-pyrrolo[3.2-d]virimi substituted at position 71. Regarding gin derivatives.

Purine nucleoside phosphorylase (PNP) converts purine nucleosides in a reversible reaction. Catalyzes the phosphorolysis of ossides. Individuals lacking PNP have impaired T-cell development. , resulting in normal humoral immunity except for normal B-cell development. Immunity decreases. Therefore, T-cell development can be selectively stimulated without compromising humoral immunity. Specific inhibitors of PNP can inhibit disorders in which activated T-cells become pathogenic. It could potentially be effective against

As a PNP inhibitor, the present invention provides a compound in which R is optionally substituted and xenyl, /chlorohexyl, or -CH, -R, where R1 is optional 2 which is an optionally substituted heteroalicyclic group, pyridinyl group or alicyclic group -Amine-7-(R)-3H.

5H-pyrroloC3,2-di pyrimidin-4-one is provided.

The present invention also provides the formula: [In the formula, R, H, NH! , or ○CH,, R2 is one or more as desired. 5 to 7 which may contain the above heteroatoms and may be optionally substituted cyclic group of carbon atoms, R3 and R4 are independently H or C3-4 alkyl M is O~4, n is O~6, p is 0~1, X is CN, , C3NH,, PO(○ H) 7, C00H1So, NH,, NH,, ○H, CNHNH,, Tetrazole , triazoles or CORs, where R5 is C1-4 alkyl, CF, ,NH , , or 0C1-4 alkyl, and Y means 0 or NH] It is aimed at compounds that Compounds of the invention are useful as PNP inhibitors. Also , the invention comprises a pharmaceutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. or excipients for selectively suppressing mammalian T-cell immunity; administration of a pharmaceutically effective amount of a compound of the invention to a patient. Provided is a method for selectively suppressing mammalian T-cell immunity without reducing efficacy. .

In one embodiment of the invention, R is -CH, -R, and R is optionally substituted. Compound 2-amino-7-(R)-3H, which is an optionally substituted heteroalicyclic group , 5H-pyrrolo[3,2-dl-pyrimidin-4-one. preferably is a 5-membered or heteroalicyclic group having oxygen, nitrogen, or sulfur as a heterocyclic atom. or a 6-membered saturated ring. More preferably, the heteroalicyclic group is a 2- or 3-te trahydrochenyl, 2-23-1 or 4-piperidinyl, 2- or 3-te trahydrofuranyl, 2-5 or 3-pyrrolidinyl, or 2-13-1 or is 4-tetrahydropyranyl. In a preferred embodiment, R1 is substituted with For example, the compound ([) is 2-amine-7-(2-piperi/nylmethyl) -38,5H-pyrrolo[3,2-di pyrimidin-4-one (IB), 2-a Mino-7-(3-piperidinylmethyl)-38,5H-pyrroloB3.2-aHpi Limin-4-one (IC), 2-amino-7-(4-hyperinylmethyl )-38,5H-pyrrolo-3,2-dll virimi/n-4-one (rD), 2-ami/-7-(2-tetrahydrofuranylmethyl)-38,5H-pyrroloC 3,2d co-pyrimidin-4-one (IE), 2-amino-7-(3-tetrahydryl Drofuranylmethyl)-3H,5H-pyrrolor3,2-al pyrimidine-4- (IF), 2-amino-7-(2-tetrahydrochenylmethyl)-38 , 5H-pyrrolo[3,2-di pyrimidin-4-one (fG), 2-allo oI 3.2-dl pyrimidine-4-oni/(IH), 2-7 minnow 7-(2- pyrrolidinylmethyl)-38,5H-pyrroloX3.2-d"pyrimidine-4- (II), 2-amino-7-(3-pyrrolidinylmethyl)-3H,5H-pyrrolidinylmethyl lolo[3,2-d]pyrimidin-4-one (IJ), 2-amine-7-(2-te (trahydropyranylmethyl)-38,5H-vilororo3.2-dl pyrimidine -4-one (IL), 2-amino-7-(3-tetrahydropyranylmethyl)- 3H,5H-pyro 13,2-di pyrimidin-4-one (IM), or 2-ami7-7-(4-tetrahydropyranylmethyl)-38,5H-piooJ 3.2 dl pyrimidi-7-4-one (IN). Another preferred example , R is halogen, hydroxy, alkokene, alkyl, or triflu It has one or two substituents selected from the group consisting of olomethyl. Halogen The term preferably refers to chloro or fluoro. As alcoquine, Preferably, it refers to lower alkoxy/, methoxy/, ethoxy, propoquine and buproquine. Including Tokin. Alkyl preferably refers to lower alkyl, including methyl and ethyl. including butyl, propyl and butyl.

In another embodiment of the invention, R is -CH, -R, where R is optional 2-amino-7-(R)-38,5, which is pyridinyl optionally substituted with H-pyrrolo[3,2-d]-pyrimidin-4-one (II) is provided. Like In desirable embodiments, R1 is unsubstituted, eg, the compound (n) is 2-amino No-7-(3-pyridinylmethyl)-38,5H-pyrrolo[3,2-d]pyri Midin-4-one (IIA), 2-ami/-7-(2-pyridinylmethyl)-3 8,5H-pyrrolo:3.2-d]-pyrimidin-4-one (IIB), or 2-amino-7-(4-pyridinylmethyl)-3H,5H-pyrrolo', 3.2 -cB-pyrimidin-4-one (IIC). In another preferred embodiment , R1 group is halogen, hydroxy, alkokene, alkyl, or trifluoro It has one or two substituents selected from the group consisting of methyl. with halogen preferably refers to chloro or fluoro. As alkoxy, preferred refers to lower alkoxy, including metkin, ethki/, propohon/, and butkin. including. Alkyl preferably refers to lower alkyl, such as methyl, ethyl, Contains propyl and butyl.

In another embodiment of the invention, the R group is unsubstituted or substituted. Compounds that are 1-12-1 or 3-cyclohexenyl or cyclohexyl (I[I)2-amino-7-(R)-38゜5H-pyrrolo[3,2-d]pyri A midin-4-one is provided.

In a preferred embodiment, R is unsubstituted, i.e. compound (In) is Mino-7-(1-cyclohexenyl)-3H,5H-pyrrolo13.2-dcopyly Midin-4-one (nlA), 2-amino-7-(2-cyclohexenyl)-3 H,5H-pyrroloj3,2-d cobyrimidin-4-one (I [[B), 2-amino No-7-(3-cyclohexenyl)-3H,5H-pyrrolo[,3,2-d]py Rimidin-4-one (IC), or 2-ami/-7-(cyclohexyl)- 3H.

5H-pyrrolo[3,2-d]pyrimidin-4-one (I[D).

In another preferred embodiment, R is halogen, hydroxy, alkoxy, alkyl at least one substituent selected from the group consisting of has. Halogen preferably refers to chloro or fluoro. Arco Preferably, the quinine is lower alkoxy, such as methquine, nidoquine, and protoquine. Contains poxi and butkin. Alkyl preferably includes lower alkyl. methyl, ethyl, propyl and butyl.

In another aspect of the invention, R is -CH, -R, and R1 is optionally Compound 2-amino-7-(R)-38, which is an alicyclic group optionally substituted with , 5H-pyrrolo[3,2-d: pyrimidin-4-one (TV).

Preferred alicyclic groups are, for example, cyclobentyl, cyclohexyl, and cyclo Monocyclic cycloparaffins such as hebutyl, 1- and 2-atamantyl, ■- norfornanyl, 2-exonorbornalyl, 2-endo-furpornaryl, 1- and 2-vincloC2,2,2]-octanyl, 1-12-13-16- 1 and 8-bicyclo[3,2,1]octanyl, and 1-12-1 and 3 -bicycloE3.3.1] polycyclic cycloparaffins such as nonanyl and 1- and fuchloroolefins such as 2-norbornenyl. Favorability An example of compound (IV) is 2-amino-7-(2-adamartylmethyl)-38,5 H-pyrrolo[3,2-d]pyrimidin-4-one (■A), 2-amino-7- (1-adamartylmethyl)-38,5H-pyrrolo[3,2-dcopyrimidine- 4-one (IVB), 2-amino-7-(cyclopentylmethyl)-38,5H -pyrrolo[3,2-d2 pyrimidin-4-one (IVC), 2-amino-7 -(cyclohexylmethyl)-38,5H-pyrrolo:3.2-dj pyrimidine -4-one (IVD), 2-amino-7-(cycloheptylmethyl)-3H,5 H-pyrrolo', 3. 2-d cobyrimidin-4-one (IVE), 2-amino -7-(1-norbornanylmethyl)-3H,5H-pyrrolo[3,2-d]pyri Midin-4-one (■F), 2-amino-7-(2-exo-norbornanylmethyl) chill)-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (IVG) , 2-amino-7-(2-endo-fluoranylmethyl')-38,5H- Pyrrolo[3,2-d]pyrimidin-4-one (IVH), 2-amino-7- (1-norbornenylmethyl)-38,5H-pyrrolo J3.2-d] pyrimidine ion-4-one (IVD, 2-amino-7-(2-norbornanylmethyl)-38 , 5H-pyrrolo'3.2-dcopiwaminon-4-one (IVJ), 2-amino- 7-(1-vinculo[2,2,2]-octanylmethyl)-38゜5H-pyrrolo [3,2-di pyrimidin-4-one (IVK), 2-ami/-7-(1- VincloC3,2,1-cooctanylmethyl)-38,5H-pyrrolo[3,2- d] Pyrimidin-4-one (IVL), 2-amino-7-(1-bicyclo[3 ,3,13nonanylmethyl)-3dan,5dan-pyrrolo[3,2-d]-pyrimidine -4-one (IVM), and 2-ami/-7-(1-noradamultifluoromethyl) )-38゜5H-pyrrolo[3,2-d3 pyrimidin-4-one (IVN) be.

In another preferred embodiment, the R3 group is halogen, hydroxy, alkokene, alkyl 1 or 2 substitutions selected from the group consisting of methyl or trifluoromethyl It has a group. Halogen preferably refers to chloro or fluoro. a Preferably, alkoxy refers to lower alkoxy/, methoxy/, ethquin, Contains Propoquine and Butoki/. As alkyl, preferably lower alkyl and includes methyl, ethyl, propyl and butyl.

Moreover, the present invention is based on the formula.

[In the formula, R1 is H, NH, or OCR, and R'' is one or more as desired. A cyclic group which may contain the above heteroatoms and may be optionally substituted. R3 and R4 are independently H or CI-47alkyl, m is O-4, n is o~6, p is o~1, X It CN.

C3NH2,P○(OH)t,C0OH,So,NH,,NH,,OH.

CNHNHI, tetrazole, triazole or C0R8, where R'C, -47ru + Ru, CF, , NHl, Mataha○cl-4 alkyl, Y is O or NH] It is directed to the compound shown in

The optionally substituted cyclic groups recited in the above formula (hereinafter referred to as chloro) is an aromatic radical containing preferably 5 to 9 atoms, a heteroaromatic group, alicyclic group, and heteroalicyclic group. Preferred optional substituents are Includes halokene, hydroxy, alkoxy/, alkyl, and trifluoromethyl. Contains. Examples of substituents are chloro, fluoro, methoxy/, ethoxy, propoquine, but methyl, ethyl, propyl, and butyl.

Preferred heteroatoms include oxygen, nitrogen, and sulfur, which can exist together in the same group. Contains. Preferred aromatic and heteroaromatic groups are phenyl, 2- or 3-chain Nyl, 2- or 3-furanyl, 2-13-1 or 4-pyrinonyl, 2- or is 3-pyrrolyl, 2-14-1 or 5-thiazolyl, 2-pyranyl, 3-or or 4-pyridazinyl, and 3-14-1 or 5-pyrazolyl.

Preferred alicyclic groups and heteroalicyclic groups are 1- or 2-adamantyl, /chloro hexyl, cyclohebutyl, 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrochenyl, 2- or 3-tetrahydropyranyl, 2-13- 1 or 4-piperinonyl, 3- or 4-pyrazolidinyl, 2-14-1 or is 5-thiasilishel, 2- or 3-piperazinyl, 2- or 3-morphol or 3- or 4-hexahydropyritacinyl.

In another embodiment of the invention, by administering compound (I) to a mammal. Selects mammalian T-cell function without reducing effects on humoral immunity provided is a method for inhibiting the bilin nucleoside phosphor inhibits lylase, thereby inhibiting T-cell formation.

In yet another aspect of the invention, an effective amount of said compound and a pharmaceutically acceptable of mammalian T-cells without reducing its effect on humoral immunity. Pharmaceutical compositions for selectively inhibiting function are provided.

Furthermore, the present invention provides an effective amount of a pharmacologically active compound of the present invention, alone. or in combination with one or more pharmaceutically acceptable carriers. Enteral administration such as oral or rectal administration, dermal administration and parenteral administration to suitable for oral administration and useful for inhibiting pirin nucleo-7-dophosphorylase activity; and to pharmaceutical compositions for treating disorders corresponding thereto.

Preferred pharmaceutical compositions include a) excipients such as lactose, dextrose, sugar, etc. Claus, mannitol, sorbitol, cellulose and/or glycine: b) Lubricants, such as porphyry, talc, stearic acid, its magnesium or Calcium salts and/or polyethylene glycol, for tablets also C ) binders, e.g. magnesium aluminum silicate, starch paste, gelatin Chin, tragacanth, methylcellulose, sodium carboquine methylcellulose and/or polyvinylpyrrolidone: if desired d) disintegrants, e.g. agar, alginic acid or its sodium salt, or an effervescent mixture, and / or e) consisting of active ingredients together with adsorbents, colorants, flavors and sweeteners. Tablets and gelatin capsules. Injectable compositions are preferably aqueous. solutions or suspensions; suppositories are advantageously fatty emulsions or suspensions; It is prepared from The composition may be sterilized and/or may contain preservatives, stabilizers, wetting agents, etc. or adjuvants such as emulsifiers, solution enhancers, salts and other additives to adjust osmotic pressure. and/or buffering agents. In addition, other therapeutically valuable It is also possible to contain substances such as Each of the compositions can be prepared by conventional mixing, granulation or coating. from about 0.1 to 75%, preferably from about 1 to 50% % active ingredient.

Formulations suitable for transdermal application include an effective amount of a compound of the invention together with a carrier. Advantageous The carrier is an absorbable pharmacologically acceptable solution that aids passage through the skin of the host. including agents. Characteristically, transdermal means are packaged with a backing material, optionally a carrier. container containing the compound, optionally at a controlled and predetermined rate over an extended period of time. It is in the form of a bandage comprising a rate controlling agent that delivers the compound to the host's skin at a rapid rate.

The invention provides an effective amount of a compound of the invention, or one or more pharmaceutically acceptable A pharmaceutical composition comprising an effective amount of the compound in combination with a carrier that is to produce a purine nucleoside in a mammal. Diseases and disorders that inhibit and respond to sphorylase activity, e.g. Methods of treating autoimmune diseases, transplant rejection, or psoriasis are provided.

Yet another aspect of the invention provides a method for inhibiting brine nucleoside phosphorylase. Amount of a compound of the invention or an effective amount to inhibit purine nucleoside phosphorylase The compound can be combined with one or more pharmaceutically acceptable carriers to make it as desired. a mammal, by co-administering them, separately or in combination, to a mammal. Phosphorolysis and substitution of antiviral or antitumor purine nucleosides in Concerning a method for inhibiting metabolic deterioration. More specifically, brynuk as known in the art Rheosides, such as 2'-deoxyguanone, 2'.

3'-dideoxyinosine, 2°,3'-dideoxyguanosine or 2',3 Relating to methods of inhibiting the phosphorolysis and metabolic deterioration of °-dideoxyadenosine do.

Furthermore, the present invention preferably combines with one or more pharmaceutically acceptable carriers. The compounds of the present invention are administered in an effective amount to inhibit purine nucleoside phosphorylase. Separately or 2° or 3'-monodeoxypurine to mammals in need of in combination with a cleoside or a 2',3'-dideoxypurine nucleoside, 2° or 3°-monodeoxypurine in a mammal by co-administering Antiviral nucleosides or 2”, 3°-dibuoki/purine nucleosides or relates to a method of enhancing antitumor effects. More specifically, retrovirus infection , e.g., HIV-retroviral infection (acquired immunodeficiency syndrome, AIDS) treatment 2",3'-dideoxypurine nucleosides known in the art for use, e.g. , 3′-dibuoquinosine, 2′,3″-dideoxygua/non or 2°,3 The present invention relates to a method for promoting or enhancing the effects of '-dideoxyadenosine. 2', 3'-dideoxypurine nucleosides can be used, for example, in biomedical pharmacology. - (Biochemical Pharmacology) 22.　3797　 (1987) as an inhibitor of HIV retroviral infection. It is known in the art that PNP is metabolically degraded by PNP. So is a pharmaceutically acceptable dose effective to inhibit HIV retroviral infection. administered. Preferably, the lowest possible effective dose is used.

The effective pharmaceutically acceptable dose of the active compound of the invention to be administered is (object), body weight, age and condition of the individual, and the mode of administration.

Pharmaceutical compositions include oral, non-prescription drugs for delivering the compound to the bloodstream of the mammal to be treated. It may be oral, suppository or other form. Oral form is for adults (50 to 70 kg) ), which contains about 1 to 150 mg of the compound, such as lactose. Mix together with pharmaceutically acceptable excipients. In a typical capsule, the 25 mg of the compound was mixed with 192 mg of lactose, 80 mg of modified starch and 3 m g of magnesium stearate. Injectable forms of the compound are also Possible dosage form tubes.

The present invention is also useful in conjunction with other therapeutic agents. I weigh less than 50kg The daily dose of 1-50 mg/kg for a 70 kg human is beta Certain anticancer drugs such as 2"-deoxy-6-thioguanoone and 2', 3 – Antiviral drugs such as dideoxyinone, which inhibit the metabolic breakdown of anti-AIDS drugs. harm These types of agents are known to be sensitive to cleavage. cutting Vaginal preparations lose their effectiveness. The compounds of the invention may reduce such cleavage. I can do it. This protection therefore enhances the effectiveness of other chemotherapeutic agents.

In method 1 for producing compound (1) of the present invention, 3-substituted propylene chloride is used as a starting material. Use onitrile. Such starting materials include a variety of materials often described in the literature. It can be obtained by Next, M.I.Rim, R.N.I.S.F. Rain, and JJ F1/X (M, 1. Lie, R, S, Klein, and J. Fox), Journal of Organism Cheap Cheap (J, Org, Cheap), 44°3826 ( 1979); M.I. Lim, R. Niss Frein, and J.J. Lee Fox (M, 1. Lig+, R, S, Klein, andJ , J, Fox), Tetrahedron Letters (Tetrahedron Le tt, ), A±, 1013 (1980); M.I. Lim and R.N. Klein (M, 1. Lill1 and R, S, Klein), Tetra Hedron Retalim, Tabli-21 Wai Len, Biei Onotar and A Rules-x Frein (M, 1. Lim, , 11. Y, Ren, B, A, 0tter, and R, S, Klein) A Journal of Orcanic Chemistry (J, Org, Chem, ), 48.780 (1983). Therefore, the compound (I) is prepared from the starting material.

In the method for producing compound (El) of the present invention, for producing compound (If), 3-(pyrinnyl)propionitrile is used as the starting material. Appropriate 3-(pi) Lysinyl) propionitrile is, for example, ammonium hydroxide/ammonium hydroxide. The corresponding 3-(pyridinyl)propionyl chloride was converted to the corresponding amide by , which is then distilled with a dehydrating agent such as pocc or 5oci+2. It can be produced by dehydration to the desired nitrile. Alternatively, the starting material The quality is determined by Proffitt, J. et al. Null of Organic Chemistry (J, Org, Chem, ), ±0. 127 (1975), Condensation of the aldehyde followed by decarboxylation gives the corresponding substituted acrylonitrile, which This was then treated with catalytic hydrogenation or with magnesium metal dissolved in methanol at 0°C. Hydrogenation to give the corresponding 3-(pyridinyl)propionitrile Manufactured by. Next, M.I. Rim, Earl Nis Frein, and J.J. Fox (M, 1. Lim, R, S, Kle in, and J, J, Fox), Journal of Organi, R.K. Mistry (J, Org, Chet), Dan.

3826 (1979): M.I. Rim, R. Niss Frein, and /A./A.Fox (M, 1.Lim, R,S, Klein, and J, J, Fox), Tetrahedron Letters (Tetrahedron L) ett, ), 21.1013 (1980); M.I. Lim and R. ・Nis Klein (M, 1. Lim and R, S, Klein), Tetrahedron Letters (Tetrahedron Lett,), 22.2 5 (1981), M.I.Lim, W.Y.Len, B.A. Osoter and Earl Niss Klein (M, 1. Lim, blind, Y, Ren, B, ^0tter, and R, S, Klein), Jhana Le of Organic Chemistry (J, Org, Chew, ), and The compound (n) is prepared from the starting material by:

Another method of making compounds of the invention involves the use of known compounds, i.e. Hemi-senylacetonitrile is used as the starting material. Compound (III) of the present invention ) is M.I.Rim, Earl Nis Kreipe and Ziaza Ziaza Fok. Kuss (M, 1. Lim, R, S, Klein.

and J, J, FOX), Journal of Organic Chemistry - (J, Org, Cheffi, ), 44.3826 (1979): Mu I Lim, Earl Nis Klein, and Zia Zia Zia Zia Fox. (M.

1, Lim, R, S, KIein, and J, J, FOX), Tetrahedro Tetrahedron Lett, 21.1013 (1 980); -r-M I Rim and R-x Klein (M, 1. Lim and R,S, Klein), Tetrahedron Letters (Tet rahedron Lett, ), 22.25 (1981); Lim, Daburi 21 Y Repebii E Onotar and R Nis Kula. In(M, 1. Lim, , W, Y, Ren, B^, 0tter, and R,S, Klein), Journal of Organic Chemistry Described in Tory (J, Org, Chem, ), ±8.780 (1983) By reacting the starting materials by applying a synthetic method that has been Manufactured. (II[A), (I[[B), or (I[[C)] Catalytic hydrogenation yields compound (I[[D).

In the method for producing compound (IV) of the present invention, 3-! convertible propio Use nitrile. Such starting materials can be prepared by various methods well described in the literature. Therefore, it can be obtained. Next, M.I.Rim, Earl Niss Klein , and Zia Zia Zia Fox (M, 1. Lim, R, S, Kl ein, and J, J, Fax), Journal of Organic Chemistry (J, Org, Chem,), 44.3828 (1979): Mu I Lim, Earl Nis Klein, and Zia Zia Zia Zia Fox. (M, 1. Lie, R, S, Klein, and J, J, Fo x), Tetrahedron Letters (Tetrahedron Lett,), 2 1.1013 (1980); M.I. Lim and R. Niss Klein (M, ILimand R, S, KIein), Tetrahedron Letters ( Tetrahedron Lett, ), 22.25 (1981); ・Lim, Daburi Ni Wai Jin, B.A. Onotar and Earl Nis. Tarain (M, 1. Lim, , W, Y, Ren, B, A, 0 tter, and R, S, Klein), The National of Organi, Re-Chemistry (J, Org, Chem, ), ±dan, 780 (198 By applying the synthesis method described in 3), the compound ( IV) is prepared.

formula· According to another aspect of the present invention, the 2-amino compound ( R'=NH,) and intermediates thereof are provided.

The first step of the method consists of optionally substituted ammonium acetate. A cyclic aldehyde, which may be an acetic acid, is added to the anoacetic acid in a molar ratio of about 1/1 to 115. 3-Cyclo-substituted pentanedinitri This includes obtaining the compound as an intermediate. In the second step, the 3-/clopenta dinitrile with an alkyl formate such as ethyl formate and sodium hydride or is a metal-containing base such as sodium alkoxide, e.g. sodium methoxide. in a molar ratio of about 1 to 2/3 to 6/1 to 3 with a strong base such as, at a temperature of about 20 to 65°C. for about 10 hours to 8 days to form 3-cyclo-2-formylpentandinium. Tolyl is obtained as a further intermediate. The next step is the 3-cyclo-2-formyl Pentanedinitrile can also be converted to glycine alkyl ester hydrochloride and sodium acetate. or ammonium in a molar ratio of about 1 to 2/1.5 to 4/1.5 to 4, about 20 to Methyl N-[(3-cyclo- 2,4-dicyano)-2-butenylcoglycine as an intermediate. Continued In this step, the methyl N-[(3-cyclo-2,4-dinano)-2-butyl thenylcoglycine with an alkyl chloroformate such as ethyl chloroformate and 1.5 -diazabinchro r4.3.0conon-5-ene (DBN) or 1,8-dia Zabicyclo “5.4.Ol undec-7-ene (DBU) from about 1 to 2/15 to At a molar ratio of 5/1.5 to 4, at a temperature of about 0 to 50°C, for about 10 hours to 10 days. methyl 3-ami7-4-(2-cyano-1-cyclo-ethyl)-1 -Ethyl-IH-pyrrole-1,2-dicarpooxylate is obtained as an intermediate.

The next step is to prepare the methyl 3-amino-4-(2-cyano-1-cyclo-ethyl)- 1-ethyl-IH-pyrrole-1,2-dicarpoquinlate in sodium carbonate and a base, in a molar ratio of about 2/1 to 115, at about room temperature for about 10 to 48 hours. methyl 3-amino-4-(2-cyano-1-cyclo-ethyl)-18- It involves obtaining pyrrole-2-carboxylate as an intermediate. In the next process , the methyl 3-amino-4-(2-thia/-1-/chloroethyl)-1H-pyro Ru-2-carboxylate with hendiyl isothionanate from 2/1 to 1 /2 molar ratio and reacted at about room temperature for about 30 minutes to 3 hours to form N-[4(2-nor/-1-chloroethyl)-2-methquinecarbonyl-IH -Brol-3-yl to obtain thiourea as an intermediate. In the next step, the N- Benzoyl-N-14-(2-cyano-1-/chloroethyl)-2-methoxyca Rubonyl-IH-brol-4-3-yl-1-thiourea as methyl iodide at a temperature of O to 30'C in a molar ratio of about 1/1 to 1/6 with an alkyl halide. and reacted for about 10 minutes to 10 hours to form N-penzoyl-N-[4-(2-cyano -1-cyclo-ethyl)-2-methquinecarbonyl-IH-7'roll-3-y ]-3-methylthiourea as an intermediate. In the subsequent step, the N -benzoyl-N'-[4-(2-cyano-1-cyclo-ethyl)=2-methoxy cyclocarbonyl-IH-brol-3-yl]-8-methylthiourea (approximately 1-2 molar) to about 1/1 to 1/20 of methanolic or ethanolic ammonia. The 2-amino acid of the present invention is reacted at a temperature of 20 to 130°C for about 16 to 60 hours. compound 3-cyclo-3-[2-ami7-4-oxo-3H-58-pyrrolo[3 ゜2-d]pyrimidin-7-yl]propanenitrile and 3-cyclo-3-[ 2-Methylmercapto-4-oxo-3H,5H-pyrrolo[3,2-dE pyri Mixtures of midin-7-yl]propanenitrile to prepare other compounds of the invention Obtained as an intermediate.

In a further embodiment regarding the compound represented by 2-methquine compound (R1= ○CH3) and intermediates thereof are provided. The intermediate 3-/chloro -3- C2-methylmercapto-4-oxy-3H,5H-pyrrolo[3,2- dl pyrimidin-7-yl]propanenitrile as permanganate or peroxide with an oxidizing agent such as hydrogen at a temperature of about 25 to 120°C in a molar ratio of 1/1 to 1/10. 3-/Clo 3-[2-methylsulfonyl -4-oxo-38,5H-pyroO[3,2-dl pyrimidin-7-ylnip Ropannitrile is obtained as an intermediate. In the next step, the 3-clone 3-[ 2-Methylsulfonyl-4-7rxo-38゜5H-pyrrolo[3,2-dl pyrrolo rimidin-7-yl]propanenitrile in a sodium chloride solution such as sodium methoxide. um alkoxide in a molar ratio of about 1/1 to 1/10 and a temperature of about 25 to 100"C. The 2-methquine compound of the present invention, 3-cyclo-3- [2-methquine-4-oxo-38,5H-pyrrolo[3,2-all pyrimidine] -7-yl]propanenitrile is obtained.

In a further aspect, methods of making compounds where R1 is hydrogen are provided. mentioned above The methyl 3-ami7-4-(2-cyano-1-cyclo-ethyl)-18-pyro -2-carboxylate intermediate methylformamide dimethyl acetal and For about 1 to 10 days at a temperature of about 25 to IOO'C with a molar ratio of about 1/1 to 1/4 The reaction produced methyl 4-(2-noanor 1-/chloroethyl)-3-[N-(dimethyl tylaminomethylene) amino]-1H-pyrrole-2-carboxylate in Obtained as an intermediate. The next step is to prepare the methyl 4-(2-7ano-1-cyclo-ethyl )-3-[N-(dimethylaminomethylene)ami/]-LH-pyrrole-2-ka Ruboxylate is about 1/1 to 1/1 that of meta/ethanolic or ethanolic ammonia. The present invention was prepared by reacting at a molar ratio of 1/20 at a temperature of about 20 to 130°C for about 10 to 68 hours. Compound 3-cyclo-3-[4-oxo-3H,5H-pyrrolo[3,2-d] and obtaining pyrimidin-7-ylcoprobannitrile.

As will be apparent to those skilled in the art, variations on the above method may be made without departing from the spirit thereof. Useful in preparing various compounds of the invention. For example, in the formula of the present invention, “ Compounds having different values of carbon atoms Can be obtained either by measuring or descending the process by the required number . In addition, reactions involving several intermediates can be performed using known techniques to or oxygen atoms need to be protected.

The following non-limiting examples are provided to describe the invention in more detail. Example All parts and percentages are by weight unless otherwise specified. nine The proportions of the solvent mixture used as eluent in chromatography depend on the volume.

Example 1 In this example, 3-(3-pyridinyl)propionitrile is prepared. magnetic stirring bar Three-necked flask with thermometer, isobaric addition funnel, and argon inlet. Set the reflux condenser. Freshly powdered potassium hydroxide (6.6 g , 0.1 mol) and anhydrous acetonitrile (150 mQ) into the flask, 3-Pyridinecarboxaldehyde (10, 7g.

01 mol) was added dropwise over about 5 minutes and heated under reflux for an additional 3 minutes. Flow. The resulting hot reaction mixture was poured into an ice/water mixture (100 g) and the resulting solution The liquid was extracted with CH-CL (3x 100 m), dried with Na, SO, Evaporation gave crude 3-(3-pyridinyl)acrylonitrile, which was converted to C HCl2. by column chromatography on 7 lica gel using as eluent and refine it. Yield 3.3g (25.6%) 99% of acrylonitrile (2,662g 50.02%) under alcon atmosphere The stirred solution in ethanol 100+J was added with a drop of 4% aqueous sodium hydroxide followed by boron water. treated with 0.378 g (0.01 mol) of sodium chloride. Rough borohydride Two more additions of 0.378 g of sodium are made at 4 hour intervals. Mix compound a at room temperature. Stir overnight, dilute with water, extract with EtOAc, and dry over Na, S04.

The solvent was removed under reduced pressure and the resulting crude product was dissolved in chloroform/methanol (40 /1) was subjected to chromatography on a silica gel column using as eluent. 2.2 g (84.6%) of product are obtained as a colorless oil.

big and man j In the synthesis of the present invention, the 3-(3-pyridinyl)propionitrile of Example 1 was Further processing. 3-(3-pyridinyl)propionite under dry nitrogen atmosphere Ril 0.661 g (5.0 mmol), sodium hydride 0.240 g ( 10.0 mmol), and 1.11 g (15.0 mmol) of ethyl formate. Water Tetrahydrofuran 20ml (48ml) while protecting the medium temperature mixture from air and moisture. Stir for an hour.

Evaporate the volatiles and leave a solid residue with 15 ml of cold water! Add 6N cold salt to the medium solution at O'C. Adjust pH to 6 with acid. The resulting oily mixture was extracted with CHCQ3, and the extract was diluted with water. Washed with Na2S04 and evaporated to give a dark oil This is 2-formyl-3-(3-pyridinyl)propionitrile and nitrile A mixture of starting materials. This crude product can be used in the next reaction without further purification. use

Example 3 Glycine methyl ester hydrochloride 0.942 g (7.5 mmol) and anhydrous vinegar 0.615 g (7.5 mmol) of sodium chloride was added to 0.8 g of the crude formyl compound. Add to the solution in 9 g of MeOH/HtO (4:1.50 mff) . After 24 hours, the MeOH was evaporated in vacuo and the water and oil mixture was converted into CH Extract with Cl23. Dry the CHCl23 layer with N atS O4) and evaporate. An amber oil is obtained which is applied to a silica gel column. CHCl23 2 major bands = (1) 3-(3-pyridinyl)propioni tolyl (used as starting material in the previous step), and (2) the desired enamine. It was done.

Example 4 Under a nitrogen atmosphere and with external cooling in a water bath, 0.521 g of ethyl chloroformate (4.8 mmol) and 0.513 g (3.2 mmol) of the enamine of Example 3. and 1,5-diazabicyclo[4,3,0]nocy-5-ene (DBN, 1.37 g, 11.1 mmol) in dry C HICQ2) 15 mQ solution. Ru. After stirring for 1 hour at 0°C, the solution is left at room temperature overnight. Proceeded by TLC After checking the row, further CQCO,Et　0.1mQ and DNBl,0 More mff is added to complete the conversion and the solution is left for 24 hours. volatile substances is evaporated in vacuo and the viscous residue is transferred to a short silica gel column (the main purpose of which is to improve the mobility). (removal of small DBN) to give N-protected virol, which is used in the next step without further purification.

Oshi shoulder two 0.635 g (2.0 mmol) of the N-protected pyrrole of Example 4 in MeOH5 Add 212 g (2.0 mmol) of solid Na, CO to the solution in 0 mQ. , the reaction mixture is stirred at room temperature for 48 hours and the resulting deprotected virol is separated. a The mixture was evaporated to dryness, and the residue was thoroughly triturated with 25 ml of water to remove inorganic substances. Dissolve and extract with CHCQ, <3×100 mQ). Dry the extract with Nat. SO, ), evaporated to give a viscous gum which crystallizes when dried in vacuum. , used as an intermediate without further purification. While doing so, we have made it even more thorough. Purification was carried out by column chromatography using silica gel/CHCQ3 or Either by recrystallization from toluene/cyclohexane (1:3) Can be done.

Great Emperor Mastan Example 5: 0.232 g (1.42 mmol) of benzoyl inthiocyanate 0.290 g (1.18 mmol) of unprotected pyrrole of CH, CI2, 100 m (!) dropwise into the solution. After 1 hour at room temperature, the solution was evaporated and a gummy residue The residue is stirred in Et, O/cyclohexane (1:1.20 mQ). the resulting yellow The suspension of colored solid was filtered under nitrogen pressure and the thiouraid product was purified with phosphorous pentoxide in vacuo. Dry on top.

Pig error 0.228 g (1.61 mmol) of methyl iodide was added to the thiouraid raw material of Example 6. Product 0.383g (0.94mil J%) and DBNo.

A solution of 140 g (1.12 mmol) of dry CH,CQt in 10 mQ of O'C Add. The solution was stirred at O'C for 15 min and at room temperature for 1 h, then evaporated in vacuo. make it emit Cruel CHC12, medium solution CHCI23/methanol (97.3) Chromatography on a silica gel column using Obtain a homogeneous fraction of intermediate compounds.

Example 8 Methyl of Example 7 in 100 m9 of methanol saturated with ammonia at 0'C A solution of 0.358 g (085 mmol) of the thio compound was lined with glass. Heat in a stainless steel bong at 90-95°C for 24 hours. cooled phone Evaporate the contents in vacuo to obtain the desired 2-amino compound as opposed to the 2-amino compound. intermediate compounds, henzamides, and by-products that are 2-methylthio derivatives. Get a mixture. The mixture was dissolved in methanol and the solution was mixed with about 5 g of licagel. Make a sound emit. The mixture is then carefully poured onto the top of a column chromatography column. Layer it on top of each other, then CHCM this! -/MeOH (91) to elute with C methyl thio by-product and the desired 2-ami7-7-(3-pyridinylmethyl)-38, A 5H-pyrrolo[s,2-d]pyrimidin-4-one intermediate is obtained. sock shoes - Further purification by recrystallization from boiling Improvir acetate in an apparatus.

0.0 of the pyridinylmethyl intermediate. IN　HCQC Rakuchu 601b/in”H, pressure Hydrogenate with a platinum catalyst under pressure. The catalyst is 0. IN　pto in HCl, simple water It is caused by elementalization. Once the reaction is complete, remove the catalyst by filtration under nitrogen pressure and evaporate liquid a. A solution of the residue in a minimum amount of ethanol with a large amount of Et○ Dilute slowly to obtain the hydrochloride salt of compound (rc) as a white hygroscopic solid.

Daijyūmawariyu Compound of Example 8 (IC) is tested for enzyme inhibitory activity.

A brine nucleoside phosphorylase (PNP) enzyme assay was performed in which: Observe the PNP activity (IC,.) for the compound, which as the enzyme source Using orchid lungs, [+4cl-ynone CI' (in the form of 1-hyboxanthin) Determined radiochemically by measuring the composition of edicine), 33. 39 (1980)).

2-amino-7-(R)- in which R is -CH,R, and the R group is: The following of the present invention which is 3H,5H-pyrrolo[3,2-d]pyrimidin-4-one Prepare the compound.

Example 10 R,=2-methyl-3-piperidinyl Example 11 R,=2-chloro Rho-3-piperidinyl Example 12 R,=2-trifluoromethyl-3-piperi Dinyl Example 13 R,=2-methoxy/-3-piperidinyl Example 14 R,= 2-Fluoro-3-piperidinyl The compounds are suitable 3-(substituted 3-pyridinyl) The procedure described in Examples 1 to 8 using propionitrile as starting material. Prepare from

Kise Retsu Yuj In this example, V. Boekelheide et al. l), Journal on American Chemical Society (J, ^m.

Using the method of Chem, Soc, ), E5, 3243 (1953), 3- Prepare (2-pyridinyl)propionitrile. Potassium in 160mQ of water A solution of 83.74 g of anide was dissolved in 67.59 g of freshly distilled 2-vinylpyridine. in 131.30 g of acetic anhydride was added with the addition adjusted to maintain a gentle reflux. Add with acceleration. Once the addition is complete, the resulting dark red mixture is stirred vigorously. Heat in an oil bath at 105°C for about 17 hours. Cooled reaction mixture with saturated carbonic acid Adjust pH to 8 with sodium solution. Add the mixture to CHCQs (4x 150mQ ), washed with water, dried over N a SO, and evaporated to a dark viscous oil. get. The oil is fractionally distilled in vacuo through a Vigreau column.

After a small pre-run containing 0.35 g of 2-vinylpyridine, the desired 3-(2 -pyridinyl) propionitrile as a clear fluorescent yellow to green viscous oil obtain. Yield: 59.8g; 70.4%; 86°C at boiling point 1.0mmHg Kanpei 2 Tsuchimi bifurcated text 2-amino-7-(R) where R is -CH,R, and the R4 group is -38,5H-pyrroloC3,2-d] Pyrimidin-4-one Prepare the compound below.

Example 16 R,=2-piperidinyl Example 17 R,=4-piperinonyl Practical Example 18 R, = 3-) Lifluoromethyl-4-piperidinyl Example 19 R ,=3-methoxy-2-piperidinyl Example 2OR,=3-fluoro-4-pipe Starting from lysinyl appropriate 3-(2- or 4-piperidinyl)-propionitrile The compounds are prepared by the procedures described in Examples 1-8.

Husband's plate supreme A pharmaceutical composition for intraperitoneal injection is prepared for testing compound (IC).

An intraperitoneal injection solution containing the compound of Example 8 was added to water containing 10% DMSO. dissolved in a carrier.

husband punishment 22 Compound (IC) was tested in a Lewis lattice via the test composition of Example 21. Animals were given 30 mg of compound (IC) by intraperitoneal injection; injections were given twice per day. . A control is used that receives vehicle only.

At specified times post-dose, animals are sacrificed and plasma samples prepared.

The plasma is extracted with cold 0.5N HCQO and neutralized with solid NH, HCQ.

After perchlorate removal, the extract was loaded onto a reverse phase column (Spher 1sorbODSI ) on HPLC. A significant increase in plasma inosine occurred after taking compound (rc). Observed in plasma collected from exposed animals.

Examples 23-33 The compounds prepared in Examples 10 to 20 were each added to a pharmaceutical formulation according to the preparation of Example 21. and the resulting injection solution is tested according to the procedure of Example 22. Is the plasma y/n? A significant increase is observed in plasma from animals fed the compounds of the invention.

Example 34 In this example, 3-(2-furanyl)propionitrile is prepared.

In a three-cylinder flask equipped with a condenser and drying tube, add 20 g of magnesium powder. Solution of 87.2 g of 3-(2-furanyl)acrylonitrile in 2 g of dry methanol Add to. Add more magnesium to a total amount of 145g as reaction rate allows. Add little by little. After 5 hours, evaporate the solvent until the contents become a solid paste. While cooling, adjust the pH to approximately 6.5 with 6N HCQ. a small amount of the mixture Extracted with chloroform, dried over Na, SO, and concentrated to a dark oil. do. The propionitrile is distilled in vacuo through a short blow column. obtained without batteries. Yield 49.5g (72%), boiling point 46.0 at 0.5mm ~46.5°C Example 35 In the synthesis of the present invention, 3-(2-furanyl)propionitrile of Example 34 was Further processing. Under a dry nitrogen atmosphere, 48.7 g of the propionitrile, 10.28 g of sodium hydride, 32.74 g of ethyl formate, and anhydrous Tetra 200+l of hydrofuran are stirred at room temperature for 18 hours, protected from moisture. Next Then, the volatile substances were evaporated, and the resulting yellow solid was cooled in a water bath with about 20 mQ of cold water. and adjust the solution to I) H6,O with cold 6N HCQ. Obtained heavy The oil precipitate was extracted into chloroform, the extract was washed with water, dried over Na, SO2, Evaporation gives a thin oil, which contains the crude formyl compound. Yield 53. 06g Example 36 67.05 g of glycine methyl ester hydrochloride and 43.7 g of anhydrous sodium acetate 9 g of the crude formyl compound from the previous example was added to 53.05 g of MeOH/H,O (4 : 1.1500mQ) to the medium solution.

After 24 hours, the MeOH was evaporated in vacuo and the water and oil mixture was chloroformed. Extract with holm. Dry the chloroform layer (NatS○4), evaporate and remove 59.1 g of dark brown oil are obtained.

Kantanezu Eingyu 43.68 g of ethyl chloroformate was added under a nitrogen atmosphere while being externally cooled in a water bath. 591 g of the amber oil of Example 36 and 133 g of DBN of dried CHt Add dropwise to CQv400 mQ solution. After stirring at 0 °C for 1 h, the solution was stirred at room temperature. Leave overnight. Check the progress on TLC.

After that, more CQCO, Et and DBN are added to complete the conversion and the solution is Let the liquid stand for 24 hours. Volatile substances are evaporated in vacuum and the viscous brutality is silica gel Purification on a column (the main purpose of which is the removal of DBN with low mobility) - Protected pyrrole, the corresponding pyrrole without the ethquinocarbonyl protecting group on pyrrolemit roll, and the starting propionitrile.

Example 38 A solid solution of 11.66 g of the N-protected pearl of Example 37 in 200 ml of MeOH was added. 23 g of N a x CO was added and the reaction mixture was stirred at room temperature for 24 h. and separate the obtained deprotected pyrrole. The mixture was evaporated to dryness and the residue was dissolved in 200 ml of water. Thoroughly triturate to dissolve inorganics and add CHCff-(3x Extract at 200m. The extract was dried and evaporated with N a, SO, ). A viscous gum is obtained, which crystallizes when dried in vacuum and can be further purified. (Used as an intermediate. However, more thorough purification is possible using silica gel/ Column chromatography using CHCC3 or toluene/cyclohexa This can be done either by recrystallization from (13) or by recrystallization from 4.58 g of the unprotected pyrrole of Example 38 was added to the dried cH,c Q The residue was dissolved in 100 ml of Et,O, the crystalline solid was separated almost immediately, This is collected by filtration. Heat the Et. Dilute with beef san to cyclohe. When cooled slowly, the thiourei becomes more concentrated than the solution. A de-product is obtained.

Example 40 8.70 g of methyl iodide was added to 10.68 g of the thioureide product of Example 39 and and DBN4.15g dry CH-C12t250mf! 0 in medium solution! inside Add. The solution was stirred for 15 min at o'C and 1 h at room temperature, then evaporated in vacuo. let CHCQ the residue and CHCQ the medium solution.

Chromatography on a silica gel column using Obtain a homogeneous fraction of intermediate compounds.

Example 41 25 m of methane saturated with ammonia at 0 °C (! A solution of 0.80 g (2.0 mmol) of ruthio compound was lined with glass. Heat in a stainless steel bomb at 90-95°C for 24 hours. cooled cylinder The contents of the 2-amino compound are evaporated in vacuo to form the 2-amino compound as opposed to the 2-amino compound. , a benzamide, and a mixture of by-products which are 2-methylthio derivatives.

The mixture 2: IEt, O/Cyclo with 30mf2 of beef sun for a few minutes Stir vigorously and filter the insoluble white solid, washing with Et, O. The filtrate is mostly which contained the benzamide and 2-methylthio moieties. Et, 0/ Approximately 10 g of 7 Evaporate with Lycagel. Spread the powdered residue evenly on the top of the silica gel column. Overlap, then CH (j!, /MeOH/HOAc (95: 5: Elution with 1) yields the 2-methylthio byproduct and the desired furanyl intermediate.

The intermediate was re-extracted into boiling isopropyl acetate in a Soxhlet apparatus. crystallize. The white crystals were collected in three yields and heated over phosphorus pentoxide in vacuo at 110'C. Dry for 7 hours.

A solution of 116 g (0.5 mmol) of the intermediate in 50 rr+ll of methanol was added to 62 ml of methanol. Water with 30% palladium (40 mg) on carbon for approximately 36 hours at 1 b/in' hydrogen pressure. Become basic. The catalyst was removed by filtration under nitrogen pressure and the filtrate was evaporated and treated with toluene. Reevaporate together. Boiling isopropyl acetate in a Soxhlet apparatus to remove the solid residue Recrystallize by extraction to The 2-tetrahydrofuranyl compound (IE) is Obtained as a colored crystalline solid, which was dried in vacuo over phosphorus pentoxide at 110° C. for about 6 hours. Ru. Yield 73mg (61.8%), boiling point 284-286℃ decomposition Example 42 The product of Example 41 was tested for enzyme inhibitory activity by the procedure of Example 9, and the Observe the PNP activity (IC,.) for the compound.

Example 43 A pharmaceutical composition for intraperitoneal injection is prepared for testing of compound (IE).

An intraperitoneal injection solution containing the compound of Example 41 was added to water containing 10% DMS○. dissolved in a carrier.

Example 44 Using the procedure of Example 16, compound (IE) was introduced through the test composition of Example 43. Lewis rats were given 30 mg of compound (IE) by intraperitoneal injection. , and compare and analyze the results with controls. A significant increase in plasma inosine was observed with compound (IE) observed in plasma collected from animals ingested.

K Bloody±l2Adan Rka-CH! 2-amino-7-(R )-38,5H-pyrrolo[3,2-d]pyrimidin-4-one of the present invention Prepare the following compounds.

Example 45 R,=3-tetrahydrofuranyl Example 46 R,=3-chloro- 2-tetrahydrofuranyl Example 47 R,=3-trifluoromethyl-2-te trahydrofuranyl Practical example 48 R, = 3-methquin-3-tetrahydrofuranyl Example 49 R, =3-fluoro-2-tetrahydrofuranyl 3-(furanyl)acryloni as appropriate Compounds were prepared using tolyl as the starting material and following the procedures described in Examples 34-41. Prepare.

Example 50 Under a nitrogen atmosphere, the tetrahydrofuranyl compound (TE) 50 obtained from Example 41 A solution of 0 mg and phenol crystals in 2N HBr2OmQ was prepared at 40°C. Stir for 8 hours. Evaporate the solvent in vacuo at low temperature and decant the residue. Wash with several more mQ of EttO to remove any tribromophenol. Applicable A suspension of the residue in water was adjusted to pH 7 with IN NaOH to liberate the bromoalcohol. Obtained as a base. Collect the solid, wash with cold water, and dry at room temperature.

A solution of the bromoalcohol in anhydrous dimethylacetamide is cooled in a water bath and isomolyzed. Processing is performed using PB rs for 1 hour. The solution was stirred at room temperature for 1 h, then an air pump and a dry ice trap, the dimethylacetamide is stored in vacuum at low temperature. Evaporate with. A suspension of the residue in ice/water was adjusted to pH 7 using IN NaOH. A crude reaction product containing a 1,4-dibromo compound is obtained. Filter and cool After washing with water and drying at room temperature, the resulting product was washed with sodium chloride in 50% ethanol/water. Reflux with sodium sulfate or alternatively N,N-dimethylacetic acid. Warm with Na, S in toamide solution; remove solvent under vacuum and wash residue with water. The 2-tetrahydrochenyl compound was purified by washing to remove NaBr and adjusting the pH to approximately 7. The compound of Example 50 was precipitated with enzyme inhibitory activity (IG) as in Example 9. and observe the PNP activity (I Cso) of the compound.

Example 52 A pharmaceutical composition for intraperitoneal injection is prepared for testing of compound (IG).

An intraperitoneal injection solution containing the compound of Example 50 was added to water containing 10% DMS○. It is prepared by dissolving it in a carrier.

Husband Arashi Δ Mutual Yu Using the procedure of Example 16, compound (IG) was introduced through the test composition of Example 52. Lewis was given 30 mg of compound (IG) by intraperitoneal injection; Analyze results relative to controls. Significant increase in plasma inosine or intake of compound (IG) Observed in plasma collected from animals.

K woodcutter 2-Amino-7-(R) where R is -CH, -R, and the R3 group is -3H,5H-pyrrolo cs, 2-a] The following compound which is pyrimidin-4-one Prepare a bright compound.

Example 54 R,=3-tetrahydrochenyl Example 55 R,=3-chloro- 2-tetrahydrochenyl example 56 R, = 3-1-lifluoromethyl-2- Tetrahydrochenyl Example 57 R, = 3-methoxy-2-tetrahydrochenyl Example 58 R, =3-fluoro-2-tetrahydrochenyl suitable 3-(furanyl)-acrylo Compounds were prepared using nitriles as starting materials and following the procedures described in Examples 34-41. prepare something

Using the procedure of Example 1, starting with virol-2-carboxaldehyde 3-(2-pyrrolyl)propionitrile is prepared using M. According to Examples 2-8 , from the propionitrile to intermediate 2-ami/-7-(2-pyrrolylmethyl)-3 8,5H-pyrrolo[3°2-d copyrimidinol-4-one was prepared and then 2 -pyrrolidinyl compound (n) is obtained by reduction of the intermediate.

Example 60 Using the procedure of Example 1, starting with pyrrole-3-carphox/aldehyde to prepare 3-(3-pyrrolyl)propionitrile. According to Examples 2-8 , from the propionitrile to the intermediate 2-amino-7-(3-pyrrolylmethyl)-3 8,58-pyrrolo[3°2-d]pyrimidin-4-one was prepared and then 3- The pyrrolidinyl compound (IJ) is obtained by reduction of the intermediate.

Example 61 Using the procedure of Example 1, 3-(2-pyranecarboquinaldehyde was used) Prepare ranyl) propionitrile. According to Examples 2-8, the propionitri intermediate 2-amino-7-(2-pyranylmethyl')-3H,5H-pyrrolo 3,2-d] pyrimidin-4-one and then 2-tetrahydro- The pyranyl compound (IL) is obtained by reduction of the intermediate.

Example 62 Using the procedure of Example 1 and using 3-bilanecarboxaldehyde as the starting material 3-(3-pyranyl)propionitrile is prepared. According to Examples 2-8, the from propionitrile to intermediate 2-amino-7-(3-pyranylmethyl)-38, 5H-pyrrolo[3,2-d copyrimidin-4-one was prepared and then 3-te The trahydro-pyranyl compound (IM) is obtained by reduction of the intermediate.

Example 63 Using the procedure of Example 1 and using 4-bilanecarboxaldehyde as the starting material 3-(4-pyranyl)propionitrile is prepared. According to Examples 2-8, the intermediate 2-amino-7-(4-pyranylmethyl)-38 from propionitrile, 5H-pyrrolo[3,2-d]pyrimidin-4-one was prepared and then 4-te The trahydro-pyranyl compound (IN) is obtained by reduction of the intermediate.

Oshio 64 Methyl of Example 7 in 100 ml of methanol saturated with ammonia at 0°C A solution of 0.358 g (0.85 mmol) of the thio compound was placed on a glass lining. Heat at 90-95°C for 24 hours in a stainless steel cylinder. cooled bong Evaporate the contents in vacuo to obtain the desired 2-amino compound as opposed to the 2-amino compound. intermediate compounds, benzamides, and by-products that are 2-methylthio derivatives. Get a mixture. The mixture was dissolved in methanol and the solution was mixed with silica gel (approximately 5 g). Evaporate together. The mixture was then applied to the top of a silica gel chromatography column. This was then eluted with CHCQs/MeOH (91). together with the 2-methylthio by-product and the desired 2=amino-7-(3-pyridinylmethyl) thyl)-38,58-pyrrolo[3°2-d]pyrimidin-4-one, compound (n A) can be obtained. Recrystallization from boiling isopropyl acetate in a Soxhlet apparatus Further purification is performed by

K-hi dish Dango Compound of Example 64 (IIA) is tested for enzyme inhibitory activity.

A purine nucleoside phosphorylase (PNP) enzyme assay was performed to determine whether the compound We observed PNP activity (ID, , ) for [ Measuring the formation of [1*-C]-hyboxanthin from "-C]-inosine Determined radiochemically by

Toyotaka Ooku 2-Amino-7-(R) in which R is -CH, -R, and the R1 group is -3H,5H-pyrrolo[3,2-d]pyrimidin-4-one Prepare a bright compound.

Example 66 R,=2-pyridinyl, Example 67 R,=4-pyrimidinyl, Example 68 R,=3-chloro-2-pyrimidinyl Using rimidinyl appropriate 3-(pyridinyl)-propionitrile as starting material The compounds are prepared by the procedures described in Examples 1-7.

Example 69 A pharmaceutical composition for intraperitoneal injection is prepared for testing compound (IIA). Example An intraperitoneal injection solution containing 64 compounds was dissolved in a vehicle containing 10% DMSO. Understand.

Hujin Retsuyu A Compound (mA) was added to a Lewis lattice via the test composition of Example 69. Animals were given 30 mg of compound (I[A) by intraperitoneal injection, and injections were given twice a day. cormorant. A control is used that receives vehicle only.

At specified times post-dose, animals are sacrificed and plasma samples prepared.

The plasma was soaked in cold 0.5N HCf! Extract O, T and neutralize with solid N H, HCO, Te. . After removal of perchlorate, the extract was loaded onto a reverse phase column (SpherisorbODS+ ) on HPLC. A significant increase in plasma inosine was observed after ingesting the compound (DA). Observed in plasma collected from exposed animals.

Examples 71-73 The compounds prepared in Examples 66 to 68 were formulated as pharmaceuticals according to the preparation of Example 69, and the obtained The injection solution prepared is tested according to the procedure of Example 70.

A significant increase in plasma inosine was observed in plasma from animals fed the compounds of the invention. be noticed.

Example 74 In the synthesis of the present invention, 1-cyclohexenylacetonitrile is treated. drying 9.2 g of 1-cyclohexenyl acetonitrile (75, 92 mmol) in anhydrous tetrahydrofuran (THF, 10 mf!), 3.18 g (132.86 mmol) of sodium hydride and 30.0 g of ethyl formate. Added to a solution of 14 g (406°93 mmol) in 50 mf THF, the obtained The mixture is stirred at room temperature for 18 hours. The volatiles are evaporated in vacuo at room temperature.

30 mQ of water was added to the residue at 0°C and the solution was added dropwise to cold 6N HCl2. Therefore, adjust the pH to 6.0. Extract the resulting heavy oil precipitate into chloroform . The extract was washed with water and washed with Ns, So.

The obtained Yoiki layer was evaporated to give 9.6 g of a reddish-brown crude formyl compound. get as.

Glinone methyl ester hydrochloride 16.68g (132.85 mmol) and 10.89 g (132.85 mmol) of anhydrous sodium acetate was dissolved in MeOH/H Crude form of Example 74 without further purification in =O(4:1.150m12) Add to a solution of 9.6 g of compound. After 24 hours, the MeOH was evaporated in vacuo. Evaporate and extract the water and oil mixture with chloroform. Dry the chloroform layer ( (Na2SO4) and evaporated to give an amber oil, which was silicaed. Apply to Kagel column. Elution with chloroform yields the desired enamine. Collection Amount: 4g Example 76 Ethyl chloroformate 3.04 g (2 8.06 mmol) was added to 4.12 g (18.70 mmol) of the enamine of Example 75. ) and 1,5-diazabicyclo[4,3,0 nynon-5-ene (DBN, 6 ．． 96 g, 56.11 mmol) of dry CH,CQ, in solution in 100 mQ Drip. After stirring for 1 hour at 0°C, the solution is left at room temperature overnight. TLC Teshin After checking the rows, CQCOt Et 0, 5 mQ and D B N Additional 3,0 mQ is added to complete the conversion and the solution is left for 24 hours.

The volatile substances are evaporated in vacuo and the viscous residue is transferred to a silica gel column (its main purpose is The N-protected virol was obtained by purification (which involved removal of DBN with low mobility). , which is used in the next step without further purification.

Example 77 N-protected pyrrole of Example 763. Og (10,26 mmol) of MeOH1 2.71 g of solid NatcOs (25°65 mmol) in solution at 00 mC ) was added, the reaction mixture was stirred at room temperature for 48 hours, and the resulting deprotected pyrrole was separated. Let go. The mixture was evaporated to dryness and the residue was thoroughly triturated with 50 mQ of water. Dissolve inorganic substances, CHCQ.

(3 x 10 mg). Dry the extract with N atS O4) and evaporate. A viscous gum was obtained and purified on a silica gel column using CHCQ as the eluent. refine. Yield: 12.04g + Melting point: 125°C Kanwangpoyu 1 Example 77: 0.76 g (4.65 mmol) of benzoyl inthiocyanate 0.91 g (4.13 mmol) of unprotected virol of dry CH,CQ, Add dropwise to the solution at 30 mσ. After 1 hour at room temperature, the solution was evaporated to leave a cam-like residue. Trituration with methanol gives the thioureide. Yield 0.70g + melting point 1 70°C Example 79 0.678 g (4.78 mmol) of methyl iodide was added to the thioureide of Example 78. Product 0.630 g (1,64 mmol) and DBNO, 230 g (1, 85 mmol) in dry C HtCQ t'D OmQ at o'C. Add. The solution was stirred at O'C for 15 min and at room temperature for 1 h, then evaporated in vacuo. let A solution of the residue in CHCρ3 was passed through a silica gel column using CHCl23 as the eluent. Chromatography above yields a homogeneous fraction of the methylthio intermediate compound.

Yield 07g Example 80 Methyl of Example 7 in 50 mQ of methanol saturated with ammonia at o'C A solution of 070 g (1, furimmol) of the thio compound was poured into a glass-lined bathtub. Heat in a stainless steel bong at 90-956C for 24 hours. cooled cylinder The contents of the compound were evaporated in vacuo to form the compound as opposed to the 2-amino compound (I[IA). compound (I[[A), benzamide, and a by-product that is a 2-methylthio derivative. Get a mixture. The mixture was stirred vigorously for several minutes with approximately 50 mQ of Et,0. The insoluble white solid is filtered and washed with Et,O. Liquid a is used for most of the It contained benzamide and 2-methylthio components. EtzO - insoluble solid Evaporate 0.342 g of solution in MeOH with approximately Log of silica gel . The powdered residue was layered evenly on top of a 7-silica gel column, which was then transferred to CH Elute with CQ3/MeOH/HOAc (95:5:1) to obtain 2-methylthio The product and the desired 2-amine product (InA) are obtained. (IIIA) Recrystallize by extraction into boiling isopropyl acetate in a Slee apparatus. white color The crystals are collected in three yields and dried in vacuo over phosphorus pentoxide at 110° C. for 7 hours. Collection rate 44%, melting point 280℃ decomposition Elemental analysis C,, H,, N, O・0.6H, O and t, T, calculated value (%) C, 59 ,78;H,6,35;N 23.23 actual value (%)C,59,98:H6,4 6+N, 23.15 1 Yu The compound of Example 80 is tested for enzyme inhibitory activity. Brinnucleosidoho A sphorylase (PNP) enzyme assay was performed to determine the PNP activity for the am (ID,.) from [”-C]-inosine using bovine lung as the enzyme source. Determined radiochemically by measuring the formation of “-C]-hyboxanthin (Biomedeicine, 33. 39 (1980) ), IC, at 1 mM phosphate. is 1.9μM and 50mM For phosphate, the IC, is 19 μM.

Example 82 Using the procedures described in Examples 74 to 80, 2- and 3-silanes were used as starting materials, respectively. Compound (IIIB) and (I[I C) is produced. The compound was tested as in Example 81 and showed significant fermentation. elementary inhibitory activity is observed.

2-amino-7-(R)-3H,5H-pyrrolo[3,2 -d] The following compounds of the present invention which are pyrimidin-4-ones are prepared.

Example 83 R=3-methyl-2-cyclohexenyl Example 84 R=2-cyclo Rho-3-cyclohexenyl Example 85 R=3-trifluoromethyl-1-cyclo Lohexenyl Example 86 R=3-methoxy-1-cyclohexenyl Example s7 R=2-fluoro-3-cyclohexenyl appropriately substituted cyclohexenylacetonyl Compounds were prepared using tolyl as the starting material using the procedures described in Examples 74-81. Prepare.

Example 88 A pharmaceutical composition for intraperitoneal injection is prepared for testing compound (IA). Compound( An intraperitoneal injection solution containing I[[A] was added to an aqueous carrier containing 10% DMSO. dissolve.

Example 89 Compound (IIIA) was purified via the test composition of Example 88 by Lewis Rats were given 30 mg of compound (II[A) by intraperitoneal injection; Do it twice. A control is used that receives vehicle only.

At specified times post-dose, animals are sacrificed and plasma samples prepared.

The plasma is extracted with cold 0.5N HCf204 and neutralized with solid NH,HCO3.

After removal of perchlorate, the extract was applied to a reverse phase column (SpherisorbODSI). Attach to HPLC above. A significant increase in plasma inosine occurs after taking compound (I [IA)] observed in plasma collected from animals exposed to

Oshiretsudan Bungoyu 1 Compounds prepared as in Examples 83-87 were formulated as pharmaceuticals according to Example 88. and the resulting injection solution is tested according to the procedure of Example 89. Is it plasma inosine? A significant increase is observed in plasma from animals fed the compounds of the invention.

Example 95 2-Amino-7-(1-cyclohexenyl)-3H,5H-pyrrolo[3,2-c 13. Compound (■D) is prepared using pyrimidin-4-one as an intermediate. the middle A solution of 0.2 g (0.86 mmol) of ethanol in 50 mQ of ethanol was added to 451 b/i Hydrogenated with 10% Pd-C (50 mg) at n' for 16 hours and passed through Celite. Filter hot. The filtrate was evaporated to dryness and the residue was crystallized from hot ethanol to give compound ( Obtain I[[D]: yield 157 mg (78%), melting point > 300'C decomposition element content Analysis C1tH+*N, O-0, EtOH taken, T, calculated value (%) C, 61, 80 , H, 7,10, N, 23.51 Actual value (%) C, 61,95; H, 7,43; N, 23.56 Example 96 The compound (IIID) prepared in Example 95 was treated as an enzyme inhibitor as in Example 81. Test for harmful activity. IC, at 1 mM phosphate. Ha is 1.3 μM. IC, at 50mM phosphate. is 145 μM.

Example 97 In this example, M. Ohno et al. Organic Chemistry (J, Org, Chem,), 53. 128 5 (1988) using a modified method of 3-(2-adamantane)propylnitri Prepare the sample. 2-bromoadamantane 20g (9296 mmol); Bu , 5nH 32.46g (111.5 mmol), acrylonitrile 9.86g (185,92 mmol), and 740 mg of AIBN toluene 28OmQ The medium solution is stirred at reflux temperature for 3 hours. The reaction mixture was diluted with aqueous ammonia (0.4 M, 5 00 mf, and the organic layer was washed with water, dried over magnesium sulfate, and evaporated. let Distill the atrocities at 110-118°C (approximately 0.2 mmHg): combine the fractions. Crude 3-(2-adamantyl)propionitrile containing tin complex impurities Obtain a sample and add it to hexane followed by hexane/ethyl acetate 97:3 and hexane. Purify on a silica gel column using 95:5 chlorine/ethyl acetate. Yield: 19.4g ( 53.4%); Melting point: semi-solid Example 98 In the synthesis of the present invention, the 3-(2-adamantyl)propionitrile of Example 97 further process the file. 3-(2-adamantyl)propylene under a dry nitrogen atmosphere. Pionitrile 7.0g (36.99 mmol), sodium hydride 1.7g (73.95 mmol) and 75 ml of anhydrous tetrahydrofuran. Heat in a water bath at 52°C for 15 minutes to obtain 13.69 g of ethyl formate (184,89 A solution of 1 mmol) in 100 ml of THF is added over a period of 45 minutes. 50～ After 2 hours at 55°C, N a H0, 8 g and HCO, Et 7.5- a second portion of the mixture is added and the reaction mixture is stirred for about 2 days. HCO,E t7.5m Add a third portion of 8g of Q and NaHo and let sit at room temperature for about 24 hours (unreacted). The nitrile can be inserted into the next step and recovered in the first purification step). intense pace Stir overnight and cool to room temperature. Volatile substances are evaporated under reduced pressure and the remaining Dissolve the pale yellow crust in a minimum volume of approximately 150 mf2 of 0°C cold water. 6N H Adjust the pH of the solution to 6 by addition of Cl2 and add CHCQ, (3x 100 m 12) Extract. The extract was washed with water, dried over N a SO and Evaporate in air to obtain a rich amber color. Further purification of this crude product Use it in the next reaction instead.

Example 99 Glinone methyl ester hydrochloride 6.96 g (55,46 mmol) and Add 4.55 g (55.46 mmol) of sodium acetate to M e OH/H , ○ (4:1.500 mQ) to a solution of 8.0 g of the crude formyl compound. Ru. After 24 hours, the MeOH was evaporated in vacuo and the water and oil mixture was cooled. Extract with loloform. Dry the chloroform layer (Na, 804) and evaporate. An amber oil is obtained, which is applied to the /licagel column. Dissolve in chloroform Two major bands: (1) 3-(2-adamantyl)-propionite (used as starting material in the previous step), and (2) the desired enamine.

Yield 6g Example 100 2.82 g of ethyl chloroformate ( 26.0 mmol) and 5.0 g (17.34 mmol) of the enamine of Example 99. and 1.5-diazavinchro L4.3.0]-/7-5-7 (seal DBN-, , 6,46 g, 52.0 mi'J mol) of dried CH = CQ! 50 m Add to the solution in Q. After stirring for 1 h at 0 °C, the solution was left at room temperature overnight. do. After checking the progress with TLC, C(ICo, Et　1.81mQ and Add another 3.23 g of DBN to complete the conversion and leave the solution for 24 hours. . The volatile substances were evaporated in vacuo and the viscous residue was transferred to a silica gel column (its main purpose is the removal of DBN with low mobility) to obtain N-protected pyrrole. This is used in the next step without further purification.

Example 101 6.0 g (16,59 mmol) of the crude N-protected pyrrole of Example 100 Solid N at COs in solution in O8100m (!) 4,39 g (41, 49 mmol) and the reaction mixture was stirred at room temperature for 48 h, resulting in a deprotected Separate the pyrrole. The mixture was evaporated to dryness and the residue was tritiated thoroughly with 50 mQ of water. Dissolve inorganic substances and extract with CHCQ3C3x 100m+2) . The extract was dried (Na, SO,) and evaporated to give a viscous gum; Crystallize by trituration with ether. Yield 4g: Melting point 162 ~163°C Example 102 Example 10: 1.22 g (7.47 mmol) of benzoylisothio/anate 1.91 g (6.62 mmol) of unprotected virol of 1 dry CH* CQ-50m Add dropwise to solution in Q. After 1 hour at room temperature, the solution was evaporated and the gas The sticky residue was dissolved in Et to 100 mQ, and the crystalline solid was dissolved almost immediately. To separate. Heat the Et, O filtrate to boiling temperature and dilute with beef saline to an equal volume of hot cyclohydrate. Ru. Cool the solution slowly to obtain more thioureide product. Collection j12. 81g (95%): Melting point 193-194°C Example 103 2.46 g (17.39 mmol) of methyl iodide was added to the thioureide of Example 102. 2.7 g (5,98 mm) of product and 82 g (6,5 mm) of product 7 mmol) of dry CH,CQ, solution in 50 ml.

Add at °C. The solution was stirred at O'C for 15 min, at room temperature for 1 h, then in vacuo. to obtain a crude sample of the methylthio intermediate compound.

Collection! 2.78g (crude) Example 104 of Example 103 in 150 ml of methanol saturated with ammonia at 00C. A solution of 2.78 g (5.18 mmol) of methylthio compound was added to glass lining. Heat at 90-95°C for 24 hours in a clean stainless steel cylinder. cool down The contents of the bomb were evaporated in vacuo to react with the 2-amidium/compound (1’V’A). The compound (IVA), benzamide, and 2-methylthio derivative A mixture of by-products is obtained. The mixture was heated with approximately 75rr N2 of Et,O for several minutes. Stir vigorously for a while and filter the insoluble white solid and wash with Et, O. The filtrate is mostly Contains most of the benzamide and 2-methylthio components.

Et, 〇 - A solution of 1.388 of the insoluble solid in Me OH was added to approximately 25 g of silica gel. evaporate with the liquid. Place the powdered residue evenly on the top of the silica gel column, This was then eluted with CHCQ-/MeOH/HOAc (95:5:1). A 2-methylthio by-product and the desired 2-amino product (IVA) are obtained. (I VA) by extraction into boiling isopropyl acetate in a Soxhlet apparatus. crystallize White crystals were collected in three yields and heated over phosphorus pentoxide in vacuo at 110 °C. Dry for 7 hours. Yield 51.6%, melting point > 350°C decomposition elemental analysis Cl7H2t NhO" 0.21MeOH" 0.22H! As ○, Calculated value (%) C, 66,88, H7, 59; N 18.12 Actual value (%) C, 66,86:H7,59;N, 18.12 The enzyme inhibitory activity of the compound of Example 104 test about. Brine nucleoside phosphorylase (PNP) enzyme assay ), find the PNP activity (ID50) for the compound, and find the enzyme source. Using bovine lung as Determined radiochemically by measuring the formation of tin (biomedicine) Biomedicine), 33. 39 (1980)).

At 1 mM phosphate, the IC6° is 0.090 μM; IC for salt. is 2.5 μM.

R or -CH, -R, and the R group is a 2-adamartyl group as shown below. -amino-7-(R)-38,5H-pyrrolo[3,2-d3pyrimidin-4-o The following compounds of the invention are prepared.

Example 106 R,=2-(1-methyl)-adamantyl Example 107 R, =2-(1-chloro)-adamantyl Example 108 R, =2-(1-trif fluoromethyl)-adamantyl 109 R, = 2-(1-methoxy)-adamane Chill Example 110 R,=1-(1-fluoro)-agemanthyl appropriate 3-( Examples 98-1 using 2-adamantyl)-propionitrile as the starting material The compounds are prepared by the method described in 04.

Examples 111-116 RJ<-CH, -R, and the R group is a 1-adamartyl group as shown below. 2-amino-7-(R)-3H,5H-pyrrolo'L3゜2-d]pyrimidine- The following compounds of the invention, which are 4-ones, are prepared.

Example 111 R, = 1-(2-methyl)-adamantyl Example 112 R, =1-(2-chloro)-adamantyl Example 113 R, =1-(2-trif fluoromethyl)-adamantyl Example 114 R, = 1-(2-methoxy)-adamantyl Example 115 R, =1-(2-fluoro)-adamantyl Example 116 R, =1-adamanty using the appropriate 3-(1-adamantyl)-propionitrile as the starting material, The compounds are prepared by the procedures described in Examples 98-104.

Example 117 A pharmaceutical composition for intraperitoneal injection is prepared to test compound (IVA). combination The intraperitoneal injection solution containing IVA was added to an aqueous carrier containing 10% DMSO. Dissolves in the body.

Example 118 Compound (TVA) was tested in Lewis (Lewis) via the test composition of Example 117. Animals were given 30 mg of compound (I [[A)] by intraperitoneal injection; Do it twice. A control is used that receives vehicle only.

At specified times post-dose, animals are sacrificed and plasma samples prepared.

The plasma is extracted with cold 0.5N HCQO4 and neutralized with solid NH,HCO. past After removal of chlorate, the extract was loaded onto a reverse phase column (SpherisorbODS+). Subject to HPLC. A significant increase in plasma inosine was observed upon ingestion of the compound (IVA). observed in plasma collected from animals.

Shi119-129 The compounds prepared in Examples 106 to 116 were used for the preparation of Example 117. The resulting injection solution is tested according to the procedure of Example 118. blood A significant increase in plasma inosine was observed in plasma from animals fed compounds of the invention. be done.

Example 130 In this example, 3-7 clopentyl propionitrile is prepared.

57.7 g (0.36 mmol) of 3-cyclopentylpropionyl chloride in water/ Add dropwise to 400 ml of a large excess of concentrated ammonia hydroxide cooled in a salt bath. white solid The heavy body suspension was stirred overnight, collected by filtration, washed with cold water, and boiled for 2 hours. Recrystallize from s/y). A glossy white plate of the amide was placed on phosphorus pentoxide in a vacuum. Dry with. Yield: 31°6g (82.3%); Melting point: 122°C 23.5 g (0,168 mmol) of the amide while being protected from atmospheric moisture. A solution of POCQ in 150 mQ is heated at 120° C. for 1 hour.

The oil bath was cooled to about 70°C, excess POCQ was distilled off under vacuum, and the cooled residue Pour over about 300g of water. By carefully adding solid Na, Co, The mixture is neutralized and extracted with several portions of Et, O.

The dried (Na2SOa) extract was evaporated to give a clear, pale yellow oil. This is then distilled in vacuo to obtain the desired nitrile. Yield: 16°86g (82 %), boiling point 88.0-88.5℃/8.7mm, MS (EI): m/z 122 (MH)”: IR (cap film), 2245 cm-’ (CN );'HNMR, δ1.67 (q, 2゜CHt CH-CN), 2, 3 6 (t, 2, CH-CN), 6 approximately 1.11.1.63 in complex multiplet. 1.86 (Cyclopentyl proton) Example 131 In the synthesis of the present invention, 3-cyclopentylpropionitrile from the previous example was further processing. 3-Cyclopentylpropionitrile 1 under dry nitrogen atmosphere 4.8 g (0.12 mol), sodium hydride 5.8 (0.24 mol), and A mixture of 300 mQ of anhydrous tetrahydrofuran and anhydrous tetrahydrofuran was heated at 52°C for 15 minutes in a water bath. Then, a solution of 13°3 g (0.18 mol) of ethyl formate in 100 mf2 of THF was Add over a period of minutes. After 2 hours at 50-55°C, 9 g of NaHl and and a second portion of 5.0 mff of HCO, Et, followed within 30 minutes. Add third portion of O,Et (unreacted nitrile is inserted into next step, first (recovered during the purification process). Stir the thick paste overnight and cool to room temperature. Vol. The emitting substances were evaporated under reduced pressure and the remaining pale yellow crust was washed with a minimum volume of cold line fishing. 0 ml at approx. 0°C. The pH of the solution was adjusted to 6.0 by adding 6N HCQ. Adjust to 0 and extract with CHCQ3 (3x 100mj). Wash the extract with water and dried over Na, So, and evaporated in vacuo to give a thick amber oil. Ru. 15.6 g of this crude product is used in the next step without further purification.

1%”ヱ Gly7 dimethyl ester hydrochloride 19.31g (0,154 mol) and anhydrous vinegar 12.61 g (0,154 mol) of sodium chloride was added to the crude formyl from the previous example. Added to a solution of 15.6 g of the compound in MeOH/H*○ (4:1.500 mg) Add. After 24 hours, the MeOH was evaporated in vacuo and a mixture of water and oil is extracted with chloroporum. Dry the chloroform layer (Na2SO2) and evaporate. An amber colored oil is obtained which is applied to the licage column. Chloroporum 2 major bands eluted with (1) 3-/clopentylpropionitrile 8° 22 g (66.7 ml of the nitrile used as starting material in the previous step) mole or 55.6%), and (2) 345 g of the desired enamine (present in the starting material). MS (FAB ): 223 (M+H)” Example 133 2.53 g of ethyl chloroformate (2 3.3 mmol) and 345 g (46.6 mmol) of the enamine from Example 36 above. and DBN5.78g (46.6 mmol) of dry CH2CQ w50m Add warm solution to Q medium solution. After stirring for 1 hour at ooc, the solution is left at room temperature overnight.

After checking the progress with TLC, CQC○zEt 0.5mC and DBN3 ．． Add more 0r12 to complete the conversion and leave the solution for 24 hours. volatility The material was evaporated in vacuo and the viscous residue was removed through a short phosphoric gel column (the primary purpose of which was 4.50 g of N-protected pyrrole (98%) was obtained and used in the next step without further purification.

Kanou Δ Joshu 4.50 g (15.3 mmol) of the N-protected pyrrole of the previous example in MeOH1 Add solid Na, CQ 31.62g (15.3 mmol) to the solution in 00mQ The reaction mixture is stirred at room temperature for 48 hours and the resulting deprotected pyrrole is separated.

The mixture was evaporated to dryness and the residue was thoroughly triturated with 50 mQ of water to remove inorganics. Dissolve and extract with CHCQ3 (3x 100 mC). Dry the extract N　a　　S　O4), evaporated to give a viscous gum, which was dried in vacuo. The substance then crystallizes and is suitable for use as an intermediate without further purification. be. Yield N2.97g (87.4%). However, even more thorough refining , /Rikakel/CHCl! , using column chromatography or toluene This can be done either by recrystallization from silane/fuclohexane (1:3). .

Example 135 Example 1: 2.62 g (16.03 mmol) of benzoyl isothiocyanate 2.97 g (13.36 mmol) of unprotected pyrrole of 34 dry CH,C Q, dropwise into the solution in 100mQ. After 1 hour at room temperature, the solution explodes and forms a gummy Dissolve the residue in 100 mQ of Et,O and separate the crystalline solid almost immediately. . Yield: 1.75. The Et, O filtrate was heated to boiling, and an equal volume of warm chloride was added. Dilute with Sun. Upon slow cooling, more of the thioureide product 1 is released from the solution. 58 g are obtained. Total yield 3.33g (64.6%). small amount of thioureide The product is recrystallized from hot Et, 0/ml milk powder (15 m4 each). Melt Point 123-125°C0M5 (FAB): 386 (M+H)”.

Elemental analysis C7゜Ht　s　N　303S・0.45CaHre Calculated value ( %) C, 64,40; H, 6,76; N, 9.93 Actual value (%) C, 64,51 , H, 7, 10; N, 9.93 Example 136 2.60 g (18.32 mmol) of methyl iodide was added to the thiourei of Example 135. 3.21 g (8.33 mmol) of product and DBN1.

24 g (9.99 mmol) of dry CH, (J!) was added to a solution in 80 mQ. Add at °C. The solution was stirred at 0 °C for 15 min, at room temperature for 1 h, then in vacuo. Evaporate with. The cruel solution in CHCQ3 was purified using CHC (2, A homogeneous fraction of the methylthio intermediate compound is subjected to chromatography on a liquid vesicle. get. Yield 2.46g (74%) Example 137 Methylated Example 136 in 150 mQ methanol saturated with ammonia at 0°C. A solution of 2.07 g (5.18 mmol) of ruthio compound was lined with glass. Heat at 90-95°C for 24 hours in a stainless steel cylinder. cooled bottle The contents of the chamber were evaporated in vacuo to remove the 2-amino compound (IVC) as opposed to the 2-amino compound (IVC). Compound (IVC), benzamide, and by-products that are 2-methylthio derivatives You get a mixture of things. The mixture was stirred vigorously for several minutes with Et, 0, 75 mQ. Stir and filter the insoluble white solid, washing with Et, O. The filtrate is It contained nzamide and 2-methylthio components.

Et, 〇 - A solution of 1.138 of the insoluble solid in Me OH was added to approximately 1 og of silica. evaporate with the liquid. The powdered residue was passed through a silica gel column (95:5:1). Elution yielded 252 mg of 2-methylthio by-product (MS (FAB): 264 (M+H)”) and 679 mg of the desired 2-amine product (IC) (56,4 %). (IVc) to boiling isopropyl acetate in a Soxhlet apparatus. Recrystallize by extraction. The white crystals were collected in three yields and dried over phosphorus pentoxide in vacuo. Dry at 110°C for 7 hours. Yield 540mg (44.9%); Melting point 324 ~326°C decomposition, MS (FAB): 233 (M+H)”: Elemental analysis C, ,H,,N,O as Calculated value (%) C, 62,05; H, 6,94; N, 24.12 Actual value (%) C ,62,04;H,7,11:N,24.48 Example 138 The compound of Example 137 is tested for enzyme inhibitory activity by the procedure of Example 9.

IC, at 1 mM phosphate. is O0298M and at 50mM phosphate is TCS, is 1.8 μM.

Cold service and Dannu A name 2-amino-7-(R ) -3H,5H-pyrroloC3,2-d]pyrimidin-4-one of the present invention Prepare the following compounds.

"J Example 139 R, = 3-methylcyclopentyl implementation fl114OR, = 2- Chlorocyclopentyl Example 1'41 R,=3-)lifluoromethylcyclope Example 142 R,=3-methoxyclopentyl Examples 130-137 using (lopentyl)-propionitrile as starting material The compounds are prepared by the method described in .

cold sputum winter A pharmaceutical composition for intraperitoneal injection is prepared to test the compound (IC). Applicability The intraperitoneal injection solution containing the compound (IVC) was added to an aqueous carrier containing 10% DMSO. Dissolves in the body.

Kangemasujo 44 Using the procedure of Example 112, compound (IVC) was added to the test composition of Example 143. Lewis et al. injected intraperitoneally and compare the results with controls. Compound (IVC) A significant increase in plasma inosine was observed in plasma collected from animals ingested with be done.

Example 145 In this example, 3-cyclohexylpropionitrile is prepared.

Cyclohexanepropionic acid (50 g; 0.32 mol) and thionyl chloride (152 g: 1.28 mol) was left overnight. , and then evaporated to an oily residue. This brutality is reduced to 28% ammonia water at 25℃. (270 ml) in portions and the mixture is stirred for about 2 hours. raw obtained The product is collected by filtration, washed with cold water and recrystallized from approximately 2 liters of boiling water. . The shiny white plate-like crystals of this amide are dried in vacuo over P,○; Yield: 45.5 g.

in SOCI, (200.3 g; 1.68 mol), protected from moisture. A solution of the above amide (45.5 g, 0.293 mol) in water is refluxed for about 6 hours.

The oil bath was cooled to about 70'C and the excess 5OCI was distilled off under vacuum to the cooled residue. Pour over water (300g). Add solid NaIC to the mixture carefully. Neutralize with and extract several times with Et and O. Dry (at N atS 04) The extracted extract was evaporated to give a clear pale yellow oil. Distill this in a vacuum , obtain the desired nitrile: yield 42.0 g Example 146 3-Cyclohexylprobionitrile of Example 145 was used in the synthesis of the present invention. , further processing. 3-Cyclohexylpropionitrile under dry N, atmosphere (22,3 g, 0.16 mol), sodium hydride (5,38,0,224 mol) ), and anhydrous tetrahydrofuran (120 ml) in a water bath at 52°C. Heat for 15 minutes and dissolve ethyl chloride (55.4 g, 0 ．． 75 mol) solution is added over 45 minutes. After 2 hours at 50-55°C, 2 Add Na, H (2.0 g) and HCO, Et (5.0 ml). Unreacted nitrile is inactive in the next step and must be recovered in the first purification step. The reaction mixture is stirred at 55° C. for about 3 days and then cooled to room temperature.

The volatiles were evaporated under reduced pressure, and the remaining pale yellow colored skinned autumn leaves were washed with a minimum amount of cold water (approximately 75 m Dissolve in 1) at 0°C.

This solution was adjusted to 1) H6,O by addition of 6N HCl and CHCl-(3 xlOOml) and extract. The extracts were washed with H2O and dried on N a 1S O4. and evaporate in vacuo to give a thick amber oil. This crude production The following reaction glycine methyl ester hydrochloride (30, 60 g, 0.24 mol) and anhydrous sodium acetate (19.99 g, 0.24 mol) ) of the above example in MeOH/HzO (4:1.500 ml). Add to a solution of the prepared formyl compound (25.22 g). 24 hours later, M e O The H is evaporated in vacuo and the water and oil mixture is extracted with CHCl. CH Dry the Cl layer (with Na, So) and evaporate to give an amber oil. . Apply this to a glue gel column. Elution with CHCl3 reveals two major bands. (1) 3-cyclohexylpropionitrile (starting from the previous step) (used as raw material) and (2) desired enamine, yield 16g0 Example 1 48 Under a nitrogen atmosphere, add ethyl chloroxate (1.38 g, l 2.7 mmol). Enamine of Example 147 (2,0 g) in dry CH, CI, (50 ml) , 8.46 mmol) and DBN (2.1 g.

169 mmol) dropwise with external cooling in a water bath. O After stirring for 1 hour at 'C, the solution is left at room temperature overnight.

After checking the progress with TLC, further add ClC0,Et (0.5ml) and DB The conversion is completed by adding N (t 5 ml) and the solution is left for 24 hours. Volatile The fraction was evaporated in vacuo and the viscous residue was purified on a short glue gel column (mainly The goal is to remove DBN with low mobility) to obtain N-blocked pyrrole.

This is used in the next step without further purification.

Example 149 N-blocked pyrrole (2 , 6 g, 8.43 mmol), solid Nazc○3 (2.23 g, 21 ○7 mmol) was added and the reaction mixture was stirred at room temperature for 48 hours. Separate the locked pyrrole. The mixture was evaporated to dryness and the residue was dissolved in H2O (50 ml). Thoroughly pulverize with CHCl 3 (3X 100 m) to dissolve inorganic substances. Extract with l). The extract was dried (N a , S O,), evaporated and A viscous rubbery substance is obtained. This was purified using silica gel using CHCl as the eluent. Purify on column; yield 1.67 g (84%); m, p, 73-74 °C0 Big Blood Toyokami J Ryo Hendiyl isocyanate (0.74 g, 4.02 mmol) was added to dry CH!　 Deprolylated pyrrole (of Example 149) in CI t (20ml) 0.95 g) dropwise. After 1 hour at room temperature, the solution was evaporated and the rubber When the residue was dissolved in Et, ○ (100 ml), a crystalline solid was almost immediately separated. Let go. Et, ○Heat the filtrate to boiling and extract with an equal volume of warm cyclohexane. . Upon gradual cooling, more thioureide product is obtained from the solution: total yield 1 41 g (88%); m, p, 156-157 °C0 Methyl iodide (1,1 g, 7 ．． 6. Dried CH, CI! Example 1 in (20ml) 50 thioureido product (0.96 g, 2.61 mmol) and 1,5-di Solution of azabicyclo[43°0]nor-5-nene (0.38 g, 3.0 mmol) Add o’c to. The solution was stirred at 0 °C for 15 min, at ambient temperature for 1 h, then Evaporate in vacuo. CHCl, solution of cruelty in CHCl.

Chromatography on a silica gel column using Obtain a homogeneous fraction of the intermediate compound: Yield 0.92 ga Soukou Plate 5 liters Example 151 in 50 ml MeOH saturated with NH, at 0°C of methylthio compound (0.8 g, 1.93 mmol) on the surface with a glass. Heat in a covered stainless steel bomb at 90-95°C for 24 hours. cold The contents of the cooled cylinder were evaporated in vacuo to form compound (IVD), benzamide. , and 2-methylthio derivatization as for the 2-amino compound (IVD) A mixture of by-products is obtained. This mixture was mixed with about 75 ml of Et and O. Stir vigorously for a minute and filter off the insoluble white solid, washing with Et, O. In the filtrate , contained mostly benzamide and 2-methylthio components. Et, ○non A solution of the soluble solid (0,390 g) in MeOH was added with approximately 10 g of silica gel. evaporate to. Powdered residue is layered evenly on top of the gel ram, then eluted with CHCl, /Me○H/HOAc (95:5:1) to A methylthio by-product and the desired 2-amino product (IVD) are obtained. (IVD ) by extraction into isopropyl acetate in a Soxhlet apparatus. It recrystallizes. The white crystals were collected in three parts and heated in vacuum at 110°C. = Dry on Os for 7 hours; yield 49%, mp>300'C; Elemental analysis, as CI3H, 5N40 Calculated value (%): C, 63,39, H, 7,36, N, 22.74 Actual value (%): C, 63, 50, H, 7, 74, N, 22.67 Example 153 The compound of Example 152 is tested for enzyme inhibitory activity as in Example 105.

For 1 mM phosphate, IC. is 0.037 gM, and 50 mM phosphene At default, the IC5° is 2.2 μM.

Cold weather ±54 The compound of Example 152 was tested to determine the toxicity of 2-deoxyguanosine (d-Guo). Measuring effectiveness in augmentation [D.A. Shebanoch (D, A., Sc. hewach et al., Cancer Research, vol. 46 , p. 519 (1986), and J.C., 5ir. Agents and A ctions), Vol. 21, p. 253 (1987)]. CCRF-CEM Cells are grown in RPMI-1640 medium. Suspension cultures of these cells d-Guo at a predetermined concentration (562 μM) and various concentrations of the compound were added to 24, 48, and 72 hours later, cell counts were determined using a Coulter cartridge. At the counter. From these data, IC,. cells between O and 72 hours as the concentration of compound required to reduce the increase in number by 50% of that of the control culture. Calculated to be 20 gM.

Compound 2-amino-7-(3-methylcyclohexylmethyl)-3H.

Prepare 5H-pyrrolo[3,2-cll pyrimidin-4-one. First, 3- The above except that (3-methylbenzyl)-propionitrile is used as the starting material. Using the procedures described in Examples 146-152, the aryl derivatives 2-amino-7 -(3-methylbenzyl)-3H,5H-pyrrolo[3,2-d'l pyrimidine -4-one is produced. A in trifluoroacetic acid (TFA) (20 ml) Reel derivative (0.2g.

0.78 mmol) with PtO at 60 1 b/i n' for 24 hours Hydrogenate for a while. The catalyst is filtered off through a bed of Celite and the filtrate is evaporated. metabolize the residue Grind with nol and leave overnight in the refrigerator.

The resulting crystallized trifluoroacetate precipitates from solution and is collected by filtration. TF Suspend A salt in 8 ml of H2O, adjust the pH to 8 with concentrated NH and ○H, and treat with ultrasound. Ru. The pure product is collected, washed with H,O and dried: yield 165 mg (81 %); mp282°C0 elemental analysis, C,, HtON, as o Calculated value (%): C, 64,60; H, 7,74; N, 21.52 Actual value (%): C, 64,24; H, 7,96; N, 21.51 Example 156 3-(3-trifluoromethylbenzyl)-bropionitrile as starting material 2-amino-7- (34 liters) was prepared by repeating the procedure described in Example 155 using fluoromethylcyclohekifluoromethyl)-38,5H-pyrrolo-[3,2-d ] Preparation of pyrimidin-4-one. Yield 69%; mp 165°C.

Elemental analysis, C, 8, 7N, OF, ・0.6H, ○ Calculated value (%): C, 5 1,72; H, 5,64; N, 17.23 Actual value (%): C, 51,82: H , 5, 71; N, 16.81 Example 157 The compound described in Example 155 was tested for enzyme inhibitory activity as in Example 105. do. At 1mM bosphate, the Ic50 is. , 025gM, and 50mM In Pos7A1-, IC,o is O,0,820 compound described in Example 156. Test for enzyme inhibitory activity as in Example 105. At 1mM phosphate ,IC,. is 0.020 gM and at 50 mM phosphate, the IC6° is 0. ．． 740 gM In this example, 2-bromosic in toluene (300 ml) Lohebutane (25,57 g; 144.38 mmol); B+, +, 5 nH ( 50.42 g; 173.26 mmol), acrylonitrile (1532 g; 288.77 mmol) and a solution of AIBN (1.13 g), 3-Cyclohebutylpropionitrile is prepared according to the procedure of Example 97.

Yield: 16 g Hmp oil.

Fallen Emperor Toyotoshi Tatsuyu The 3-cyclohebutylpropionitrile of Example 159 was used in the synthesis of the present invention. , further processing. 3-cycloheptylpropionitrile under dry N atmosphere (8.5 g, 56.19 mmol), sodium hydride (2.6 g, 112. 3’l mol) and anhydrous tetrahydrofuran (100 ml) in a hot water bath. Ethyl formate (2 0.81g.

280.99 mmol) is added over 45 minutes. 50-55°C 2 After an hour, a second dose of NaH (1,35 g) and HCO.

Add Et (to, 4 g) and add a third HCO, Et within 30 minutes. (Unreacted nitrile is inactive in the next step and is recovered in the first purification step.) ). The thick paste is stirred overnight and then cooled to room temperature. Vol. The residue was evaporated under reduced pressure and the remaining pale yellow crust was washed with a minimum amount of cold water (approximately 150 m Dissolve in 1) with O'C. This solution was adjusted to pH 60 by addition of 5N HCI. Separate and extract with CHCls (3×100 ml). extract in H2O Washed with ・Obtain a dark colored oil. This crude product can be used in the next reaction grid without further purification. Synmethyl ester hydrochloride (9.35 g, 74.47 mm + J moles) and anhydrous Sodium acetate (6.10 g, 74.47 mmol) was dissolved in MeOH/H,O (4 : l, 250 ml) of the crude formyl compound of Example 160 (8.9 g ; 49.65 mmol). After 24 hours, M e OH Evaporate in vacuo and extract the water and oil mixture with CHCl. CHCl The three layers were dried (at 04 Nats) and evaporated to give an amber oil. Ru. Apply this to a silica gel column. When eluted with CHCl3, two major Bands are obtained: (1) 3-cyclohebutylpropionitrile (previous step (used as starting material) and (2) the desired enamine, which is CHCl 3/Et, ○ Recrystallize from the mixture; Yield 6.18g; m, p, 57~ 58℃.

Example 162 Under a nitrogen atmosphere, ethyl chloroformate (4.01 g, 37.03 mm!J mol) was Enamine of Example 161 (6,18 g, 24.69 mmol) and DBN (9°19 g, 74.04 mmol) Add dropwise to the solution while externally cooling in a water bath. Stir at 0℃ for 1 hour. After that, the solution is left at room temperature overnight. After checking the progress with TLC, further CIC○ Add S+:t (5 ml O) and DBN (3.0 ml) to complete the conversion. , leave the solution for 24 hours. Evaporate the volatiles in vacuo and remove the viscous residue with a short sieve. Purification on Kagel column (main purpose is to remove DBN with low mobility), N-blocked virol is obtained. This should not be further purified (used for the next step). There is.

Example 163 Example 162 (7) N-pro, virol trichloride in MeOH (100 ml) (7.8 g, 24.19 mmol) of solid Na.

Add COs (6.41 g, 60.48 mm) to the reaction mixture chamber. After stirring at room temperature for 48 hours, the resulting deblocked virol separates. Steam the mixture The mixture was evaporated to dryness, and the residue was sufficiently ground with H and O (50 ml) to dissolve the inorganic matter. Obtain an extracted mush with CHCl, (3xlOOml). This, /Rikakel/CH Purified by column chromatography using Cl: yield 4 g; m, p , 88-89°C.

Yutaka Ouse↓64 Benzoyl isocyanate (1.5 g, 8.96 mmol) was added to dry CH, CI , (50 ml) of the deblocked virol of Example 163 (1,99 g, 7.95 mmol) dropwise.

After 1 hour at room temperature, the solution was evaporated and the gummy residue was dissolved in Et,○ (100 ml). The crystalline solid then separates almost immediately. Et.

○ Heat the filtrate to boiling and extract with an equal volume of warm cyclohexane.

Upon gradual cooling, more thioureide product is obtained from the solution; yield 2.8 9g (88%); m, p, 158-159°C.

Example 165 Methyl iodide (1.7 g, 11.96 mmol) was added to dry CH*Clt (80 The thioureide product of Example 164 (1.7 g, 4.1 mmol) in ) and DBN (0.56 g, 4.52 mmol) at ooC. Ru. The solution was stirred at OoC for 15 min and at ambient temperature for 1 h, then evaporated in vacuo. let A solution of the residue in CHCl was purified by silica gel using CHCl as eluent. chromatography on a column to obtain a homogeneous image of the methylthio intermediate compound. get a minute.

Cold man↓lヱ Real IP+ in 50 ml MeOH saturated with NH at 0°C A solution of 165 methylthio compound (1.72 g, 4.02 mmol) was added to a glass plate. Heat at 90-95℃ for 24 hours in a stainless steel cylinder lined with Ru. The contents of the cooled bomb are evaporated in vacuo to give compound (IVE), benzene. amide, and 2-methylthiamine as a 2-amino compound (IVE). A mixture of by-products, which are derivatives of fluorine, is obtained. This mixture was mixed with about 75 ml of Et, ○. Stir vigorously for several minutes and filter off the insoluble white solid, washing with Et,0. filter The liquid contained mostly benzamide and 2-methylthio components. E A MeOH solution of the O-insoluble solid (0,850 g) was added to approximately 10 g of silica gel. evaporate with the liquid. Evenly layer the powdered residue on top of the silica gel column. , then eluted with CHCl3/MeOH/HOAc (95:5:1). , yielding the 2-methylthio by-product and the desired 2-amino product (IVE). ( IVE) is extracted into boiling isopropyl acetate in a Soxhlet apparatus. recrystallize by The white crystals were collected in three parts and heated at 110°C in vacuum. , P, ○, dried for 7 hours; yield 54%, mp>300°C decomposition; Elemental analysis, C,,H,. As N40 Calculated value (%): C, 84, 60, H, 7°74. N, 21.52 actual measurement value (%)・ C, 64, 78, H, 8, 01, N, 21.61 Example 167 The compound of Example 166 is tested for enzyme inhibitory activity as in Example 105.

For 1 mM phosphate, IC. is 0.030 gM, and 50 mM phosphene IC, is 0.840 gM.

Example 168 Using the procedure of Example 97, 3-(1-norbornanyl)-propionitrile was prepared. Produced from 1-bromonorbornane, 3-(2-norbornanyl)-propioni Tolyl (mixture of 2-exo and 2-endo) from 2-bromonolbornane Manufacture. According to Examples 98-104, these propionitrile were converted into compounds (IVF), IV(G) and (IVH).

Example 169 Using the procedure of Example 97, 3-(1-bicyclo[3,2,1]octanyl)- Propionitrile, 3-(2-vinculo[3,2,1i octanyl)-propylene Onitrile, 3-(3-pink O[3,2,1i octanyl)-propionite lyl, and 3-(8-bicyclo[3,2,1]octanyl)-propionitri 1-bromobi/li0 [3, 2, 1 co-octane, 2-promobi, respectively. Bisik o [3,2,t] octane, 3-promo vincro [3,2,11 octane and 8-promobicyclo[3,2,1]octane. implementation According to Examples 98-104, these propionitrile were mixed with compounds (IVL) and and related 2-bicyclo[3,2,1F octanyl, 3-vincro[3,2,1] Conversion to octanyl and 8-vinclo[3,2,1]octanyl derivatives.

61”14 (1972) using a modification of the procedure disclosed in 61”14 (1972). ] Oct-6-one is reacted with trimethylsulfoxonium iosite, epoxide is obtained, which is then treated with boron trifluoride etherate to obtain an epoxide. 6-bicyclo[,3,,2,1]octane by converting to aldehyde Prepare ruboxyaldehyde. Hand of Dutch Patent No. 6.610.204 in a pyridine/toluene solution with a catalytic amount of ammonium acetate. By refluxing for 72 hours, this aldehyde was condensed with cyanoacetic acid and the corresponding Acrylonitrile is obtained. Next, this acrylonitrile is (F’rof 1tt) et al., Journal on Organic Chemistry ( J, Org.

40, p. 127 (1975). Hydrogenation using palladium-on-carbon catalyst in alcohol to give 3-(6-vinc) ro[3,2,1]octanyl)-propionitrile is obtained. Examples 98-104 Accordingly, this propionitrile can be converted into 6-bicyclo[ Convert to 3,2,1-stone octanyl derivative.

Ōokuba】Yu” Using the procedure of Example 97, 3-(l-vinculo[3,a,B nonanyl)-pro Pionitrile and 3-(3-vincroc3.3.t:nonanyl)-propylene Onitrile was converted into 1-promobicyclo[3°3, ij nonane and 3 - Promo Vincro L3.3.1] produced from nonane. Examples 98-104 Therefore, these propionitrile compounds (IVM) and the related 3-vinc E3.3 1] Convert to notnyl derivative.

Example 1-! Vinculo[3,3,1]nonan-9-one was reacted according to the procedure of Example 171. to form the corresponding aldehyde, from which the corresponding 3-substituted propionite 9-vinchloC3, which is related to compound (IVM) 3,1] into a nonanyl derivative.

Example 173 Following the procedure of Example 170, 2-vinculo[3,3,1]nonanecarpoki/a reacting the aldehyde to form the corresponding 3-substituted propionitrile, then This is a 2-bicyclo[3,3,11 nonanyl derivative related to compound (IVM). Convert to

Example 174 Using the procedure of Example 97, 3-(1-fluadamantyl)-propionitrile is produced from 1-promonolatamancune and 3-(2-noradamantyl)-propylene. Ropionitrile is produced from 2-bromofluadamantane. Examples 98-10 4 to convert these propionitrile to the final compound (IVN) .

Example 175 Following the procedure of Example 170, 3-noradamantane carbo-bovine dialdehyde was reacted. correspondingly to form the corresponding 3-substituted propionitrile, which is then converted into the compound (IVN) to a related 3-fluadamantyl derivative.

Example 176 Following the procedure of Example 170, noradamantan-7-one was reacted to give the corresponding from which the corresponding 3-substituted propionitrile is prepared. This was then converted into a 7-fluadamantyl derivative related to compound (IVN). exchange.

Example 177 Using the procedure of Example 97, 3-(1-bicyclo[2,2,]octanyl)propylene Pionitrile is prepared from 1-promovincro[2,2,2E octane and 3- (2-vinculo[2,2,23octanyl)propionitrile Produce H from chlorine, 2.2.22 octane. According to Examples 98-104, this These propionitrile compounds (IVK) and related 2-bicycloC2,2 , 23 into the octanyl derivative.

Kanpei Commercial Yul Using the procedure of Example 97, 3-(1-fluhornenyl)propionitrile was added to 1 - produced from bromonolbornene. According to Examples 98-104, this propylene Convert onitrile to compound (IVI).

Example 179 Using the procedure of Example 170, 5-fluvocine-2-carboxaldehyde (2 - a mixture of endo and 2-exo) to react with the corresponding 3-substituted propionyl A nitrile is formed which is then converted to compound (IVJ).

K blood plate manufacturer In this example, the above intermediate compound was manufactured by Siemens, C.P. enz, (i, P,); Engelhard, H. H,) [Hemi 7'/Engineering] Berichte (Chet Ber,), 1962, 95, p. 195].

/a/acetic acid (25.38 g, 298.38 mmol), 2,3.5-tricloyl Robenzaldehyde (25.0 g, 119.35 mmol), ammonium acetate (500mg), toluene (120ml), and birinone (65ml) mixed 16 in a flask equipped with a Dean-Stark collector and a reflux condenser. Heat to reflux for an hour. The solvent was evaporated in vacuo and the residue was extracted with CHCl, H2 Washed with O, dried (NatS O) and evaporated to give the crude product. Ru. This was carried out using a silica gel column using a hexane-EtOAc mixture as eluent. Purify by mucochromatography. Yield 123.69g (73%); mp 90~91°C0 In this example, the above intermediate compound is prepared. in THF (100ml) NaH (1,56 g, 65.05 mmol) and ethyl formate (14,78 g, 199.51 mol) of Example 180 at room temperature under a nitrogen atmosphere. Substituted pentanedinitrile (10.17 g, 37.17 mmol) was added to obtain The reaction mixture was stirred for 24 hours. The volatiles are evaporated in vacuo at room temperature. water (50 ml) was added to the residue at 0-5 °C and the solution was dissolved in 30% concentrated HCI (V/V ) to adjust the pH to 5-6. The heavy oil was extracted with ethyl acetate, Hto (1 Wash (×100 ml) and dry (MgSO, Te). Ethyl acetate The oil layer is evaporated to give a reddish-brown oil (11.0 g). This is further refined Use in the next step without washing.

In this example, the above intermediate compound is prepared. Glycine methyl ester hydrochloride ( 8.17 g, 65.06 mmol) and sodium acetate (5.33 g, 65 ．． 06 mmol) in a mixture of MeOH (80 ml) and H2O (20 ml) of the crude formyl compound of Example 181 (110 g) in The resulting solution is stirred at room temperature for 22 hours. After evaporating the solvent at room temperature, the residue was dissolved in acetic acid. Chill and extract. The organic layer was washed (with H,O) and dried (with MgSO4). Evaporate to obtain an oil. Fura/Ukaram using CHCl as eluent Soot the pure desired enamine by chromatography Obtained as a mixture of lance isomers.

This is recrystallized from MeOH. Yield 110.41g (75%), mp14 2~143°C0 In this example, the above intermediate compound is prepared. Dry CH, CI.

Example 182 (7) enamine (10,0 g) in (100 ml).

A solution of 26.84 mlJ mol) was cooled to 0°C and 1,5-dia Zabincro [4,3,OF no-5-nene (10,53g, 8479 mmol) and then with ethyl chloroformate (6.90 g, 6357 mmol). Ru. The solution is stirred at O'C for 1 hour and then at room temperature for 48 hours. Volatile matter in vacuum Evaporation gives a viscous dark gum. This was carried out using CHCl as the eluent. Purify by flash column chromatography on lica gel using .

All fractions containing the desired N-protected pyrrole were collected and evaporated to give an effervescent clear A pale yellow substance is obtained. This was stirred in MeOH (100 ml) and the crystalline Obtain a substance. This is recrystallized from CHCl, -MeOH. Yield 8.92g (7 4.7%), mp160-161°C.

In this example, the above intermediate compound is prepared. in MeOH (300ml) N-protected pyrrole of Example 183 (8.6 g).

1934 mmol) was mixed with Na2COs (5.12 g, 48°34 mmol). mol) and the reaction mixture was stirred at room temperature for 17 h. Locked pyrrole separates. Solid sodium carbonate was removed by filtration and M e. Wash thoroughly with OH. Reduce the volume of the filtrate to 25ml and store it in the refrigerator. After standing for 1 hour, 523 g of crystalline product are obtained. When the mother liquor is further concentrated, An additional 0.14 g of pure product was obtained. Total loss ff16.45g (89.5% ), mp　7L-181'C.

In this example, the above intermediate compound is prepared. in dichloromethane (looml) Suspension of pyrrole (5.83 g, 15.64 mol J mol) of Example 184 in Benzoylisothio/anate (2.88 g, 17.5 g) was added to the solution at room temperature under nitrogen. 64 mmol) is added.

The reaction a mixture is stirred for 30 minutes and the desired thioureido compound is separated. that Further, benzoylisothionoa (0.5 ml) was added to the solution, and the mixture was re-denatured for 30 minutes. Stir for a minute. Explode the solvent to dryness and triturate the bright yellow residue with methanol. Ru. The white crystalline material was isolated by filtration and purified from a chloroform-ether mixture. The desired thioureido compound is obtained as an analytically pure sample. Collection In this example, the above intermediate Prepare the compound. Example 18 in dry CHtcIt (200ml) 5 (675 g, 12.6 mmol) and 1,5-diaza Solution of vinclo[4,3°0]nor-5-nene (1,76 g, 14.20 mmol) The solution was cooled to 0°C and treated with methyl iodide (5.20 g, 36.65 mmol). Ru. The reaction mixture is stirred at 0°C for 10 minutes and then at room temperature for 1 hour.

The solvent was evaporated at room temperature and the residue was extracted with CHCl, H,O (2X 50ml) The glassy foam ( 6.95 g) is obtained. This is used in the next step without further purification.

K Whip Plate Upper Danyu In this example, the above compounds A and B are prepared. Compound A is a compound of the present invention. Compound B is an intermediate. Example 18 in MeOH (200ml) A solution of the methylthio intermediate of 6 (6.90 g, 12.54 mmol) was added at 0 °C. , in a stainless steel cylinder saturated with ammonia and covered with glass, 1 Heat at 00°C for 20 hours. Bring the reaction mixture to room temperature and evaporate the solvent at room temperature. . The crude mixture was purified with furanone on silica gel using CHCl3 as eluent. Purification by two-column chromatography yields 8B (1.1 g, 21%) , mp290-291°C, was obtained, followed by CHC], -MeOH (95: 5) Pure 8A (2,76g, 575%), mp284-285℃, was gotten.

Example 188 The compound of the invention of Example 187 is tested for enzyme inhibitory activity.

A brine nucleoside phosphorylase (PNP) enzyme assay is performed. here The PNP activity (IC,.) of compound (8A) was found in calves. [14C]-inosine to [+4C2,-hypoxa radiochemically determined by measuring the formation of chlorine [biomedicine] Biomedicine), 1980, vol. 33, p. 39. 1mM phosphene At IC,. is o, 64 gM, and at 50 mM phosphate, IC, . is 1oμM.

3-(3-chlorophenyl)-benzene according to the procedure described in Examples 180-187. Using notandinitrile as discovery material, 3-(3-chlorophenyl)-3- [2-Ami/-4-oxo-3H,5H-pyrrolo[3゜2-dHpyrimidine-7 -yl)propanenitrile is prepared. Yield 545%, mp! 57-158°C.

Example 190 The following compounds are also prepared following the procedures described in Examples 180-187 (1-9 ).

3-Aryl-3-(2-amino-4-oxo-3H,5H-pyrrolo [3゜2 -d3　pyrimidin-7-yl)propanenitrile In the formula, aryl is the following: (1) phenyl, 2゜3-dichlorophenyl, 3-methylphenyl and 3-methoxyphenyl, (2) chenyl (2- and 3-), (3 ) furanyl (2- and 3-), (4) pyridinyl (2-13-1 and 4-) , (5) pyrrolyl (2- and 3-), (6) thiazolyl (2-24-1 and 5-), (7) 2-pyrazinyl, (8) pyridazinyl (3- and 4-), and and (9) pyrazolyl.

Example 191 Appropriately substituted pentanes/nitrates according to the procedures described in Examples 180-187 Starting from ril, the following compounds 10-14 and 21 are prepared. Compound 15 ~20 and 22 are prepared from the corresponding unsaturated aryl analogs of Example 190 . In this method, the nitrile group of the unsaturated analogue is first removed by acid or base catalysis. converted to an amide group by hydrolysis, and then converted to an unsaturated aryl group by known catalytic reduction. After converting the nitrile group into a saturated R1 group, the amide is reconverted to a nitrile by known dehydration methods. Convert.

3-(Substituted)-3-(2-amino-4-oxo-3H,5H-pyrrolo[3゜2- cB pyrimidin-7-yl)propanenitrile In the formula, R/l is each of the following l○) 1-atamantyl, 11) 2-atamantyl, 12) cyclohexyl xyl, 13)/chlorheptyl, 14) cyclopentyl, 15) tetrahydro Furanyl, 16) Tetrahydrochenyl, 17) Tetrahydropyranyl, 18) Pyrazolidinyl, 19) Thiazolidinyl, 20) Piperazinyl, 21) Morpholy and 22) hexahydrobilitazinyl.

In this example, the above compound 3-(2-amino-4-oxo-38,5H-pyrrolo g [3,2-drpyrimidin-7-yl)-3-phenylpropanenitrile make The compound obtained in Example 187 in warm ethanol (250 ml) Compound A (2.0 g, 5.22 mm!J mol) and dimethylformamide (DMF ) (150 ml) in the presence of triethylamine (264 g, 50 eq.) , over 30% Pd/C catalyst (1.0 g) at atmospheric pressure. After 5 hours, When the reaction is complete, the catalyst is filtered off under N pressure. The solid obtained by sputtering the filtrate was Grind with 2C, sonicate and dry. Yield 11.28g (88%), mp 168-170'C.

Example 193 The compound prepared in Example 192 was tested for enzyme inhibitory activity as in Example 188. experiment. For 1 mM phosphate, IC. teeth. 023gM and 50mM For sphate, the IC,, is 4.7 gM In this example, the above compound 3-(2-alpha Mino-4-oxo-3H,5H-pyrroloC3,2-d2. Pyrimidine-7-i )-3-phenylpropanoic acid is prepared. 6N HCI (3.0ml) medium A solution of the compound obtained in Example 192 (0200 g, 072 mmol) was added to 1 Heat to reflux for 8 hours. The solvent was evaporated in vacuo and the residue was combined with H,O (6 ml). Grind and adjust the pH to 10 with concentrated aqueous ammonia. Collect insoluble matter by filtration, Readjust the pH of the solution to 6.8. Collect the white substance that precipitates, wash it with water, dry it and , 0.19 g (89%).

m+) 290°C decomposition.

Example 195 The compound prepared in Example 194 was tested for enzyme inhibitory activity as in Example 188. experiment. At 1mM phosphate, Ic5o is 0.01271-1 and 50 In mM phosphate, IC6° is 0.19 gM In this example, the above compound 3- (2-amino/-4-oxo-38,5H-pyrrolo[3,2-d3 pyrimidi/- 7-yl)-3-phenylpropanamide is prepared. JH, S○, (05m1 ) of the compound obtained in Example 192 (0,200 g, 072 mmol) The solution was stirred at room temperature for 20 hours, then poured onto crushed ice (5.0 g) and diluted with concentrated NH, Adjust pH to 6.8 with OH. The precipitated solid was collected, washed with H2O, and dried. ,○ Obtain 180g. mp199-201°C decomposition.

Lost Emperor Twisting Work Joyu The compound prepared in Example 196 was tested for enzyme inhibitory activity as in Example 188. experiment. For 1mM phosphate, the IC7° is 0.20gM and for 50mM phosphate. In Sphate, ICs. is 6.6 μM.

Example 198 In this example, the above compound 3-(2-amino-4-oxo-3H,5H-virolo E3.2-d3 Biwamidin-7-yl)-3-phenylpropanoic acid methyl s Prepare the tell. Thionyl chloride (0.2 g, 0.17 mmol) was stirred at 0 °C. Add to stirred methanol (4.0ml). Compound obtained in Example 194 (0, 2 g, 0 mmol) are added and the mixture is stirred at room temperature for 18 hours. solvent Semi-solid Get a chunk of. This was applied to silica gel using CHCl, -MeOH as the eluent. Purify on column. Yield fi0.1g0 The compound prepared in Example 198 is tested for enzyme inhibitory activity.

Significant activity (ICs.) is found.

In this example, 3-(2-amino-4-oxo-38,5H-pyrrolo[3°2- Prepare dHpyrimidin-7-yl)-3-cyclohebo/rubropanic acid. bird Compound obtained in Example 194 (8) in fluoroacetic acid (TFA) (15 ml) A solution of 3 mg, 0.28 mmol) was mixed with PLO, (83 mg) at 60 Hydrogenate at 1 b/in' for 24 hours. The catalyst is separated by filtration through a Celite layer, and the filtrate is Evaporate at 25°C.

The residue was suspended in H2O (8 ml), adjusted to pH 8.5 with conc. Filter through a tman filter paper to remove brown impurities. Colorless filtrate to pH 6.8 The precipitated compound is filtered, washed with H,O and dried. Yield 65m g (77%). mp>3Q○°c0 Example 200 The compound prepared in Example 1 Test for enzyme inhibitory activity as in 88. At 1mM Nasphate, IC6 ゜ is 0O97μM, and at 30mM phosphate, IC6o is l　OμMX A compound of the present invention is prepared in which P○ (○H). Compound 2 of Example 192 The tolyl group is converted to the corresponding amide by treatment with sulfuric acid. Hoffmano decomposition reaction Convert the amide to the corresponding amine using Next, add biryllium salt to this to the corresponding pirinnium salt. Conversion of this salt to the corresponding halide is achieved using sodium bromide. This was then treated with triethyl phosphite. and convert it to a phosphonate ester. Using trimethylsilyl bromide, this When we hydrolyze the ester of Sulfonic acid is obtained.

Example 203 In this example, by increasing the carbon number from -m:○ to 7m'' to 1, A compound of the invention is produced. The nitrile group of the compound of Example 192 was replaced with the corresponding alkali group. Reduced to dehyde. This is then converted into the corresponding alcohol. phosphorus tribromide This alcohol is converted to the corresponding alkyl bromide using Then cyan This is converted into the nitrile compound of the invention in which m is 1 using potassium chloride.

Ooku Garu A In this example, a compound of the present invention in which rpJ is 1 and "Y" is oxygen is manufactured by R. Ru. The alcohol which was RHed as an intermediate in the above example was converted into diethyl chloride phosphonate. methyl to the corresponding diethylphosphonomethyl ether. this The ethyl group of the ester was removed using trimethylsilyl bromide to yield the phosphonic acid. Ru.

Great storm mutual j In this example, a compound of the present invention in which 7Yj is NH and rXJ is So, NH, Manufacture things. The nitrile group of the compound of Example 192 was dissolved in an acidic medium (usually 0.0 amines using standard catalytic reduction with palladium in (IN~INHCI) Give back. It is then converted to sulfamide using sulfamoyl chloride.

Kankan week l tsushaku In this example, the methylamine intermediate prepared in the previous example was reacted with chloroacetic acid. Compounds of the invention in which rXJ is COOH and rYJ is NH by prepare something

Samurai dish Matadanyu In this example, the methylamine intermediate prepared in Example 206 was converted into diethyl phosphonate. and react the resulting product with trimethylsilyl bromide. By doing so, "x" becomes PO(OH).

and rYJ is NH.

Example 208 In this example, the alcohol intermediate prepared in Example 203 was converted to sulfamoyl chloride. By reacting with, rXJ is SO, NH, and "Y" is oxygen. A compound of the invention is prepared.

hanjufeng l liaoyu In this example, R1 is HSR" or phenyl, R3 and R4 are hydrogen, m is 0, n Compounds of the invention are prepared in which p is 1 and p is 01x is CN. Mu Il Rim (Mu-Ill Lim) et al., Journal on Organic Chemistry (J, Org, Chem), vol. 44, no. 22, p. 3826 (1979) ) using a variation of the procedure disclosed in . Compound 1 of Example 184 and dimethylform The mixture with amide dimethyl acecool was allowed to react at room temperature for 2 days and then in vacuo. Evaporate to dryness. Crystallize the residue to obtain pure N~(dimethylamino)methylene derivatives. Get a body. This is cyclized with saturated methanolic ammonia to give the desired final product. obtain.

Example 210 In this example, R1 is OCH, R2 is phenyl, R'' and R4 are hydrogen, and m is Compounds of the invention are prepared in which 0, n is 1 and p is CN. Example 187 The S-methyl group is oxidized to methyl sulfone using compound B. then , by treatment with sodium methoxide in methanol. Convert to final methoxy compound.

Example 211 In this example, compounds of the invention are prepared where X is tetrazole. Example 19 Catalytic salification of compound No. 2 in dimethyl sulfoxide (DMF) Treatment with lithium azide at too’c in the presence of ammonium yields the desired tetra Get Razor.

Example 212 In this example, a compound of the present invention in which X is a triazole is prepared by R. Example 19 Treatment of compound 8 with hydrazine hydrate provides the corresponding hydrazide. then , which is treated with an iminoether to give the desired triazole.

Example 213 The compound prepared in Example 189 was tested for enzyme inhibitory activity as in Example 188. experiment. For 1mM phosphate, the IC6° is 0,012μM and 50mM For phosphates, IC, is 2. OμM This practical example shows the amidination of the present invention. A compound is prepared, ie, a compound in which X in the above general formula is CN　HN　Ht.

Compound A of Example 187 was prepared with sodium methoxide in methanol at room temperature. React for 20 hours to obtain the methyl-imitate intermediate. This intermediate is then meta- Reaction with ammonia in alcohol gives the amidine product.

Claims (16)

[Claims] 1. R is cyclohexenyl, cyclohexyl, or CH2-R1, and R1 is an optionally substituted heteroalicyclic group, pyridinyl or alicyclic group; A compound 2-amino-7-(R)-3H,5H-pyrrolo[3,2-d]pyrimi Zin-4-one. 2. R is -CH2-R1, R1 is optionally substituted 2-, 3-, or 4-piperidinyl, 2- or 3-tetrahydrofuranyl, 2- or 3 -tetrahydrothienyl, 2- or 3-pyrrolidinyl, 2-, 3-, or 4 -tetrahydropyranyl, or 2-, 3-, 4-pyridinyl. Compounds listed. 3. R is optionally substituted cyclohexyl or 1-, 2-, or or 3-cyclohexenyl. 4. R is -CH2-R1, R1 or optionally substituted cyclopentyl cyclohexyl, cycloheptyl, 1- or 2-adamantyl, 1- or is 2-noradamantyl, 1-norbornanyl, 2-exo-norbornanyl, 2-endo-norbornanyl, 1- or 2-bicyclo[2.2.2]octani 1-, 2-, 3-, 6-, or 8-bicyclo[3.2.1]octanyl, 1-, 2-, 3-, or 9-bicyclo[3.3.1]nonanyl, or 1- or 2-norbornenyl. 5. formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R1 is H, NH2, or OCH3, and R2 is one or more as desired. optionally substituted with 5 to 7 carbon atoms, which may contain any of the above heteroatoms; Good cyclic group, R3 and R4 are independently H or C1-4 alkyl, m is 0-4 , n is 0-6, p is 0-1, X is CN, CSNH2, PO(OH)2, COOH , SO2NH2, NH2, OH, CNHNH2, tetrazole, or triazo COR5 (wherein R5 is C1-4 alkyl, CF3, NH2, or OC 1-4 alkyl), Y means O or NH] . 6. Claim 5, wherein R1 is NH2, R3 and R4 are H, m is O, and n is 1. Compound. 7. 6. A compound according to claim 5, wherein R2 is phenyl. 8. 6. A compound according to claim 5, wherein X is CN, COOH, or CONH2. 9. R2 is an optionally substituted 5- or 6-membered aromatic group or is a heteroaromatic group, or an optionally substituted alicyclic group with a 5- to 9-membered ring 6. The compound according to claim 5, which is a group or a heteroalicyclic group. 10. Administering a compound according to any one of claims 1 to 8 or 9 to a mammal. , the compound is activated by purine nucleoside phosphorylase and thereby T-cells. in mammals without exhibiting a reducing effect on humoral immunity consisting of inhibiting cyst formation. A method for selectively suppressing mammalian T cell function. 11. a) In the presence of ammonium acetate, an optionally substituted cyclic Reaction of aldehyde with cyanoacetic acid yields 3-cyclo-substituted pentanedinitrile ; b) reacting the 3-cyclo-pentanedinitrile with an alkyl formate and a base; 3-Cyclo-2-formylpentanedinitrile was obtained: c) the 3-cyclo-2-formyl Lumylpentanedinitrile with glycine methyl ester hydrochloride and sodium acetate Methyl N-[(3-cyclo-2,4-dishya -2-butenyl]glycine; d) The methyl N-[(3-cyclo-2,4-dicyano)-2-butenyl]glycyl reacting with an alkyl chloroformate and DBN or DBU to form 3-amino-4 -(2-cyano-1-cyclo-ethyl)-1-ethyl-1H-pyrrole-1,2 -methyl dicarboxylate: then e) the 3-amino-4-(2-cyano-1 -cyclo-ethyl)-1-ethyl-1H-pyrrole-1,2-dicarboxylic acid methyl 3-amino-4-(2-cyano-1-cyclo-ethyl)- Manufacturing a chemical compound consisting of the process of obtaining methyl 1H-pyrrole-2-carboxylate How to do it. 12. Furthermore f) 3-amino-4-(2-cyano-1-cyclo-ethyl)-1H -Methyl pyrrole-2-carboxylate is reacted with benzoyl isothiocyanate. N-benzoyl-N'-[4-(2-cyano-1-cyclo-ethyl)-2-methyl Toxycarbonyl-1H-pyrro-3-lyl]thiourea is obtained: g) the N-benzoyl-N'-[4-(2-cyano-1-cyclo-ethyl)-2 -Methoxycarbonyl-1H-pyrro-3-lyl]thiourea to an alkyl halide N-benzoyl-N'-[4-(2-cyano-1-cyclo-ethyl) )-2-methoxycarbonyl-1H-pyrrol-3-yl]S-methylthiou then h) the N-benzoyl-N'-[4-(2-cyano-1-cyano- Chlo-ethyl)-2-methoxycarbonyl-1H-pyrrol-3-yl]-S- 3 by reacting methylthiourea with methanolic or ethanolic ammonia. -cyclo-3-[2-amino-4-oxo-3H-5H-pyrrolo[3,2-d] pyrimidin-7-yl]propanenitrile and 3-cyclo-3-[2-methyl Mercapto-4-oxo-3H,5H-pyrrolo[3,2-d]pyrimidine-7- 12. The method according to claim 11, comprising the step of obtaining a mixture of yl]propanenitrile. 13. Furthermore i) 3-cyclo-3-[2-methylmercapto-4-oxo-3H , oxidation of 5H-pyrrolo[3,2-d]pyrimidin-7-yl]propanenitrile 3-cyclo-3-[2-methylsulfonyl-4-oxo-3H, 5H-pyrrolo[3,2-d]pyrimidin-7-yl]propanenitrile is obtained; Come on, j) The 3-cyclo-3-[2-methylsulfonyl-4-oxo-3H,5H-pi Lolo[3,2-d]pyrimidin-7-yl]propanenitrile was added to sodium alkali 3-cyclo-3-[2-methoxy-4-oxo-3H,5 Step of obtaining H-pyrrolo[3,2-d]pyrimidin-7-yl]propanenitrile 13. The method of claim 12, comprising: 14. Furthermore f) 3-amino-4-(2-cyano-1-cyclo-ethyl)-1H -Methyl pyrrole-2-carboxylate to dimethylformamide dimethyl acetal 4-(2-cyano-1-cyclo-ethyl)-3-[N-(dimethyl Methyl aminomethylene)amino]-1H-pyrrole-2-carboxylate was obtained: in, g) The 4-(2-cyano-1-cyclo-ethyl)-3-[N-(dimethylamino) methylene)amino]-1H-pyrrole-2-carboxylate to a methanolic atom. 3-Cyclo-3-[4-oxo-3H,5H-pyrrolo[3 , 2-d]pyrimidin-7-yl]propanenitrile. The method described in 1. 15. cyclic substituent is phenyl, 2- or 3-thienyl, 2- or 3-furani 2-, 3-, or 4-pyridinyl, 2- or 3-pyrrolyl, 2-, 4- , or 5-thiazolyl, 2- or 3-pyrazinyl, 3- or 4-pyridazi Nyl, 3-, 4-, or 5-pyrazolyl, 1- or 2-adamantyl, cyclo Claim 1: Lopentyl, cyclohexyl, cyclotyl, or morpholinyl The method described in 1. 16. formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ or ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by the formula [wherein R1 and R2 have the same meanings as in the claims].