Derivatives of variolin b, method for their preparing, intermediate compounds and pharmaceutical composition

FIELD: organic chemistry, chemical technology, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel derivative of variolin B of the general formula (I) or their pharmaceutically acceptable salts possessing antitumor activity. In the general formula (I) radical R1 means aromatic group representing aromatic group representing phenyl optionally substituted with nitro-group, amino-group or alkyl-substituted amino-group, or aromatic group represents 5-6-membered heterocycle with two nitrogen atoms or sulfur atom as heteroatoms optionally substituted with (C1-C12)-alkyl, -OH, unsubstituted amino-group or amino-group substituted with (C1-C4)-acyl, phenyl-(C1-C4)-alkyl wherein phenyl group can be substituted with -OR1, or (C1-C12)-alkylthio-group, (C1-C12)-alkyl- or phenylsulfonyl, (C1-C12)-alkyl- or phenylsulfinyl or -OR1 wherein R1 is chosen from (C1-C12)-alkyl or phenyl; R2 represents hydrogen atom; R3 represents oxo-group when a dotted line is between nitrogen atom to which R2 is bound and carbon atom to which R3 is absent, or R2 is absent when R3 represents optionally protected amino-group wherein a substitute is chosen from (C1-C4)-acyl, phenylsulfonyl and (C1-C4)-alkylphenylsulfonyl when a dotted line forms a double bond between nitrogen atom to which R2 is bound and carbon atom to which R2 is bound; R4 represent hydrogen atom. Also, invention relates to a method for synthesis of compounds of the invention and to intermediate substances for their realization. Also, invention relates to a pharmaceutical composition based on variolin B derivatives.

EFFECT: improved method of synthesis, valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 5 sch, 1 tbl, 50 ex

 

The present invention relates to the derivatives of varioline Century

Variolin A (1), variolin In (2), variolin D (3) and N(3')-methyltetrahydrofuran In (4) represent a small group of heterocyclic substances of marine origin, selected from the Arctic sponge Kirkpatrickia varialosa in 1994, see Tetrahedron, 1994, 50, 3987-3992, and Tetrahedron, 1994, 50, 3993-4000. They have the usual tricyclic structure pyrido-[3',2':4,5]pyrrolo[1,2-c]pyrimidine. This structure has no precedent in the natural products either terrestrial or marine origin. Previously published two papers describing synthetic related structures, see Chem. Ber., 1974, 107, 929-936, and Tetrahedron Lett., 2000, 41, 4777-4780.

An important feature of these compounds is their biological activity: variolin In is the most active, with cytotoxic activity against cell lines R, and is also effective against Herpes simplex; it is inactive against other microorganisms, see Tetrahedron, 1994, 50, 3987-3992. Variolin And also shows a significant cytotoxic activity against cell lines R. N(3')-Methyltetrahydrofuran In inhibiting the growth Sacharomyces cerevisae and shows in vitro activity against the cell line HCT 116. Variolin D inactive in all assays. I believe that the different activity of these alkaloids shows the biological is the resource value aminopyrimidines cycle in (2), the oxidized form in (1) and restored pyrimidine in (4), in contrast methoxycarbonylamino Deputy in varioline D.

This invention relates to methoxyaniline with cytotoxic activity and, as expected, useful as anticancer agents.

Summary of the invention

In one aspect the invention relates to compounds of formula (I)

where R1represents an aromatic Deputy;

R2represents hydrogen or Deputy, when the dotted line is absent, or R2absent when the dotted line represents the relationship, and forms a double bond between the nitrogen is attached to R2and the carbon attached to R3;

R3is oxoprop =O, when the dotted line is absent, or is a substitute, when the dotted line represents the relationship, and forms a double bond between the nitrogen is attached to R2and the carbon attached to R3;

R4represents hydrogen or Deputy;

and their pharmaceutically acceptable salts.

The group R1as a rule, is an aromatic cycle with 4-10 cyclic atoms, preferably 5, 6 or cyclic atom is mi, and most preferably 6 cyclic atoms. The present invention allows the condensed cyclic system. The cycle may contain one or more heteroatoms, and suitable option includes 1-3 cyclic heteroatoms, selected from nitrogen atoms, oxygen or sulfur, in particular 2 heteroatoms. Particularly preferred nitrogen heteroatoms, and an example of R1is pyrimidine cycle, in particular, Deputy 4 pirimidil, i.e. a group of the formula

Aromatic cycle can be substituted, for example, one or more groups selected from alkyl, alkoxy, thioalkyl, halogen, amino, substituted amino, halogenoalkane, alkoxyalkyl, aryl, hydroxy, carboxy, alkoxycarbonyl or other conventional groups, including mesyl group. Hereinafter referred to other groups that can be used as alternates.

R2when present, represents preferably a hydrogen and a protecting group for nitrogen, or some other alternate. Examples of protective groups for the nitrogen, such as methoxymethyl or tosyl, well known, and need not give details. Examples of other substituents are any groups that you can substitute in this position by the interaction of the compound where R1represents the t of a hydrogen. More generally, reference to other groups is given in this description later.

R3is oxoprop or may be a Deputy, which can be introduced by reaction of exocoetidae, including amino, substituted amino, including, protected amino, and thioalkyl. More generally, reference to other groups is given in this description later.

R4represents hydrogen or a Deputy, such as alkoxy, in particular methoxy, hydroxy, halogen, in particular chlorine, or another group, you can enter the nucleophilic substitution or other method of derivatization, including thioalkyl or mesyl. When R4represents hydrogen, the compounds are derivatives of deoxyuridine Century When R4represents hydroxy, the compounds are derivatives of varioline Century More generally, reference to other groups is given in this description later.

R1represents, preferably, 4-pyramidalnou group, substituted in position 2. Suitable substituents are amino group and its derivatives, such as N-acyl, in particular, N-acetyl. Assumed and the other substituents, such as alkoxy or alkylthio, in particular, methylthiourea.

R2preferably absent.

R3represents, preferably, an amino group and aprosodia, such as N-acyl, in particular, N-acetyl.

R4preferably represents hydrogen.

Dotted line, preferably, represents the relationship.

Especially preferred class of compounds are those compounds of formula (I), in which

R1represents, preferably, 4-pyramidalnou group, substituted in position 2 amino, N-acyl, in particular, N-acetyl, alkylthio, in particular, methylthiourea, alkyl - or arylsulfonyl, in particular, methanesulfonyl, or alkyl - or arylsulfonyl, in particular, methanesulfonyl;

R2no;

R3represents an optionally protected amino group or N-acyl, in particular, N-acetyl; and

R4represents hydrogen, hydroxy or methoxy.

The invention also relates to pharmaceutically acceptable salts.

Examples of substituents that can be used in the present invention, is HE, OR', SH, SR', SOR', SO2R', NH2That other', N(R')2, NHCOR', NH(COR')2, NHSO2R', C(=O)R', CO2H, CO2R', (C1-C12)-alkyl and (C1-C12-halogenated, and each group R' chosen, independently, from the group consisting of HE, (C1-C12)-alkyl, (C1-C12)-halogenoalkane, aryl (which may be optionally substituted by a group selected from among (C1 -C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkylthio, NH2, (C1-C6)-alkylamino, di-(C1-C6)-alkylamino, NO2CN and halogen-free), aralkyl or arylalkyl (aryl group which may be optionally substituted by a group selected from among (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkylthio, NH2, (C1-C6)-alkylamino, di-(C1-C6)-alkylamino, NO2CN and halogen, and where R1represents a group of formula N(R')2or NH(COR')2group R' may be the same or different, or two groups R', together with the nitrogen atom to which they are attached, form a 5-12-membered heterocycle.

Definitions used in the present invention, the alkyl group may be a group with a linear or branched chains and preferably contain from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, still preferably from 1 to about 6 carbon atoms, and most preferably 2, 3 or 4 carbon atoms. Especially preferred alkyl groups in the compounds of the present invention are methyl, ethyl and propyl, including isopropyl. Used in this description, the term "alkyl", unless otherwise indicated, refers to both cyclizes them, and acyclic groups, although cyclic group containing at least three cyclic carbon atom.

Halogenoalkane groups represent alkyl groups (including cycloalkyl group)with the above values are substituted by one or more halogen atoms (preferably fluorine, chlorine, bromine or iodine) and containing preferably from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, still preferably from 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms. Especially preferred halogenoalkane groups in the compounds of the present invention are methyl, ethyl and various, including ISO-propyl group, substituted by 1, 2 or 3 halogen atoms that can be the same or different, in particular, vermeil, perchloromethyl, trifluoromethyl, trichloromethyl.

Preferred alkeneamine and alkyline group in the compounds of the present invention contain one or more unsaturated linkages and from 2 to about 12 carbon atoms, preferably from 2 to about 8 carbon atoms, still preferably from 2 to about 6 carbon atoms, and even more preferably 2, 3 or 4 carbon atoms. The terms "alkenyl" and "quinil"used in this description, include the AK to cyclic, and acyclic groups, although, as a rule, the preferred linear and branched acyclic group.

Preferred CNS group in the compounds of the present invention include groups containing one or more (but preferably only one) oxygen linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, still preferably from 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms.

Preferred ancilliary in the compounds of the present invention contain one or more (but preferably only one) simple thioester linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, and more preferably from 1 to about 6 carbon atoms. Ancilliary with 1, 2, 3 or 4 carbon atoms are particularly preferred.

Preferred alkylsulfonyl group in the compounds of the present invention include groups containing one or more sulfoxide (SO) groups and from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, and more preferably from 1 to about 6 carbon atoms. Especially preferred are alkylsulfonyl group with 1, 2, 3 or 4 carbon atoms.

Preferred alkyl is offonline group in the compounds of the present invention include groups, containing one or more sulfanilic (SO2) groups and from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, and more preferably from 1 to about 6 carbon atoms. Especially preferred are alkylsulfonyl group with 1, 2, 3 or 4 carbon atoms.

Preferred alcoholnye group in the compounds of the present invention include groups containing one or more carbonyl (CO) groups and from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, and more preferably from 1 to about 6 carbon atoms (including the carbonyl carbon). Especially preferred are alcoholnye group with 1, 2, 3 or 4 carbon atoms, in particular formyl, acetyl, propylaniline, Butyrina and isobutylene group.

Preferred alkylamines in the compounds of the present invention contain one or more (but preferably only one) NH-linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, and more preferably from 1 to about 6 carbon atoms. Especially preferred are alkylamino with 1, 2, 3 or 4 carbon atoms, in particular, the group methylamino, ethylamino, propylamino, butylamino.

Preferred dialkylamino inside the eniah of the present invention contain one or more (but preferably, only one) of the nitrogen atom connected to two alkyl groups, each of which may contain from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, and more preferably from 1 to about 6 carbon atoms. Alkyl groups may be the same or different. Especially preferred are dialkylamino, where each alkyl group contains 1, 2, 3 or 4 carbon atoms, in particular dimethylamino group, diethylamino, N-methylethylamine, N-ethylpropylamine, dipropylamine, dibutylamine and N-methylbutylamine.

Preferred alkanolamines in the compounds of the present invention contain at least one link NH-CO-, attached to an alkyl group containing from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, and more preferably from 1 to about 6 carbon atoms. Especially preferred are alkanolamines with 1, 2, 3 or 4 carbon atoms, in particular, the group formylamino, acetylamino, propionamido, bucillamine. The acetylamino group is particularly preferred.

Preferred dialkanolamine in the compounds of the present invention contain one nitrogen atom associated with two alkanolamine groups having the above value, which may be the same or different and is each of which contains from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, and more preferably from 1 to about 6 carbon atoms. Especially preferred are dialkanolamine, where each alcoolica group contains 1, 2, 3 or 4 carbon atoms, in particular, the group deformylase, formylamino, diatsetilamino, dipropylamino, dibutylamino. Group diatsetilamino is especially preferred.

Preferred alkylsulfonamides in the compounds of the present invention contain at least one link NH-SO2is attached to an alkyl group containing from 1 to about 12 carbon atoms, preferably from 1 to about 8 carbon atoms, and more preferably from 1 to about 6 carbon atoms. Especially preferred are alkylsulfonyl with 1, 2, 3 or 4 carbon atoms, in particular, the group methanesulfonamido, ethanolamine, propanolamine, butanesulfinamide.

Examples of specific compounds according to this invention include compounds(1), (2), (5), (16), (18) and (21) on the following pages, as well as the connection denoted by (20A), which in figure 4 is an intermediate connection between the compounds (20) and (21), where R2no, R3represents acetamido, R4represents hydrogen, and R1is a 2-metaltype is kidin-4-yl, which compound of formula

The present invention also relates to pharmaceutical compositions containing a compound according to this invention and a pharmaceutically acceptable carrier, and to the use of compounds according to this invention when getting medicines. It also relates to methods of treatment.

Examples of pharmaceutical compositions include any solid forms (tablets, pills, capsules, granules and the like) or liquid form (solutions, suspensions or emulsions) with suitable composition for oral, local or parenteral administration, and they may contain the pure compound or its combination with any carrier or other pharmacologically active compounds. You may need sterility of such compositions, when administered parenterally.

The introduction of such compounds or compositions can be accomplished in any suitable way, such as intravenous infusion, in the form preparations for oral administration, intraperitoneal and intravenous way. It is preferable to use the infusion for up to 24 hours, preferably for 2 to 12 hours, most preferably 2 to 6 hours. Especially desirable short-term infusion, allowing treatment without leaving the hospital for the night. However, the infusion of which may last for 12-24 hours or even longer if it is necessary. The infusion can be performed with suitable intervals, for example, in 2-4 weeks. Pharmaceutical compositions containing the compounds of the invention can be delivered using encapsulation in liposomes or nanospheres using compositions with delayed release or any other delivery method.

The exact dosage of the compounds will vary depending on the specific composition, method of application and the particular situation of the host and the tumor from which they treat. You should take into account other factors such as age, body weight, sex, diet, time of administration, rate of excretion, condition of the patient, a combination of medicines, sensitivity to impacts and the severity of the disease. The introduction can be performed continuously or periodically within a tolerated dose.

The present invention also relates to pharmaceutical compositions for combination therapy comprising compound according to this invention and at least one other therapeutically active compound. Another connection may possess antitumor activity, or may have some other activity for use in combination with anti-tumor activity of the compounds according to this invention.

Other medicines can be part of the th same composition or may be submitted in the form of a separate composition for administration at the same or a different time. Features of another drug is not specifically limited, and suitable candidates are

a) medicines with antimitoticheskim action, particularly aimed at elements of the cytoskeleton, including modulators of microtubules, such as taxonomie drugs (such as Taxol, paclitaxel, Taxotere, docetaxel), podophyllotoxin or Vinca alkaloids (vincristine, vinblastine);

b) antimetabolites drugs, such as 5-fluorouracil, cytarabine, gemcitabine, purine analogues, such as pentostatin, methotrexate;

(C) alkylating agents such as nitrogen-containing derivatives of mustard gas (such as cyclophosphamide or ifosfamide);

d) medicines designed to DNA, such as anthracycline drugs adriamycin, doxorubicin, pharmorubicin or epirubicin;

e) drugs aimed at topoisomerases such as etoposide;

f) hormones and agonists or antagonists hormones, such as estrogens, antiestrogens (tamoxifen and related compounds) and androgens, flutamide, leiprorelina, goserelin, cyproteron or octreotide;

g) medicines designed to signal transduction in tumor cells, including derivatives of antibodies, such as Herceptin;

h) alkylating drug means is a, such as containing platinum drugs (cisplatin, carboplatin, oxiplatin, paraplatin), or nitrosoanatabine;

i) drugs potentially affecting metastasis of tumours such as inhibitors of matrix-metalloproteinases;

(j) means of gene therapy and antisense funds;

k) therapeutic drugs based on antibodies;

l) other bioactive compounds of marine origin, especially didemnin, such as aplidine, or ecteinascidin, such as Et-743;

m) antiemetic drugs, in particular, dexamethasone.

The cytotoxicity of the compounds according to this invention, obtained according to scheme 4, is illustrated by the following data IC50 in μm.

ConnectionP-388A-549HT-29
50,360,040,04
21>30,160,16
20A>30,290,29
variolin0,850,170,09

The invention also relates to the synthesis of compounds based on 7-azaindole, or at a later stage. Receiving tricyclic of pyridopyrimidines (11)based on 7-azaindole, DOS is Haut by litvinovna on carbon 2, the introduction of the side chain With2and subsequent cyclization. The reaction of heteroaryl combinations used for the introduction of the fourth aromatic cycle.

Thus, the present invention relates to a method for producing compounds according to this invention, including interaction optionally substituted 5-halogenide[3',2':4,5]-pyrrolo[1,2-c]pyrimidine or 8,9-dihydro-5-halogenide-[3',2':4,5]pyrrolo[1,2-c]pyrimid-9-she derivational aromatic compound, such as stannylene connection, especially trimethylaniline connection, in particular, derived trimethylenediamine. Then, the resulting product can be injected into the interaction to replace the deputies. Amino or other reactive substituents in the source connection can be protected, and then remove the protective group.

Thus, the preferred intermediate compounds in this invention are compounds of the formula

where X represents halogen, and R2, R3and R4have the above values, in particular, when X represents iodine, R2represents a protective group, R3represents a protected amino group, and R4represents hydrogen, hydroxy or methoxy.

Approach to the synthesis of variolin In time is by using as a target of deoxyuridine In (5). Previously, the synthesis was based on getting the usual tricyclic system pyridopyrimidines from 7-azaindole. The key stage is heteroaryl combination with the purpose of introducing pyrimidine substituent, catalyzed Pd(0).

The introduction contains a functional group chain of two carbons in 2nd position 7-azaindole, see J. Org. Chem., 1965, 30, 2531-2533 reach by reacting 2-nitipaisalkul with 2 palmitoylethanolamide (6), which itself is obtained in a yield of 75% of dimethylacetal 2-aminoacetaldehyde, protecting the amino group by reacting with phthalic anhydride in CH2Cl2at 140°C for 15 minutes, followed by hydrolysis acetamino group with 10% HCl at boiling under reflux. Litvinovna 7-azaindole previously described only for its N-phenylsulfonyl derived, see Tetrahedron, 1997, 53, 3637-3648. Use the method described Katritzky, see J. Am. Chem. Soc., 1986, 108, 6808-6809, including 2-litvinovna the lithium salt of 1-carboxylic acid, obtained in situ, because the perfect solution is found using 1-phenylsulfonyl-7-azaindole, and also excluded are two distinct phases of introduction and removal of the N-protective group. Thus, the interaction of bility-derivative (7) with the aldehyde (6) gives the alcohol (8) with the release of 44%. Protection of the alcohol in the form of a simple t is trihydroxypyrimidine ether gives a mixture of diastereomers, which is not divided, because both symmetry center later in the synthesis of lost. Hydrazines phthalimide residue gives the amine (9) with a quantitative yield, which is converted into tetrahydropyrimidin (10) opening 76% handling triphosgene in CH2Cl2with diisopropylethylamine (DIEPA) as the basis. Dihydropyrimido (11) are obtained after removal of the hydroxy protecting group by acid hydrolysis, followed by dehydration of the alcohol through mesilate (scheme 1).

Scheme 1. Synthesis of pyrido[3',2':4,5]pyrrolo[1,2-C]pyrimidine-1-she (11)9

i: n-BuLi, THF, -78aboutWith up to room temperature (CT);

ii: CO2, -78aboutC;

iii: tert-BuLi, THF, -78aboutC;

iv: 5 THF, -78aboutWith up to CT, 44%;

v: DHP, HCl-benzene, CHCl3(87%);

vi: NH2NH2·H2O, EtOH (100%);

vii: (Cl3O)2CO., DIPEA, CH2Cl2, CT (76%);

viii: 4N HCl, CH2Cl2(100%);

ix: MsCl, TEA, CH2Cl2that 0oC (95%).

On the basis of previously performed experiments heteroaryl combination with 7-azaindole, see Synthesis, 1999, 615-620, and litvinovna dihydropyrrolo[1,2-c]pyrimidine-1-ones, see J. Soc. Chem. Perkin Trans., I, 1999, 249-255, developed derivatization (14) of the halogen derivatives with a protective group (13). Protection of tricyclic pyrimidine (11) is achieved through metalh ormational ester in DMF using sodium hydride as base to obtain (12). Halogenoalkane (12) using N-bromosuccinimide (NBS) or iodine with potassium hydroxide gives (13A) (80%) and (13b) (62%), respectively. What halogen is introduced on the C-5, confirmed by comparing the spectra of1H-NMR: the singlet N-5 (6,41 ppm is present in (12), but not present in the spectra of (13A) and (13b). Unfortunately, you cannot allocate a derivative of tin (14), for example, (13A) butyllithium with subsequent quenching by chloride trimethylamine, see Synthesis, 1999, 615-620, gives a complex mixture that cannot be separated. Attempts to make the interchange of iodine and tin by processing (13b) hexamethyldisilane in dioxane with catalyst Pd(PPh3)4bring to a mixture of (14) and (12) in the ratio 7:3, but select (14) the method of column chromatography failed.

Scheme 2

i: MOMCl, NaH, DMF, 0°C (87%);

ii: NBS, CH2CI2, 0°C (80%);

ii: I2, KOH, DMF, 0°C (62%).

Change the strategy of combination reaction, and this time use trimethylenediamine (15) and iodine-7-azaindole (13b). Getting pyrimidine (15), see Tetrahedron, 1989, 45, 993-1006, improves with the use of Pd(OAc)2and PPh3in THF, and reduced the number of TBAF and reaction time compared to those described in earlier work.

A solution of iodine-containing derivative (1 mmol), (15) (3 mmol), catalyst a or b and Lil (3 mmol) in dioxane (20 ml) is refluxed for 5 hours. The solvent is evaporated and the residue purified column flash chromatography. The reaction mix between (13b) and (15) in all conditionsthe experiment gives a mixture of (12) and (16), which cannot be separated (table 1).

Table 1.

The reaction mix between (13b) and (15) in dioxane
(15)/(13b)andKatal./League.bLiCl/CuIc16/12d%e
1,1And3/--2:156
1,2In3/--2:152
2In3/0,13:153
a: molar ratio;

b: A=Pd(PPh3)4, 0.1 equivalent; In=Pd2(dba)3, 0.1 equivalent), and PPh3, 0.2 equivalent;

C: relative to 1 equivalent 13b;

d: the ratio measured by the method of1H-NMR;

e: exit (16) is calculated by the method of1H-NMR of crude reaction mixture.

Because of the difficulty of clearing (16) is the introduction of a new protective group. Iodine-containing compound (17), different from (13b) protective group, are synthesized by reaction (11) with mozillateam and sodium hydride in DMF followed yo what funding through NIS.

The reaction mix between (17) and trimethylsilylacetamide (15) gives the tetracyclic compound (18), but with the release of only 10%, even when using the reaction conditions specified in table 1 for a combination of (13b) and (15).

Scheme 4. Synthesis of deoxyuridine

Scheme 2

i: TsCl, NaOH, DMF (40%);

ii: NIS, CHCl3, CT (80%);

iii: 15, Pd2(dba)3, PPh3, LiCl, CuI (10%);

iv: TMSCl, HMDSA, 2,6-lutidine;

v: NH3, 150oC, 60 f/d2(30% in two stages);

vi: Ac2Oh, THF (75%);

vii: NIS, CHCl3(95%);

viii: iii, then HCl-Meon (45%);

ix: m-CPBA, CH2Cl2that 0about(90%);

x: NH4OH, dioxane, 80about(90%).

The following approximation is the functionality of the C-loop by turning pyrimidone (11) in CodeDomProvider (20). Derivatives get About 19-similarobama (11) TMSCl and hexamethyldisilazane (HMDSA) as cilleruelo agent with subsequent nucleophilic substitution by ammonia, see Lebgs Ann. Chem., 1975, 988-1002. Acylation of amine (19) and halogenoalkane free position π-enriched cycle are with excellent output.

Heteroaryl combination of (20) and (15) in the same reaction conditions and with the same catalyst as before, gives a mixture of acylated and deprived of the protective groups of amines, which when methanolysis with dry HCl in methanol to give the amine (21) with the release of 45%. ethoxyaniline In (5) is obtained by replacing metalcorp new pyrimidine cycle on the amino group. Oxidation (21) using m-chloroperbenzoic acid, followed by the replacement of the obtained sulfone to the amino group using ammonium hydroxide gives (5) high output, see Tetrahedron, 1989, 45, 993-1006, and A.R. Katrizky, C.W. Rees, Comprehensive Heterocyclic Chemistry, Pergamon Press, Oxford, 1984, vol.3, page 111.

A more General scheme of the synthesis is as follows.

Reagents

i: n-BuLi, THF, -78aboutWith up to CT;

ii: CO2, -78aboutC;

iii: tert-BuLi, THF, -78aboutC;

iv: 6, THF, -78aboutWith up to CT;

v: DHP, HCl, benzene, CHCl3that Δ;

vi: NH2NH2·H2O, EtOH, Δ;

vii: (Cl3CO)2CO., DIPEA, CH2Cl2, CT;

viii: 4N HCl, CH2Cl2;

ix: MsCl, tea, CH2Cl2that 0aboutC;

x: MOMCl or TsCl, NaH, DMF, 0aboutC;

xi: NBS/NIS, CH2Cl2that 0aboutWith, or I2, KOH, 0aboutC;

xii: 15 PM, Pd2(dba)3, PPh3, LiCl, CuI, dioxane, Δ;

xiii: TMSCl, HDMSA, lutidine, D;

xiv: NH3, 150oC, 60 f/d2;

xv: Ac2O, THF, CT;

xvi: NIS, CHCl3that 0aboutC;

xvii: TsN=CCl2, DIPEA, CH2Cl2, CT;

xviii: 4h. HCl, CHCl3, CT;

xix: MsCl, tea, CH2Cl2, CT;

XX: NIS, CHCl3, -30aboutC;

xxi: dry Meon-HCl or 48% HBr Δ.

Bicyclic Conn. 11b (X=OMe) is obtained from 4-methoxy-7-azaindole, see J. Heterocyclic Chem., 1989, 26, 317, with the same subsequent vzaimodeistvie, as the case 11a. Turning 11b 19b carried out with only 22% through On-sililirovanie trimethylsilylpropyne (TMSCl) and hexamethyldisilazane (HMDSA) with subsequent nucleophilic substitution by ammonia. The acylation 19b and iodination received acetyl derivatives give todatetime 20b.1H-NMR 20b shows two independent AB-aromatic systems due to pairs of protons H3-H4 and H7-H8. Catalyzed by palladium combination 20b and 2-acetylamino-4-trimethylenediamine (27) followed by treatment with acid gives On-methylaniline In (5b). Channelmarketing (27) are obtained with a yield of 40% from 4-chloro-2-methanesulfonamido, see Heterocycles, 1977, 8, 229, by nucleophilic substitution methanesulfonyl groups ammonia in ISO-D with subsequent acylation AU2Oh and by the interchange of halogen and metal in dioxane using hexamethyldisilane and Pd(PPh3)4as a catalyst.

Education pyrimidinone cycle does not include the improvement of receiving tricyclic systems 19. Tricyclic compounds 22A-C are obtained from 9a-by interacting with the N-dihlormetilen-4-methylbenzenesulfonamide, see Chem. Ver., 1966, 99, 1252, and DIPEA in CH2Cl2with the subsequent removal Of the protective group and dehydration. N-Totalprestige 23 get this way from 22 through acid catalyzed removal Of the protective group to follow what she dehydration, as described for the conversion of 10→11. Removal of N-tosylamide group of 23 is performed with the use of Na in ammonia or Na in naphthalene, and get 19 with moderate output.

The reaction of heteroaryl combination of 23 and scannerprinter 27 under conditions similar to those described earlier, gives 25 with very good output.

The removal of the protective group for the N-acetyl can be done by methanolysis Meon in HCl acid catalyzed. The transition 25A→26 may be implemented by the processing HBr. The connection 26 is a new derivative of varioline In, protected by only one nitrogen.

Several derivatives of varioline In, three of them with only one change: 5A represents dehydroxylation, 5b is mutilation and 26 is tosylation Century

Remove Totila 26 can be performed in the same conditions as in the case 23, and will get variolin Century

Using similar experimental procedures of 23 you can get a connection 25s, and derivatives formed by pyrimidine cycle.

The previous experiment shows anticipated good results in the combination of tin-containing heteroaromatic derivatives and 13b, 17, and 24, and in the General formula get different R1.

Developed a universal synthesis procedure that can be used is to be not only for the synthesis of derivatives of this group of alkaloids of marine origin, but also to obtain derivatives other natural products.

In this application claims the priority of an earlier filing. What if the filing is not included in the text of this specification, are included as a reference.

Examples of inventions

Example 1

2-(1-Hydroxy-2-phthalimidomethyl)-7-azaindole (8A)

To a cooled (-78° (C) a solution of 7-azaindole (7.6 g, 64 mmol) in dry THF (150 ml), add n-BuLi (44 ml, 1.6 M solution in hexane) and the mixture is stirred for 10 minutes Through the mixture for 40 min bubbled dry CO2. The solvent is evaporated and the residue is dissolved in a fresh portion of dry THF (400 ml). The solution is cooled to -78°and added tert-BuLi (42 ml of a 1.7 M solution in hexane). The mixture is stirred for 20 minutes Add slowly a solution of palmitoylethanolamide (14 g, 71 mmol) in THF (400 ml). After 1.5 hours the reaction is quenched with saturated aq. a solution of NH4Cl (100 ml)and the organic solvent is evaporated. The mixture was dissolved in CH2Cl2and washed with water. The organic solution is dried and evaporated. The mixture is purified column flash chromatography. Elution with a mixture of CH2Cl2and acetone (95/5) to give 7-azaindole (3.8 g, 50%) and a mixture of CH2Cl2and Meon (98/2) to give 8A (8.7 g, 44%) as a white solid.

TPL 231-232°C (CH2Cl2/Meon).

IR (KBr) (3200 (m, NH),1760 (s, C=O), 1704 (s, NCO), 1427 (m, C-N), 1395 (m, C-O).

1H-NMR (DMSO-d6, 200 MHz) δ 3,88 (DD, J and 13,6 6,0, 1H, H2'), of 4.00 (DD, J 13,6 and 7.8, 1H, H2'), is 5.06 (DDD, J 7,8, the 6.0 and 5.2, 1H, H1'), of 5.83 (d, J 5,2, 1H, OH), 6,34 (d, J 1,8, 1H, H3), of 6.99 (DD, J 8.0 and 4.8, 1H, H5), 7,81-7,88 (m, 4H, Ph), 7,89 (DD, J 8.0 and 1.4, 1H, H4), 8,14 (DD, J 4.8 and 1,4,1H, H6), 11,75 (users, 1H, NH).

13C-NMR (DMSO-d6, 75 MHz) δ 43,6 (t, C2'), 64,4 (d, C1'), 96,8 (d, C3), 115,4 (d, C5), to 119.8 (s, C3a), 123,0 (d, Ph-β), uniforms, 127.6 (d, C4), 131, 6mm (with himself Ph), 134,3 (d, Ph-α), 140,8 (s, C2), to 142.1 (d, C6), of 148.6 (s, C7a), 167,7 (s, Ph-CO).

MC (EI) m/z 308 (M+l, 6), 307 (M+, 25), 244 (8), 160 (43), 147 (phthalimid, 100), 119 (azaindole, 52).

Element. analysis: for C17H13N3O3calculated: (66,44), N (4.26 Deaths), N (13,67); found: C (65,11), N (4.26 Deaths), N (13,37).

Example 2

2-(1-Hydroxy-2-phthalimidomethyl)-4-methoxy-7-azaindole (8b)

Following the above method, from 4-methoxy-7-azaindole (3.55 g, 24 mmol) in THF (75 ml), n-BuLi (16,5 ml of 1.6 M solution in hexane), tert-BuLi (16 ml, 1.7 M solution in hexane) and the solution palmitoylethanolamide (5 g, 26 mmol) in THF (100 ml) to obtain the crude mixture, which purify column flash chromatography. Elution with a mixture of CH2Cl2and acetone (95/5) to give 4-methoxyethanol from 2.06 g, 58%), and a mixture of CH2Cl2and Meon (98/2) to give 8b (3,68 g, 43%) as a white solid.

TPL 225-226°C (CH2Cl2/Meon).

IR (KBr) ν 3500 (s, NH/OH), 1702 (s, C=O), 1594 (m), 1395 (m).

1H-NMR (DMSO-d6, 200 MHz) δ 3,88 (s, 3H, Me), and 3.8 (DD, J 13.8 and 6,0, 1H, H2'), of 3.95 (DD, J 13.8 and 7,8, 1H, H2'), 5,00 (DDD, J 7,8, the 6.0 and 5.1, 1H, H1'), 5,73 (d, J 5,1, 1H, OH), 6,30 (d, J 1,8, 1H, H3), to 6.58 (d, J 5,4, 1H, H5), 7,83 (m, 4H, Ph), 8,02 (d, J 5,4, 1H, H6), 11,65 (user., 1H, NH).

13C-NMR (DMSO-d6, 75 MHz) δ 43,6 (t, C2'), 55,3 (square, Me)64,2 (d, Cl'), 94,0 (d, C5), and 97.8 (d, C3), 109,5 (s, C3a), 123,0 (d, Ph-β), 131, 6mm (with himself Ph)134,1 (d, Ph-α), 138,1 (s, C2), 144,2 (d, C6), 150,3 (s, C7a*), 158,5 (C, C4*), 167,7 (s, Ph-CO),

MC (EI) m/z 338 (M+l, 4), 337 (M+, 20), 319 (M-H2About, 44), 177 (100).

Element. analysis: for C18H15N3O4·1/4H2O calculated: C (63,25), N (4,57), N (12,29); found: C (63,32), N (4,54), N (12,07).

Example 3

4-Chloro-2-(1-hydroxy-2-phthalimidomethyl)-7-azaindole (8C)

Following the above method, from 4-chloro-7-azaindole (5 g, 33 mmol) in THF (100 ml), n-BuLi (20 ml, 1.6 M solution in hexane), tert-BuLi (20 ml, 1.7 M solution in hexane) and the solution palmitoylethanolamide (7.5 g, 39 mmol) in THF (140 ml) to obtain the crude mixture, which purify column flash chromatography. Elution with a mixture of CH2Cl2and acetone (95/5) to give 4-chlorothymol (4 g, 80%), and a mixture of CH2Cl2and Meon (98/2) to give 8C (1.5 g, 12%) as a white solid.

1H-NMR (DMSO-d6, 200 MHz) δ 3,86 (m, 1H, H2'), 3,95 (m, 1H, H2'), free 5.01 (m, 1H, H1'), of 5.92 (d, J 5,2, 1H, OH), 6,41 (s, 1H, H3), 7,14 (d, J 5,6, 1H, H5), to 7.84 (m, 4H, Ph), 8,11 (d, J 5,6, 1H, H6), 11,75 (user., 1H, NH).

13C-NMR (DMSO-d6, 75 MHz) δ 43,6 (t, C2'), and 64.3 (d, Cl'), 94,9 (d, C3), 115,3 (d, C5), 118,7 (s, C3a), 123,0 (d, Ph-β), and 11.6 (s, himself Ph), 133,3 (s, C2), 134,3 (d, Ph-α), 142,2 (s, C4), of 142.8 (d, C6), and 49.2 (s, C7a), 167,7 (s, Ph-CO),

MC (EI) m/z 342 (M+l, 4), 341 (M+, 20), 323 (M-H2O, 44), 177 (100).

Example 4

2-[2-Phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole

To a solution of 8A (10.2 g, 33 mmol) in CHCl3(1 l) is added 6 n HCl solution in dry benzene (180 ml). To a mixture of 2,3-dihydropyran (46 ml, 330 mmol). The reaction mixture is refluxed for 7 hours. After cooling, the mixture was washed with saturated aq. a solution of NaHCO3, dried and evaporated. The mixture is purified column flash chromatography. Elution with a mixture of CH2Cl2and Meon (97/3) to give 2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (10.8 g, 87%) as a mixture of diastereoisomers (1:1) as a white solid.

IR (film) ν 1717 (s, C=O), 1390 (m, C-0), 1026 (m, C-O).

1H-NMR (DMSO-d6, 200 MHz) of 1.30 and 1.80 (m, 6H, H3", H4 ' and H5"), of 3.25 to 3.45 (m, 2H, H2'), 3,80, 3,98, 4,22 and to 4.38 (m, DD, J 14.0 and 4,4, DD, J 14,8 and 2.0 and DD, J 14.0 and 9,4, 2H, h6"), 4,58 and 4,72 (DD, J 3.2 and 2.8 and DD, J of 3.4 and 3.0, 1H, H2"), and 5.30 and of 5.39 (DD, J 8.4 and 5.2 b and DD, J of 9.2 and 4.0,1H, H1'), 6,47 and 6,51 (d, J 1.8 and d, J 1,8, 1H, H3), 7,08 and to 7.15 (DD, J 8,2 4,8 and DD, J of 8.2 and 5.2, 1H, H5), of 7.69 (m, 2H, Ph-β), 7,86 (m, 2H, Ph-α), 7,86 (m, 1H, H4), and 8,43 8,63 (DD, J 4.8 and 1.6 and DD, J 5.0 and a 1.7,1H, H7), to 10.8 and 12.5 (user., 1H, NH).

13C-NMR (CDCl3, 50 MHz) 8 and 18,8 19,9 (t, C3*), and 25,0 25,2 (t, C4*), 30,2 and 30.8 (t, C5'*), 41,6 and 42.8 (t, C6"), 61,8 and 63.6 (t, C2'), 69,3 and 71.7 (d, Cl'), 95,5 and 97.9 (d, C2) 100,3 and 100.8 (d, C3), 115,9 (d, C5), 120,6 and 120.7 (s, C3a), of 123.2 and 123,4 (d, Ph-β), 128,7 and to 128.8 (d, C4), 131,8 and 132,0 (with himself Ph), 133,9 and 134,0 (d, Ph-α), 136,5 and 137,8 (s, C2), 143,1 (d, C6), 148, 7mm and 149,2 (s, C7a), 168,1 (s, Ph-CO).

MC (EI) m/z 391 (M+, 1), 307 (M-THP, 9), 147 (38), 85 (100).

Element. analysis: for C22H21N3O4·1/2H2O calculated: C (65,99), N (5,54), N (10,49); found: C (66,02), N (5,80), N (10,28).

Example 5

4-Methoxy-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)-oxyethyl]-7-azaindole

Following the same way as for 2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole, 8b (3.8 g, 11 mmol) in CHCl3(350 ml), 6N. HCl solution in benzene (35 ml) and 2,3-dihydropyran (10 ml, 110 mmol) to obtain 4-methoxy-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (of 3.07 g, 65%) as a mixture of diastereoisomers (1:1).

IR (film) ν 1714 (s, C=O), 1392 (m, C-O), 1026 (m, C-O).

1H-NMR (CDCl3, 300 MHz) of 1.30 and 1.80 (m, 6H, H3", H4 ' and H5"), of 3.25 to 3.45 (m, 2H, H2'), 3,99, and to 4.01 (s, 3H, OMe), 3,96, 4,08, 4,28 and 4,39 (DD, J 13.5 and 3,9, DD, J 13.8 and 4,6, DD, J 13.8 and 8.5 and DD, J 13.5 and a 9.6, 2H, H6"), 4,57 and 4.73 (ushort, J 3.2 and usert, J 3,4, 1H, H2"), and a 5.25 5,33 (DD, J 6.9 and 2.4 and DD, J 9.9 and 4,1, 1H, H1'), 6,54 and 6,58 (users and users, 1H, H3), 6,56 and 6,62 (d, J 5.7 and d, J 5,7,1H, H5), to 7.68 (m, 2H, Ph-β), 7,83 (m, 2H, Ph-α), and scored 8.38 to 8.57 (d, J 5.7 and d, J 5,7, 1H, H7), 11,7 (user., 1H, NH),

13C-NMR (CDCl3, 50 MHz) δ of 18.9 and 19.5 (t, C3*), and 25,0 25,3 (t, C4*), 30,2 and 30.7 (t, C5'*), 42,0 43,0 and (t, C6"), 55,4 (square, MeO), 61,7 and 62.9 (t, C2'), 69,4 and 71,5 (d, Cl'), 94,4 and to 95.3 (d, C2), 97,7 (d, C5), of 97.8 and 10.1 (d, C3)110,5 (s, C3a), 123,1 and of 123.2 (d, Ph-β), 132,1 and 132,1 (with himself Ph), 133,8 and 133,9 (d, Ph-α), 134,0 and to 135.2 (s, C2), 144,9 and RUB 145.1 (d, C6), to 150.6 and 151,1 (s, C7a*), 159,8 (C, C4*), 168,1 (s, Ph-CO).

MC (El) m/z 422 (M+1, 2), 421 (M+, 4), 337 (M-THP, 15), 177 (100).

MS high. bit., m/z for C23H23N3O5calculated 421,1637; found 421,1625.

Example 6

4-Chloro-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)-oxyethyl]-7-azaindole

Following the same way as for 2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole, 8 (1.3 g, 3.8 mmol) in CHCl3(50 ml), 6N. HCl solution in benzene (5 ml) and 2,3-dihydropyran (1.7 ml, 19 mmol) to obtain 4-chloro-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (1.0 g, 63%) as a mixture of diastereoisomers (1:1).

1H-NMR (CDCl3, 300 MHz) δ of 1.30 and 1.80 (m, 6H, H3", H4 ' and H5"), of 3.25 to 3.45 (m, 2H, H2'), 3,96-4,39 (m, 2H, H6"), 4,58 and 4,72 (m, 1H, H2"), and 5.30 and of 5.40 (DD, J 8.4 and 4.4 and DD, J of 9.2 and 4.0, 1H, H1'), 6,58 and 6,63 (d, J 2.2 and d, J 2,2, 1H, H3), 7,13 and then 7.20 (d, J 5,2, d, J 5,2, 1H, H5), of 7.70 (m, 2H, Ph-β), 7,86 (m, 2H, Ph-α), 8,35 and 8,55 (d, J 5,2, d, J 5,2, 1H, H7), 11,7 (user., 1H, NH).

13C-NMR (CDCl3, 300 MHz) δ of 18.9 and 19.5 (t, C3*), and 25,0 25,3 (t, C4*), 30,2 and 30.8 (t, C5'*), 41,8 and 42,9 (t, C6"), 61,9 and 63.5 (t, C2'), 69.2 and 71,6 (d, Cl'), 95,5 and 96,4 (d, C2), 98,8 and to 100.7 (d, C3), 116,1 (d, C5), 116,3 (, C3a), 123,1 and 123,3 (d, Ph-p), 131,7 and 132,0 (with himself Ph), 133,8 and 133,9 (d, Ph-α), 134,0 (s, C2), 143,2 and br143.3 (d, C6).

MS (EI) m/z 426 (M+l, 2), 425 (M+, 5), 341 (M-THP, 14), 177 (100).

Example 7

2-[2-Amino-1-(2,3,5,6-tetrahydropyran-2-yl)oxia the yl]-7-azaindole (9a)

To a solution of 2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (10.2 g, 26 mmol) in EtOH (630 ml) was added NH2NH2·H2O (1,53 ml, 31 mmol). The mixture is refluxed for 3 hours. The solvent is evaporated, the residue dissolved in CH2Cl2and washed with saturated aq. a solution of NaHCO3. The aqueous layer was extracted three times with CH2Cl2. The organic solutions are combined and evaporated, and get a mixture of diastereomers (1:1) 9a (6,72 g, 100%) as a pale orange solid.

IR (film) ν 3200 (m, NH), 1421 (m, C-N), 1022 (m, C-O).

1H-NMR (CDCl3, 200 MHz) δ 1,40-1,90 (m, 6H, H3", H4 ' and H5"), 3,20 (m, 2H, H2'), 3,48, and 3,90 (m, 1H, H6"), 4,60 and 4,85 (ushort, J 3.5 and m, 1H, H2"), 4,85 and equal to 4.97 (m and usert, J 5,7, 1H, H1'), 6,32, and to 6.43 (s, 1H, H3), 7.03, and 7,07 (DD, J 6.6 and 4.8 and DD, J 6.6 and 5,0, 1H, H5), 7,85 and of 7.90 (DD, J 6.6 and 1,4, 1H, H4), 8,29 and at 8.36 (DD, J 4.8 and 1.4 and DD, J 5.0 and 1,4, 1H, H7), up 10.9 and 12.5 (user., NH).

13C-NMR (CDCl3, 75 MHz) δ and 19,7 20,0 (t, C3*), a 25.1 and 25.3 (t, C4*), 30,6 and 30.9 (t, C5'*), 45,3 and 47,3 (t, C6"), 62,9 and 63.5 (t, C2'), 73,4 and 75.5 (d, Cl'), 96,1 and 97,3 (d, C2), and 99.8 and 99.9 (d, C3), 115,6 (d, C5)120,7 (, C3a), 128,4 and 128,5 (d, C4), 138,3 and 139,0 (s, C2), 142,2 and 142,3 (d, C6), 148,5 and of 149.0 (s, C7a).

MC (CI, CH4) m/z 263 (M+1,15), 262 (M+, 100).

MS high. bit., m/z for C14H19N3O2·N calculated 262,1555; found 262,1557.

Example 8

2-[2-Amino-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-4-methoxy-7-azaindole(9b)

Following the same method as for 9a, 4-methoxy-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (2.9 g, 10 mmol) in EtOH (100 ml) and NH2NH2·H2O (420 μl, 15 mmol) after interaction within 3 hours receive a mixture of diastereomers (1:1) 9b (1.9 g, 95%).

IR (film) ν 3150 (m, NH), 1590 (m, C=C), 1329 (m, C-N), 1114 (m, C-O).

1H-NMR (CDCl3, 200 MHz) δ 1,40-1,90 (m, 6H, H3-H5"), 3,19 (m, 2H, H2'), 3,48, and 3,90 (m, 1H, H6"), 3,99, and of 4.00 (s, 3H, MeO), 4,60 and is 4.85 (m, 1H, H2"), 4,85 and equal to 4.97 (m and ushort J 5,7, 1H, H1'), and 6.42 per 6,51 (s, 1H, H3), 6,51 and 6,55 (d, J 5,4, 1H, H5), 8,23 and 8,30 (d, J 5,4, 1H, H7).

13C-NMR (CDCl3, 75 MHz) δ 20,0 (t, C3*), to 25.2 and 25.4 (t, C4*), 30,7 and 30.9 (t, C5'*), 45,4 and 47.4 (t, C6"), 55,4 and 55,5 (square, MeO), 62,9 and 63,4 (t, C2'), 73,5 and 75.5 (d, Cl'), 94,7 and 96.1 (d, C2"*), 97,1 and 99.6 (d, C3), which is 97.6 (d, C5), 110,5 (s, C3a), br135.8 and to 136.5 (s, C2), 144,3 and 144,4 (d, C6), 150,3 151, 3mm and (C, C4*), 159,4 and 159,5 (s, C7a*).

MC (CI, CH4) m/z 291 (M+, 2), 262 (M-CH2NH3, 12), 190 (M-THPO, 8), 177 (100).

Example 9

2-[2-Amino-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-4-chloro-7-azaindole (-9)

Following the same method as for 9a, 4-chloro-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (950 mg, 2.2 mmol) in EtOH (50 ml) and NH2NH2·H2O (250 μl, 4.4 mmol) after interaction within 3 hours receive a mixture of diastereomers (1:1) 9c (640 mg, 97%).

1H-NMR (CDCl3, 200 MHz) δ 1,40-1,90 (m, 6H, H3-H5"), 3,19 (m, 2H, H2'), 3,50 I3,95 (m, 1H, H6"), 4,60 and is 4.85 (m, 1H, H2") 4,85 and equal to 4.97 (ushort, 1H, H1'), 6,46 and is 6.54 (s, 1H, H3), 7,07 and 7.10 (d, J5,4, 1H, H5), 8,19 and of 8.25 (d, J 5,4, 1H, H7).

13C-NMR (CDCl3, 75 MHz) δ and 19,8 20,1 (t, C3*), a 25.1 and 25.3 (t, C4*), 30,6 and 30.9 (t, C5'*), 45,2 and 47.1 (t, C6"), 63,1 and 63.7 (t, C2'), 73,1 and a 75.1 (d, Cl'), 96,0 and 96,4 (d, C2"*), 98,3 and 100.2 (d, C3), 115, 8mm (d, C5), 120,1 and to 120.4 (C, C4), 135,6 and br135.8 (s, C4), 139,1 and 139,8 (s, C3a), 142,4 and 142,5 (d, C6), 148,9 and at 149.5 (s, C7a).

MC (CI, CH4) m/z 295 (M+, 2), 266 (M-CH2NH3, 12), 194 (M-HPO, 8), 177 (100).

Example 10

6,7,8,9-Tetrahydro-6-(2,3,5,6-tetrahydropyran-2-yl)-occipied[3',2':4,5]pyrrolo[1,2-c]pyrimidine-9-he (10A)

A solution of 9a (7,4 g, 28 mmol) and DIPEA (5 ml, 28 mmol) in CH2Cl2(300 ml) is gradually added to a solution of triphosgene (2,82 g, 10 mmol) in CH2Cl2(740 ml)and the mixture was stirred at room temperature for 30 minutes the Organic mixture was washed with saturated aq. a solution of NH4Cl and water. The organic solution is dried and evaporated, and get a mixture of diastereomers (1:1) 10A (6,06 g, 76%).

IR (KBr) ν 3252 (m, NH), 1716 (s, C=O), 1407 (m, C-N), 1302 (m, C-O).

1H-NMR (CDCl3, 200 MHz) δ of 1.40 and 1.80 (m, 6H, H3-H5"), 3,45-4,00 (m, 2H, H7 and H6') and 4,94 (m, 1H, H2"), 5.04 and 5,10 (DD, J 3.2 and 3.0, and J 4,4 1H, H6), 6,56 and 6,59 (c, 1H, H5), 6,79 and 7,00 (user., 1H, NH), 7.20 and 7,22 (DD, J 7.6 and 4.8 and DD, J 8.0 and 4.8, 1H, H3), 7,89 and to 7.93 (DD, J 7.6 and 1.8 and DD, J 8.0 and 1.8, 1H, H4), 8,54 and to 8.57 (DD, J 4.8 and 1.8 and DD, J 4.8 and 1,4, 1H, H2).

13C-NMR (CDCl3, 50 MHz) δ 18,9 19,3 and (t, C4'), to 25.3 and 25.4 (t, C5'), to 30.1 and 30.4 (t, C3'), 43,5I 45,3 (t, C6'), 62,2 and 62.6 (t, C7), 63,2 and 64,3 (d, C6), 95,7 and 96.7 (d, C2'), to 102.3 and 103.7 (d, C5), 118,6 (d, C3), 121,3 and to 121.7 (s, C4a), 129,1 and to 129.2 (d, C4), 133,5 and 136,1 (s, C5a), 145, 2mm and 145,6 (d, C2), 148,0 and 148,1 (s, C10a), 149,8 and to 150.2 (s, C9).

MC (CI, CH4) m/z 289 (M+1, 6), 288 (M+, 25), 204 (M-THP, 23), 85 (THP, 100).

MS wiser., m/z for C15H17N3O3·N calculated 288,1348; found 288,1352.

Example 11

6,7,8,9-Tetrahydro-6-(2,3,5,6-tetrahydropyran-2-yl)oxy-4-methoxypyridine[3',2':4,5]pyrrolo[1,2-c]pyrimidine-9-he (10b)

Following the same method as for 10A, triphosgene (20 mg, 0.7 mmol) in CH2Cl2(3 ml), 9b (58 mg, 0.20 mmol) and DIPEA (34 μl, 0.20 mmol) in CH2Cl2(3 ml) for 30 min at room temperature to obtain the crude mixture, which purify column flash chromatography. Elution with a mixture of CH2Cl2and Meon gives a mixture of diastereomers (1:1) 10b (40 mg, 63%).

IR (KBr) ν 3258 (m, NH), 1714 (s, C=O), 1566 (m, C=N), 1290 (m, C-O).

1H-NMR (CDCl3, 200 MHz) δ of 1.40 and 1.80 (m, 6H, H3', H4' and H5'), 3,45, and 3.95 (m, 2H, H6'), of 3.65 and 3.75 (m, 2H, H7), of 4.00 (s, 3H, MeO), 4,67 and 4,94 (m, 1H, H2'), 4.99 and 5,07 (m, 1H, h6), of 6.20 and 6.30-in (user, 1H, NH), 6,65 and of 6.66 (s, 1H, H5), 6,69 (d, J 5,9, 1H, H3), 8,44 and 8,46 (d, J 5,9, 1H, H2).

13C-NMR (CDCl3, 50 MHz) δ and 18,7 19,4 (t, C4'), to 25.3 and 25.4 (t, C5'), to 30.1 and 30.3 (t, C3'), 43,5 and 45.3 (t, C6'), 61,9 and 62.6 (t, C7), 62,9 and 63,9 (d, C6), 95,5 and 96,2 (d, C2'), 99,6, 100,6 and 101,1 (d, C3 and C5), 130,9 (s, C5a), 147,3 and a 147.7 (d, C2), 149,9 and 150,3 (s, C10a or C4), 159,7 (C, C9).

MS (EI) m/z 318 (M+1, 2), 317 (M+, 28), 233 (22), 217 (66), 216 (65), 177 (10), 85 (THP, 100).

MS high. bit., m/z for C16H19N3O4calculated 317,1376; found 317,1383.

Example 12

6,7,8,9-Tetrahydro-6-hydroxypurine[3',2':4,5]pyrrolo[1,2-c]pyrimidine-9-he

To a solution of 10A (6 g, 21 mmol) in CH2Cl2(400 ml) is added 4 N. hydrochloric acid (450 ml). After stirring for 45 min at room temperature, the two layers separated. The organic solution is extracted with 4 N. hydrochloric acid. The aqueous solution is filtered and evaporated, and get 6,7,8,9-tetrahydro-6-hydroxypurine[3',2':4,5]pyrrolo[1,2-c]pyrimidine-9-he (5 g, 100%) in the form of the hydrochloride as a light orange solid.

Hydrochloride 6,7,8,9-tetrahydro-6-hydroxypurine-[3',2':4,5]pyrrolo[1,2-c]pyrimidine-9-she

IR (KBr) ν 3500 (s, OH), 1721 (s, C=O), 1638 (m, C-C), 1503 (m, C=N).

1H-NMR (CD3OD, 300 MHz) δ 3,61 (DD, J of 13.0 and 5.0, 1H, H7), of 3.77 (DD, J 13,0 and 4.0, 1H, H7), 5,23 (DD, J of 5.0 and 4.0, 1H, H6), 7,05 (s, 1H, H5), 7,86 (DD, J 8.0 to 6.0, 1H, H3), 8,56 (DD, J 6.0 and 1,2, 1H, H2), 8,86 (DD, J 8.0 and 1,2, 1H, H4).

13C-NMR (CD3OD, 75 MHz) δ 45,8 (t, C7), 59,6 (d, C6), 101,9 (d, C5), 119,0 (d, C3), 127,1 (s, C4a), 124,3 (d, C4), 137,4 (s, C5a), 139,4 (d, C2), 141,9 (s, C10a), of 149.0 (s, C9).

MC (CI, NH3) m/z 205 (M+1, 3), 204 (M+, 4), 180 (100), 163 (50), 130 (90).

MS high. bit., m/z for C10H10N3O3calculated 204,0773; found 204,0772.

A solution of the hydrochloride 6,7,8,9-tetrahydro-6-hydroxypurine-[3',2':4,5]pyrrolo[1,2-c]pyrimidine-9-it is saturated in the N. a solution of Na2CO3long-term extracted with CH2Cl2and get a paired basis.

6,7,8,9-Tetrahydro-6-hydroxypurine[3',2':4,5]pyrrolo[1,2-c]pyrimidine-9-he

IR (KBr) ν 3400 (m, NH/OH), 1707 (s, C=O), 1468 (m, C-N), 1408 (m, C-N), 1297 (m, C-O).

1H-NMR (DMSO-d6, 300 MHz) δ of 3.27 (m, 1H, H7), 3,42 (m, 1H, H7), the 4.90 (DD, J 9.3 and 5,1,1H, H6), 5,88 (d, J 5,1,1H, OH), is 6.54 (s, 1H, H5), 7,21 (DD, J 7.4 and 4,2, 1H, H3), 7,88 (user., 1H, NH), 7,99 (userd, J of 7.4, 1H, H2), 8,30 (userd, J 4,2, 1H, H4).

13C-NMR (DMSO-d6, 75 MHz) δ 41,0 (t, C7), and 55.7 (d, C6), 95,4 (d, C5), 113,8 (d, C3), of 116.7 (s, C4a), to 124.2 (d, C4), 135,4 (s, C5a), to 139.3 (d, C2), 142,9 (s, Se*), 143,8 (C, C9*).

Example 13

6,7,8,9-Tetrahydro-6-hydroxy-4-methoxypyridine[3',2':4,5]-pyrrolo[1,2-c]pyrimidine-9-he

To a solution of 10b (25 mg, 0.08 mmol) in CH2Cl2(5 ml) is added 4 N. hydrochloric acid (5 ml) and the mixture is stirred at room temperature for 45 minutes the Organic solution is separated and extracted with 4 N. hydrochloric acid. The aqueous solution is filtered and evaporated, and get 6,7,8,9-tetrahydro-6-hydroxy-4-methoxypyridine[3',2':4,5]pyrrolo[1,2-c]pyrimidine-9-he (20 mg, 95%) in the form of the hydrochloride as a light orange solid.

IR (film) ν 3244 (m, NH), 1718 (s, C=O), 1627 (s, NCO), 1505 (m ON), 1298 (m, C-O).

1H-NMR (CD3OD, 200 MHz) δ of 3.56 (DD, J 13,6 and 4.8, 1H, H7), 3,71 (DD, J and 3.6 to 13.6, 1H, H7), the 4.29 (s, 3H, MeO), 5,11 (DD, J of 4.8 and 3.6, 1H, H6), 6,91 (s, 1H, H5), 7,40 (d, J 6,9, 1H, H3), 8,42 (d, J 6,9, 1H, H2).

13C-the Mr (DMSO-d 6, 75 MHz) δ 48,9 (t, C7), 60,5 (square, Me), 62,3 (d, C6), of 101.7 (d, C5), 105,5 (d, C3), 117,4 (s, C4a), 137,0 (s, C5a), 140,6 (d, C2), 141,4 (s, C10a), 151,9 (s, C9), 169,0 (C, C4).

MC (El) m/z 234 (M+l, 12), 233 (M+, 77), 215 (M-H2O, 17), 55 (100).

MS high. bit., m/z for C11H11N3O3calculated 233,0800; found 233,0813.

Example 14

8,9-Dihydropyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-9-he (11a)

To a cooled (0° (C) to a solution of 6,7,8,9-tetrahydro-6-hydroc-dipyrido[3',2':4,5]-pyrrolo[1,2-c]pyrimidine-9-it (1 g, 4.2 mmol) and tea (1,74 ml, 13 mmol) in CH2Cl2(20 ml) is added dropwise MsCl (320 μl, 4.2 mmol). The reaction mixture was stirred for 30 min at the same temperature, and the organic solution washed with saturated aq. a solution of NH4Cl and water. The organic solution is dried and evaporated, and receive without additional purification 11a (730 mg, 95%) as a white solid.

TPL 265-266° (Meon).

IR (KBr) ν 3424 (m, NH), 1721 (s, C=O), 1691 (m, NCO), 1633 (m, C=C), 1408 (m, C=N), 1380 (m), 1303 (m).

1H-NMR (DMSO-d6, 300 MHz) δ 6,50 (d, J 7,4, 1H, H6), 6,60 (s, 1H, H5), 6,97 (DD, J 7.4 and 5,3, 1H, H7), 7,37 (DD, J 8.0 and a 4.7, 1H, H3), 8,08 (DD, J 8.0 and 1.7, 1H, H4), 8,39 (DD, J 4.7 and 1,7, 1H, H2), 10,81 (userd, J 5,3, 1H, NH).

13C-NMR (DMSO-d6, 75 MHz) δ 94,9 (d, C5), 98,0 (d, C6), to 119.8 (d, C3), 123,1 (s, C4a), of 127.5 (d, C4), USD 128.0 (d, C7), 137,0 (s, C5a), 142,5 (d, C2), 145,6 (s, C10a*), 146,7 (C, C9*).

MC (EI) m/z 186 (M+l, 18), 185 (M+, 15), 157 (M-CO, 10)

(CI, NHs) m/z 204 (M+18, 12), 187 (M+2,14), 186 (M+l, 100), 109 48).

MS high. bit., m/z for C10H7N3O calculated 185,0589; found 185,0593.

Example 15

8,9-Dihydro-4-methoxypyridine[3',2':4,5]pyrrolo[1,2-c]-pyrimidine-9-he (11b)

Following the same method as for 11a, 6,7,8,9-tetrahydro-6-hydroxy-4-methoxypyridine[3',2':4,5]pyrrolo[1,2-c]pyrimidine-9-she (113 mg, 0.42 mmol), tea (195 μl, 1.25 mmol) and MsCl (32 μl, 0.42 mmol) in CH2Cl2(20 ml) for 30 min received without additional purification 11b (74 mg, 85%) as a white solid.

IR (KBr) ν 3380 (m, NH), 1721 (s, C=0), 1693 (m, NCO), 1633 (m, C=C), 1500 (m, C=N), 1294 (m, C-0).

1H-NMR (DMSO-d6, 200 MHz) δ 3,98 (s, 3H, Me), 6,44 (d, J 7,5, 1H, H6), is 6.54 (s, 1H, H5), 6,89 (DD, J 7.5 and 2,0,1H, H7), of 6.96 (d, J 5,5, 1H, H3), compared to 8.26 (d, J 5,5, 1H, H2).

13C-NMR (DMSO-d6, 75 MHz) δ 55,5 (square, Me), 92,6 (d, C5), the 98.9 (d, C6), 101,0 (d, C3), of 124.7 (d, C7), 114,0 (s, C4a), 134,1 (s, C5a), 144,9 (d, C2), 146,5 (s, C9), of 147.7 (s, C10a), 159,1 (C, C4).

MC (El) m/z 216 (M+l, 17), 215 (M+, 100), 214 (M-l, 11), 200 (M-Me, 59), 172 (48).

MS high. bit., m/z for C11H9N3O2calculated 215,0694; found 215,0690.

Example 16

8,9-Dihydro-8-ethoxymethylene[3',2':4,5]pyrrolo[1,2-c]-pyrimidine-9-he (12)

To a cooled (0° (C) to a solution of 11a (250 mg, 1.4 mmol) in DMF (10 ml) is added NaH (65 mg, 1.6 mmol). The mixture is stirred for 10 min and added dropwise MOMCl (103 μl, 1.4 mmol). The mixture was stirred at 0°C for 1 hour and quenched with water is th (1 ml). The solvent is evaporated, and the residue is dissolved in CH2Cl2. The organic solution was washed with aq. a solution of Na2CO3, evaporated and the residue purified column flash chromatography. Elution with a mixture of CH2Cl2and Meon (95/5) to give 12 (267 mg, 87%) as a white solid.

IR (film) ν 1711 (s, C=O), 1642 (m, NCO), 1393 (m, C-O), 1175 (m, C-O).

1H-NMR (CDCl3, 300 MHz) δ to 3.41 (s, 3H, Me), from 5.29 (s, 2H, CH2), 6,37 (d, J 7,5, 1H, H6), 6,41 (s, 1H, H5), 7,81 (d, J 7,5, 1H, H7), 7,26 (DD, J of 7.8 and 4.8, 1H, H3), of 7.90 (DD, J 7.8 and 1,2, 1H, H4), charged 8.52 (DD, J 4.8 and 1,2, 1H, H2).

13C-NMR (CDCl3, 50 MHz) δ 56,9 (square, Me), 78,0 (t, CH2), with 95.9 (d, C5), a 99.6 (d, C6), 119,5 (d, C3), 123,3 (s, C4a), to 127.9 (d, C4), 128,1 (d, C7), 135,1 (s, C5a), 143,7 (d, C2), 146,2 (s, C9), 147,1 (s, C10a).

MS (El) m/z 230 (M+l, 30), 229 (M+, 100).

MS high. bit., m/z for C12H11N3O2calculated 229,0851; found 229,0850.

Example 17

8,9-Dihydro-8-(4-methylphenylsulfonyl)pyrido[3',2':4,5]-pyrrolo[1,2-c]pyrimidine-9-he

To a cooled (0° (C) to a solution of 11a (500 mg, 2.7 mmol) in DMF (30 ml) is added NaH (130 mg, 3.2 mmol). The mixture is stirred for 10 minutes and add a solution of p-toluensulfonate (570 mg, 3.0 mmol) in DMF (10 ml). The mixture is stirred at room temperature for 1 hour and quenched with water (1 ml). The solvent is evaporated and the residue dissolved in AcOEt. The organic solution was washed with aq. a solution of Na2CO 3, evaporated and the residue purified column flash chromatography. Elution with a mixture of hexane and CH2Cl2(1/1) gives 8,9-dihydro-8-(4-were-sulfonyl)pyrido[3',2':4,5]-pyrrolo[1,2-c]pyrimidine-9-he (360 mg, 40%) as a white solid.

IR (KBr) ν 1737 (s, C=O), 1642 (m, NCO), 1393 (s, 502), 1175 (m).

1H-NMR (CDCl3, 200 MHz) δ to 2.42 (s, 3H, Me), of 6.45 (d, J 8,0, 1H, H6), 6.48 in (s, 1H, H5), 7,27 (DD, J of 8.2 and 4.7, 1H, H3), 7,34 (d, J 8,4, 2H, H3' and H5'), the 7.65 (d, J 8,0, 1H, H7), of 7.90 (DD, J of 8.2 and 1.4,1H, H4), of 8.09 (d, J 8.4 and, 2H, H2' and H6'), 8,53 (DD, J 4.7 and 1,4, 1H, H2).

13C-NMR (CDCl3, 50 MHz) δ 21,8 (square, Me)98,3 (d, C5), 100,2 (d, C6), 118,5 (s, C4'), 120,1 (d, C3), 123,6 (s, C4a), 123,7 (d, C4), of 128.6 (d, C7), of 129.6 (d, C3' and C5'), 129,8 (d, C2' and C6'), 133,8 (s, C5a), 141,8 (s, Cl'), 144,6 (d, C2), 146,0 (C, C9).

MC (El) m/z 340 (M+l, 7), 339 (M+, 32), 184 (M-Ts, 100).

MS high. bit., m/z for C17H13N3O3S calculated 339,0677; found 339,0682.

Example 18

8,9-Dihydro-5-bromo-8-ethoxymethylene[3',2':4,5]pyrrolo-[1,2-c]pyrimidine-9-he (13A)

To a solution of 12A (100 mg, 0.44 mmol) in CH2Cl2(30 ml) at 0°add NBS (78 mg, 0.44 mmol)and the mixture stirred for 10 minutes the Mixture was diluted with CH2Cl2(50 ml), and washed three times with saturated aq. a solution of NaHCO3. The organic layer is dried and evaporated, and receive without additional purification 13A (107 mg, 80%) as a pale yellow solid.

IR (KBr) ν 1715 (s, C=O), 1640 (m, OS), 1092 (m, C-O).

H-NMR (CDCl3, 300 MHz) δ 3,39 (s, 3H, Me), from 5.29 (s, 2H, CH2), to 6.43 (d, J 7,8, 1H, H6), of 6.90 (d, J 7,8, 1H, H7), 7,33 (DD, J 8.1 and 4,8, 1H, H3), 7,86 (DD, J 8.1 and 1,5, 1H, H4), 8,54 (DD, J 4.8 and 1,5, 1H, H2).

13C-NMR (CDCl3, 50 MHz) δ 57,0 (square, Me), 77,1 (s, C5), 78,3 (t, CH2), 97,7 (d, C6), 120,1 (d, C3), the 122.7 (s, C4a), a 126.7 (d, C4), to 129.2 (d, C7), to 132.8 (s, C5a), 144, 8mm (d, C2), 146,2 (s, C9), 146,5 (s, Sa).

MC (EI) m/z 310 (81BrM + 1,5), 309 (81BrM+, 50), 308 (79BrM + 1,5), 307 (79BrM+, 50), 45 (MOM, 100).

MS high. bit., m/z for C12H1079BrN3O2calculated 306,9957; found 306,9956.

Example 19

8,9-Dihydro-5-iodine-8 ethoxymethylene[3',2':4,5]pyrrolo-[1,2-c]pyrimidine-9-he (13b)

To a cooled (0° (C) to a solution of 11a (100 mg, 0.44 mmol) in DMF (4 ml) at the same time add iodine (220 mg, 0.8 mmol) and KOH (94 mg, of 1.66 mmol). The mixture is stirred for 30 min at 0°C. the Mixture is quenched with an aqueous solution (25 ml) of 0.5% NH3and 0.1% Na2S2O5. The solution is extracted with AcOEt, and the organic solution washed twice with saturated aq. a solution of NaHCO3. The organic layer is dried and evaporated, and get 13b (96 mg, 62%) without any further purification in the form of a light yellow solid.

IR (film) ν 3200 1714 (s, C=O), 1637 (m, C=C), 1089 (m, C-O).

1H-NMR (CDCl3, 300 MHz) δ of 3.45 (s, 3H, Me), are 5.36 (s, 2H, CH2), 6,46 (d, J 8,1, 1H, H6), of 6.99 (d, J 8,1, 1H, H7), 7,40 (DD, J 8.1 and 4,8, 1H, H3), 7,81 (DD, J 8.1 and a 1.8, 1H, H4), 8,59(DD, J of 4.8 and 1.8, 1H, H2).

13C-NMR (CDCl3, 50 MHz) δ 54,5 (s, C5), 57,1 (square, Me), to 78.3 (t, CH2), a 99.6 (d, C6), to 120.3 (d, C3), output reached 125.5 (s, C4a), of 128.6 (d, C4), 129,8 (d, C7), to 136.5 (s, C5a), 144,9 (d, C2), 146,0 (s, C9), 146,3 (s, C10a).

MC (CI, MNC) m/z 357 (M+2, 5), 356 (M+1,30), 230 (100),

MS high. bit., m/z for C12H10IN3O2calculated 354,9820; found 354,9823.

Example 20

2-Methanesulfonyl-4-trimethylaniline (15)

To a solution of 4-iodine-2-methanesulfonamide (800 mg, 3.2 mmol), gestaltisticka (1 ml, 4.8 mmol), Pd(OAc)2(45 mg, 0.31 mmol) and PPh3(90 mg, of 0.62 mmol) in THF (10 ml) is added dropwise TBAF (5 ml, 1 M solution in THF). The mixture is stirred at room temperature for 1.5 hours. The solvent is removed in vacuo and the residue purified column chromatography on neutral aluminium oxide. Elution with a mixture of hexane and AcOEt (99/1) to give 15 (585 mg, 65%) as a colourless oil.

IR (film) ν 1539 (m, C=N), 1402 (m), 1306 (m), 1196 (m).

1H-NMR (CDCl3, 200 MHz) δ 0,34 (s, 9H, 3Me), of 2.54 (s, 3H, Me), was 7.08 (d, J 4,5, 1H, H5), compared to 8.26(d, J 4,5, 1H, H6),

13C-NMR (CDCl3, 75 MHz) δ 9,5 (square, Me)14,0 (square, Me)124,5 (d, C5), 153,6 (d, C6), 171,4 (C, C2).

MC (EI) m/z 291 (120SnM+, 50), 276 (120SnM-Me, 100).

MS high. bit., m/z for C8H14N2S120Sn calculated 290,9977; found 290,9973.

Example 21

8,9-Dihydro-5-iodine-8-(4-methylphenylsulfonyl)pyrido-[3',2':4,5]pyrrolo[1,2-c]pyrimi the in-9-he (17)

To a cooled (0° (C) to a solution of 11a (200 mg, 0.59 mmol) in CH2Cl2(20 ml) is added by portions NIS (133 mg, 0.59 mmol) and the mixture stirred for 30 min at the same temperature. The mixture was diluted with CH2Cl2(50 ml) and washed twice with water. The organic layer is dried and evaporated, and receive 17 (218 mg, 80%) without any further purification in the form of a light yellow solid.

IR (film) ν 1735 (s, C=O), 1636 (s, NCO), 1395 (m, C-N), 1368 (s, SO2), 1175 (m), 1075 (m).

1H-NMR (CDCl3, 300 MHz) δ of 2.38 (s, 3H, Me), to 6.43 (d, J 8,3, 1H, H6), 7,30 (m, 3H, H3, H3' and H5'), to 7.68 (DD, J 8.1 and 1,5, 1H, H4), 7,72 (d, J 8,3, 1H, H7), of 8.04 (d, J 8,4, 2H, H2' and H6'), 8,49 (DD, J 4.8 and 1,5, 1H, H2).

13C-NMR (CDCl3, 75 MHz) δ 21,7 (square, Me)56,9 (s, C5), 100,0 (d, C6), is 120.7 (d, C3), 123,8 (s, C4'), 125,3 (d, C4), 125,7 (s, C4a), 129,0 (d, C7), 129,5 (s, C1'), of 129.6 (d, C3' and C5', 129,7 (d, C2' and C6'), 133,3 (s, C5a), 135,0 (s, C10a), 145,5 (d, C2), 146,1 (C, C9).

MC (EI) m/z 466 (M+l, 8), 465 (M+, 36), 310 (M-Ts, 100),

MS high. bit., m/z for C17H12IN3O3S calculated 464,9646; found 464,9649.

Example 22

8,9-Dihydro-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-c]pyrimidine-9-he (18)

A solution of 17 (50 mg, 0.11 mmol), 2-methanesulfonyl-4-trimethylenediamine (93 mg, 0.32 mmol), Pd2(dba)3(11 mg, to 0.011 mmol), PPh3(6 mg, of 0.022 mmol), LiCl (14 mg, 0.32 mmol) and CuI (4 mg, to 0.011 mmol) in dioxane (2 ml) is boiled fix refrigerator for 5 hours. The solvent is evaporated and the crude residue purified column flash chromatography. Elution with a mixture of CH2Cl2, Meon and aq. solution of NH3(4/4/2) network 18 (4 mg, 12%).

1H-NMR (DMSO-d6, 300 MHz) δ 2,60 (3H, s, MeS), 7,20 (1H, d, J 6,3, H7), 7,42 (1H, DD, J 7.5 and 4.2, and H3), was 7.45 (1H, d, J 5,7, H5'), of 7.70 (1H, d, J 6,3, H6), by 8.22 (1H, d, J 4.2, and H2), 8,39 (1H, d, J 5,7, H6'), 8,73 (1H, d, J of 7.5, H4).

MC (APCI) AP-m/z 309 (M+, 20), 308 (M-l, 90), 307 (M-2, 100); AP+m/z 331 (M+Na, 10), 310 (M+l, 20), 309 (M+, 25).

Example 23

9 Aminopyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine (19a)

From 11a

To a solution of 11a (500 mg, 2,70 mmol) in 2,6-lutidine (40 ml) and HMDSA (60 ml) was added TMSCl (400 μl, 2,70 mmol) and the mixture is refluxed for 15 hours. Add TMSTf (100 μl, 0.27 mmol) and the mixture bubbled NH3for 15 min at 0°C. a Mixture of closed steel autoclave and heat at 150°C for 8 hours (60 f/d2). The solvent is evaporated and the crude residue purified column flash chromatography. Elution with a mixture of CH2Cl2and Meon (98/2) to give 19a (150 mg, 30%) as a pale yellow solid.

From 23a

To a solution of 23a (20 mg, 0.06 mmol) in liquid NH3(8 ml) at -78°With small portions add Na to until the blue color will not be stored within 10 minutes Add portions NH4Cl until then, until the blue color disappears and the reaction mixture is stirred at anatoy temperature until until evaporated solvent. The solid residue is dissolved in water and extracted with CH2Cl2. The organic solution is dried and evaporated, and get 19a (4 mg, 38%) as a yellow solid.

TPL 214-215°C (decomp.), (CH2Cl2/hexane).

IR (KBr) ν 3452 (m, NH), 3304 (m, NH), 1654 (m, C=C), 1618 (m, C=C), 1570 (m, C=N), 1403 (m, C-N).

1H-NMR (DMSO-d6, 300 MHz) δ of 6.49 (s, 1H, H5), 6,72 (d, J 6,6, 1P, H6), 6,80 (user., 1H, NH), 7,30 (d, J 6,6, 1H, H7), 7,42 (DD, J 7,8 and 4.6, 1H, H3), 8,14 (DD, J 7,8 and 1.5, 1H, H4), with 8.33 (DD, J of 4.6 and 1.5, 1H, H2), at 8.60 (user., 1H, NH).

13C-NMR (DMSO-d6, 75 MHz) δ and 88.8 (d, C5), 101,0 (d, C6), 119,6 (d, C3), 122,9 (s, C4a), of 127.5 (d, C4), 136,8 (s, C5a), 138,9 (d, C2), 139,4 (d, C7), 141,8 (s, C10a), 148, 8 persons (s, C9).

MC (EI) m/z 185(M+1,15), 184 (M+, 100), 183 (M-1, 7).

MS high. bit., m/z for C10H8N4calculated 184,0749; found 184,0747.

Example 24

9-Amino-4-methoxypyridine[3',2':4,5]pyrrolo[1,2-c]pyrimidine (19b)

From 11b

Following the same method as for 19a, mixed 11b (60 mg, 0.27 mmol), HMDSA (30 ml), 2,6-lutidine (15 ml) and TMSCl (36 μl, 0.27 mmol). The reaction time is 15 hours. Add TMSTf (12 μl, 0.06 mmol)and the mixture bubbled NH3for 15 min at 0°C. the reaction Time is in a steel autoclave for 8 hours, then heated at 150°C (60 f/d2). The solvent is evaporated and the crude residue purified column flash chromatography. Elution with a mixture of CH2Cl2and Meon (99/1) to give 19b (13 mg, 22%), and LWIR is a mixture of CH 2Cl2and Meon (95/5) to give 11b (9 mg, 15%).

From 23b

To a solution of 23b (200 mg, 0.54 mmol) in THF (25 ml) at 0°With added dropwise the previously received the green solution of Na in the naphthalene in THF (1,43 ml, 0.54 mmol). The solution is stirred for 20 min at room temperature, is added dropwise Na in naphthalene in THF (7.2 ml, 2,70 mmol) and the mixture is stirred for 15 minutes the Solvent is removed and the crude residue dissolved in AcOEt. The organic solution extracted three times 4 N. HCl. The aqueous layers are combined alkalinized NaHCO3and extracted with CH2Cl2. The organic solution is dried and evaporated, and the residue is purified column flash chromatography. Elution with a mixture of CH2Cl2and Meon (95/5) to give 19b (27 mg, 23%) as a pale yellow solid

1H-NMR (CDCl3+CD3OD, 300 MHz) δ to 4.01 (s, 3H, Me), of 6.45 (s, 1H, H5), is 6.61 (d, J 6,6, 1H, H6), to 6.75 (d, J 5,6, 1H, H3), 7,14 (d, J 6,6, 1H, H7), 8,18 (d, J 5,6, 1H, H2).

13C-NMR (CDCl3+CD3OD, 75 MHz) δ 55,6 (square, Me)87,5 (d, C5), 100,6 (d, C6), 102,2 (d, C3), 114,3 (s, C4a), RUR 134.4 (s, C5a), 136,0 (d, C2), 141,7 (d, C7), of 142.8 (s, C10a), of 149.0 (s, C9)158,8 (C, C4).

MC (EI) m/z 215 (M+l, 7), 214 (M+, 36), 213 (M-l, 6), 199 (M-Me, 36), 57 (100).

(ES+) m/z 216 (M+2, 20), 215 (M+1, 100).

Example 25

9 Acetylaminophenol[3',2':4,5]pyrrolo[1,2-c]pyrimidine

To a solution of 19a (250 mg, of 1.36 mmol) in THF (20 ml) is added acetic anhydride (200 μl, 2.04 mmol) and the mixture premesis the Ute at room temperature for 20 hours. The solvent is removed and the residue dissolved in CH2Cl2. The solution was washed with saturated aq. a solution of NaHCO3. The organic layer is dried and evaporated. The crude residue is purified column flash chromatography. Elution with a mixture of CH2Cl2and Meon (99/1) gives 9-acetaminophine-up[3',2':4,5]pyrrolo[1,2-c]pyrimidine (225 mg, 75%) as a brown-yellow solid.

TPL 160-161°C (CH2Cl2/hexane).

IR (KBr) ν 3150 (m, NH), 1708 (s, C=O), 1626 (m, NCO), 1574 (m, C=N), 1372 (m, C-N), 1269 (m).

1H-NMR (CDCl3, 300 MHz) δ 2,63 (s, 3H, Me), 6,53 (s, 1H, H5), 6,97 (d, J 6,6, 1H, H6), 7,41 (DD, J 8.0 and 4.8, 1H, H3), 7,51 (d, J 6,6, 1H, H7), 8,10 (DD, J 8.0 and 1.5, 1H, H4), to 8.41 (DD, J 4.8 and 1,5, 1H, H2).

13C-NMR (CDCl3, 75 MHz) 6 26,2 (square, Me), 90,5 (d, C5), 107,2 (d, C6), 119,6 (d, C3), 122,8 (s, C4a), 128,4 (d, C4), 136,0 (s, C5a), to 136.5 (d, C2), 139,6 (d, C7), 141,3 (s, C10a), 142,3 (s, C9), 170,0 (s, CO).

MC (EI) m/z 227 (M+l, 3), 226 (M+, 18), 184 (M-Ac, 100).

MS high. bit., m/z for C12H10N4About calculated 226,0855; found 226,0852.

Element. analysis: for C12H10N4O calculated: C (63,71), N (4,46), N (24,77); found: C (63,65), N (4,59), N (24,80).

Example 26

9-Acetylamino-4-methoxypyridine[3',2':4,5]pyrrolo[1,2-c]-pyrimidine

To a solution of 19b (16 mg, 0.08 mmol) in THF (2 ml) is added acetic anhydride (10 μl, 0.05 mmol) and the mixture is stirred at room temperature for 20 hours. The solvent is removed and the residue dissolved in CH2/sub> Cl2. The solution was washed with saturated aq. a solution of NaHCO3. The organic layer is dried and evaporated. 9-Acetylamino-4-methoxypyridine[3',2':4,5]pyrrolo[1,2-c]pyrimidine (17 mg, 95%) is obtained without any additional purification.

1H-NMR (CDCl3, 300 MHz) δ 2,60 (s, 3H, Me), 4,07 (s, 3H, Me), 6,60 (s, 1H, H5), PC 6.82 (d, J 5,7, 1H, H3), of 6.96 (d, J 6,6, 1H, H6), 7,47 (d, J 6,6, 1H, H7), 8,29 (d, J 5,7, 1H, H2).

13C-NMR (DMSO-d6, 75 MHz) 26,3 (square, Me)and 55.8 (square, Me), at 88.1 (d, C5), to 100.7 (d, C6), to 107.7 (d, C3), 114,1 (s, C4a), 134,5 (s, C5a), to 135.9 (d, C2), to 142.1 (d, C7), 159,5 (s, C4), USD 170.1 (C, CO).

MC (ES) m/z 258 (M+2, 30), 257 (M+1, 100).

Example 27

9-Acetylamino-5-jumpered[3',2':4,5]pyrrolo[1,2-c]-pyrimidine (20A)

To a cooled (0° (C) to a solution of 9-acetylaminophenol-[3',2':4,5]pyrrolo[1,2-c]pyrimidine (100 mg, 0.44 mmol) in CH2Cl2(20 ml) is added by portions NIS (100 mg, 0.44 mmol). The mixture is stirred for 15 minutes the Solution was diluted with CH2Cl2(50 ml) and washed twice with water. The organic layer is dried and evaporated, and receive 20A (142 mg, 93%) as a brownish-yellow substance.

TPL 163-164°C (decomp.), (CH2Cl2/hexane).

IR (KBr) ν 3050 (m, NH), 1694 (m, C=0), 1573 (m, C=N), 1372 (m, C-N), 1307 (m).

1H-NMR (CDCl3, 200 MHz) δ 2,63 (s, 3H, Me)6,94 (d, J 6,4, 1H, H6), 7,47 (DD, J of 8.2 and 4.8, 1H, H3), to 7.61 (d, J 6,4, 1H, H7), to 7.93 (DD, J of 8.2 and 1.6, 1H, H4), 8,40 (DD, J 4.8 and 1,6, 1H, H2).

13C-NMR (CDCl3, 75 MHz) δ 26,4 (square, Me)46,7 (s, C5), 107,0 (d, C6), 120,6 (d, C3), 125,2 (who, C4a), to 128.8 (d, C4), 136,9 (s, C5a), 138,6 (d, C7), 140,9 (d, C2), 141,5 (s, C10a), 142,7 (C, C9)to 170.2 (C, CO).

MC (EI) m/z 353 (M+1, 3), 352 (M+, 22), 310 (M-Ac, 100).

MS high. bit., m/z for C12H9IN4O calculated 351,9821; found 351,9821.

Element. analysis: for C12H9IN4O calculated: C (40,93), N (2,58), N (15,91); found: C (40,91), N (2,64), N (15,79).

Example 28

9-Acetylamino-5-iodine-4-methoxypyridine[3',2':4,5]pyrrolo[1,2-c]pyrimidine (20b)

To a cooled (0° (C) to a solution of 9-acetylamino-4-methoxypoly-up[3',2':4,5]pyrrolo[1,2-c]pyrimidine (20 mg, 0,078 mmol) in CH2Cl2(15 ml) is added by portions NIS (18 mg, 0,078 mmol). The mixture is stirred for 15 minutes the Solution was diluted with CH2Cl2(50 ml) and washed twice with water. The organic layer is dried and evaporated, and receive 20b (27 mg, 93%).

1H-NMR (CDCl3, 200 MHz) δ 2,61 (s, 3H, Me), 4,08 (s, 3H, Me), at 6.84 (d, J 5,7, 1H, H3), 6,97 (d, J 6,6, 1H, H6), EUR 7.57 (d, J 6,6, 1H, H7), 8,31 (d, J 5,7, 1H, H2).

13C-NMR (CDCl3, 75 MHz) δ 26,3 (square, Me)and 55.8 (square, Me), 101,2 (d, C6), to 107.7 (d, C3), 114,1 (s, C4a), 133,5 (s, C5a), 137,7 (d, C2), 142,5 (d, C7), 142,6 (s, C10a), to 151.8 (s, C9), 170,4 (s, C4), 176,8 (s, CO).

MC (ES+) m/z 384 (M+2,15), 383 (M+l, 100), 192 (M+22+, 50), 191 (M+l2+, 22).

Example 29

9-Amino-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-c]pyrimidine (21) and 9-acetylamino-5-(2-methanesulfonamido-4-yl)pyrido[3',2':4,5]pyrrolo[1,2-c]-pyrimidine

A solution of 20A (13 mg, of 0.37 mmol), 2-methanesulfonyl-4-three-Metallurgicheskaya (93 mg, 1.10 mmol), Pd2(dba)3(76 mg, 0.07 mmol), PPh3(39 mg, 0.15 mmol), LiCl (47 mg, 1.10 mmol) and CuI (14 mg, 0.07 mmol) in dioxane (10 ml) is refluxed for 1.5 hours. The organic solvent is removed and the resulting oil was dissolved in CH2Cl2. The organic solution is extracted four times 4 N. HCl and the aqueous solution is alkalinized solid Na2CO3. The aqueous solution is extracted with CH2Cl2. The organic layer is evaporated and the residue purified column flash chromatography. Elution with a mixture of CH2Cl2and Meon (99/1) gives 9-acetylamino-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-c]pyrimidine (21 mg, 16%) as a yellow solid and a mixture of CH2Cl2and Meon (95/5) to give 21 (30 mg, 26%) as a yellow solid.

A solution of 9-acetylamino-5-(2-methanesulfonamido-4-yl)-pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine (15 mg, 0,043 mmol) in 5 BC HCl/MeOH (5 ml) is refluxed for 1 hour. The solvent is removed and the residue is dissolved in saturated aq. a solution of Na2CO3. The solution is extracted with CH2Cl2. The organic solvent is evaporated and get 21 (12 mg, 90%).

When the interaction is repeated and carried out the treatment with HCl/ MeOH directly before cleaning column flash chromatogra the iej, get 21 (45%) as the only reaction product.

9-Amino-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-c]pyrimidine (21)

TPL p.223-224°C (CH2Cl2/hexane).

IR (KBr) ν 3390 (m, NH), 1632 (m, C=C), 1557 (m, C=N), 1517 (m), 1464 (m, C-N), 1265 (m).

1H-NMR (CDCl3, 300 MHz) δ of 2.68 (s, 3H, Me), 7,33 (d, J 5,4, 1H, H5'), 7,49 (DD, J 8.4 and 4,8, 1H, H3), 7,58 (d, J 6,6, 1H, H7), to 7.68 (d, J 6,6, 1H, H6), 8,40 (DD, J 4.8 and 1,6, 1H, H2), 8,48 (d, J 5,4,1H, H6'), 8,73 (DD, J of 8.4 and 1.6, 1H, H4).

13C-NMR (CDCl3, 50 MHz) δ 14,4 (square, MeS), 100,3 (s, C5), 102,1 (d, C6), 112,6 (d, C5'), is 120.7 (d, C3), 122,0 (s, C4a), of 128.6 (d, C4), 138, 7mm (s, C5a), 140,3 (d, C2), to 142.1 (s, Sa), 143,4 (d, C7), 149,8 (s, C9), 156,5 (d, C6'), 161,2 (s, C4'), 172,3 (C, C2').

MC (EI) m/z 309 (M+1, 7), 308 (M+, 33).

MS high. bit., m/z for C15H12N6S calculated 308,0844; found 308,0839.

UV (Meon) λ 217 (16,324), 252 (21,415), 400 (11,692).

9-Acetylamino-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-c]pyrimidine

TPL 160-162°C (CH2Cl2/hexane).

IR (KBr) ν 1704 (s, C=O), 1620 (m, C=C), 1556 (m), 1536 (m, C=N), 1517 (m), 1502 (m), 1476 (m, C-N), 1265 (m).

1H-NMR (CDCl3, 200 MHz) δ to 2.67 (s, 3H, Me), 2,69 (s, 3H, MeS), was 7.36 (d, J 5,2, 1H, H5'), 7,58 (DD, J of 8.2 and 4.8, 1H, H3), 7,83 (d, J 6,6, 1H, H7), to 7.93 (d, J 6,6, 1H, H6), charged 8.52 (DD, J 4.8 and 1,4, 1H, H2), 8,54 (d, J 5,2, 1H, H6'), 8,77 (DD, J of 8.2 and 1.4,1H, H4).

13C-NMR (CDCl3, 75 MHz) δ 14,4 (square, MeS), 26,4 (square, Me), 104,5 (s, C5), 107,4 (d, C6), level 113.0 (d, C5'), 121, 1million (d, C3), to 121.6 (s, C4a), of 129.5 (d, C4), 137,7 (s, C5a), 141,0 (d, C2), 141,1 (d, C7), 142,5 (s, C10a), br143.3 (s, C9), 156,8 (d, C6'), 160,7 (s, C4'), to 170.2 (C, C2'), 172,7 (s, CO).

p> MC (EI) m/z 351 (M+1, 3), 350 (M+, 33), 308 (M-Ac, 100).

MS high. bit., m/z for C17H14N6OS calculated 350,0949; found 350,0940.

UV (Meon) λ 255 (25,480), 400 (17,710).

Example 30

9-Amino-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-c]pyrimidine

To a cooled (0° (C) a solution of 21 (20 mg, 0.07 mmol) in CH2Cl2(5 ml) is added m-SRV (32 mg, 0.13 mmol). The mixture is stirred for 30 minutes Add saturated aq. a solution of Na2S2O3(1 ml) and the mixture is alkalinized with saturated aq. a solution of Na2CO3. The organic layer is separated and the aqueous layer was extracted with CH2Cl2. The organic solutions are combined, dried and evaporated, and get a 9-amino-5-(2-methanesulfonamido-4-yl)pyrido[3',2':4,5]-pyrrolo[1,2-c]pyrimidine (20 mg, 90%).

IR (KBr) ν 3388 (m, NH), 1635 (m, C=C), 1569 (m), 1519 (m, C=N), 1467 (m), 1267 (s, s=O).

1H-NMR (CDCl3, 300 MHz) δ 3,03 (s, 3H, Me), 7,53 (DD, J of 8.2 and 4.8, 1H, H3), 7,63 for 7.78 (m, 3H, H7, H6 and H5'), 8,42 (DD, J 4.8 and 1,4,1H, H2), 8,73 (d, J 5,4, 1H, H6'), 8,84 (DD, J of 8.2 and 1.4, 1H, H4).

13C-NMR (CDCl3, 300 MHz) δ 40,3 (square, Me), 99,5 (s, C5), 102,2 (d, C6), 116,5 (d, C5'), 121,3 (d, C3)121,9 (s, C4a), 129,1 (d, C4), 140,0 (s, C5a), 140,8 (d, C2), 143,8 (s, Sa), 144,6 (d, C7), 150,0 (s, C9), 157,3 (d, C6'), 162,6 (s, C4'), 163,5 (C, C2').

MC (EI) m/z 324 (M+, 47), 261 (M-SOMe, 100); (ES+) m/z 326 (M+2,20), 325 (M+1, 100).

Example 31

9-Amino-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-c]pyrimidine

Method And

To a solution of 9-amino-5-(2-methanesulfonamido-4-yl)Piri-up[3',2':4,5]pyrrolo[1,2-c]pyrimidine (50 mg, 0.16 mmol) in CH2Cl2(15 ml) at room temperature add m-SRV (88 mg, 0.36 mmol). The mixture is stirred for 2 hours. Add saturated aq. a solution of Na2S2O3(1 ml) and the mixture is alkalinized with saturated aq. a solution of Na2CO3. The organic layer is separated and the aqueous layer was extracted with CH2Cl2. The organic solutions are combined and evaporated, and get a 9-amino-5-(2-methanesulfonamido-4-yl)pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine (50 mg, 91%) as a pale orange solid.

Method In

To a solution of 21 (200 mg, of 0.65 mmol) in CH2Cl2(50 ml) is added m-SRV (320 mg, of 1.30 mmol). The mixture is stirred for 2 hours at room temperature. Add saturated aq. a solution of Na2S2O3(5 ml) and the mixture is alkalinized with saturated aq. a solution of Na2CO3. The organic layer is separated and the aqueous layer was extracted with CH2Cl2. The organic solutions are combined, dried and evaporated, and get a 9-amino-5-(2-methanesulfonamido-4-yl)pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine (201 mg, 91%).

TPL 118-189°C (CH2Cl2/hexane).

IR (film) ν 3340 (m, NH), 1569 (m, C=C), 1517 (m), 1462 (m), 1262 (s, s=O2).

1H-I Is R (CDCl 3, 300 MHz) δ to 3.41 (s, 3H, Me), 7,56 (DD, J 8.1 and 4,8, 1H, H3), of 7.69 (d, J 6,6, 1H, H7), 7,78 (d, J 5,7, 1H, H5'), 7,80 (d, J 6,6, 1H, H6), 8,44 (DD, J 4.8 and 1,5, 1H, H2), is 8.75 (d, J 5,7, 1H, H6'), 8,84 (DD, J for 8.1 and 1.5, 1H, H4).

13C-NMR (DMSO-d6, 50 MHz) δ 39,8 (square, Me), 97,4 (s, C5), 101,0 (d, C6), 118,4 (d, C5'), to 121.0 (s, C4a), 121,2 (d, C3), of 128.6 (d, C4), 130,3 (s, C5a), to 140.5 (d, C2), br143.3 (s, Sa), 146,8 (d, C7), 149,9 (s, C9), 157,5 (d, C6'), 161,5 (s, C4'), 165,2 (C, C2').

MC (CI, NH3) m/z 342 (M+2, 6), 341 (M+1, 20), 340 (M+, 100), 309 (M-O2, 5), 263 (M-SO2Me, 25).

MS high. bit., m/z for C15H12N3O2S calculated 340,0742; found 340,0740.

Example 32

9-Amino-5-(2-aminopyrimidine-4-yl)pyrido[3',2':4,5]pyrrolo-[1,2-c]pyrimidine (5A)

Method And

A solution of 9-amino-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-c]pyrimidine (25 mg, 0.04 mmol) in dioxane (3 ml) and 23% aq. a solution of NH3(5 ml) is heated in a sealed tube at 80°C for 6 hours. The mixture is cooled and the solvent is removed. The residue is dissolved in saturated aq. a solution of Na2CO3and the solution is repeatedly extracted with CH2Cl2. The organic layers are dried and evaporated. The crude substance is purified column flash chromatography. Elution with a mixture of CH2Cl2and Meon (97/3) to give 5A (18 mg, 90%) as a yellow solid.

Method In

A solution of 20A (120 mg, 0.36 mmol), 27 (200 mg, to 0.72 mmol), Pd2(dba)3(75 mg, 0.06 mmol), PPh3(35 mg, 0.14 mmol who), LiCl (42 mg, 1.10 mmol) and CuI (12 mg, 0.06 mmol) in dioxane (4 ml) is refluxed for 1.5 hours. The organic solvent is removed and the oil obtained is dissolved and refluxed in HCl/MeOH for 1 hour. The solvent is evaporated and the residue dissolved in CH2Cl2. The organic solution is extracted four times 4 N. HCl and the aqueous solution is alkalinized solid Na2CO3. The aqueous solution is extracted with CH2Cl2. After evaporation of the solvent the mixture was purified column flash chromatography. Elution with a mixture of CH2Cl2and Meon (95/5) to give 5A (50 mg, 54%) as a yellow solid.

TPL 160-162°C (CH2Cl2/hexane).

IR (film) ν 3332 (m, NH), 1632 (m, C=C), 1574 (m, C=N), 1454 (m, C-N), 1262 (m).

1H-NMR (DMSO-d6, 500 MHz) δ 6,63 (user., 2H, 2'NH2), 7,12 (d, J 5,5, 1H, H5'), to 7.64 (d, J 8.0 and 4,4, 1H, H3), of 7.70 (d, J 6,6, 1H, H7), 7,76 (d, J 6,6, 1H, H6), 8,29 (d, J 5,5, 1H, H6'), 8,51 (DD, J 4A and 1.4, 1H, H2), charged 8.52 (user., 1H, 9NH), 8,99 (DD, J 8.0 and 1.4, 1H, H4), 9,35 (user., 1H, 9NH).

13C-NMR (DMSO-d6, 50 MHz) δ 99,5 (s, C5), of 101.7 (d, C6), 106,8 (d, C5'), is 120.7 (d, C3), to 121.6 (s, C4a), 129,1 (d, C4), 138,2 (s, C5a), 140,1 (d, C2), of 142.8 (s, Sa), 143,8 (d, C7), 149,7 (s, C9), 158,0 (d, C6'), 161,4 (s, C4'), 163,5 (C, C2').

MS (ES+) m/z 279 (M+2, 20), 278 (M+l, 100), 277 (M+, 10).

MS high. bit., m/z for C15H11N7calculated 277,1075; found 277,1071.

UV (Meon) 225 (36,010), 250 (34,126), 350 (20,942), 400 (26,481).

Example 33

9-Amino-5-(2-am is loperimide-4-yl)pyrido[3',2':4,5]pyrrolo-[1,2-c]pyrimidine (5b)

Follow the same method as for 5A (the way In). The mixture 20b (26 mg, 0.07 mmol), 27 (32 mg, 0.11 mmol), Pd2(dba)3(15 mg, 0.014 mmol), PPh3(7 mg, 0,028 mmol), LiCl (9 mg, 0.21 mmol) and CuI (3 mg, 0.014 mmol) in dioxane (3 ml) is refluxed for 1 hour. After purification column flash chromatography receive 5b (8 mg, 38%).

1H-NMR (CDCl3, 200 MHz) (a 4.03 (s, 3H, Me), make 6.90 (d, J 5,4, 1H, H3), was 7.08 (d, J 5,4, 1H, H6), 7,50 (d, J 5,4, 1H, H7), 7,54 (d, J 5,0, 1H, H5'), of 8.28 (d, J 5,4, 1H, H2), of 8.47 (d, J 5,0, 1H, H6').

MC (ES+) m/z 308 (M+1, 100), 307 (M+, 20).

Example 34

9 Tosylamide-6-tetrahydropyrimido[3',2':4,5]-pyrrolo[1,2-c]pyrimidine (22A)

A solution of 9a (235 mg, 0.88 mmol) and DIPEA (505 μl, to 1.98 mmol) in CH2Cl2(20 ml) is gradually added to the solution TsNCCl2(250 mg, 0,99 mmol) in CH2Cl2(20 ml). The solution is stirred for 30 min and washed with water. The organic solution is dried, filtered and evaporated, and get the crude reaction product, which is purified column flash chromatography. Elution with a mixture of DCM and the Meon (99/1) gives 22A (235 mg, 60%) as a pale orange solid.

IR (film) ν 3312 (m, NH), 1639 (s, N=C), 1472 (m, C-N), 1277 (m, C-O).

1H-NMR (CDCl3, 200 MHz) δ of 1.40 and 1.80 (m, 6H, H3', H4' and H5'), of 2.38 (s, 3H, Me), 3,45-4,00 (m, 4H, H7 and H6')and 4.65 and 4.95 (ushort, 1H, H2'), 5.02 and of 5.05 (ushort, 1H, H6), 6,59 and 6.61 (s, 1H, H5), 7.20 and 7,21 (DD, J of 7.8 and 4.8, 1H, H3), 7,2 (d, J of 8.4, 2H, Ts), 7,84 and a 7.85 (DD, J 7,8 and 1.5, 1H, H4), to 8.12 (d, J8,4, 2H, Ts), 8,40 (user., 1H, NH), 8,50 and charged 8.52 (DD, J 4.8 and 1,5, 1H, H2).

13C-NMR (CDCl3, 50 MHz) δ to 18.7 and 19.1 (t, C4'), 21,5 (kV, Ts), to 25.2 and 25.3 (t, C5'), and 29.9 and 30.3 (t, C3'), 43,1 and 44.7 (t, C6'), to 62.2 62.5 (t, C7), and 62.6 and 63,8 (d, C6), 95,7 and 96,8 (d, C2'), 104,1 and 105,5 (d, C5), 119,2 (d, C3), 121,5 (s, C4a), 126,4 (d, Ts), to 129.2 (d, Ts), to 129.2 (d, C4), 131,9 and 134,7 (s, C5a), 140,0 and 142,5 (s, Sa), 145,6 and 145,9 (d,C2), 148,1 (C, C9).

MC (El) m/z 440 (M+, 1), 376 (M-SO2, 19).

Example 35

4-Methoxy-9-tosylamide-6-tetrahydropyrimido-[3',2':4,5]pyrrolo-[1,2-c]pyrimidine (22b)

Following the methodology for 22A, 9b (1 g, 3,44 mmol), DIPEA (1.9 ml, 7,58 mmol) and TsNCCl2(952 mg, of 3.78 mmol) get the connection 22b (1,05 g, 65%) as a pale orange solid.

1H-NMR (CDCl3, 200 MHz) δ of 1.40 and 1.80 (m, 6H, H3', H4' and H5'), of 2.38 (s, 3H, Me), 3,45-3,95 (m, 4H, H7 and H6'), of 3.97 (s, 3H, Me), 4.62, and 4,95 (ushort, 1H, H2'), free 5.01 (m, 1H, H6), 6,69 (m, 1H, H3 and H5), 7,26 (d, J 8,4, 2H, Ts), 8,10 (d, J 8,4, 2H, Ts), to 8.41 and 8,42 (d, J 5,8, 1H, H2).

13C-NMR (CDCl3, 50 MHz) δ 18,5 19,3 and (t, C4'), 21,6 (square, Ts), to 25.2 and 25.3 (t, C5'), 30,0 and 30.2 (t, C3'), 43,3 and 44,9 (t, C6'), 55,6 (square, Me), 61,9 and 62.3 (t, C7), 62,7 and 63.5 (d, C6), 95,5 and 96,4 (d, C2'), 101,3 (d, C3), 101,5 and 102,9 (d, C5), 126,2 (s, C4a), 126,5 (d, Ts), to 129.2 (d, Ts), is 129.3 and 129,5 (s, C5a), 132,2 (s, Ts), 142,5 (s, Sa), 147,6 and 147,9 (d, C2), 159,7 (C, C9).

Example 36

4-Chloro-9-tosylamide-6-tetrahydropyrimido-[3',2':4,5]pyrrolo[1,2-c]pyrimidine (22b)

Following the methodology for 22A, 9 (175 mg, 0.59 mmol),DIPEA (225 μl, of 1.30 mmol) and TsNCCl2(164 mg, of 0.65 mmol) to obtain compound 22 (165 mg, 60%).

IR (film) ν 3309 (m, NH), 1634 (s, N=C), 1471 (m, C-N), 1358 (m, SO2), 1280 (m, C-O).

1H-NMR (CDCl3, 200 MHz) δ of 1.40 and 1.80 (m, 6H, H3', H4' and H5'), of 2.38 (s, 3H, Me), 3,45-3,95 (m, 4H, H7 and H6')and 4.65 and 4.95 (m, 1H, H2'), free 5.01 (m, 1H, H6), of 6.71 and 6,72 (s, 1H, H5), 7,24 and of 7.25 (d, J 5,4, 1H, H3), 7,27 (d, J 8,0, 2H, Ts), 8,10 (d, J 8,4, 2H, Ts), 8,39 and 8.41 (d, J 4,8, 1H, H2) 8,48 (user., 1H, NH).

13C-NMR (CDCl3, 50 MHz) δ and 18,8 19,1 (t, C4'), 21,6 (square, Ts), to 25.2 and 25.3 (t, C5'), 30,0 and 30.3 (t, C3'), 43,1 and 44.7 (t, C6'), at 62.5 and 62.6 (t, C7), 63,3 and 63.6 (d, C6), 95,8 and 96,8 (d, C2'), 101,9 and 103,2 (d, C5), 119,3 (d, C3), RUB 127.3 (s, C4a), 126,4 (d, Ts), to 129.2 (d, Ts), 132,2 (s, Ts), 135,5 and to 136.4 (s, C5a), 139,8 (s, Ts), 142,6 (s, C10a), 145,8 and 146.2 (d, C2), 147,9 and 148,1 (C, C9).

MC (EI) m/z 475 (M+, 1), 410 (M-SO2, 20),

Example 37

9 Tosylamide-6-hydroxypurine[3',2':4,5]pyrrolo-[1,2-c]-pyrimidine

Dissolve 22A (210 mg, 0.48 mmol) in CH2Cl2(25 ml), add 4 N. hydrochloric acid (25 ml) and the mixture vigorously stirred for 20 minutes the Solution is alkalinized and separate the organic solution. The aqueous layer was twice extracted with CH2Cl2. The organic solutions are combined and evaporated, and the residue is purified column flash chromatography. Elution with the mixture and Meon (95/5) gives 9 tosylamide-6-hydroxypurine[3',2':4,5]pyrrolo-[1,2-c]pyrimidine (160 mg, 95%) as a pale yellow solid.

IR (film) ν 3315 (m, NH), 1624 (s, C=N), 1473 (s, N-C), 1276 (m, SO2), 1135 m, C-O).

1H-NMR (CDCl3, 300 MHz) δ to 2.35 (s, 3H, Me), to 3.50 (m, 1H, H7), of 3.75 (m, 1H, H7), 5,04 (user., 1H, H6), 6,55 (s, 1H, H5), 7,00 (DD, J of 7.8 and 4.8, 1H, H3), from 7.24 (d, J 8,4, 2H, Ts), 7,71, (DD, J 7,8 and 1.5, 1H, H4), 8,03 (d, J 8,4, 2H, Ts), of 8.27 (DD, J 4.8 and 1,5, 1H, H2), 8,42 (user., 1H, NH).

13C-NMR (CDCl3, 75 MHz) δ 21,5 (square, Me)45,8 (t, C7), 60,4 (d, C6), of 101.7 (d, C5), 103,7 (d, C3), 119,1 (d, C4), 122,2 (s, C4a), 126,5 (d, Ts), to 129.2 (d, Ts), 129,4 (d, C4), 136,7 (s, C5a), 139,6 (s, Ts), 142,7 (s, C10a), 144,9 (d, C2), is 147.5 (C, Ts), 148,5 (C, C9).

MC (EI) m/z 357 (M+l, 1), 356 (M+, 3), 338 (M-H2O, 2), 292 (M-SO2, 18).

Example 38

4-Methoxy-9-tosylamide-6-hydroxypurine[3',2':4,5]pyrrolo-[1,2-c]pyrimidine

Following the methodology of obtaining the previous connection, 22b (1,05 g of 2.23 mmol) to obtain compound 4-methoxy-9-tosylamide-6-hydroxypurine[3',2':4,5]pyrrolo[1,2-c]pyrimidine (819 mg, 95%) as a pale yellow solid.

IR (film) ν 3317 (m, NH), 1627 (s, C=N), 1475 (s, N-C), 1293 (m, SO2), 1139 (m, C-0).

1H-NMR (CDCl3, 200 MHz) δ to 2.35 (s, 3H, Me), to 3.50 (m, 1H, H7), of 3.75 (m, 1H, H7), 3,85 (s, 3H, Me), 5,02 (user., 1H, H6), to 6.43 (d, J 5,4, 1H, H3), of 6.52 (s, 1H, H5), from 7.24 (d, J 8,0, 2H, Ts), of 8.04 (d, J 8,0, 2H, Ts), of 8.09 (d, J 5,4, 1H, H2), to 8.41 (user., 1H, NH).

13C-NMR (CDCl3, 50 MHz) δ 21,5 (square, Me)45,9 (t, C7), 55,6 (square, Me), 60,1 (d, C6), 100,8 (d, C3), 101,4 (d, C5), 112,1 (s, C4a), 126,5 (d, Ts), is 129.3 (d, Ts), 134,3 (s, C5a), 139,6 (s, Ts), 142,7 (s, Sa), 146,7 (d, C2), are 148.6 (s, C9), 159,6 (C, C4).

Example 39

4-Chloro-9-tosylamide-6-hydroxypurine[3',2':4,5]pyrrolo-[1,2-c]pyrimidine

Following the method of obtaining the previous connection from 22 ° C (50 mg, 0.11 mmol) to obtain compound 4-chloro-9-tosylamide-6-hydroxypurine[3',2':4,5]pyrrolo[1,2-c]pyrimidine (37 mg, 90%).

IR (film) ν 3316 (m, NH), 1632 (s, C=N), 1472 (s, N-C), 1277 (m, SOz), 1082 (m, C-O).

1H-NMR (CDCl3, 200 MHz) δ to 2.35 (s, 3H, Me), 3,56 (userd, J 13,6, 1H, H7), 3,80 (dt, J 13,6 and 2.6, 1H, H7), 4,80 (user., 1H, OH), 5,10 (user., 1H, H6), is 6.61 (s, 1H, H5),? 7.04 baby mortality (d, J 5,0, 1H, H3), from 7.24 (d, J 8,2, 2H, Ts), 8,03 (d, J 8,2, 2H, Ts), 8,16 (d, J 5,0, 1H, H2), 8,46 (user., 1H, NH).

13C-NMR (CDCl3, 50 MHz) δ 21,6 (square, Me)45,7 (t, C7), 60,4 (d, C6), 101,5 (d, C5), 119,2 (d, C3), 121,4 (s, C4a), 126,5 (d, Ts), is 129.3 (d, Ts), 131,0 (s, Ts), to 136.5 (s, C5a), 137,4 (s, Ts), of 142.8 (s, Sa), 145, 2mm (d, C2), 148,3 (C, C9).

MC (EI) m/z 392 (37C1M+, 2), 390 (35C1M+, 6), 328 (35C1M-SO2, 10), 326 (35C1M-SO2, 31).

MS high. bit., m/z for C17H15ClN4O5S calculated 390,0553; found 390,0548.

Example 40

9 Tosylimines[3',2':4,5]pyrrolo[1,2-c]pyrimidine (23a)

9 Tosylamide-6-hydroxypurine[3',2':4,5]pyrrolo[1,2-c]pyrimidine (170 mg, 0.48 mmol) and tea (133 μl, 0.96 mmol) dissolved in CH2Cl2(25 ml)is added dropwise methanesulfonanilide (37 μl, 0.48 mmol) and the mixture is stirred for 20 minutes the Solution is washed with water and the organic solutions are dried and evaporated. The crude mixture was purified column flash chromatography. Elution with a mixture of CH2Cl2and Meon (98/2) gives 23a (mg, 78%) as a yellow solid.

IR (KBr) ν 3266 (m, NH), 1604 (s, C=N), 1399, 1281 (m, SO2).

1H-NMR (CD3OD, 300 MHz) δ to 2.35 (s, 3H, Me), 6,69 (s, 1H, H5), was 6.73 (d, J 7,8, 1H, H6),? 7.04 baby mortality (d, J 7,8, 1H, H7), 7,31 (d, J 8,4, 2H, Ts), 7,44 (DD, J 8.1 and 5,1, 1H, H3), to 7.99 (d, J 8,4, 2H, Ts), of 8.15 (d, J 8,1, 1H, H4), 8,46 (d, J 5,1, 1H, H2).

MC (EI) m/z 339 (M+l, 4), 338 (M+, 19), 273 (M-SO2, 100).

MS wiser., m/z for C17H14N4O2S calculated 338,0837; found 338,0841.

Example 41

4-Methoxy-9-tosylimines[3',2':4,5]pyrrolo[1,2-c]-pyrimidine (23b)

Following the method for 23a, from 4-methoxy-9-tosylamide-6-hydroxypurine[3',2':4,5]pyrrolo[1,2-c]pyrimidine (170 mg, 0.48 mmol) to obtain compound 23b (124 mg, 78%) as a pale yellow solid.

IR (KBr) ν 3266 (m, NH), 1604 (s, C=N), 1399,1293 (m, SO2), 1141.

1H-NMR (CD3OD, 300 MHz) δ to 2.35 (s, 3H, Me)to 4.01 (s, 3H, Me), to 6.57 (s, 1H, H5), only 6.64 (d, J 7,5, 1H, H6), 6,93 (d, J 6,0, 1H, H3), 6,98 (d, J 7,5, 1H, H7), 7,30 (d, J 8,1, 2H, Ts), of 8.00 (d, J 8,1, 2H, Ts), 8,30 (d, J 6,0, 1H, H2).

13C-NMR (DMSO-d6, 50 MHz) δ 21,0 (square, Me)55,9 (square, Me), 93,0 (d, C5), 101,5 (d, C6), 102,1 (d, C3), 113,9 (s, C4a), 125,9 (d, Ts), is 129.3 (d, C2, and Ts), to 132.6 (s, C5a), 142,3 (s, C10a), 143,9 (s, C9), RUB 145.1 (d, C7), to 158.4 (C, C4).

MS wiser., m/z for C18H16N4O5S calculated 368,0943; found 368,0941.

Example 42

4-Chloro-9-tosylimines[3',2':4,5]pyrrolo[1,2-c]-pyrimidine (23C)

Following the method for 23a, from 4-chloro-9-tosylamide-6-HYDR is kipyego[3',2':4,5]pyrrolo[1,2-c]pyrimidine (165 mg, 0.42 mmol) get the connection 23 ° C (104 mg, 66%) as a pale yellow solid.

IR (KBr) ν 3265 (m, NH), 1602 (s, C=N), 1396, 1281 (m, SO2), 1141.

1H-NMR (DMSO-d6, 50 MHz) δ of 2.34 (s, 3H, Me), to 6.80 (s, 1H, H5), at 6.84 (d, J 7,8, 1H, H6), 7,17 (d, J 7,8, 1H, H7), 7,37 (d, J 7,8,2H, Ts), 7,58 (d, J 4,8,1H, H3), 8,03 (d, J 7,8, 2H, Ts), 7 to 8.45 (d, J 4,8,1H, H2), 11,20 (user., 1H, NH).

13C-NMR (DMSO-d6, 50 MHz) δ 21,0 (square, Me)93,7 (d, C5), 101,3 (d, C6), 119,9 (d, C3), of 122.5 (s, C4a), 125,9 (d, Ts), 126,3 (d, C2), 129,4 (d, Ts), 133,5 (s, C5a), 135,6 (s, Ts), 142,5 (s, C10a), 143,5 (d, C7), 143,8 (s, C9), 145,3 (C, C4).

MC (EI) m/z 374 (37C1M+, 5), 372 (35C1M+, 12), 309 (37C1M-SO2, 24), 307 (35C1M-SO2, 63).

MS high. bit., m/z for C17H13ClN4O2S calculated 372,0448; found 372,0444.

Example 43

5-Iodine-9-tosylimines[3',2':4,5]pyrrolo[1,2-c]pyrimidine (24A)

To a solution of 23a (10 mg, 0.03 mmol) in CH2Cl2(5 ml) at -30°add portions of N-jodatime (7 mg, 0.03 mmol) and the mixture is stirred for 15 minutes the Solution is washed with water and the organic solution is dried, filtered and evaporated, and receive 24A (14 mg, 95%) as a yellow solid.

IR (KBr) ν 3264 (m, NH), 1599 (m, N=C), 1393 (m, C-N), 1140.

1H-NMR (CD3OD, 300 MHz) δ is 2.37 (s, 3H, Me), is 6.61 (d, J 7,5, 1H, H6), to 7.15 (d, J 7,5, 1H, H7), 7,34 (d, J 8,4, 2H, Ts), 7,46 (DD, J of 7.5 and 4.8, 1H, H3), 7,81 (DD, J of 7.5 and 1.5, 1H, H4), 8,07 (d, J 8,4, 2H, Ts), 8,46 (DD, J 4,8 and 1.5, 1H, H2).

MC (EI) m/z 464 (M+, 13), 399 (M-SO2 , 32), 338 (M-I,1), 309 (M-Ts, 5), 273 (M-SO2-I, 33), 182(M-Ts-I, 58).

MS high. bit., m/z for C17H13IN4O2S calculated 463,9804; found 463,9799.

Example 44

5-Iodine-4-methoxy-9-tosylimines[3',2':4,5]pyrrolo[1,2-c]pyrimidine (24b)

Following the method 24A, 23b (250 mg, of 0.68 mmol) to obtain compound 24b (295 mg, 95%) as a pale yellow solid.

IR (KBr) ν 3259 (m, NH), 1592 (s, C=N), 1293 (m, 802), 1142.

1H-NMR (DMSO-d6, 200 MHz) δ of 2.33 (s, 3H, Me), of 3.97 (s, 3H, Me), 6,62 (d, J 7,7, 1H, H6), 7,06 (d, J 5,6, 1H, H3), 7,18 (d, J 7,7, 1H, H7), 7,35 (d, J 8,2, 2H, Ts), 8,02 (d, J 8,2, 2H,Ts), 8,40 (d, J 5,6, 1H, H2), of 11.15 (user., 1H, NH).

13C-NMR (DMSO-d6, 50 MHz) δ 21,0 (square, Me), 56,2 (square, Me), 102,1 (d, C3), 113,9 (s, C4a), 126,1 (d, Ts), 129,4 (d, C2, and Ts), 133,9 (s, C5a), 142,6 (s, C10a), 143,4 (s, C9), RUB 145.1 (d, C7), 159,0 (C, C4).

MC (EI) m/z 494 (M+, 31), 429 (M-SO2, 65), 368 (M-I, 12), 339 (M-Ts, 15), 303 (M-SO2-I, 58), 212 (M-Ts-I, 100).

MS high. bit., m/z for C18H15IN4O5S calculated 493,9909; found 493,9891.

Example 45

4-Methoxy-9-tosylamide-5-(2-acetylpiperidine-4-yl)-pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine (25)

A solution of 24b (295 mg, of 0.60 mmol), 27 (258 mg, 0.9 mmol), Pd2(dba)3·CHCl3(120 mg, 0.12 mmol), PPh3(60 mg, 0.24 mmol), LiCl (74 mg, 1.8 mmol) and CuI (23 mg, 0.12 mmol) in dioxane (25 ml) is refluxed for one hour. The solvent is evaporated and the residue R is straut in CH 2Cl2. The organic solution is extracted four times 4 N. hydrochloric acid. Aqueous solutions combine, alkalinized solid NaHCO3and extracted with CH2Cl2. The organic solution evaporated and the residue purified column flash chromatography. Elution with a mixture of CH2Cl2and Meon (99/1) gives 23b (66 mg, 28%) and a mixture of CH2Cl2and Meon (9/1) to give 25 (209 mg, 71%) as a yellow solid.

IR (KBr) ν 3379 (m, NH), 1592 (s, C=N), 1474, 1449, 1422, 1293 (SO2), 1143.

1H-NMR (CDCl3, 200 MHz) δ to 2.41 (s, 3H, Me), 2,47 (s, 3H, Me), of 4.05 (s, 3H, Me), 6,92 (user., 1H, H3), 7,31 (d, J 8,4, 2H, Ts), 7,46 (userd, 1H, h6), 7,60 (d, J 6,6, 1H, H7), 7,98 (user., 1H, H5'), to 8.12 (d, J 8,4, 2H, Ts), scored 8.38 (user., 1H, H2), and 8.50 (user., 1H, h6').

MS (ES+) m/z 505 (M+2, 30), 504 (M+1, 100).

Example 46

4-Hydroxy-9-tosylamide-5-(2-aminopyrimidine-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-C]pyrimidine (26)

A solution of 25 (10 mg, 0.02 mmol) in HBr (48%) is refluxed for 10 minutes the Solution is alkalinized NaHCO3and extracted with CH2Cl2. The organic solution is dried, filtered and evaporated, and get 26 (7 mg, 78%) as a yellow solid.

1H-NMR (CDCl3+CD3OD, 300 MHz) δ of 2.34 (s, 3H, Me), 6,76 (d, J 6,6, 1H, h6), 7,03 (d, J 6,6, 1H, H5', 7,06 (d, J 6,6, 1H, H5'), of 7.23 (d, J 8,1, 2H, Ts), the 7.65 (d, J 6,6, 1H, H7), of 8.00 (d, J 8,1, 2H, Ts), 8,01 (d, J 6,6, 1H, N6'), 8,23 (userd, 1H, H2).

MS (ES+) m/z 449 (M+1, 10), 448 (M+, 100).

Example 47

4-Chloro-2-methanesulfonamide

Cm. Heterocycles, 1977, 8, 299. To a solution of 4-chloro-2-methanesulfonamide (5 g, 31 mmol) in CH2Cl2(100 ml) is added m-SRV (16,12 g, 94 mmol) and the mixture is stirred for 2 hours at room temperature. The mixture was washed with saturated aq. a solution of Na2S2O3and the aqueous solution is alkalinized Na2CO3. The organic layer is separated and the aqueous solution extracted with CH2Cl2. The organic layers are combined and evaporated, and receive 4-chloro-2-methanesulfonamide (5.5 g, 92%) as a white solid.

1H-NMR (CDCl3, 200 MHz) δ 3,39 (s, 3H, Me), to 7.61 (d, J 5,4, 1H, H5), 8,83 (d, J 5,4, 1H, H6).

MC (CI, CH4) m/z 192 (M35Cl+, 1), 157 (M-C1,1), 97 (100).

Example 48

2-Amino-4-chloropyrimidine

To a solution of 4-chloro-2-methanesulfonamide (5 g, 26 mmol) in ISO-D (20 ml) is added 20% aq. a solution of NH3(20 ml) and the mixture stirred for 20 min at room temperature. The mixture is extracted four times CH2Cl2and remove the organic solvent in vacuo. Get 2-amino-4-chloropyrimidine (3.3 g, 100%) as a white solid.

1H-NMR (CDCl3, 200 MHz) δ 5,26 (user., 2H, NH2), to 6.67 (d, J 5,2, 1H, H5), 8,17 (d, J 5,2, 1H, H6).

MC (CI, CH4) m/z 132 (37C1M+1,33), 131 (37C1M , 2), 130 (35C1M+1, 87), 129 (35C1M, 8), 97 (100), 94 (M-C1, 53).

Example 49

2-Acetylamino-4-chloropyrimidine and 4-chloro-2-diacetylpyridine

A solution of 2-amino-4-chloropyrimidine (500 mg, 3.9 mmol) in acetic anhydride (20 ml) is refluxed for 30 minutes the Solvent is removed in vacuum and the remaining oil is dissolved in saturated aq. a solution of Na2CO3. The aqueous solution is extracted with CH2Cl2. The organic solution is dried and evaporated, and get the oil, which is purified column flash chromatography. Elution with a mixture of CH2Cl2and hexane (2/1) to give 4-chloro-2-diacetylpyridine (122 mg, 16%) as a white solid and CH2Cl2give 2-acetylamino-4-chloropyrimidine (270 mg, 45%) as a white solid.

2-Acetylamino-4-chloropyrimidine

1H-NMR (CDCl3, 200 MHz) δ of 2.51 (s, 3H, Me),? 7.04 baby mortality (d, J 5,3, 1H, H5), 8,17 (d, J 5,3, 1H, H6).

13C-NMR (CDCl3, 50 MHz) δ 25,3 (square, Me), 116,0 (d, C5), 157,5 (s, C4), 159,2 (d, C6), 161,8(C, C2).

MC (EI) m/z 173 (37C1M, 5), 171 (35C1M, 16), 131 (37C1M-Ac, 32), 129 (35C1M-Ac, 100).

4-Chloro-2-diacetylpyridine

1H-NMR (CDCl3, 200 MHz) δ of 3.32 (s, 6H, 2Me), was 7.45 (d, J 5,2, 1H, H5), 8,76 (d, J 5,2, 1H, H6).

13C-NMR (CDCl3, 50 MHz) δ 26,3 (square, Me), 121,2 (d, C5), 160,0 (d, C6), to 163.1 (s, C4), 171,6 (C, C2).

MC (CI, CH4) m/z 215 (37C1M, 1), 214 (37C1M -1, 3), 213 (35C1M, 1), 212 (35C1M-1, 5), 174 (37C1M-Ac, 32), 172 (35C1M-Ac, 100).

Example 50

2-Acetylamino-4-trimethylaniline (27)

A solution of 2-acetylamino-4-chloropyrimidine (170 mg, 1.0 mmol), hexamethyldisilane (400 μl, 1.8 mmol) and Pd(PPh3)4(40 mg, 0.03 mmol) in dioxane (6 ml) is refluxed for 1 hour. The solvent is removed in vacuo and the residue purified column chromatography on neutral aluminium oxide. Elution with a mixture of hexane and AcOEt (7/3) to give 27 (240 mg, 80%) as a white solid.

1H-NMR (CDCl3, 300 MHz) δ of 0.36 (s, 9H, 3Me), of 2.53 (s, 3H, Me), 7,13 (d, J 4,8, 1H, H5), 7,98 (user., 1H, NH), 8,35 (d, J 4,8, 1H, H6).

13C-NMR (CDCl3, 75 MHz) δ -9,5 (square, 3Me), 25,3 (square, Me), to 124.4 (d, C5), 154,7 (d, C6).

MC (EI) m/z 300 (120SnM+, 1), 285 (120SnM-Me, 34) 270 (120SnM-2Me, 1), 255 (120SnM-3Me, 6), 244 (120SnM-3Me-Ac, 30), 136 (M-SnMe3, 100).

BIOLOGICAL ACTIVITY

The study of antitumor activity

Cell culture. Cells maintained in logarithmic growth phase in minimum essential medium Needle, containing the equilibrium salt Needle, 2.0 mm L-glutamine, not mandatory amino acids, sodium bicarbonate (EMEM/neaa); supplemented with 0% fetal calf serum (FCS), 10-2M sodium bicarbonate and 0.1 g/l penicillin-G + streptomycin sulfate.

The screening procedure of the sample was carried out to determine and compare the antitumor activity of these compounds, using an adapted version of the method described by Bergeron et al. (1984). Used line of tumor cells P-388 (suspension culture of lymphoid tumors of mice DBA/2), A-549 (monoclonal culture human lung carcinoma) and HT-29 (monoclonal culture of human carcinoma of the colon).

Cells P-388 were sown in 16 mm wells at a concentration of 1×104cells per well in 1 mm aliquot MEM 5FCS containing the indicated concentration of drug. A separate part of cultures that do not contain drugs, were sown as control growth to ensure that the cells remain in the exponential growth phase. All determinations were carried out twice. After incubation for three days at 37°C, 10% CO2with 98% humidity atmosphere, determine the approximate value of the IC50by comparing the growth of cells in the wells along with medication and growth of cells in the control wells.

A-549 and HT-29 were sown in 16 mm wells at a concentration of 2×104cells per well in 1 mm aliquot MEM 5FCS containing the indicated concentration of drug. A separate part of cultures that do not contain drugs, were sown as control growth to ensure that the cells remain in exponential the phase of growth. All determinations were carried out twice. After incubation for three days at 37°C, 10% CO2with 98% humidity atmosphere, the wells were stained with 0.1% Crystal Violet. Determined the approximate value of the IC50by comparing the growth of cells in the wells along with medication and growth of cells in the control wells.

Sources of information

1. Raymond J. Bergeron, Paul F. Cavanaugh, Jr., Steven J. Kline, Robert G. Hughes, Jr., Gary T. Elliot and Carl W. Porter. Antineoplastic and antiherpetic activity of spermidine catecholamide iron chelators. Biochem. Bioph. Res. Comm. 1984, 121(3), 848-854.

2. Alan C. Schroeder, Robert G. Hughes, Jr. and Alexander Bloch. Effects of Acyclic Pyrimidine Nucleoside Analoges. J. Med. Chem. 1981, 24 1078-1083.

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LC502.82E-05E-053.55E-052.92E-05
LOVOGI501.34E-06E-063.81E-067.12E-07
TGI2.82E-05E-061.52E-05 2.92E-06
LC501.43E-06E-053.59E-052.92E-05
LOVO-DOXGI505.53E-07E-061.25E-066.65E-07
TGI1.44E-06E-054.64E-052.15E-06
LC505.05E-06E-053.59E-052.92E-05
HELAGI501.51E-07E-063.26E-067.00E-07
TGI1.86E-06E-051.42E-052.72E-06
LC501.82E-05E-053.59E-051.21E-05
HELA-APLGI503.58E-07
TGI4.49E-06
LC501.91E-05
CoedSoy is .64 CoedCoed
DU-145GI503.10E-053.75E-05
TGI3.28E-053.75E-05
LC503.28E-053.75E-05
LN-caPGI502.84E-061.71E-05
TGI7.89E-063.75E-05
LC501.99E-053.75E-05
IGROVGI502.23E-053.75E-05
TGI3.28E-053.75E-05
LC503.28E-053.75E-05
SR-BR3GI501.44E-053.75E-05
TGI3.28E-053.75E-05
LC503.28E-053.75E-05
MEL-28/td> GI501.46E-06
TGI3.75E-05
LC503.75E-05
A-549GI503.84E-052.17E-053.75E-05
TGI3.84E-053.28E-053.75E-05
LC503.84E-053.28E-053.75E-05
K-562GI503.16E-052.64E-051.82E-07
TGI3.28E-053.75E-055.60E-07
LC503.28E-053.75E-053.35E-06
PANC-1GI509.24E-063.75E-05
TGI2.47E-053.75E-05
LC503.28E-053.75E-05
HT-29GI503.84E-052.09E-053.7E-05
TGI3.84E-053.28E-053.75E-05
LC503.84E-053.28E-053.75E-05
LOVOGI503.28E-053.75E-05E-08
TGI3.28E-053.75E-05E-06
LC503.28E-053.75E-05E-05
LOVO-DOXGI502.33E-053.75E-05
TGI3.28E-053.75E-05
LC503.28E-053.75E-05
HELAGI502.27E-053.75E-05
TGI3.28E-053.75E-05
LC503.28E-053.75E-05
HELA-APLGI50
TGI
LC50

CoedCoedCoedCoed
DU-145GI507.50E-07E-07
TGI2.31E-06E-06
LC503.35E-05E-05
LN-caPGI505.02E-08E-07
TGI2.15E-07E-06
LC501.82E-06E-06
IGROVGI501.06E-06E-06
TGI3.00E-06E-06
LC503.35E-05E-06
SR-BR3GI507.97E-07E-06
TGI1.65E-06E-06
LC504.15E-06E-05
MEL-28GI50E-07
TGIE-06
LC50E-06
A-549GI505.56E-07E-07
TGI1.18E-06E-07
LC502.50E-06E-06
K-562GI501.10E-06E-06E-06E-05
TGI2.70E-06E-05E-06E-05
LC50E-05E-05E-06
PANC-1GI501.70E-061.21E-06
TGI1.30E-05E-05
LC503.35E-05E-05
HT-29GI501.07E-06E-06
TGI3.78E-06E-06
LC503.35E-05E-05
LOVOGI501.10E-06E-06E-06E-07
TGI3.35E-06E-05E-05E-06
LC503.35E-05E-05E-05E-06
LOVO-DOXGI503.18E-07E-07
TGI1.84E-06E-06
LC503.35E-05 E-05
HELAGI504.65E-07E-07
TGI1.79E-06E-06
LC503.35E-05E-05
HELA-APLGI50
TGI
LC50

1. The compound of formula (I)

where R1means an aromatic group, a represents an aromatic group, a represents phenyl, optionally substituted by a nitro-group, amino group or alkyl substituted amino group, or an aromatic group is a 5-6-membered heterocycle with two nitrogen atoms or a sulfur atom as heteroatoms, optionally substituted C1-12the alkyl, HE, unsubstituted amino or amino substituted With1-4-acyl, phenyl-C1-4the alkyl in which the phenyl group may be substituted OR1; or (C1-12alkylthiol,1-12alkyl - or phenylsulfonyl the Ohm, With1-12alkyl - or phenylsulfinyl or or1where R1choose from C1-12the alkyl or phenyl,

R2represents hydrogen;

R3is oxoprop - =O, and when the dashed line between the nitrogen is attached to R2and the carbon attached to R3missing , or

R2no, R3represents an optionally protected amino group, where the Deputy is selected from C1-4-acyl, phenylsulfonyl and C1-4-alkylphenolate, when the dotted line forms a double bond between the nitrogen is attached to R2and the carbon attached to R3,

R4represents hydrogen, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1is a 4-pyrimidinyl group.

3. The compound according to claim 2, where 4-pyrimidinyl group is substituted.

4. The compound according to any one of the preceding paragraphs, where R2when present, represents hydrogen.

5. The compound according to any one of the preceding paragraphs, where R3is oxoprop.

6. The compound according to any one of claims 1, 2 or 3, where the dotted line represents a bond.

7. The connection according to claim 6, where R1is a 4-pyramidalnou group substituted in the 2-ω p is the situation amino, N-acyl, methylthio, methanesulfonyl or methanesulfonyl; R2is absent; R3represents an optionally protected amino group, where the Deputy is selected from C1-4-acyl, phenylsulfonyl and C1-4-alkalinemanganese; R4represents hydrogen.

8. The compound according to claim 1, which represents 8,9-dihydro-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-C]pyrimidine-9-it formula

9. The compound according to claim 1, which represents a 9-amino-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-C]pyrimidine of the formula

10. The compound according to claim 1, which represents a 9-acetylamino-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-C]pyrimidine of the formula

11. The compound according to claim 1, which represents a 9-amino-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-C]pyrimidine of the formula

12. The compound according to claim 1, which represents a 9-amino-5-(2-methanesulfonamido-4-yl)pyrido-[3',2':4,5]pyrrolo[1,2-C]pyrimidine of the formula

13. The compound according to claim 1, which represents a 9-amino-5-(2-aminopyrimidine-4-yl)pyrido[3',2':4,5]pyrrolo[1,2-C]pyrimidine of the formula

14. The connection is giving according to any one of claims 1 to 13 as an active ingredient to obtain drugs for cancer treatment.

15. Pharmaceutical composition having antitumor activity containing a compound according to any one of the preceding paragraphs and a pharmaceutically acceptable carrier.

16. The method of obtaining the compounds of formula I according to any one of claims 1 to 13, including the interaction of the optionally substituted 5-halogenide[3',2':4,5]pyrrolo[1,2-e]pyrimidine or 8,9-dihydro-5-halogenide[3',2':4,5]pyrrolo[1,2-e]pyrimid-9-it with the corresponding derivatives of aromatic compounds, optionally followed, if necessary, modification and/or substitution of one or more of the substituents present in the compound of formula I, obtained after interaction with the derived aromatic compounds.

17. The method according to clause 16, where the aromatic derivative is a derivative of Staniloae.

18. The intermediate connection representing a 5-halogenide[3',2':4,5]pyrrolo[1,2-C]pyrimidine or 8,9-dihydro-5-halogenide[3',2';4,5]pyrrolo-[1,2-e]pyrimid-9-it formula

where X represents halogen, R2, R3and R4have the meanings indicated in claim 1, or R2- protective group selected from C1-4-alkoxymethyl,1-4alkylsulfonyl, phenylsulfonyl,1-4alkylphenolate.

19. The intermediate connection p, g is e X represents iodine, R2represents a protective group, R3represents a protected amino group.

20. The method according to 17, where stannylene connection is trimethylaniline connection.

21. The method according to claim 20, where trimethylaniline connection is trimethylenediamine.

22. The method according to clause 16, including modification and/or substitution of one or more of the substituents present in the compound of formula I, obtained after interaction with the derived aromatic compounds.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

The invention relates to new imidazolidine formulas (I) and (II) in which a is a =N-CR=CR-CR=, =CR-N=CR-CR=, =CR-CR=N=CR or = CR-CR= CR-N= ; B represents-NR-C(R)2-C(R)2-C(R)2C(R)2-NR-C(R)2-C(R)2, -C(R)2-C(R)2-NR-C(R)2or C(R)2-C(R)2-C(R)2-NR, where R is hydrogen, R1is hydrogen, unsubstituted or substituted C1-20-alkyl, C1-20-alkylene-NR3-Q-X-R4where Q represents-CO-or-SO2-, X is a simple bond, -O - or-NR3and R4- aryl, heteroaryl, heterocyclyl or1-20-alkyl or C2-20alkenyl

The invention relates to tetracyclic analogues of camptothecins formula (I), where R1, R2, R3, R4, R5and R10such as defined in the claims

The invention relates to novel analogues of camptothecin, in particular to the compounds corresponding to the following formulas (I) and (II), as well as their racemic or enantiomeric forms or combinations of these forms, where the substituents have the values

The invention relates to the field of medicine

The invention relates to new alkaloids of the formula I

< / BR>
present in various parts of Mappia foetida, and their pharmaceutical use and use them as the new synthons for preparing compounds with antitumor and antiviral activity, the same products are new synthons for new analogues of camptothecin and palidino

FIELD: organic chemistry, medicine, oncology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel tricyclic compounds, their pharmaceutically acceptable salts and solvates useful for inhibition of activity of farnesyl-protein-transferase. Invention describes compound of the formula (1.0): or its pharmaceutically acceptable salt or solvate wherein one among a, b, c and d means nitrogen atom (N) or -N+O-, and other a, b, c and d mean carbon atom and wherein each carbon atom comprises radical R1 or R2 bound to indicated carbon atom; or all a, b, c and d mean carbon atom wherein each carbon atom comprises radical R1 or R2 bound to indicated carbon atom; broken line (- - -) means optional binds; X means N or -CH when optional bond is absent, and it means carbon atom (C) when optional bond presents; when optional bond between carbon atom 5 and carbon atom 6 presents then only a single substitute A presents bound with carbon atom 5, and only a single substitute B presents bound with carbon atom 6, and A and B fifer from hydrogen atom (H); if optional bind between carbon atom 5 and carbon atom 6 is absent then two substitutes A present bound with carbon atom 5, and two substitutes B bound with carbon atom 6 wherein at least one of two substitutes A or one among two substitutes B mean H and wherein at least one of two substitutes A or one of two substitutes B has value distinct from H, and other radical are described in the invention claim. Also, invention disclosed a pharmaceutical composition comprising such compounds, a method for inhibition of anomalous growth of cells and methods for treatment of proliferative diseases as cancer.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

52 cl, 2 tbl, 505 ex

FIELD: medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes dipeptide-nitrile inhibitors of cathepsin K, their pharmaceutically acceptable salts or their esters that are used in therapeutic or prophylaxis treatment of disease of morbid state mediated by cathepsin K.

EFFECT: valuable medicinal properties of inhibitors.

3 cl, 11 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (U): or its pharmaceutically acceptable salt wherein X is chosen from -NR1, sulfur atom (S); Y1 and Y2 represent oxygen atom (O); Z represents O; m = 0 or 1; A is chosen from a direct bond, (C1-C6)-alkyl; R1 is chosen from hydrogen atom (H), alkyl; R3 and R6 are chosen independently from H, alkyl, halogenalkyl, heteroalkyl, cycloalkyl, aryl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heterocycloalkyl-alkyl, alkylaryl, heteroaryl, arylalkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl or heterocycloalkyl; R4 is chosen from H, alkyl; R5 represents a bicyclic or tricyclic group comprising two or three ring structure wherein each of that comprises from 3 to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl wherein each ring structure is joined with the next ring structure through a direct bond, through -O-, through -S-, through (C1-C6)-alkyl, through (C1-C6)-heteroalkyl, through (C1-C6)-alkynyl, through carboxy-(C1-C6)-alkyl, or it is condensed with the next ring structure wherein heteroalkyl represents heteroatom-substituted alkyl comprising one heteroatom chosen from N, O and S. Also, invention describes compounds of formulae (Ib), (Ic) and (Id) given in the invention description, pharmaceutical composition and using these compounds in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

17 cl, 3 tbl, 17 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I): wherein X represents -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO2N(R6), -N(R7)SO2; m = 1 or 2; A is chosen from a direct bond, (C1-C6)-alkyl; R1 represents hydrogen atom (H); each R2 and R3 is chosen independently from H, alkyl, aryl, alkylaryl, arylalkyl; each R4 is chosen independently from H, (C1-C3)-alkyl; R6 is chosen from H, alkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, arylalkyl, heteroaryl-alkyl; R2 and R6 can join to form a ring comprising up to 7 ring atoms, or R3 and R6 can join to form a ring comprising up to 7 ring atoms, or R4 and R6 can join to form a ring comprising up to 7 ring atoms; R5 represents monocyclic, bicyclic or tricyclic group comprising one or two ring structures wherein each of that comprises up to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl and possibly substituted; when R5 represents bicyclic group then each ring structure is bound with the next ring structure through a direct bond, through -O-, through (C1-C6)-alkyl or condensed with this next ring structure; R7 is chosen from (C1-C6)-alkyl. Also, invention describes compound of the formula (II) given in the description, pharmaceutical compositions and using compound of the formula (I) or the formula (II) in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes and representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of inhibitors and pharmaceutical compositions.

20 cl, 3 tbl, 6 ex

FIELD: medicine, oncology.

SUBSTANCE: method involves using an antitumor preparation prepared by using the apparatus-program complex (APC) "IMEDIS-TEST". Method involves blood sampling in a patient, its diluting in physiological solution in the ratio 1:1 followed by addition of the preparation "MP-antiprotein-blocker" and diluted blood in contour APC "IMEDIS-TEST". Then method involves effect with this preparation on blood in regimen "transfer" followed by returning blood in patient body. Then method involves carrying out treatment involving detoxification of body in 1, 14, 21, 28, 35 and 42 days of treatment using Glauber's salt (sodium sulfate decahydrate) as a laxative agent and also cleansing enema and fractional dose of citrus juice (40-50 ml) in the ratio 1:1 with water for 10-12 h and aqueous-turpentine bath. Then method involves carrying out the monocarrot diet for 12 days from 2-d to 13-th day of treatment inclusively; basic nutrition - each 6 days after detoxification comprising: a dose of olive oil before eating (30-35 g) with lemon juice in the ratio 1:1, in 25-30 min a dose of 100-120 ml of carrot-beet juice in the ratio 1:1, in 25-30 min a dose of 200-250 ml kefir infusion prepared from crude buckwheat grain, and a dose of 0.3 g of pepsin or 10-15 ml of pepsidil, a dose of 3.0-5.0 ml of horse radish roots infusion with lemon juice, a dose of 50-60 ml of medicinal herbs aqueous species. Method provides antitumor effect based on disturbance of cancer cells nutrition and normalization of body normal cells nutrition and recovery of metabolism and detoxification of the patient body. Invention can be used in treatment of malignant tumors of different localization and development stage.

EFFECT: enhanced effectiveness of diagnosis and treatment.

1 tbl, 2 ex

FIELD: medicine, oncology, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to a pharmaceutical composition designated for treatment of tumors and tumor metastasis. The composition comprises: (i) at least one antibody or its functionally intact derivative comprising a binding site that binds with the epitope ErbB1(Herl1) of receptor and (ii) at least one agent inhibiting angiogenesis being optionally in common with a pharmaceutically acceptable carrier, diluting agent or excipient used in the combined therapy in treatment of tumors and tumor metastasis. Using the proposed composition can result to the possible synergetic enhancing inhibitory effect of each specific therapeutic agent with respect to inhibition of tumor cells proliferation and providing the enhanced effective treatment as compared with individual agents using separately.

EFFECT: enhanced effectiveness of therapy.

25 cl, 1 ex

FIELD: medicine, oncology, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an antitumor agent. Anti-tumor liposomal preparation based on a mixture of flavolignans or their extracts prepared from spotted milk thistle (Silybium) fruits is made in liposomal formulation with particles size 100-500 nm. The preparation contains additionally vector component of peptide nature bound covalently to lipids of liposome envelope. As a vector component of peptide nature protein is used chosen from the group of representatives of family factors of epithelium growth, transforming growth factors, oncofetal proteins, endothelium growth factors and fibroblast growth factors, or the group active peptide fragments of protein said above. Above described preparation possesses the enhanced antitumor effect and its delivery rate to a tumor target-cell is increased. Invention can be used as an antitumor agent.

EFFECT: valuable medicinal property of preparation.

1 tbl, 2 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a novel using compounds representing derivatives of pyroindolone for preparing medicaments useful as anticancer medicaments.

EFFECT: valuable medicinal properties of derivatives.

4 cl, 1 tbl, 3 ex

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention describes a medicament used in treatment of liver disease by prevention of invasion onset of portal vein. This agent represents the effective medicament containing menatetrenone as an active component used in treatment/prophylaxis of liver disease. Indicated agent used in treatment/prophylaxis of liver disease is the effective medicament against liver cancer, in particular, against DCP (des-γ-carboxyprothrombin)-positive liver cancer. Agent used in aims for treatment/prophylaxis of liver disease contains menatetrenone as an active component, it improves prognosis significantly after carrying out the anticancer therapy and possesses the excellent effect directed on prevention of liver cancer relapses.

EFFECT: valuable medicinal property of agent.

4 cl, 2 tbl, 10 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: agents are used modulating stem cells proliferation when treating people and animals and accelerating recovery process after peripheral blood chemotherapy.

EFFECT: enhanced effectiveness of treatment.

79 cl, 28 dwg, 44 tbl

FIELD: medicine, cardiology, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to development of a complex from vegetable raw, vitamins, amino acids, trace elements and macroelements used in treatment of cardiovascular system diseases in carrying out the supporting therapy. Agent used in treatment of cardiovascular system in carrying out the supporting therapy contains as active components vitamins, bioflavonoids, trace elements, macroelements, extracts from medicinal plants, red grape polyphenol complex, broccoli concentrate, borage oil, L-cysteine, L-glutathione, D,L-methionine, and special supplements as cellulose, silicon dioxide, stearic acid, magnesium stearate and hydroxypropylcellulose, and this agent is made as a tablet formulation in the definite content of components per one tablet, in mg. Agent is designated in carrying out the supporting therapy in hypertensive disease of I-II degree, ischemic heart disease I-II of the functional class , neurocirculatory dystonia of different types. Agent is prescribed in the dose one tablet 1-2 times before eating or with food by course for one month. "AngioTonik" is agent able to provide body by all nutrient substances that are necessary for normal function of cardiovascular system.

EFFECT: valuable medicinal properties of agent.

5 cl, 5 tbl, 3 dwg

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