Naphthalene derivatives

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable acid-additive salts. The compounds under the present invention are active to bind cannabinoid (CB) receptor. In general formula (I) , X stands for -S-, -S(=O)-, -S(=O)2-, -S(=O)2N(H)-, -P(=O)(OCH3)-, -P(=O)(OH)-, -N(H)-, -N(CH3)-, -N(H)C(=O)N(H)-, -C(=O)-, -C(=O)O-, -N(H)C(=O)-, -C(H)(OH)-, -C(H)=N-, -C(H)=C(H)-, -CH2N(H)-or -C(=NH)-; R1 stands for phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, benzimidazolyl, 2-oxo-1,3-dihydrobenzimidazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl or indanyl which can be optionally substituted; R2 stands for hydrogen, -OR4 or -N(R5)R6; R3 stands for hydrogen; cyano; oxadiazolyl, piperazinyl or tetrazolyl optionally substituted with methyl; -C(=O)R7, -OR8 or N(R9)R10. Besides, the invention concerns method of producing compound of formula I and to pharmaceutical composition active to bind cannabinoid (CB) receptor, containing compound of formula I as an active component.

EFFECT: higher efficiency of compounds.

5 cl, 14 ex

 

The present invention relates to new naphthalene derivatives, processes for their preparation, to their use as pharmaceuticals and to the containing pharmaceutical compositions.

More specifically one of the objects of the present invention is a compound of formula I

where

X represents-S-, -S(O)-, -S(O)2-, -S(O)2NH-, -P(O)(och3)-, -P(O)(OH)-, -NH-, -N(CH3)-, -NHC(O)NH-, -C(O)-, -C(O)O-, -NHC(O)-, -CH(OH)-, -CH=N-, -CH=CH-, -CH2NH - or-C(=NH)-;

R1denotes aryl or heteroaryl;

R2denotes hydrogen, OR4or NR5R6;

R4stands With1-C8alkyl or C2-C8alkenyl;

R5and R6independently of one another denote hydrogen, C1-C8alkyl or C(O)(C1-C8)alkyl; and

R3denotes hydrogen, cyano, heteroaryl, heteroseksualci, C(O)R7, OR8or NR9R10;

R7IT denotes, WITH1-C4alkoxy, NH2, NHCH2C(O)OH or aryl;

R8denotes hydrogen, C1-C8alkyl, S(O)1-C4alkyl or C(O)-aryl; and

R9and R10independently of one another denote hydrogen, C1-C8alkyl or C2-C4alkenyl; provided that when X represents-C(O)- and R2and R3denote hydrogen or R2 denotes N and R3denotes 4-methoxy, R1means neither 1-naphthyl or 4-methoxy-1-naphthyl;

in free base form or in the form of an acid additive salt.

In the context of the present description the term aryl or heteroaryl refer to 6-membered ring or bicyclo consisting of two condensed rings, or one 6-membered and one 5-membered ring, where one or more carbon atoms independently from each other may be replaced by an atom selected from the series comprising oxygen, nitrogen and sulfur. Examples are6-C10aryl, C1-C9heteroaryl and C6aryl condensed with a 5 - or 6-membered aliphatic or heteroaromatics ring, for example naphthyl, 1,2,3,4-tetrahydronapthalene, phenyl, indolyl, chinoline, ethenolysis, 1,2,3,4-tetrahydroquinoline, benzothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzotriazolyl, indanyl, oxadiazolyl, pyrazolyl, triazolyl and tetrazolyl.

Examples of geterotsiklicheskie are piperidinyl, piperazinil and morpholinyl.

It should be borne in mind that the above compounds may bear in its structure, the substituents, for example one or more substituents selected from a range that includes IT; nitro; halogen; cyano; COOH; C(O)NH2; C(O)NHNHC(O)CH3; C(NH2)=NOH; C1-C4alkyl; S-C1-C4lkyl; With1-C8alkoxy, C5-C10aryl, such as phenyl; C1-C4-heteroaryl, such as oxadiazolyl; C1-C5-N-heteroseksualci, such as morpholinyl or piperidinyl; C(O)O-C1-C4alkyl or NR11R12where R11and R12independently of one another denote hydrogen, C1-C4alkyl, C(O)NHOC1-C4alkyl, S(O)1-C4alkyl or SO2-C1-C4alkyl, where the substituents in turn may be substituted by the Deputy, selected from a range that includes IT; a nitro-group; NH2;1-C4alkyl; C1-C4alkoxygroup; C1-C4alkoxygroup, HE substituted; (C3-C6cycloalkyl; N-(C1-C4alkyl)2; phenyl or morpholinyl.

For example, in the radical R is aryl or heteroaryl can be unsubstituted or can be substituted by one or more substituents selected from the series. including IT; COOH; C(O)NH2; nitro; halogen; cyano; C(NH2)=NOH; C1-C4-N-heteroaryl; C1-C5-N-heteroseksualci; C1-C4alkyl; S-C1-C4alkyl; C1-C8alkoxy and NR11R12where R11and R12independently of one another denote hydrogen, C1-C4alkyl, C(O)NHOC1-C4alkyl, S(O)1-C4alkyl or SO2-C1With 4alkyl; where C1-C4alkyl, C1-C8alkoxy and C1-C5-N-heteroseksualci in turn can be unsubstituted or can be substituted for IT; C1-C4by alkyl; C1-C4alkoxygroup; C1-C4alkoxygroup, HE substituted; (C3-C6cycloalkyl; N-(C1-C4by alkyl)2; phenyl; or morpholinyl;

moreover, in the radical R3oxadiazolyl, piperazinil or tetrazolyl can be replaced by stands;

in the radical R4With1-C8the alkyl may be unsubstituted or may be substituted by HE, C(O)O-C1-C4the alkyl, morpholinyl, piperidinyl, phenyl or oxadiazolyl; and phenyl and oxadiazolyl in turn can be unsubstituted or can be substituted With1-C4the alkyl, C1-C4alkoxy-, nitro-group, NH2or N(C1-C4by alkyl)2;

in the radical R5or R6With1-C4the alkyl may be unsubstituted or may be substituted by morpholinyl;

in the radical R8With1-C4the alkyl may be unsubstituted or may be substituted by C(O)HE, C(O)och3C(O)NHNHC(O)CH3or oxadiazole, substituted C1-C4the alkyl.

Compounds according to the invention may be in free form or in the form of an acid additive salt. It should be kept in view is, under the volume of the subject invention the compounds of formula I in free form or in salt form, for example in the form of triptoreline or hydrochloride. Suitable for pharmaceutical use according to the invention pharmaceutically acceptable acid additive salts include primarily hydrochloride.

In formula I the radicals independently of one another, in combination with each other or in any combination or subcombination preferably have the following meanings:

(a) X represents-S-, -S(O)-, S(O)2-, -S(O)2NH-, -P(O)(och3)-, -P(O)(OH)-, -NH-, -N(CH3)-, -NHC(O)NH-, -NHC(O)-, -C(O)-, -C(O)O-, -CH(OH)-, -CH-N-, -CH=CH-, -CH2NH - or =NH)-; preferably-NH-C(O)-, -C(O)O - or-CH2NH-, more preferably-C(O)- or-C(O)O-;

(b) R1denotes phenyl, 4-methoxyphenyl, 2-hydroxy-3-methoxyphenyl, 2,3-acid, 3,4-acid, 4-[2-(morpholine-4-yl)ethoxy]phenyl, 4-[3-(hydroxy)propoxy]phenyl, 4-butoxyphenyl, 3-(NHC(O)NHOCH3)-4-phenoxyphenyl, 4-dimethylphenyl, 4-acetamidophenyl, naphthyl, 4-carboxyethyl, 4-aminocarbonylmethyl, 4-hydroxynaphthyl, 4-C(NH2)=NOH)-naphthyl, 4-fornuft-1-yl, 4-canonity, 3-nitronate-1-yl, 4-nitronate-1-yl, 3-aminoet-1-yl, 4-aminoet-1-yl, 4-dimethylaminomethyl-1-yl, 4-metaxilat-1-yl, 4-[4-(hydroxy)butoxy]naphthyl, 4-intoximeter, 4-[2-(morpholine-4-yl)ethoxy]naphthyl, 3-(dimethylamino)naphthyl, 3-methylsulfonylmethyl, 4-IU ralfinamide, 4-(1,2,4-triazole-1-yl)naphthas-1-yl, 4-(1H-tetrazol-5-yl)naphthyl, 4-(pyrazole-1-yl)naphthyl, 4-(imidazol-1-yl)naphthyl, 1,2,3,4-tetrahydronaphthalen-5-yl, indan-4-yl, indol-7-yl, quinoline-8-yl, quinoline-4-yl, quinoline-3-yl, quinoline-5-yl, isoquinoline-5-yl, isoquinoline-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroquinolin-8-yl, 6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl, 5-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl, 7-pentoxyresorufin-4-yl, 5,7-dimethyl-2,1,3-benzothiadiazole-4-yl, 5-chloro-2,1,3-benzothiadiazole-4-yl, 2,1,3-benzothiadiazole-4-yl, 2,1,3-benzoxadiazole-4-yl, 7-pentoxil-2,1,3-benzoxadiazole-4-yl, 2-oxo-7-pentoxil-1,3-dehydrobenzperidol-4-yl, 2-(NHCH2phenyl)-7-phenoxybenzamide-4-yl, 2-(NHCH2cyclohexyl)-7-phenoxybenzamide-4-yl, 2-(NH(CH2)3N(CH2CH3)2)-7-phenoxybenzamide-4-yl, 2-(NH(CH2)3CH3)-7-phenoxybenzamide-4-yl, 2-(4-methylpiperazin-1-yl)-7-phenoxybenzamide-4-yl, 2-(NH(CH2)2OH)-7-phenoxybenzamide-4-yl, 2-(NH(CH2)2O(CH2)2OH)-7-phenoxybenzamide-4-yl, 2-methyl-7-phenoxybenzamide-4-yl, 7-phenoxybenzamide-4-yl; first of all, naphthyl, 4-hydroxynaphthyl, 4-fornuft-1-yl, 4-canonet-1-yl, 4-nitronate-1-yl, 4-dimethylaminomethyl-1-yl, 4-metaxilat-1-yl, 4-[4-(hydroxy)butoxy]naphthyl, 4-(1,2,4-triazole-1-Il)naphthas-1-yl, 4-(pyrazole-1-yl)naphthyl, 4-(imidazol-1-yl)naphthyl, 1,2,3,4-tetrahydronaphthalen-5-yl, indan-4-yl, hin is lineal, the quinoline-8-yl, quinoline-4-yl, isoquinoline-5-yl, 7-pentoxyresorufin-4-yl, 5-chloro-2,1,3-benzothiadiazole-4-yl, 2-(NHCH2phenyl)-7-phenoxybenzamide-4-yl, 2-(NH(CH2)3CH3)-7-phenoxybenzamide-4-yl or 7 - phenoxybenzamide-4-yl, more preferably naphthyl, 4-fornuft-1-yl, 4-canonet-1-yl, 4-dimethylaminomethyl-1-yl, 4-(1,2,4-triazole-1-yl)naphthas-1-yl, 4-(imidazol-1-yl)naphthyl, 1,2,3,4-tetrahydronaphthalen-5-yl, indan-4-yl, quinoline-8-yl, isoquinoline-5-yl or 5-chloro-2,1,3-benzothiadiazole-4-yl;

(C) R2denotes hydrogen, -O-(CH2)2CH3, -O-(CH2)3CH3, -O-(CH2)4CH3, -O-(CH2)5CH3, -O-(CH2)6CH3, -O-(CH2)3CH(CH3)2, 2-(morpholine-4-yl)ethoxy, 2-(piperidine-1-yl)ethoxy, 2-(4-methoxyphenyl)ethoxy, 2-(phenyl)ethoxy, 2-(4-nitrophenyl)ethoxy, 2-(4-dimethylaminophenyl)ethoxy, 2-(4-AMINOPHENYL)ethoxy, 2-(2-nitrophenyl)ethoxy, 2-(2-AMINOPHENYL)ethoxy, 2-(2-dimethylaminophenyl)ethoxy, 3-(morpholine-4-Il)propyloxy, 3-(piperidine-1-yl)propyloxy, -O-(CH2)3C(O)och2CH3, -O-(CH2)4C(O)och2CH3, -O-(CH2)2OCH2CH3, -O-CH2C(O)och3, -O-CH2-(2-methyl)oxadiazol-5-yl, -O-CH2-(2-ethyl)oxadiazol-5-yl, -O-CH2-(2-propyl)oxadiazol-5-yl, O-CH2SN=SNSN2CH3(Z) and (E), -O-(CH2)3 HE, -O-(CH2)4OH, -O-(CH2)5OH, -N-[2-(morpholine-4-yl)ethyl]-N-(CH2)3CH3, -NH-(CH2)3CH3, -NH-(CH2)4CH3, -NHC(O)(CH2)3CH3, -N(CH3)(CH2)3CH3or-N(CH3)(CH2)4CH3; preferably hydrogen, -O-(CH2)2CH3, -O-(CH2)3CH3, -O-(CH2)4CH3, -O-(CH2)5CH3, -O-(CH2)3CH(CH3)2, 2-(morpholine-4-yl)ethoxy, O-CH2SN=SNSN2CH3(Z) and (E), -NH-(CH2)3CH3, -NH-(CH2)4CH3, -N(CH3)(CH2)3CH3or-N(CH3)(CH2)4CH3; more preferably-O-(CH2)3CH3, -O-(CH2)4CH3, -O-(CH2)3CH(CH3)2, -O-CH2SN=SNSN2CH3(Z) and (E), -NH-(CH2)3CH3, -NH-(CH2)4CH3, -N(CH3)(CH2)3CH3or-N(CH3)(CH2)4CH3;

(g) R3denotes hydrogen, 7-HE, 8 HE, 7-och37-och2(O)HE, 7-och2C(O)och3, 7-OCH2C(O)NHNHC(O)CH3, 7-[-O-CH2-(2-methyl)-1,3,4-oxadiazol-5-yl], 7-OC(O)CH3, 7-OC(O)-naphthyl, 3-C(O)HE, 7-C(O)HE, 3-C(O)och3, 7-C(O)NH2, 8-OC(O)-naphthyl, 3-C(O)NHCH2C(O)OH, 7-cyano, 6-NH2, 7-NH2, 6-(CH 3)2, 7-N(CH3)2A 6-NHCH2CH=CH2, 6-N(CH2CH=CH2)2, 7-(piperazine-1-Il), 7-(4-methylpiperazin-1-yl), 7-(1H-tetrazol-5-yl), 7-(1-methyl)tetrazol-5-yl), 7-(2-methyl)tetrazol-5-yl) or 7-(2-methyl)-1,3,4-oxadiazol-5-yl; preferably hydrogen, 7-HE, 8 HE, 7-OC(O)CH3or 6-NHCH2CH=CH2; more preferably hydrogen, 7-HE-or 7-OC(O)CH3.

In addition, in the present invention, a method for obtaining compounds of formula I, which is that the aryl or heteroaryl fragment is subjected to interaction with the corresponding substituted naphthalene, and then if necessary make additional derivatization using methods known to experts in this field.

More specifically, in the invention, a method for obtaining compounds of formula I, namely, that carry out the following stages (a) interactions of the compounds of formula II

where R1has the above meaning and R13represents-OH, -SH, -I, -Cl, 1,8-bis(dimethylamino)naphthyl-, -COOH, -NH2, -N, -carbonitril, -O-trifloromethyl or-C(O)Cl, with a compound of formula III

where R2and R3have the above values, Y represents-O-, -S(O)2O-, -P(O)(och3)is a simple bond, -C(O)O-, -C(O)- or-B(OH)2and R1 means, for example, hydrogen, -I, -Cl, receiving the compound of formula Ia

where R1, R2and R3have the values indicated above and X' represents-CO-, -S-, -P(O)(och3)-, -NH-, -S(O)2NH-, -C(O)O-, -CH=N-, -CH(OH)-, -NHC(O)NH-, -C(=NH)-, or (if specified radical linked to the nitrogen atom, R1) -S(O)2-; or

(b) the conversion of compounds of formula Ia to the compound of formula IB

where R1, R2and R3have the above meanings and X is-SO-, -S(O)2- (which can be obtained by using process (b), if the component with which it is bound, R1means (C), -N(CH3)-, -P(O)HE-, -CH2NH-, -CH=CH - or (when linking via a carbon atom of the radical R1) -S(O)2-

and the allocation thus obtained compounds of formula Ia and formula IB in free form or in salt form.

Process (a) can be performed in the usual manner, for example as described in examples 1-14.

For process (b)

(I) to obtain the compounds of formula IB, where X is-SO - or-S(O)2-you can apply compound of formula Ia, where X' represents-S -, and meta-chlorbenzoyl acid, for example, as described in example 2;

(II) for obtaining the compounds of formula IB, where X is-P(O)IT is possible to apply the compound of formula Ia, where X' about the mean-P(O)(och 3and trimethylsilylmethyl, for example, as described in example 3;

(III) to obtain the compounds of formula IB, where X is-N(CH3)-you can apply compound of formula Ia, where X' denotes-NH - and methyliodide, for example, as described in example 4;

(IV) to obtain the compounds of formula IB, where X is-CH2NH-, you can apply a compound of formula Ia, where X' denotes-CH=N - NR3- pyridine, for example, as described in example 8.

Processing of reaction mixtures and purification of the thus obtained compounds can be accomplished using known methods.

Acid additive salts can be obtained from the free bases of the known method and Vice versa. As suitable acid additive salts of the present invention can be applied, for example, hydrochloride.

The initial compounds of formulas II and III can be obtained, for example, according to the methods described in the examples 2, 3, 5, 6, 12, 13 and 14; or can be used known compounds or they can be obtained by methods analogous to known methods.

Compounds according to the invention and their pharmaceutically acceptable acid salt additive, referred to in this description as the agents according to the invention have valuable pharmacological properties, as set out in experiments in vitro and in animals, and therefore they can be applied as a pharmacist is logical devices.

In particular, the agents according to the invention possess activity against the binding of cannabinoid (CB) receptor. More specifically, the agents according to the invention possess activity against human CB1-receptor. The interaction of the agents according to the invention with cannabinoid receptor can be demonstrated in the experiments on the evaluation of their activity against displacement, for example, [3H]CP55940 from human cannabinoid receptors, expressed, for example, in the cell line of reaction, for example, according to the following test method.

Test I: analysis of the receptor binding CB1

Mixture for analysis contains 75 μl of the suspension of membranes [membrane of the cell line of reaction, transfection human CB1 receptors obtained from the firm Receptor Biology, Beltsville, Maryland; 133 mg/ml in buffer for analysis (50 mm Tris-HCl, 2.5 mm etc, 5 mm MgCl2, 5 mg/ml BSA, pH 7.4), approximately 10 µg/well)], 25 μl WGA-YS granules [granules of yttrium silicate, sensitized by agglutinins from wheat germ, firm Amersham (40 mg/ml, 1 mg/well)], 50 μl of test compound in 4%DMSO and 50 μl of radioligand {[3N]SR (180 CI/mmol), firm New England Nuclear; the final concentration 0,125 nm in buffer for analysis}. All the components are mixed, shaken at room temperature for 2 h, and then count the radioactivity with OSU counter Topcount. Ninasimone binding estimate in the presence of 10 μm (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanon (Tocris).

For the agents according to the invention the values of Kirange from 1 nm to 100 μm, preferably from 10 nm to 2 μm. The values of the IC50calculated using the program ORIGIN using the approximation of experimental data by a logarithmic curve. Values of Kicalculated on the basis of values IC50using the equation of Cheng-Prusova (Ki=IC50/(1+([L]/Kd)), where [L] is the ligand concentration.

The agents according to the invention is most useful for treating or preventing chronic pain, especially inflammation such as chronic inflammatory pain, inflammatory diseases, e.g. inflammatory diseases of the Airways such as chronic obstructive pulmonary disease (COPD), or asthma, rhinitis, inflammatory bowel disease, cystitis, such as interstitial cystitis, pancreatitis, uveitis, inflammatory skin diseases and rheumatoid arthritis.

The specific activity of compounds as analgesics can be confirmed by standard methods, for example using the following test.

Test II: a model of neuropathic pain

Action against the attachment of hyperalgesia assessed using a model of neuropathic pain, induced by the imposition of partial ligature on the sciatic nerve according to the method described Seltzer and others (1990). In General, the method is that of Wistar rats (weighing 120-140 g) is subjected to anesthesia, exposing the left sciatic nerve at the level of mid-thigh using a small incision and compress it to 1/3-1/2 of the thickness of the nerve by applying a tight ligature of the suture material 7.0. The wound closed using a conventional suture material for muscle tissue and skin parentheses and opilivayut powder antibiotic aureomycin. Animals allowed to recover, and after 12-15 days after surgery they conduct experiments.

Mechanical hyperalgesia assessed by measuring the amount of force at which there is OTDELENIE legs while increasing the pressure on the dorsal surface of the paw using analgesiometer (firm Ugo-Basile, Milan), designed for a maximum load of 250, the Threshold force at which OTDELENIE feet, as measured on the ipsilateral (on which is superimposed a ligature)and contralateral (which is not imposed ligature) paw up (prior to dose) and at 6 h after drug administration or the media. Data is expressed as the limit values of the force (g)at which there is OTDELENIE paws and the percentage reversal of hyperalgesia, which rasschitat shall comply with the following formula:

Efficiency is expressed as the values of D50i.e. the dose required to produce 50%reversal of hyperalgesia.

For the agents according to the invention the value of D50range from 0.1 to 100 mg/kg

Thus, the agents according to the invention can be applied as agonists of cannabinoid receptor, for example, for the treatment of pains of different origin or etiology, and as anti-inflammatory agents and/or antigenically (anti) funds for the treatment of inflammatory reactions, diseases or conditions, as well as for the treatment of allergic reactions. Thanks analgesic/anti-inflammatory profile can be used to treat associated with inflammation pain, for the treatment of hyperalgesia and primarily for the treatment of severe chronic pain. They can be used, for example, for the treatment of pain, inflammation and/or edema, for example, trauma-related, for example, associated with burns, sprains, fractures or the like, the consequences of surgical intervention, such as post-operative analgesics, as well as for treatment-related inflammation pain of different origin, for example, for the treatment of pain in the bones and joints (osteoarthritis), rheumatoid arthritis, rheumatic diseases, endosement, gout, pain in cancer, myofascial pain is (muscle damage, fibromyalgia), chronic neuropathic pain, e.g. diabetic neuropathy, phantom limb pain and perioperative (encountered during surgery) pain (General surgery, gynecological surgery). In addition, they can also be used to treat pain, such as angina pectoris, menstruation or cancer. In addition, they can be used as anti-inflammatory/anti-edema agents, for example, for the treatment of inflammatory skin diseases such as psoriasis and eczema.

The agents according to the present invention can also be used as a muscle relaxant of smooth muscle, for example, for treatment of spasms of the gastrointestinal tract or uterus, for example, for the treatment of glaucoma/intraocular pressure, for example, for the treatment of Crohn's disease, ulcerative colitis or pancreatitis and for the treatment of muscle spasticity and tremor, for example, in multiple sclerosis.

For the above indications, doses of the agents according to the invention, of course, vary depending, for example, from the owner, route of administration and the nature and seriousness of the subject to treatment status, as well as on the relative effectiveness of specific agent used according to the invention. The required amount of active substance can be evaluated, for example, using known methods of in vitro assays IP vivo, determining how long a specific concentration of the active substance in the blood plasma remains acceptable to provide a therapeutic action level. In General determined that satisfactory results in animals are when ingested by (r.o.) daily doses of from about 0.01 to about 20.0 mg/kg For a person corresponding to a daily dose of from about 0.7 to about 1400 mg/day, r.o., for example, from about 50 to 200 mg (person weighing 70 kg), which is injected as a single dose or in divided doses up to 4 times a day or using a form with a continuous release. Suitable for this purpose oral medicines contain from about 1.75 or 2.0 to about 700 or 1400 mg of the agent according to the invention in combination with appropriate pharmaceutically acceptable diluent or carrier.

In an alternative embodiment, the agents according to the invention can be applied topically, for example in the form of cream, gel or the like, for example, for the treatment of the above-described conditions of the skin, or by inhalation, for example, in the form of a dry powder, for example, for the treatment of asthma.

Examples of compositions containing the agent according to the invention are, for example, solid dispersion, an aqueous solution, for example containing solubilizers agent, microemulsion and suspense what I for example, the hydrochloride of the compound of formula I in a concentration of from 0.1 to 1%, such as 0.5 percent. The composition can aboveright using a suitable buffer to a pH of, for example, from 3.5 to 9.5, for example to a pH of 4.5.

The agents according to the invention can also be used as chemical agents in the conduct of scientific research.

The agents according to the invention can be entered in vivo, either individually or in combination with other pharmaceutical agents effective in the treatment of diseases and conditions causing or accompanying the activation of CB1-receptor, including inhibitors of cyclooxygenase-2 (MOR-2), such as specific inhibitors MOR-2 (e.g., celecoxib and rofecoksib) and non-steroidal anti-inflammatory drugs (NSPs) (for example, acetylsalicylic acid, derivatives of propionic acid)antagonists vanilloideae receptor, tricyclic antidepressants (e.g., Anafranil®, Asendin®, Aventyl®, Elavil®, Endep®, Norfranil®, Norpramin®, Pamelor®, Sinequan®, Surmontil®, Tipramin®, Tofranil®, Vivactil®, Tofranil-PM®), anticonvulsive means (e.g., gabapentin) and agonists GABAIn(gamma-aminobutyric acid) (for example, L-baclofen).

The pharmaceutical compositions according to the invention, intended for separate administration of the components in the composition, for administration in the form of fixed the composition, i.e. a single galenical composition comprising at least two components, you can get a well-known method, and you can enter them enterline, for example oral or rectal, and parenteral, mammals, including humans, and they contain a therapeutically effective amount of at least one with pharmacological efficacy component individually or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral administration.

A new pharmaceutical composition contains, for example, from about 0.1 to about 99.9 percent, preferably from about 20 to about 60% of active substances. Pharmaceutical compositions for joint therapy, administered enterally or parenterally represent, for example, the composition being in the form of standard dosage forms, such as a covered sugar pills, tablets, capsules or suppositories, and also ampoules. Unless specified otherwise, get them well-known method, for example using conventional mixing, granulation, coating sugar coating, dissolving or lyophilization. It should be borne in mind that the number is included in the composition of a component contained in one of the camp is artney dose of each dosage form, not necessarily constitute an effective amount since the necessary effective amount can be administered using a few standard doses.

In particular, a therapeutically effective amount of each of the components in the composition, can be administered simultaneously or sequentially and in any order, and the components can be entered separately or in the form of a fixed composition. For example, the method according to the invention the slowdown in the development or treatment of proliferative diseases may include (I) introduction of the component (a)included in the composition in free form or in the form of a pharmaceutically acceptable salt, and (II) the introduction of the component (b)included in the composition in free form or in the form of a pharmaceutically acceptable salt, simultaneously or sequentially in any order in amounts which together are therapeutically effective, preferably in quantities of synergistic action, for example, in daily doses that meet specified in the present description quantities. The individual components included in the composition, can be entered separately at different points in time during treatment or at the same time as divided or combined compositions. In addition, the concept is the introduction also includes the use of prodrugs of the component, included in the composition, which is converted in vivo into a component that is part of the composition. Thus, it should be borne in mind that under the scope of the present invention cover all such regimes of simultaneous or alternating treatment and the term "introduction" should be interpreted accordingly.

The effective dose of each of the members of the composition components may vary depending on the particular compound or applied pharmaceutical compositions, routes of administration, the condition to be treated, the severity of the condition to be treated. Thus, the regimen of medicines chosen, taking into account various factors, including route of administration, and renal and hepatic function of the patient. Attending physician, Clinician or veterinarian specializing in this field can easily determine and prescribe the effective amount of the individual active substances required to prevent, counter or stop the development of the state. The optimal concentration of active ingredients in the range in which it is possible to achieve effective action, not accompanied by toxicity, obtained using the regimen of medicines that are developed with consideration of the kinetics of achieving active substances oblasteista. In General, it is established that animal satisfactory results were obtained when ingested by (r.o.) daily doses comprising from about 0.01 to about 20.0 mg/kg For a human daily dose of from about 0.7 to about 1400 mg/day, r.o., for example from about 50 to 200 mg (for a person weighing 70 kg), which is convenient to introduce in a single dose or divided doses (up to 4 times a day) or in the form of a continuous release. Accordingly, suitable oral dosage forms contain from about 1.75 or 2.0 to about 700 or 1400 mg

In accordance with the foregoing objects of the present invention are:

(1) the agent according to the invention, intended for use as a cannabinoid receptor, for example for use in any of the above indications;

(2) a Pharmaceutical composition comprising as active ingredient an agent according to the invention together with a pharmaceutical acceptable diluent or carrier. Such a composition can be prepared generally accepted method.

(2') the Pharmaceutical composition intended for treating or preventing the disease or condition, which plays a role or is involved activation of the cannabinoid receptor, comprising the agent according to the invention and novtel is.

(3) a Method of treating any of the above diseases in a patient in need of such treatment, which consists in conducting effective amount of an agent according to the invention;

(3') a Method of treating or preventing the disease or condition, which plays a role or is involved activation of the cannabinoid receptor, namely, that the needy in the mammal is administered a therapeutically effective amount of an agent according to the invention.

(4) the Use of an agent according to the invention for preparing a medicinal product intended for treating or preventing the disease or condition, which plays a role or is involved activation of cannabinoid receptor;

(5) the Method as defined above, providing for joint introduction, for example, simultaneously or sequentially a therapeutically effective amount of the agonist ST., e.g. agent according to the invention and a second drug substance used, for example, indicated in the present description indications.

(6) a composition comprising a therapeutically effective amount of the agonist ST., e.g. agent according to the invention and a second drug substance, for example, intended for use in any of the above indications.

The preferred compound of formula I for use with the according to the invention is the compound of example 1. This compound is an effective agonist ST., in particular CB1-agonist in vitro (Ki=0,015±0,004 μm). The value of D50for models of neuropathic pain, used in test II, the compounds of example 1 is 0.18 mg/kg r.o.

Abbreviations used in the examples:

BINAP2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
DHMdichloromethane
DYADSdiisopropylsalicylic
DIAN,N-diisopropylethylamine
DMAP4-dimethylaminopyridine
DMFdimethylformamide
DMSOthe sulfoxide
Deposbis[(2-diphenylphosphino)phenyl] ether
DFFAdefenestrated
MJPBKmeta-chloroperbenzoic acid
MS 4Åmolecular sieves with mesh size 4Å
PdCl2dppf·CH2Cl2the complex of 1,1'-bis(diphenylphosphino)
periodiacally(II) and dichloromethane
Pd2dba3Tris(dibenzylideneacetone)dipalladium(0)
Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0)
THFtetrahydrofuran
tert-BuOKtert-piperonyl potassium

The invention is illustrated in more detail in the examples below.

Example 1: Obtaining naphthalene-1-yl-(4-petrosinelli-1-yl)methanone

(a) 20 g of 1-naphthol and 21.2 ml NEt3and 1.7 g of dimethylaminopyridine dissolved in 300 ml of methylene chloride at room temperature (RT). The solution is cooled to 10°C. for 15 min added dropwise to 20.9 ml nafolklore in 100 ml of methylene chloride. After conventional processing receive naphthalene-1-yl-(naftalinov-1-yl)methanon.

(b) 29,0 g of naphthalene-1-yl-(naftalinov-1-yl)methanone add portions to the suspension containing 14.3 g of aluminium chloride in 100 ml of toluene, and stirred for 2 h at 140°C. After conventional treatment get naphthalene-1-yl-(4-petrosinelli-1-yl)methane is.

(C) of 11.0 g of naphthalene-1-yl-(naftalinov-1-yl)methanone and 6.1 g of potassium carbonate in 130 ml of acetone is stirred for 15 min at the temperature of reflux distilled. Then within 2 minutes and add a solution containing 6.8 ml 1-bromopentane in 20 ml of acetone, and the suspension is stirred for 22 hours at a temperature of reflux distilled. After conventional processing and subsequent chromatography receive naphthalene-1-yl-(4-petrosinelli-1-yl)methanon. Melting point: 72-75°C (propan-2-ol); GHUR: retention time (min): 8,15 [GHUR method: column type Kingsorb 3 micron C18 (30×4.6 mm). Gradient elution: 10-100% acetonitrile in 0.1% triperoxonane acid in water for 7 min, then 100% acetonitrile for 3 min].

1H NMR (400 MHz, CDCl3): δ 9,02 (d, 1H), 8,43 (d, 1H), of 8.25 (d, 1H), 8,01 (d, 1H), 7,95 (d, 1H), of 7.70 (t, 1H), 7,62-to 7.50 (m, 6H), of 6.68 (d, 1H), 4,19 (t, 2H), 2.0-was 1.94 (m, 2H), 1,6-and 1.54 (m, 2H), 1,49-of 1.44 (m, 2H), 0,99 (t, 3H).

MC m/z (%): 369,1 (M+H, 100); IR (ν, cm-1): 1633 (C=O)

In the following examples obtain the compounds of formula I according to the invention, where R2denotes-O-(CH2)4CH3(Approx. indicates the example).

/tr>
Approx.XR1R3
2-S-naphthylN
3-S(O)-naphthylN
4-S(O)2-naphthylN
5-P(O)(och3)-naphthylN
6-P(O)(OH)-naphthylN
7-S(O)-4-methoxyphenylN
8-S(O)2-4-methoxyphenylN
9-S(O)-4-acetamidophenylN
10-S(O)2-4-acetamidophenylN
11-S(O)2-1,2,3,4-tetrahydroquinolin-1-ylN
12-S-4-acetamidophenyl N
13-S(O)2NH-5,7-dimethyl-2,1,3-benzothiadiazole-4-ylN
14-P(O)(OH)-4-methoxyphenylN
15-P(O)(OH)-4-dimethylphenylN
16-P(O)(och3)-the quinoline-8-ylN
17-S-3,4-acidN
18-S(O)-3,4-acidN
19-S(O)2-3,4-acidN
20-P(O)(och3)-indol-7-ylN
21-P(O)(OH)-the quinoline-8-ylN
22-S(O)2 -6-methoxy-1,2,3,4-tetrahydroquinolin-1-ylN
23-P(O)(OH)-indol-7-ylN
24-NH-naphthylN
25-S(O)2NH-naphthylN
26-N(CH3)-naphthylN
27-C(O)O-naphthylN
28-NH-4-methoxyphenylN
29-CH(OH)-naphthylN
30-CH=NnaphthylN
31-CH=CH-naphthylN
32-C(O)O- 1,2,3,4-tetrahydronaphthalen-5-ylN
33-C(O)O-indan-4-ylN
34-CH2NH-naphthylN
35-C(O)O-5-chloro-2,1,3-benzothiadiazole-4-ylN
36-C(O)O-isoquinoline-5-ylN
37-C(O)O-the quinoline-5-ylN
38-C(O)O-the quinoline-8-ylN
39-NHC(O)NH-naphthylN
40-NHC(O)-1,2,3,4-tetrahydroquinolin-1-ylN
41-NHC(O)-6-methoxy-1,2,3,4-tetrahydroquinolin-1-ylN
42 -CH2NH-(5,7-dimethyl)-2,1,3-benzothiadiazole-4-ylN
43-CH2NH-2,1,3-benzothiadiazole-4-ylN
44-CH2NH-2,1,3-benzoxadiazole-4-ylN
45-C(NH)-4-methoxymethylN
46-C(O)O-1,2,3,4-tetrahydroquinolin-8-ylN
47-CH(OH)-naphthyl3-C(O)och3

The following examples are obtained according to the invention the compounds of formula I, where X represents S(O):

No.R1R2R3
48naphthyl-O-(CH2)3CH38-HE
49-O-(CH2)3CH38-OC(O)-naphthyl
50naphthyl-O-(CH2)4CH36-N-(CH2CH=CH2)2
51naphthyl-O-(CH2)4CH36-NHCH2CH=CH2
52naphthyl-O-(CH2)4CH37-OC(O)-naphthyl
53naphthyl-O-(CH2)4CH37-OC(O)-methyl
54naphthyl-O-(CH2)4CH37-HE
55naphthyl-O-(CH2)4CH3-7-och2C(O)och3
56naphthyl-O-(CH2)4CH3-7-och2(O)HE
57 naphthyl-O-(CH2)4CH36-NH2
58naphthyl-O-(CH2)4CH37-OCH2C(O)NHNHC(O)CH3
59naphthyl-O-(CH2)4CH37-[O-CH2-(2-methyl)-1,3,4-oxadiazol-5-yl]
60naphthyl-O-(CH2)4CH37-(4-methylpiperazin-1-yl)
61naphthyl-O-(CH2)4CH37-(piperazine-1-Il)
62naphthyl-O-(CH2)4CH37-NH2
63naphthyl-O-(CH2)4CH36-N(CH3)2
64naphthyl-O-(CH2)4CH37-N(CH3)2
65naphthyl-O-(CH2)4CH37-cyano
66naphthyl-O-(CH2)4CH37-(1H-tetrazol-5-yl)
67naphthyl-O-(CH2)4CH37-och3
68naphthyl-O-(CH2)4CH37-(1-methyltetrazol-5-yl)
69naphthyl-O-(CH2)4CH37-(2-methyltetrazol-5-yl)
70naphthyl-O-(CH2)4CH37-C(O)NH2
71naphthyl-O-(CH2)4CH37-C(O)HE
72naphthyl-O-(CH2)4CH33-C(O)och3
73 naphthyl-O-(CH2)4CH33-C(O)HE
74naphthyl-O-(CH2)4CH37-(2-methyl-1,3,4-oxadiazol-5-yl)
75naphthyl-O-(CH2)4CH33-C(O)NHCH2C(O)OH
764-forafter-O-(CH2)4CH37-OC(O)CH3
774-forafter-O-(CH2)4CH37-HE
784-(1,2,4-triazole-1-yl)naphthyl-O-(CH2)4CH37-HE

The following examples are obtained according to the invention the compounds of formula I, where X represents S(O) and R stands for hydrogen:

No.R1R2
798-hydroxy-1,2,3,4-tetrahydroxy the Jn-1-yl -O-(CH2)4CH3
801,2,3,4-tetrahydroquinolin-1-yl-O-(CH2)4CH3
81naphthyl-O-(CH2)4CH3
824-nitronate-1-yl-O-(CH2)SN3
834-aminoet-1-yl-O-(CH2)4CH3
844-dimethylaminomethyl-1-yl-O-(CH2)4CH3
854-metaxilat-1-yl-O-(CH2)4CH3
863-nitronate-1-yl-O-(CH2)4CH3
873-aminoet-1-yl-O-(CH2)4CH3
88the quinoline-4-yl-O-(CH2)4CH3
89the quinoline-3-yl -O-(CH2)4CH3
90the quinoline-2-yl-O-(CH2)4CH3
913-(dimethylamino)naphthyl-O-(CH2)4CH3
92the quinoline-8-yl-O-(CH2)4CH3
93isoquinoline-1-yl-O-(CH2)4CH3
944-forafter-O-(CH2)4CH3
954-canonity-O-(CH2)4CH3
964-(1,2,4-triazole-1-yl)naphthyl-O-(CH2)4CH3
974-1H-tetrazol-5-inafter-O-(CH2)4CH3
984-(4-hydroxy)butoxyethyl-O-(CH2)4CH3
994-intoximeter -O-(CH2)4CH3
1004-(2-morpholine-1-yl)ethoxyethyl-O-(CH2)4CH3
1013-methylsulfonylmethyl-O-(CH2)4CH3
1024-methylsulfonylmethyl-O-(CH2)4CH3
1034-(pyrazole-1-yl)naphthyl-O-(CH2)4CH3
1044-(imidazol-1-yl)naphthyl-O-(CH2)4CH3
1054-carboxymethyl-O-(CH2)4CH3
1064-aminocarbonylmethyl-O-(CH2)4CH3
1074-hydroxynaphthyl-O-(CH2)4CH3
1084-(C(NH2)=NOH)naphthyl-O-(CH2)4CH3
109 naphthyl2-(morpholine-4-yl)ethoxy
110naphthyl-O-(CH2)3CH3
111naphthyl-O-(CH2)2CH3
112naphthyl2-(piperidine-1-yl)ethoxy
113naphthyl2-(4-methoxyphenyl)ethoxy
114naphthyl2-(phenyl)ethoxy
115naphthyl2-(4-nitrophenyl)
116naphthyl2-(4-dimethylaminophenyl)ethoxy
117naphthyl2-(AMINOPHENYL)ethoxy
118naphthyl3-(morpholine-4-yl)propyloxy
119naphthyl2-(2-nitrophenyl)ethoxy
120naphthyl -NH-(CH2)3CH3
121naphthyl-O-(CH2)4C(O)och2CH3
122naphthyl-O-(CH2)3C(O)och2CH3
123naphthyl2-(2-AMINOPHENYL)ethoxy
124naphthyl2-(2-dimethylaminophenyl)ethoxy
125naphthyl3-(piperidine-1-yl)propyloxy
126naphthyl-N-[2-(morpholine-4-yl)-ethyl]-N-(CH2)3CH3
127naphthyl-NH-(CH2)4CH3
128naphthyl-O-(CH2)3HE
129naphthyl-O-(CH2)5OH
130naphthyl-O-(CH2)4OH
131 naphthyl-O-(CH2)5CH3
132naphthyl-O-(CH2)6CH3
133naphthyl-N-(CH3)(CH2)3CH3
134naphthyl-N-(CH3)(CH2)4CH3
135naphthyl-O-(CH2)2OCH2CH3
136naphthyl-O-CH2C(O)och3
137naphthyl-O-CH2-(2-methyl)oxadiazol-5-yl
138naphthyl-O-CH2-(2-ethyl)oxadiazol-5-yl
139naphthyl-O-CH2-(2-propyl)oxadiazol-5-yl
140naphthyl-O-(CH2)3CH(CH3)2
141naphthyl-NHCO)(CH 2)3CH3
142naphthylO-CH2SN=SNSN2CH3(Z)
143naphthylO-CH2SN=SNSN2CH3(E)
144phenyl-O-(CH2)3CH3
1452-hydroxy-3-methoxyphenyl-O-(CH2)3CH3
1462,3-acid-O-(CH2)3CH3
1474-(butoxy)phenylN
1484-[2-(morpholine-4-yl)ethoxy]phenylN
1494-[3-(hydroxy)propoxy]phenylN
1502-methyl-7-phenoxybenzamide-4-ylN
1517-phenoxybenzamide-4-ylN
1527-ethoxybenzothiazole-4-yl N
1533-(NHC(O)NHOCH3)-4-phenoxyphenylN
1542-oxo-7-pentoxil-1,3-dehydrobenzperidol-4-ylN
1552-(NHCH2phenyl)-7-phenoxybenzamide-4-ylN
1562-(NHCH2cyclohexyl)-7-phenoxybenzamide-4-ylN
1572-(NH(CH2)3N(CH2CH3)2)-7-phenoxybenzamide-4-ylN
1582-(NH(CH2)3CH3)-7-phenoxybenzamide-4-ylN
1592-(4-methylpiperazin-1-yl)-7-phenoxybenzamide-4-ylN
1602-(NH(CH2)2OH)-7-phenoxybenzamide-4-ylN
1612-(NH(CH2)2O(CH2)2OH)-7-phenoxybenzamide-4-ylN
1622-oxo-3-methoxy-7-pentoxil-1,3-dehydrobenzperidol-4-ylN

The following example presents obtained according to the invention the compound of formula I. where X represents C(O):

R1R2R3
1634-(imidazol-1-yl)naphthyl-O-(CH2)4CH37-HE

Connection receive primarily according to the following methods:

Receiving method 1: synthesis of ketones

Receiving method described in example 1 is used to obtain the compounds of examples: 29, 81, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 121, 122, 123, 124, 125, 128, 129, 130, 131, 132, 135, 136, 137, 138, 139, 140, 142, 143, 144, 147, 148, 149.

Example 2: Synthesis of sulfides, sulfones and sulfoxidov

The method used to obtain the compounds of examples: 2, 3, 4, 7, 8, 9, 10, 12, 17, 18, 19.

(a) 1-iodine-4-petrosinelli: a Solution of 1-introxication (6,41 g, and 29.9 mmol) in acetonitrile (120 ml) is treated with N-yogakriya (10.1 g, with 44.9 mmol) and stirred for 6 h at 82°C. After cooling to room temperature the reaction mixture was partitioned between 1 m knso3(185 ml) and toluene (2×185 ml). Organicheskoi the phase washed with water, dried over Na2SO4and concentrate. After rapid chromatography (cyclohexane) to obtain 9.0 g (89%) of product as crystals slightly pinkish color. EI-MS (m/z 340 (M+).

(b) 1-(1-Naphthalenesulfonyl)-4-petrosinelli: a Mixture containing 1-iodine-4-petrosinelli (0.68 g, 2.0 mmol), tert-BuOK (0.40 g, 3.0 mmol), 1-naphtyl (of 0.48 g, 3.0 mmol), Depos (120 mg) and Pd2dba3(80 mg) in toluene (16 ml), incubated for 2 h at 90°C. After cooling to room temperature the reaction mixture was washed with water (16 ml) and filtered through Hyflo. The organic phase is dried over Na2SO4and concentrate. After rapid chromatography (cyclohexane/acetone) gain of 0.62 g (80%) of product as colorless crystals.

(C) 1-(1-naphthalenesulfonyl)-4-petrosinelli: a Solution of 1-(1-naphthalenesulfonyl)-4-introxication (112 mg, 0.3 mmol) in DHM (3 ml) is stirred with MJPBK (74 mg, 0.3 mmol) for 2 h at 0°C. the Reaction mixture was partitioned between DHM (3 ml) and 1M, knso3(6 ml). The organic phase is washed with water (3 ml), dried over Na2SO4and concentrate. After rapid chromatography (cyclohexane/acetone) to obtain 94 mg (80%) of product as colorless crystals.

(g) 1-(1-Naphthylmethyl)-4-petrosinelli: a Solution of 1-(1-naphthalenesulfonyl)-4-introxication (112 mg, 0.3 mmol) in DHM (3 ml) is stirred with MJPBK (148 mg, 0.9 mmol) in which Uchenie 2 h at 0°C, and then for 2 h at room temperature. The reaction mixture was partitioned between DHM (3 ml) and 1M, knso3(6 ml). The organic phase is washed with water (3 ml), dried over Na2SO4and concentrate. After rapid chromatography (cyclohexane/acetone) to obtain 91 mg (73%) of product as colorless crystals.

Example 3: Synthesis of esters of phosphinic acid

The method is applicable for producing compounds of examples: 5, 6, 14, 15, 16, 20, 21, 23.

(a) Methyl ester of (4-petrosinelli-1-yl)phosphinic acid: a Solution of anhydrous crystalline N3RHO2(1,46 g, 21.9 mmol) in a mixture of toluene/THF (1:1, 11 ml) was treated with NA(OMe)3(9.6 ml, 87,7 mmol) and stirred for 1 h at 0°C and then for 2 h at room temperature. The mixture was added to a solution of 1-iodine-4-introxication (3,65 g of 10.7 mmol) and NEt3(1,64 ml of 11.8 mmol) in acetonitrile (27 ml). After adding (Ph3R)2PdCl2(376 mg, 0.54 mmol) the reaction mixture was kept at 90°C for 4 h After cooling to room temperature the reaction mixture was concentrated. After rapid chromatography (DHM/methanol) to obtain 2.16 g (69%) of product as a brownish oil. EI-MS (m/z 292 (M+).

(b) Methyl ester naphthalene-1-yl-(4-petrosinelli-1-yl)phosphinic acid: a Mixture containing methyl ester (4-petrosinelli-1-yl)phosphino the Oh of the acid (339 mg, 1.2 mmol), NEt3(of 0.18 ml, 1.3 mmol), 1-naphthalide (0.17 ml, 1.2 mmol), Depos (81 mg) and Pd2dba3(60 mg) in acetonitrile (3 ml), incubated at 90°C for 3 hours After cooling to room temperature the reaction mixture was partitioned between water (6 ml) and toluene (2×6 ml). The combined organic phases are washed with water (6 ml), dried over Na2S04and concentrate. After rapid chromatography (DHM/methanol) to obtain 246 mg (50%) of product as a yellowish oil.

(C) Naphthalene-1-yl-(4-petrosinelli-1-yl)phosphinic acid: a Solution of methyl ester naphthalene-1-yl-(4-petrosinelli-1-yl)phosphinic acid (156 mg, 0.38 mmol) in acetonitrile (1.5 ml) is treated with trimethylsilylimidazole (0.1 ml, 0.75 mmol) and stirred at room temperature for 1 h, the Reaction mixture was partitioned between 1M Na2CO3(4 ml) and toluene (4 ml). The aqueous phase is acidified with HCl solution (1.5 ml) and extracted with toluene (2×4 ml). The combined extracts dried over Na2SO4and concentrate. After rapid chromatography (DHM/methanol/NH3) obtain 127 mg (83%) of product as a colorless foam.

Synthesis of amines

The method is applicable for producing compounds of examples; 24, 26, 28.

(a) Naphthalene-1-yl-(4-petrosinelli-1-yl)amine: a Mixture containing 1-iodine-4-petrosinelli (1,02 g, 3.0 mmol), tert-BuONa (0,29 g, 4.2 mmol), -naphtylamine (0,43 g, 3.6 mmol), 2-(di-tert-butylphosphino)biphenyl (of 53.7 mg) and Pd2dba3(was 155.3 mg) in toluene (6 ml), incubated for 40 min at 80°C. After cooling to room temperature the reaction mixture is filtered through silica gel and concentrated. After rapid chromatography (cyclohexane/ethyl acetate) gain of 0.85 g (80%) of product as colorless crystals.

(b) Methylnaphthalene-1-yl-(4-petrosinelli-1-yl)amine: a Solution of naphthalene-1-yl-(4-petrosinelli-1-yl)amine (154 mg, 0.40 mmol) in DMF (1.7 ml) is treated with NaH (75%, 18 mg of 0.56 mmol) and methyliodide made (0.13 ml, 2.2 mmol) and stirred at 50°C for 18 hours After cooling to room temperature the reaction mixture was partitioned between water (4 ml) and toluene (2×4 ml). The combined organic phases are dried over Na2SO4and concentrate. After rapid chromatography (DHM/methanol) to obtain 70 mg (48%) of product as a foam light brown color.

Example 5: Synthesis of sulfonamides

The method is applicable for producing compounds of examples: 11, 13, 22, 25.

(a) Sodium salt of 4-petrosinelli-1-sulfonic acid: a Mixture of 4-hydroxynaphthalene-1-sulfonic acid (14,07 g, 40 mmol), NaOH (3.2 g, 80 mmol), n-pencillamine (10 ml, 80 mmol) and DMSO (200 ml) was stirred at 60°C for 2 hours After cooling to room temperature the reaction mixture is treated with water (400 ml) and neutralized with 6N HCl (15 ml). After stirring for 30 min at 0°C. the product is collected by filtration, washed with water and dried in vacuum, obtaining of 12.6 g (100%) of colorless crystals, tpl.275-285°C.

(b) 1-(4-Petrosinelli-1-sulfonyl)-1,2,3,4-tetrahydroquinolin: a Mixture of sodium salt of 4-petrosinelli-1-sulfonic acid (147 mg, 0.5 mmol) and DHM (3 ml) is treated with thionyl chloride (43 μl, 0.6 mmol) and stirred at room temperature for 30 minutes the Resulting clear solution is treated with DIEA (86 μl, 0.5 mmol) and 1,2,3,4-tetrahydroquinoline (95 μl, 0.75 mmol) and stirred at room temperature for 18 hours, the Reaction mixture was partitioned between water (3 ml and DHM (2×3 ml). The organic phase is washed with water (3 ml), dried over Na2SO4and concentrate. After rapid chromatography (toluene) to obtain 79 mg (39%) of product as a colorless oil.

Example 6: Synthesis of amides

The method is applicable for producing compounds of examples: 79, 80, 163.

(a) 4-Petrosinelli-1-carbaldehyde: a Mixture of 4-hydroxynaphthalene-1-carbaldehyde (1,72 g, 10 mmol), NaOH (to 0.48 g, 12 mmol), n-interbreed (1.5 ml, 12 mmol) and DMSO (10 ml) was stirred at 50°C for 4 h After cooling to room temperature the reaction mixture is treated with water (20 ml) and 2n. HCl (1.5 ml, pH 4). After extraction with toluene (2×20 ml) the combined organic phases are washed with water, dried on the Na 2SO4and concentrate. After crystallization (cyclohexane) to obtain 2.15 g (89%) of product in the form of brownish crystals, tpl.67-68°C.

(b) 4-Petrosinelli-1-carboxylic acid: a Solution containing 4-petrosinelli-1-carbaldehyde (1.9 g, 7.8 mmol) and 2-methyl-2-butene (39 ml) in tert-BuOH (150 ml), treated with a solution of NaClO2(7,05 g, 78 mmol) and NaH2RHO4·H2On (7,53 g, 55 mmol) in water (62 ml). After stirring at room temperature for 17 h, the product is collected by filtration, washed with water and dried in vacuum, obtaining 1.92 g (95%) of brownish crystals, tpl.190-202°C.

(in) (3,4-Dihydro-2H-quinoline-1-yl)-(4-petrosinelli-1-yl)methanon: a Mixture of 4-petrosinelli-1-carboxylic acid (103 mg, 0.4 mmol) and DHM (2 ml) is treated with thionyl chloride (34,6 μl, 0.48 mmol) and DMF (0.2 ml) and stirred at 40°C for 1 h the Resulting clear solution is treated with DIEA (103 μl, 0.6 mmol), 1,2,3,4-tetrahydroquinoline (80 mg, 0.6 mmol) and DMAP (4,9 mg, 0.04 mmol). After keeping at the temperature of reflux distilled 42°C for 3 h, the reaction mixture was partitioned between 1 m knso3(4 ml) and DHM (2×4 ml). The combined organic phases are washed with water, dried over Na2SO4and concentrate. After rapid chromatography (cyclohexane/acetone) to obtain 78 mg (52%) of product as crystals of greenish C the ETA.

Example 7: Synthesis of esters

The method is applicable for producing compounds of examples: 27, 32, 33, 35, 36, 37, 38, 46

Naphthalene-1-silt ether 4-petrosinelli-1-carboxylic acid:

A solution of 4-petrosinelli-1-carbaldehyde (121 mg, 0.5 mmol) in CCl4(2 ml) is treated with tert-BuOCl (8,82M, 170 μl, 1.5 mmol) and stirred at 50°C for 1 h After adding DIEA (0.3 ml, 1.7 mmol) and 1-naphthol (216 mg, 1.5 mmol) the mixture is refluxed for 2 h and partitioned between 1 m knso3(5 ml) and DHM (2×5 ml). The combined organic phases are dried over Na2SO4and concentrate. After rapid chromatography (cyclohexane/acetone) to obtain 82 mg (43%) of product as colorless crystals.

Example 8: Synthesis Iminov and amines

The method is applicable for producing compounds of examples: 30, 34, 42, 43, 44.

(a) Naphthalene-1-yl-[1-(4-petrosinelli-1-yl)methylidene]amine: a Solution containing 4-petrosinelli-1-carbaldehyde (to 48.5 mg, 0.2 mmol), 1-naphtylamine (28,6 mg, 0.2 mmol) in DHM (1 ml), treated with molecular sieves with a particle size of 4Å (80 mg) and stirred at room temperature for 2 hours the Mixture is filtered through Hyflo, dried over Na2SO4and concentrate. After rapid chromatography (cyclohexane/ethyl acetate) to obtain 60 mg (82%) of product as yellow crystals.

(b) Naphthalene-1-yl-(4-petrosinelli the-1-ylmethyl)amine: a solution containing naphthalene-1-yl-[1-(4-petrosinelli-1-yl)methylidene]amine (24 mg, 0.07 mmol) and NR3pyridine (16,3 μl, 0.13 mmol) in THF (0,65 ml), stirred at room temperature for 16 hours, the Reaction mixture was concentrated and partitioned between water (2 ml) and DHM (2 ml). The organic phase is dried over Na2SO4and concentrate. After rapid chromatography (cyclohexane/acetone) to obtain 14 mg (58%) of product as a colorless oil.

Synthesis of ureas

The method is applicable for producing compounds of examples: 39, 40, 41.

1-Naphthalene-1-yl-3-(4-petrosinelli-1-yl)urea: a Solution containing 4-petrosinelli-1-carboxylic acid (103 mg, 0.4 mmol) and 1,8-bis(dimethylamino)naphthalene (86 mg, 0.4 mmol) in THF (0.8 ml), stirred at room temperature for 30 minutes After adding DFFA (86 μl, 0.4 mmol) and (1 1-naphtylamine (229 mg, 1.6 mmol) the mixture was kept at 100°C for 6 h and partitioned between 2M HCl (8 ml) and DHM (2×8 ml). The combined organic phases are washed with 1M Na2CO3and water, dried over Na2SO4and concentrate. After rapid chromatography (cyclohexane/acetone) to obtain 78 mg (49%) of product in the form of brownish crystals.

Example 10: Synthesis of bisaillion method Friedel-

The method is applicable for producing compounds of examples: 48, 49, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 94, 95, 96, 97, 98, 99, 100, 101, 102 103, 104, 105, 106, 107, 108, 141, 145, 146.

(4-Fornatale-1-yl)-(4-petrosinelli-1-yl)methanon: a Solution of 4-fluoro-1-naphthoic acid (0.5 g, 2,63 mmol) in anhydrous DHM (10 ml) is treated with stirring at room temperature for oxalylamino (0.52 g, 4.1 mmol), and then add a few drops of anhydrous DMF. After the termination of allocation of gas bubbles clear solution is cooled to 4°C in an ice bath and add one serving of aluminium chloride (0.7 g, a 5.25 mmol). After stirring at 4°C for 20 min add 1-petrosinelli (0,563 g, 2,63 mmol) and the reaction mixture is allowed to gradually throughout the night to warm to ambient temperature. The reaction mixture is distributed between ethyl acetate (50 ml) and water (250 ml.), and perform the extraction. The aqueous phase is optionally washed with fresh ethyl acetate (2×50 ml). The combined organic phases are dried (anhydrous MgSO4), filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel using device Biotage (company Dyax Corp.), using as eluent cyclohexane:ethyl acetate (9:1), resulting in getting the desired product (0,996 g, 98%).

Example 11: Synthesis of alkilaminometilen

The method is applicable for producing compounds of examples: 60, 61, 64, 120, 126, 127, 133, 134.

(a) 4-(naphthalene-1-carbonyl)naphthalene-1-silt ether triftormetilfullerenov acid: Three is timetosleep anhydride (3.1 ml, 18,43 mmol) is added slowly to a solution of (4-hydroxynaphthalene-1-yl)naphthalene-1-ylmethanone (5.0 g, 16,76 mmol) in pyridine (15 ml) at 0°C in an atmosphere of inert gas. The reaction mixture was stirred at 0°C for 30 min and then allowed to warm to ambient temperature for 24 hours then the reaction mixture was poured onto water and extracted three times DHM. The combined organic extracts are washed successively with water, dilute aqueous HCl solution, water and saline solution. The organic phase is dried over anhydrous MgSO4and concentrated in vacuo. The residue is purified via Express chromatography (10% simple ether/cyclohexane)to give the desired product (5,56 g, 77%).

(b) Naphthalene-1-yl-(4-butylaminoethyl-1-yl)methanon: a Solution of 4-(naphthalene-1-carbonyl)naphthalene-1-silt ether triftormetilfullerenov acid (308 mg, 0,716 mmol) and n-butylamine (of 62.8 mg, 0,859 mmol) in anhydrous toluene (3 ml) is added to the atmosphere of inert gas to the mixture containing palladium(II) acetate (3.2 mg, 0.014 mmol), BINAP (10 mg, to 0.016 mmol) and tert-piperonyl sodium (96 mg, 1,002 mmol). The mixture was kept at 80°C for 4 h After cooling, the mixture is diluted with ethyl acetate and filtered through a filter of celite. The filtrate is evaporated in vacuum, obtaining a pinkish-brown residue. It is cleaned by rapid chromatography (10% simple ether/cyclohexane), the floor is nd the desired product (85 mg, 34%) and 30 mg of regenerated the original product.

(C) [4-{Butyl(2-morpholine-4-retil)amino}naphthalene-1-yl]-naphthalene-1-ylmethanol: a Solution of naphthalene-1-yl-(4-butylaminoethyl-1-yl)methanone (65 mg, 0.18 mmol) in anhydrous DMF (4 ml) in an atmosphere of inert gas is treated with NaH (60%, 28.8 mg, to 0.72 mmol). After 20 minutes add in the form of one portion of the hydrochloride of N-(2-chloroethyl)of the research (37 mg, 0.2 mmol) and the reaction mixture was stirred at 80°C for 2 hours After cooling to room temperature the reaction mixture was partitioned between water and ethyl acetate. The combined organic phases are dried over anhydrous MgSO4and concentrated in vacuo. After rapid chromatography (cyclohexane/ethyl acetate) to obtain 29 mg (34%) of the desired product and 26 mg of regenerated the original product.

(d) 8-(Naphthalene-1-carbonyl)-5-petrosinelli-2-silt ether triftormetilfullerenov acid: a Solution of (7-hydroxy-4-petrosinelli-1-yl) naphthalene-1-ylmethanone (1.2 g, of 3.13 mmol) in anhydrous pyridine (12 ml) is treated with stirring at room temperature triftormetilfullerenov anhydride (0.88 g, of 3.13 mmol) and the mixture is stirred under nitrogen atmosphere for 48 hours the Solvent is removed under reduced pressure and the residue diluted with sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic extracts washed with water,dried (MgSO 4) and remove the solvent under reduced pressure. The residue is purified using the rapid chromatography on silica gel (cyclohexane:ethyl acetate 9:1)to give the desired product (1.0 g, 67%).

(e) [7-(4-Methylpiperazin-1-yl)-4-petrosinelli-1-yl]naphthalene-1-ylmethanol: a Mixture containing 8-(naphthalene-1-carbonyl)-5-petrosinelli-2-silt ether triftormetilfullerenov acid (40 mg, 0,084 mmol), N-methylpiperazine (20 mg, 0.2 mmol), cesium carbonate (38 mg, 0.12 mmol), palladium(II) acetate (2 mg, 10 mol.%) and BINAP (8 mg, 15 mol.%) in anhydrous dioxane (0.5 ml), with stirring, maintained at 80°C in argon atmosphere for 30 hours the Mixture is cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The combined organic extracts washed with water, dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified using GHUR. All fractions containing the product, alkalinized with sodium bicarbonate and extracted with ethyl acetate. The organic extracts are combined, dried (MgSO4) and evaporated, getting the product in the form of the free base (12 mg, 31%).

Example 12: Synthesis of substituted bisaillion

The method is applicable for producing compounds of examples: 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 62, 63, 65, 66, 67, 68, 69, 70, 71, 74, 76, 77, 78.

(a) 8-(Naphthalene-1-carbonyl)-5-petrosinelli-2-carbonitrile: a Mixture containing 8-(n is Talin-1-carbonyl)-5-petrosinelli-2-silt live trifter methanesulfonic acid (1.0 g, of 2.09 mmol), cyanide zinc (0,294 g, 2.51 mmol) and Pd(PPh3)4(0,121 mg, 0.1 mmol, 5 mol.%) in anhydrous DMF (10 ml), kept under stirring in an argon atmosphere at 90°C for 3 hours the Mixture is cooled to room temperature, diluted with water, extracted three times with ethyl acetate and filtered, nerastvorim product through the filter of celite. The combined organic extracts washed with water, dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane:ethyl acetate 9:1)to give the desired product (0,53 g, 65%).

(b) Diallyl-(4-bromo-3-forfinal)amine: a Mixture containing 4-bromo-3-ftoranila (17,47 g, 91,9 mmol), Allbreed (23,72 g, 251,1 mmol) and potassium carbonate (26.7 g, of 193.5 mmol) in acetone (200 ml)with stirring and refluxed for 24 hours the Solvent is removed under reduced pressure and the residue diluted with water and extracted twice with ethyl acetate. The combined organic extracts washed with water, dried (MgSO4) and evaporated in vacuo. The residue is purified by chromatography on silica gel (cyclohexane)to give the desired product (15,27 g, 62%).

(b) Diallyl-(11-ocatillo[6.2.1.0_2,7]undeca-2,4,6,9-tetraen-4-yl)amine: a Solution of diallyl-(4-bromo-3-forfinal)amine (15,55 g, 57.6 mmol) in anhydrous simple ether (30 ml) and anhydrous furan (30 ml) obrabecim the Ute with stirring a solution of n-utility in hexane (36 ml, 57.6 mmol; 1.6 m solution) at -70°C in argon atmosphere. After 1 h the mixture is allowed to warm to room temperature and stirred for 4 hours the Reaction is stopped by addition of water and extracted three times with ethyl acetate. The combined organic extracts washed with brine, dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (eluent source cyclohexane, final eluent cyclohexane:ethyl acetate 19:1)to give the desired product (5.4 g, 39%).

(g) 7-Diallylmalonate-1-ol: a Solution of diallyl-(11-ocatillo [6.2.1.0_2,7]undeca-2,4,6,9-tetraen-4-yl)amine (4,48 g, 18,74 mmol) in methanol (45 ml) and concentrated hydrochloric acid (4.5 ml) with stirring and refluxed for 5 hours the Solvent is removed under reduced pressure and the residue diluted with water, neutralized with solid sodium bicarbonate and extracted three times with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (eluent source cyclohexane, final eluent cyclohexane:ethyl acetate 19:1)to give the desired product (3,67 g, 82%).

(d) Diallyl-(8-petrosinelli-2-yl)amine: To a solution containing n-pentanol (0.18 g, 2.1 mmol) and triphenylphosphine (0.55 g, 2,1 shall mol) in anhydrous TTF (10 ml), add with stirring a solution of 7-diallylmalonate-1-ol (0.5 g, 2.1 mmol) and DYADS (0.45 ml, 2.1 mmol) in anhydrous THF (10 ml). After stirring overnight the mixture was diluted with brine and extracted three times with ethyl acetate. The combined organic extracts washed with brine, dried (MgSO4) and evaporated to dryness. The residue is purified by chromatography on silica gel (eluent source cyclohexane, final eluent cyclohexane:ethyl acetate 98:2)to give the desired product (0.28 g, 43%).

(e) (6 Diallylamine-4-petrosinelli-1-yl)naphthalene-1-ylmethanone; To the suspension containing anhydrous aluminium chloride (0.24 g, is 1.81 mmol) in anhydrous DHM (30 ml), with stirring, add aftercare (0,205 ml of 1.36 mmol) at 0°C under nitrogen atmosphere. After 15 min added dropwise a solution of diallyl-(8-petrosinelli-2-yl)amine (0.28 g, 0,906 mmol) in anhydrous DHM (5 ml) and the mixture allowed to warm to room temperature and stirred under nitrogen atmosphere overnight. The mixture was washed with saturated sodium bicarbonate solution (pH 8) and the aqueous phase is additionally extracted three times with diethyl ether. The combined organic phases are washed with water, dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (eluent source cyclohexane, final eluent cyclohex the EN:ethyl acetate 98:2), receiving the desired product (0.32 g, 75%).

(W) 5-Petrosinelli-2-ol: a Mixture containing naphthalene-1,6-diol (10.0 g, 62.5 mmol), 1-bromopentane (of 7.75 ml, 62.5 mmol) and sodium hydroxide (2.5 g, 62.5 mmol) in DMSO (100 ml), incubated at 100°C for 6 hours After cooling to room temperature the mixture is diluted with water and three times extracted with ethyl acetate. The combined organic extracts are washed several times with water, dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (initial eluent cyclohexane:ethyl acetate 97:3, final eluent cyclohexane:ethyl acetate 90:10)to give undivided a mixture of desired product and isomer 6-petrosinelli-1-ol (6,18 g, 43%), and first eluted twice alkilirovanny product, 1,6-bis(pentyloxy)naphthalene.

(C) 5-petrosinelli-2-silt ether acetic acid: a Solution containing a mixture of 5-petrosinelli-2-ol/6-petrosinelli-1-ol (6,18 g, 26.8 mmol) in DHM (100 ml)under stirring in the presence of the NEt3(4,4 ml of 31.6 mmol) is treated dropwise at 0°With a solution of acetylchloride (2,24 ml of 31.5 mmol) in DHM (30 ml). After heating to room temperature and stirring for 3 h the reaction mixture was washed with brine, dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified using chromatogra the AI on silica gel (1.5% ethyl acetate in cyclohexane), receiving the desired product (4,56 g, 56%) and isomer 6-petrosinelli-1 silt ether acetic acid (1.0 g, 13%).

(and) 8-(naphthalene-1-carbonyl)-5-petrosinelli-2-silt ether acetic acid: To a suspension of anhydrous aluminium chloride (4.42 g, 33,09 mmol) in anhydrous DHM (290 ml) under stirring at 0°C under nitrogen atmosphere is added dropwise a solution of nafolklore (3,7 ml of 24.8 mmol) in anhydrous DHM (35 ml). After 15 minutes, add a solution of 5-petrosinelli-2-silt ether acetic acid (4.5 g, 16,54 mmol) in anhydrous DHM (70 ml) and the reaction mixture allowed to warm to room temperature and stirred for 20 hours the Mixture was washed with saturated sodium bicarbonate solution, separated phase and remove DHM under reduced pressure. The residue is dissolved in diethyl ether and washed with water, dried (MgSO4) and the solvent is removed under reduced pressure. After purification by chromatography on silica gel (1-3% ethyl acetate in cyclohexane) to obtain the desired product (4.8 g, 68%) and 8-(naphthalene-1-carbonyl)-5-petrosinelli-2-silt ether naphthalene-1-Carbo new acid (2.1 g), which is formed as a result of substitution of acetyl groups naftilan.

(l) (7-Hydroxy-4-petrosinelli-1-yl)naphthalene-1-ylmethanol: a Solution containing 8-(naphthalene-1-carbonyl)-5-petrosinelli-2-silt ether acetic acid (4.8 g, and 11.2 mmol) and 8-(naphthalene-1-CT is of IMT-5-petrosinelli-2-silt ether naphthalene-1-carboxylic acid (2.1 g, 3.9 mmol) in methanol (70 ml)is refluxed under stirring in the presence of 5M NaOH solution (20 ml) for 3 hours After cooling to room temperature the mixture is diluted with water, acidified with acetic acid and extracted three times with ethyl acetate. The combined extracts washed with water, dried (MgSO4) and the solvent is removed under reduced pressure. The residue is recrystallized from ethyl acetate, obtaining the desired product (3.7 g, 64%) as a solid bright yellow color.

Example 13: Synthesis of aryl-heteroaryl ketones

The method is applicable for producing compounds of examples: 45, 92, 93.

(a) Isoquinoline-1-yl-(4-petrosinelli-1-yl)methanon: To a solution of 1-iodine-4-introxication (419 mg, 1.232 metric mmol) in THF (8 ml) at -78°C. (bath acetone/dry ice) is added dropwise n-BuLi (0,99 ml, 2.5m in hexane). After a few minutes, a precipitate of yellow. After stirring for 30 min added dropwise via syringe a solution of isoquinoline-1-carbonitrile (210 mg, 1,364 mmol) in THF (2 ml)to give a red solution. The reaction mixture is removed from the cooling bath and allowed to warm to temperatures above 3, there is Formed a solution of a bright blue color. Then add diluted sulfuric acid (2.5 ml, 10 vol.%) and the mixture is stirred at room temperature for 45 minutes Then the reaction mixtures is ü diluted with ethyl acetate and the solution washed with saturated aqueous sodium bicarbonate to alkaline pH (pH paper), aqueous sodium thiosulfate solution (×2) and with brine; dried over anhydrous Na2SO4and concentrate on a rotary evaporator. The crude product chromatographic on silica gel (gradient elution: cyclohexane/ethyl acetate 9/1, then 5/1, then 2/1), getting mentioned in the title compound as a viscous oil bright yellow (270 mg, 59%).

(b) 4-Pentyloxy-1-naphthaleneboronic acid: To a cooled (bath: dry ice/acetone) solution of 1-iodine-4-introxication (0,993 g of 2.92 mmol) in THF (10 ml) in anhydrous atmosphere of argon is added dropwise via syringe n-BuLi (2.5m in hexane, 2.4 ml, 6.0 mmol). The reaction mixture becomes dark yellow and a precipitate. After incubation for 0.5 h at a temperature of the cooling bath is added dropwise with a syringe to add trimethylboron (0,66 ml, 5.8 mmol). The reaction flask is removed from the cooling bath, and the product is yellow quickly within a few minutes it becomes colorless. After 1.5 h add sulfuric acid (20 vol.%, 3 ml) and the resulting suspension is distributed between ethyl acetate and water. The organic layer was washed with aqueous sodium thiosulfate solution (×2) and brine solution, dried (over anhydrous Na2SO4) and evaporated on a rotary evaporator. The residue is dissolved in a minimum volume DHM and bring in silicagel column, which elwi the comfort cyclohexane/ethyl acetate (1/1), getting Bronevoy acid (267 mg, 35%).

(in) (4-Petrosinelli-1-yl)quinoline-8-ylmethanol: dried three-neck with flame flask equipped with an inlet device for the gas and the membrane, making 8-hydroxybenzenesulfonate (122,8 mg, 0,442 mmol), 4-pentyloxy-1-naphthaleneboronic acid (124,5 mg, 0,482 mmol), anhydrous potassium carbonate (199,7 mg, 1,447 mmol), complex PdCl2dppf·CH2Cl2(10.5 mg, 0,0128 mmol, firm Avocado) and sodium iodide (150 mg). The reaction flask is subjected to vacuum (shallow vacuum and clean the carbon monoxide from the container (3 cycles). Using the syringe, add 3 ml of anisole and after stirring the reaction mixture orange is placed in a pre-heated up to 80°C oil bath. After 3 hours add an additional portion of anisole (1 ml) and the reaction mixture was stirred over night at 80°C. the Reaction mixture, which acquires a black color, allow to warm to room temperature and diluted with ethyl acetate and water. The organic layer is washed with brine (×2), dried over anhydrous Na2SO4and concentrate on a rotary evaporator. The crude product chromatographic on silica gel (cyclohexane/ethyl acetate, 5/1), getting mentioned in the title compound in the form of oil green (52 mg, 32%).

Example 14: Synthesis of benzimidazolone. of benzimidazole and is of benzotriazole

The method is applicable for producing compounds of examples: 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162.

(a) N-(2-Pentyloxy-phenyl)ndimethylacetamide: 2-Acetamidophenol (5 g, 33,09 mmol) dissolved in anhydrous DMF (35 ml) at room temperature. Add cesium carbonate (17,25 g, 52,53 mmol)and then 1-bromopentane (x 6.15 ml, 49,61 mmol) and the mixture was stirred at 60°C for 16 hours, the Reaction mixture was cooled to room temperature, diluted with water (400 ml) and extracted with ethyl acetate (3×100 ml). An ethyl acetate extracts are combined, washed with saturated salt solution, dried (MgSO4), filtered and concentrated under reduced pressure, obtaining a product with a sufficient degree of purity (of 6.02 g, 82%).

(b) N-[5-(Naphthalene-1-carbonyl)-2-pentyloxide]ndimethylacetamide: In a dry flask, purged with anhydrous nitrogen, suspended aluminum chloride (the 5.45 g, 40,86 mmol) in anhydrous 1,2-dichloroethane (50 ml). The suspension is cooled with a bath of ice/water, then added in one portion to a solution of 1-naftorpovid (4,51 ml, 29, 96 mmol) in anhydrous 1,2-dichloroethane (10 ml). After 10 minutes add N-(2-pentyloxide)ndimethylacetamide (of 6.02 g, 27,24 mmol) and the reaction mixture allowed to warm to room temperature over night. The mixture was poured onto a mixture of ice-water and 5M aqueous sodium hydroxide solution (enough for alkalizing water layer), stirred for 15 the ins and extracted with ethyl acetate (4×100 ml). The organic extracts are combined and washed with saturated salt solution (100 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was then purified using chromatography on silica gel, using a device type Biotage (90 g column; the company Dyax Corp.) and cyclohexane:ethyl acetate (2:1) as eluent, obtaining the product as a thick oil (3,68 g, 36%). Get more 5,64 g contains a small amount of impurities of the product, which is of sufficient purity for use in subsequent reactions.

(C) (3-Amino-4-pentyloxide)-naphthalene-1-ylmethanol: N-[5-(naphthalene-1-carbonyl)-2-pentyloxide]ndimethylacetamide (1.78 g, of 4.75 mmol) dissolved in methanol (20 ml) at room temperature. Add hydrochloric acid (10 M, 20 ml) and the mixture was kept at the temperature of reflux distilled for 1 h, the Reaction mixture was evaporated to dryness under reduced pressure, partitioned between saturated aqueous sodium bicarbonate and ethyl acetate and extracted with another portion of ethyl acetate (3×100 ml). An ethyl acetate extracts are combined, washed with saturated salt solution, dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product in the form of a non-viscous oil brown. Its purified on silica gel using device type Biotage (90 g column) and cyclohexane:those who acetate (4:1) as eluent, the resulting pure product (0.97 g, 61%).

(g) 3-[5-(Naphthalene-1-carbonyl)-2-pentyloxide]-1-methoxylation: di-tert-BUTYLCARBAMATE (1,833 g, 8.4 mmol) dissolved in anhydrous DHM (20 ml) at room temperature and add DMAP (0,733 g, 6 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then add a solution of (3-amino-4-pentyloxide)naphthalene-1-ylmethanone (2.0 g, 6 mmol) in anhydrous DHM (10 ml). The mixture is stirred at room temperature for 30 minutes Add DIEA (1,045 ml, 6 mmol) and hydrochloride methoxylamine (0,501 g, 6 mmol) and the reaction mixture was stirred at room temperature for 4 h, the Reaction mixture is treated with water (200 ml) and extracted with DHM (3×75 ml). DHM extracts are combined, washed with saturated salt solution, dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product. This product chromatographic on silica gel, using a device type Biotage (with cartridge 40 g) and cyclohexane:ethyl acetate (4:1) as eluent, resulting in a gain of 1.25 g of the desired product along with 0.66 g of product containing additional tert-butoxycarbonyl group. The product is dissolved in a mixture DHM-triperoxonane acid (1:1, 6 ml) and stirred at room temperature for 2 hours Volatiles removed by eigendom pressure and the residue partitioned between DHM (20 ml) and saturated aqueous sodium bicarbonate (50 ml). This mixture is extracted with another portion DHM (x ml) and DHM extracts are combined, washed with saturated salt solution, dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the desired product (1.88 g, 77%).

(d) 1-Methoxy-7-(naphthalene-1-carbonyl)-4-pentyloxy-1,3-dehydrobenzperidol-2-he: 3-[5-(naphthalene-1-carbonyl)-2-pentyloxide]-1-methoxymetopon (650 mg, 1.6 mmol) dissolved in anhydrous DHM (60 ml) under nitrogen atmosphere, the solution is cooled to 0°C and added in several portions bis(triptoreline)iadanza (757 mg, of 1.76 mmol). The reaction mixture is allowed to warm to room temperature for 1.5 hours, then add water (200 ml). The mixture is extracted with DHM (3×100 ml) and DHM extracts are combined, washed with saturated salt solution (100 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product as brown oil. Product chromatographic on silica gel, using a device type Biotage (with cartridge 40 g) and cyclohexane:ethyl acetate (3:1) as eluent, resulting in getting the desired product (0.34 g, 53%).

(e) 4-(Naphthalene-1-carbonyl)-7-pentyloxy-1,3-dehydrobenzperidol-2-antipsoriatic: 1-Methoxy-7-(naphthalene-1-carbonyl)-4-pentyloxy-1,3-dehydrobenzperidol-2-he (800 mg, to 1.98 mmol) was dissolved in glacial acetic acid (10 ml) and add powdered zinc (5,18g, 79,22 mmol). The mixture was incubated at 50°C and teach ultrasound for 2 h, cooled to room temperature and filtered through a bed of celite. The bed of celite washed with ethyl acetate and then remove the volatile components under reduced pressure, obtaining the product in the form of an orange oil. After purification using the device type Biotage (with cartridge 40 g) and the mixture DHM:methanol (20:1) as eluent get the desired product (0,67 g, 90%).

(W) (2-Chloro-7-pentyloxy-3H-benzimidazole-4-yl)naphthalene-1-ylmethanol: 4-(Naphthalene-1-carbonyl)-7-pentyloxy-1,3-dehydrobenzperidol-2-he (500 mg, of 1.34 mmol) was dissolved in phosphorus oxychloride (10 ml) and refluxed (oil bath temperature 105°C) for 30 minutes, the Reaction mixture was cooled to room temperature, poured into chilled on ice 2M aqueous sodium hydroxide solution to neutralize the mixture and extracted DHM (3×100 ml). United DHM extracts washed with saturated aqueous sodium bicarbonate (3×50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product (500 mg, 95%), which is used directly without further purification.

(C) Triptorelin(2 benzylamino-7-pentyloxy-3H-benzimidazole-4-yl)naphthalene-1-ylmethanone: (2-Chloro-7-pentyloxy-3H-benzimidazole-4-yl)naphthalene-1-ylmethanone (55 mg, 0.14 to m is ol) and benzylamine (1 ml), not containing impurities, stand together at 135°C for 4 h and then cooled to room temperature. The crude reaction mixture was poured onto water (10 ml), add 10%aqueous hydrochloric acid (10 ml) and the mixture extracted with DHM (4×20 ml). DHM extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product, which was purified using preparative chromatography with reversed phase (column type Dynamax 300A 18; gradient from 20% acetonitrile in water (+0.1% of triperoxonane acid) to 100% acetonitrile over 30 min), getting to 15.4 mg of the desired product.

(I) 2,3-Betacetylmethadol ether acetic acid: 2,3-Diaminophenol (3,226 g, 25,99 mmol) dissolved in acetic anhydride (50 ml) and the mixture was incubated at 70°C for 4 h the Mixture is cooled to room temperature and allowed to stand for 48 hours the precipitate is collected by filtration, washed with ethyl acetate and dried in vacuum, obtaining a solid white color (3,99 g, 61%).

(l) N-(2-acetylamino-6-hydroxyphenyl)ndimethylacetamide (CAS registration No. 116345-46-1): 2,3-Bilateralisation ether acetic acid (3,99 g, 15,96 mmol) dissolved in anhydrous methanol (50 ml) under nitrogen atmosphere. Add a solution of sodium methoxide (obtained from metallic sodium (0,404 g, 17,56 the mol) in anhydrous methanol (10 ml)and the mixture was stirred at room temperature for 16 hours The solvent is removed under reduced pressure and to the residue water is added, then acidified to pH 1 with 1M hydrochloric acid. The aqueous layer was concentrated under reduced pressure to precipitate the product, which is marked by filtration and dried in vacuum, obtaining a solid white color (1,96 g, 59%).

(m) N-(2-acetylamino-6-pentyloxide)ndimethylacetamide: N-(2-acetylamino-6-hydroxyphenyl)ndimethylacetamide (1,46 g, 7,02 mmol) dissolved in anhydrous DMF (50 ml) at room temperature. Add cesium carbonate (2,97 g, 9,13 mmol) and 1-bromopentane (1,04 ml, 8,42 mmol) and the mixture was incubated at 60°C for 20 h and then stirred at room temperature for 4 days. Add water (800 ml) and the solution extracted with DHM (4×100 ml). DHM extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining of 1.95 g of the crude product. It is recrystallized from ethyl acetate/cyclohexane, getting a pure product (0.9 g, 46%).

(n) N-(2-Acetylamino-3-iodine-6-pentyloxide)ndimethylacetamide: To a solution of N-(2-acetylamino-6-pentyloxide)ndimethylacetamide (0.9 g, 3,24 mmol) and hydrate periodni acid (129 mg, or 0.57 mmol) in a mixture of acetic acid:water:sulfuric acid (100:20:3; 10 ml) was added iodine (332 mg, 1,31 mmol). The mixture is stirred at room temperature for 16 h, diluted with 10%aqueous concrete is sodium thiosulfate (100 ml) and then extracted with DHM (1×100 ml), the ethyl acetate (1×100 ml) and diethyl ether (1×100 ml). The organic extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product which is recrystallized from ethyl acetate, obtaining the pure product (550 mg, 42%).

(o) 7-Iodine-2-methyl-4-pentyloxy-1H-benzimidazole, N-(2-Acetylamino-3-iodine-6-pentyloxide)ndimethylacetamide (100 mg, 0,248 mmol) are added to a solution of potassium hydroxide (139 mg, 2.48 mmol) in ethanol (5 ml) and water (1 ml). The mixture was kept at the temperature of reflux distilled for 3 h, allowed to stand for 2 days and then incubated at the temperature of reflux distilled for 6 h, then allowed to stand at room temperature for 8 days. Volatile components are removed under reduced pressure and the residue distributed between ethyl acetate (10 ml) and water (10 ml) and extracted with another aliquot of ethyl acetate (3×10 ml). An ethyl acetate extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product. After purification by chromatography on silica gel (Biotage cartridge 40 g) using cyclohexane:ethyl acetate (3:1) as eluent receive specified in the header of the connection (of 35.5 mg, 42%).

(p) (2-Methyl-7-pentyloxy-3H-gasoline idazole-4-yl)naphthalene-1-ylmethanol: 7-Iodine-2-methyl-4-pentyloxy-1H-benzimidazole (35 mg, is 0.102 mmol), anhydrous potassium carbonate (42 mg, 0,306 mmol), 1-naphthaleneboronic acid (19 mg, 0,112 mmol) and PdCl2dppf·CH1Cl2(3 mg, of 0.003 mmol) are mixed in anhydrous anisole (5 ml) and placed in an atmosphere of carbon monoxide. The mixture was kept at 80°C for 20 h, cooled to room temperature and diluted with water (10 ml). The mixture is extracted with DHM (2×10 ml) and ethyl acetate (3×10 ml), the organic extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product. It is cleaned by preparative GHUR with reversed phase (column type Dynamax 300Å 18 of 20% acetonitrile in water (+0.1% of acetic acid) to 100% acetonitrile over 30 min), receiving a 12.7 mg of the desired product.

(R) N-[2-(atomic charges)-6-nitrophenyl]ndimethylacetamide (CAS registration No. 69194-51-0); 2-Amino-3-NITROPHENOL (3 g, 19,46 mmol) dissolved in acetic anhydride (20 ml) and the mixture was incubated at 50°C for 16 hours After cooling to room temperature, add water (400 ml) and the mixture extracted with DHM (3×100 ml). DHM extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining mentioned in the title compound (4,14 g, 89%).

(C) N-(2-hydroxy-6-nitrophenyl)ndimethylacetamide (CAS Reg. No. 59820-29-0): N-[2-(atomic charges)--nitrophenyl]ndimethylacetamide (4,13 g, of 17.35 mmol) dissolved in anhydrous methanol (20 ml) and add fresh solution of sodium methoxide (from sodium (0.6 g, 26,03 mmol) in anhydrous methanol (15 ml)). The reaction mixture was stirred at 50°C for 2 h, cooled to room temperature and the methanol removed under reduced pressure. Add water (100 ml), the pH value was adjusted to pH 1 with 2M aqueous hydrochloric acid and the solution extracted with ethyl acetate (3×100 ml). An ethyl acetate extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and allowed to stand at room temperature for 7 days. The resulting crystals are collected by filtration and dried, obtaining the pure product (1.5 g, 44%). The mother liquor is concentrated under reduced pressure, receiving an additional portion of the crude product (2.3 g), which is of sufficient purity for use in subsequent reactions.

(t) N-(2-Nitro-6-pentyloxide)ndimethylacetamide: N-(2-hydroxy-6-nitrophenyl)ndimethylacetamide (3.8 g, 19,39 mmol) dissolved in anhydrous DMF (25 ml). Add cesium carbonate (8,83 g, 27,1 mmol) and 1-bromopentane (23,26 mmol) and the mixture was stirred at 80°C for 2 hours After cooling to room temperature, add water (400 ml) and the mixture extracted with ethyl acetate (3×100 ml). An ethyl acetate extracts are combined, washed with saturated saline solution (50 m is), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product. The product is recrystallized from ethyl acetate/n-hexane at 4°C receives specified in the header connection (1,74 g, 34%). The mother liquor is concentrated under reduced pressure, receiving an additional portion of the crude product, which was purified using chromatography on silica gel (Biotage cartridge 40 g)using a mixture of DHM:methanol (50:1) as eluent. The result is still 0,79 g (15%) specified in the connection header and 0.31 g (7%) deacetylating product, 2-nitro-6-interoception.

(u) 2-Nitro-6-interoception: N-(2-Nitro-6-pentyloxide)ndimethylacetamide (1,74 g, 6,53 mmol) dissolved in methanol (50 ml) and add 10M hydrochloric acid (25 ml). The mixture was kept at the temperature of reflux distilled for 4 h, cooled to room temperature and removing the methanol under reduced pressure. The pH value of the residue was adjusted to pH 12 with 5M aqueous sodium hydroxide and extracted with ethyl acetate (3×100 ml). An ethyl acetate extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the pure product (1,46 g, 100%).

(f) 3-Pentraxins-1,2-diamine: 2-Nitro-6-interoception (1,46 g of 6.52 mmol) was dissolved in ethyl acetate (20 ml) and the flask prodovatsja. Add 10%palladium on charcoal (50 mg) and the reaction mixture is vacuum and rinsed three times with hydrogen. The mixture is stirred for 24 h in hydrogen atmosphere using a balloon with gaseous hydrogen. Add methanol (20 ml) to facilitate solubilization and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture is blown with nitrogen, filtered through a bed of celite and concentrated under reduced pressure, obtaining a solid white color, which can be achieved by recrystallization from ethyl acetate/methanol to obtain specified in the header connection (1,007 g, 80%).

(x) 7-Pentyloxy-1H-benzimidazole: 3-Pentraxins-1,2-diamine (200 mg, of 1.03 mmol) and triethylorthoformate (2 ml) are mixed in a test tube made of glass type Pyrex and subjected to microwave irradiation power of 100 W for 30 s in a laboratory microwave installation type Labwell MW10. After removal of volatile components under reduced pressure to obtain the pure product as a cream solid color (217 mg, 100%).

(C) 4-Iodine-7-pentyloxy-1H-benzimidazole: 7-Pentyloxy-1H-benzimidazole (100 mg, 0.49 mmol) dissolved in a mixture of acetic acid:water: sulfuric acid (100:20:3; 5 ml) and add hydrate periodni acid (22 mg, 0,098 mmol)and then iodine (50 mg, 0,196 mmol). The reaction mixture was stirred at room the Oh temperature for 4 h and at 80°C for 16 hours After cooling to room temperature, add 10%aqueous sodium thiosulfate solution (100 ml) and the mixture extracted with ethyl acetate (3×25 ml). An ethyl acetate extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product. The product was then purified using chromatography on silica gel (Biotage cartridge 40 g), getting mentioned in the title compound (65 mg, 40%).

(h) Naphthalene-1-yl-(7-pentyloxy-3H-benzimidazole-4-yl)methanon: 4-Iodine-7-pentyloxy-1H-benzimidazole (65 mg, 0,197 mmol), anhydrous potassium carbonate (82 mg, 0,591 mmol), 1-naphthaleneboronic acid (37 mg, 0,217 mmol) and PdCl2dppf·CH2Cl2(9 mg, to 0.011 mmol) are mixed in anhydrous anisole (5 ml) and placed in an atmosphere of carbon monoxide. The mixture was kept at 80°C for 18 h, cooled to room temperature and diluted with water (10 ml). The mixture is extracted with DHM (2×10 ml) and ethyl acetate (3×10 ml) and the organic extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product. The product was then purified using chromatography on silica gel (Biotage cartridge 40 g), using as eluent a mixture of cyclohexane:ethyl acetate (3:1), resulting in a gain specified in the title compound (1 mg, 21%).

(W) 7-Pentyloxy-1H-benzotriazol: 3-Pentraxins-1,2-diamine (100 mg, 0,516 mmol) was dissolved in glacial acetic acid (5 ml) and water (5 ml). The reaction mixture was cooled to 0°C. and added in one portion to a cold solution of sodium nitrite (39 mg, 0,568 mmol) in water (5 ml). The reaction mixture throughout the night give to slowly warm to room temperature, diluted with water (20 ml) and extracted with DHM (3×50 ml). DHM extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining mentioned in the title compound (90 mg, 85%), which can be used without additional purification.

(y) 4-Iodine-7-pentyloxy-1H-benzotriazol: 7-Pentyloxy-1H-benzotriazol (90 mg, 0,439 mmol) dissolved in a mixture of acetic acid:water:sulfuric acid (100:20:3; 10 ml) and add hydrate periodni acid (20 mg, 0,088 mmol)and then iodine (45 mg, 0,176 mmol). The reaction mixture was stirred at 80°C for 5 hours After cooling to room temperature, add 10%aqueous sodium thiosulfate solution (10 ml) and the mixture extracted with ethyl acetate (3×25 ml). An ethyl acetate extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product. The product was then purified using chromatography on silica gel (Biotae, the cartridge 40 g), getting mentioned in the title compound (67 mg, 46%)and 124 mg mainly iodirovannoi product (4,6-dead-7-pentyloxy - 1H-benzotriazol), which is mixed to the specified header connection.

(e) Naphthalene-1-yl-(7-pentyloxy-3H-benzotriazol-4-yl)methanon: 4-Iodine-7-pentyloxy-1H-benzotriazol (67 mg, 0,202 mmol), anhydrous potassium carbonate (84 mg, 0,607 mmol), 1-naphthaleneboronic acid (38 mg, 0,223 mmol) and PdCl2dppf·CH2Cl2(17 mg, 0.02 mmol) are mixed in anhydrous anisole (5 ml) and placed in an atmosphere of carbon monoxide. The mixture was kept at 80°C for 20 h, cooled to room temperature and diluted with water (20 ml). The mixture is extracted with DHM (2×10 ml) and ethyl acetate (3×10 ml), the organic extracts are combined, washed with saturated saline solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure, obtaining the crude product. The product was then purified on silica gel (Biotage cartridge 40 g), using as eluent a mixture of cyclohexane:ethyl acetate (4:1), resulting in a gain specified in the title compound (44 mg, 61%).

Characteristics of connections

Found that compounds of the above tables have listed below the melting temperature, retention times (min) when analyzed using GHWR and/or ion weight:

td align="center"> Example
tpl.[°C]Ion mass (ion)ExampleThold.* [min]Ion mass (ion)
2118-119372 M+456,9,398 [M+H]+
388-91388 M+473,4,451,2 [M+Na]+
4143-144404 M+488,4, And371,4 [M+H]+
5418 [M+H]+4910,7,525,3 [M+H]+
6404 M+5011,1,464,4 [M+H+
793-95369 [M+H]+51 7,4, And424,3 [M+H]+
8118-120385 [M+H]+528,4, And539,2 [M+H]+
9158-160396 [M+H]+539,4,427,2 [M+H]+
10207-210412 [M+H]+549,3,385,1 [M+H]+
1178-80410 [M+H]+557.2 And457,2 [M+H]+
12378 [M-H]-569,1,443,2 [M+H]+
13454 [M-H]-575,6, And384,1 [M+H]+
14384 M+58 7.2 And499,3 [M+H]+
15400 M+598,8, And481,3 [M+H]+
16442 [M+Na]+605,1, And467,3 [M+H]+
1758-63382 [M-H]-615,1, And453,3 [M+H]+
1870-71399 [M+H]+626,1, And384,1 [M+H]+
19107-108437 [M+Na]+636,7, And412,2 [M+H]+
20407 M+647,1 And412,2 [M+H]+
21405 M+65 7,4, And394,1 [M+H]+
22439 M+666,6, And437,3 [M+H]+
23494 [M+H]+677,4, And399 [M+H]+
24355 M+686,8, And451,3 [M+H]+
25127-130418 [M-H]-697,4, And451,3 [M+H]+
26369 M+707,6, And412,3 [M+H]+
2795-100383 [M-H]-718,4, And413,3 [M+H]+
28335 M+72 10,0,427,3 [M+H]+
29370 M+738,7,413,1 [M+H]+
30367 M+748,9, And451,3 [M+H]+
31106-111366 M+758,0470,4 [M+H]+
32388 M+7610,3. 445 [M+H]+
33374 M+776,9, And;
9,4,
403 [M+H]+
34369 M+787,6, And450 [M-H]-
35426 M+79 389 M+
3692-94385 M+80373 M+
37126-130385 M+8110,8, And369,2 [M+H]+
38136-138385 M+828,1, And414,3 [M+H]+
39398 M+839,1, A384,3 [M+H]+
40799 [2M+Na]+847,5, A412 [M+H]+
41419 [M+H]+857,7, A399,3 [M+H]+
42405 M+867,, Alevel of 414.2 [M+H]+
43377 M+878,4,384,2 [M+H]+
44361 M+888,0370,3 [M+H]+
45398 [M+H]+898,7,370,4 [M+H]+
4655-60389 M+909,8,370,3 [M+H]+
47451,2 [M+Na]+917,1 And412,2 [M+H]+
92a 6.5 And370,0 [M+H]+

ExampleThold.* [min] Ion mass (ion)ExampleThold.* [min] [min]Ion mass (ion)
939,1,370,2 [M+H]+1287,4,357 [M+H]+
947,8, And386 M+1297,8,385,4 [M+H]+
957,5, And393 M+1307,4,371,4 [M+H]+
966,7, And;
9,2,
436 [M+H]+1318,4, And383 [M+H]+
979,0,437 [M+H]+1328,7, And397 [M+H]+
987,1 And455 [M+H]+1339.8,368,4 [M+H]+
9911,9,455 [M+H]+1348,0, A382,3 [M+H]+
1007,2,498 [M+H]+135371,2 [M+H]+
1016,7, And462,2 [M+H]+1368,4,371,3 [M+H]+
1026,7, And462,3 [M+H]+1376,7, And395,2 [M+H]+
1037,3, And;
10,1,
435 [M+H]+1387,0, A409,1 [M+H]+
1046,9,435 [M+H]+1397,5, And423,1 [M+H]+
1056,8, And413 [M+H]+1408,, A;
10,8,
383,2 [M+H]+
1066,3 And412 [M+H]+1417.2 And;
7,8,
382,3 [M+H]+
1076,9, And;
3,4,
385 [M+H]+1427,3, And;
10,0,
367,2 [M+H]+
1087,5, And;
6,8,
427 [M+H]+1437,3, And;
10,0,
367,2 [M+H]+
1095.5 And411 M+1449,5,305,2 [M+H]+
1109,6, And354 M+1459,2,to 351.3 [M+H]+
1119,1,341 [M+H]+1468,7, And365,4 [M+H]+
1125,9, 410,3 [M+H]+1479,1,305,2 [M+H]+
1139,5,432 M+1484.5, With a362,3 [M+H]+
1149,4,403,2 [M+H]+1495,9,307 [M+H]+
1159,5,USD 448,2 [M+H]+1505,3, And;
5,9,
373,2 [M+H]+
1167,1,446 [M+H]+1515,8, And;
5,8,
359,3 [M+H]+
1176,7,418 [M+H]+1526,1, And;
8,0
360,3 [M+H]+
1185,7,426 [M+H]+1537,6, And;
8,0
407,2 [M+H]+
1199,6,1546,8, And;
7,3,
375,2 [M+H]+
1209,3,354,3 [M+H]+1556,3, And;
7,1,
482,3
[M+h+H2O]+
1219,5,427,2 [M+H]+1567,9, And;
8,7,
470,6 [M+H]+
1229,2,413,1 [M+H]+1573,2, A;
3,6,
547,3
[M+h+H2O+MeCN]+
1237.2,418 [M+H]+1587,9, And;
8,8,
489,3
[M+h+H2O+MeCN]+
12410,6, And446 [M+H]+1594,8, And;
5,3,
457,4 [M+H]+
1256,1, And 424,2 [M+HJ+1605.4, And;
5,9,
436,3
[M+h+H2O]+
126a 6.5 And467 [M+H]+1615,2, And;
5,8,
of 480.2
[M+H+H2O]+
1279,7. In368 [M+H]+1627,6, And;
7,6,
405,3 [M+H]+
1634,6, And;
5,9
of 451.5 [M+H]+
* GHUR AS: column type Kingsorb 3 μm C18, 30×4.6 mm, gradient elution from 10% to 100% acetonitrile in water (+0.1% of triperoxonane acid) for 10 minutes
Conditions GHUR IN: column type Kingsorb of 3.5 μm C18, 50×4.6 mm, gradient elution from 10 to 100% acetonitrile in water (+0.1% of triperoxonane acid) for 10 minutes
Conditions GHUR WITH: column type Kingsorb 3 μm C18, 30×4.6 mm, gradient elution from 10 to 100% acetonitrile in water (+0.1% of triperoxonane acid) for 12 minutes

1. The compound of the formula I

where X oboznachaet is-S-, -S(=O)-, -S(=O)2-, -S(=O)2N(H)-, -P(=O)(och3)-, -P(=O)(OH)-, -N(H)-, -N(CH3)-, -N(H)C(=O)N(H)-, -C(=O)-, -C(=O)O-, -N(H)C(=O)-, -C(H)(OH)-, -C(H)=N-, -C(H)=C(H)-, -CH2N(H)- or-C(=NH)-;
R1denotes phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl, chinoline, 1,2,3,4-tetrahydroquinoline, ethenolysis, benzimidazolyl, 2-oxo-1,3-dehydrobenzperidol, benzoxadiazole, benzothiadiazole, benzotriazole or indanyl, where mentioned phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl, chinoline, 1,2,3,4-tetrahydroquinoline, ethenolysis, benzimidazolyl, 2-oxo-1,3-dehydrobenzperidol, benzoxadiazole, benzothiadiazole, benzotriazole or indanyl are unsubstituted or may be substituted by one or more substituents selected from the group comprising hydroxy; carboxy; aminocarbonyl; nitro; halogen; cyano; -C(NH2)=N-OH; tetrazolyl; 1,2,4-triazolyl; pyrazolyl; imidazolyl; piperazinil, substituted C1-C4the alkyl, C1-C4alkyl; C1-C4alkylthio; C1-C8alkoxy, which is unsubstituted or may be substituted by hydroxy or morpholinium; and-N(R11R12where R11and R12independently from each other selected from the group comprising hydrogen; C1-C4alkyl, which is unsubstituted or may be substituted by hydroxy, phenyl, C3-C6cycloalkyl, -N-(C1-C by alkyl)2or hydraxis1-C4alkoxy; -C(=O)N(H)OS1-C4alkyl; C1-C4alkylaryl and-S(=O)2-C1-C4alkyl;
R2denotes hydrogen; OR4or-N(R5R6;
where R4stands With2-C8alkenyl or1-C8alkyl, which is unsubstituted or may be substituted by hydroxy, C1-C4alkoxy, -C(=O)O-C1-C4the alkyl, morpholinyl, piperidinyl, phenyl or oxadiazolyl, where phenyl or oxadiazolyl in turn are unsubstituted or may be substituted With1-C4the alkyl, C1-C4alkoxy, nitro, amino or-N(C1-C4by alkyl)2;
R5and R6independently from each other selected from the group comprising hydrogen; C1-C8alkyl, which is unsubstituted or may be substituted by morpholinyl; and-C(=O)C1-C8alkyl;
R3denotes hydrogen; cyano; oxadiazolyl, piperazinil or tetrazolyl where these oxadiazolyl, piperazinil or tetrazolyl are unsubstituted or may be substituted by stands; -C(=O)R7, -OR8or-N(R9R10;
where R7represents hydroxy; C1-C4alkoxy; amino or-N(H)-CH2-C(=O)OH;
R8denotes hydrogen; C1-C8alkyl, which is unsubstituted or which may be substituted by carboxy, methoxycarbonyl, -C(=O)N(H)-N(H)-C(=O)-CH3; or denotes a C1-C4alkyl, substituted oxadiazolyl; -C(=O)-C1-C4alkyl or-C(=O)-naphthyl; and R9and R10independently from each other selected from the group comprising hydrogen, C1-C8alkyl or C2-C4alkenyl;
provided that (a) if X represents-C(=O)- and R2and R3denote hydrogen or R2denotes N and R3denotes 4-methoxy, R1means neither 1-naphthyl or 4-methoxy-1-naphthyl; (b) if X represents-C(=O)- or-C(H)(OH)-, R1not denotes phenyl; (b) if X represents-C(=O)- or-C(=NH) and R2or R3represent-N(R5R6, R1signifies neither dimethylaminophenyl or diethylaminophenyl; (g) if X denotes-C(H)=C(H)- or-C(H)=N-, R2does not denote hydrogen; (d) if X denotes-CH2N(H)-, R1doesn't mean 2,4-diamino-5-methylpyridin[2,3-d]pyrimidinyl; (e) if X represents-N(H)C(=O)-, R2doesn't mean the amino group; (g) if X represents-S-, -S(=O)2-, -S(=O)2N(H)-, -N(CH3)-, -P(=O)(och3)- or-C(=O)O-, R1not denotes phenyl; (C) if X represents-N(H)-, R1means neither phenyl nor 4,6-dimethylpyrimidin; (I-1) if X represents-N(H)-C(=O)-N(H)-, R2denotes methoxy, and R3denotes hydrogen, R1doesn't mean 4-methoxymethyl-1-yl; (2) what if X represents-N(H)-C(=O)-N(H)-, R2indicates ethoxy and R3denotes hydrogen, R1doesn't mean 4-ethoxyethyl-1-yl; (K) if X denotes-C(H)=N-, R2means neither methoxy or dimethylamino; (l) if X represents-P(=O)(OH) -, and R2and R3denote hydrogen, R1not denotes phenyl; and (m) if X denotes-CH2-N(H)-, and R2and R3denote hydrogen, or R2denotes methoxy, and R3denotes hydrogen, or R2denotes hydrogen, and R3denotes 2-methoxy, R1doesn't mean 2,4-diaminopurine[2,3-d]pyrimidine-6-yl;
in the form of free base or pharmaceutically acceptable acid additive salt.

2. The compound of formula I according to claim 1, where X denotes-C(=O)-, R1denotes naphthyl, R2denotes-O-(CH2)4CH3and R3denotes hydrogen.

3. The compound of formula I according to claim 2, where X denotes-C(=O)-, R1represents 1-naphthyl, R2denotes-O-(CH2)4CH3and R3denotes hydrogen.

4. The method of obtaining the compounds of formula I according to claim 1, including the interaction of the compounds of formula II

where R1matter specified in claim 1 for formula I, and R13represents-OH, -SH, -I, -Cl, 1,8-bis(dimethylamino)naphthyl-, -COOH, -NH2, -N, -carbonitril, -O-trifloromethyl, -C(=O)Cl, with a compound of formula III

where R2and R3have the meanings indicated in claim 1 for formula I, Y represents-O-, -S(=O)2O-, -P(=O)(och3)is a simple bond, -C(=O)-O-, -S(=O)- or-O-(OH)2and R14denotes hydrogen, -I, or-Cl,
obtaining the compounds of formula Ia

where R1, R2and R3have the meanings indicated in claim 1 for formula I, and X' represents-C(=O)-, -S-, -P(=O)(och3)-, -N(H)-, -S(=O)2- (when binding through the N atom in R1), -S(=O)2-N(H)-, -C(=O)-O-, -C(H)=N-, -C(H)(OH)-, -N(H)-C(=O)-N(H)- or-C(=NH)-, which, if necessary, converted into the compound of formula IB

where R1, R2and R3have the meanings indicated in claim 1 for formula I, and X is-S(=O)-, -S(=O)2-(when linking via an atom in R1), -N(CH3)-, -P(=O)(OH)-, -CH2-N(H)-, -C(H)=C(H)-
with the subsequent allocation of the thus obtained compounds of formula Ia or formula IB in free form or in the form of a pharmaceutically acceptable acid additive salt.

5. Pharmaceutical composition having activity against the binding of cannabinoid (CB) receptor, containing as active ingredient a compound of the formula I according to claim 1 in free base form or in the form of a pharmaceutically acceptable acid salt additive and at least one pharmaceutically acceptable carrier or once avicel.



 

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FIELD: organic chemistry, medicine, biochemistry.

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EFFECT: valuable medicinal and biochemical properties of compounds.

34 cl, 19 ex

FIELD: chemistry of organophosphorus compounds, chemical technology.

SUBSTANCE: invention describes a method for synthesis of monohydroperfluoroalkanes, bis-(perfluoroalkyl)phosphinates and perfluoroalkylphosphonates. Method involves treatment of at least one perfluoroalkylphosphorane with at least one base wherein base(s) are chosen from group consisting of alkali-earth metal hydroxides, metalloorganic compound in useful solvent or at least one organic base and an acid in useful reaction medium. Also, invention describes novel perfluoroalkylphosphonates and bis-(perfluoroalkyl)phosphinates, using novel perfluoroalkylphosphonates and bis-(perfluoroalyl)phosphinates as ionic liquids, catalysts of phase transfer or surfactants.

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18 cl, 19 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: disclosed are bis(oxymethyl)phosphinic acid salt of formula I and method for production thereof.

EFFECT: antituberculosis agent of decreased toxicity without losses of therapeutic activity.

3 cl, 3 dwg, 9 tbl, 1 ex

FIELD: organic chemistry, chemical technology.

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EFFECT: improved preparing method.

8 cl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

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12 cl, 15 ex

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14 cl, 1 tbl, 21 ex

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FIELD: organic chemistry, medicine, pharmacy.

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22 cl, 23 sch, 4 tbl, 501 ex

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FIELD: medicine.

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12 cl, 3 ex, 1 tbl

FIELD: chemistry.

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12 cl, 11 ex

FIELD: chemistry.

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124 cl, 52 ex, 17 tbl, 2 dwg

FIELD: organic chemistry, chemical technology, pharmacy.

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

7 cl, 3 tbl, 33 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes novel substituted benzoylcyclohexenones of the general formula (I): wherein values Q, Y, Z, R1-R5 and their possible tautomeric forms and their possible salts given in the invention claim. Invention proposes substituted benzoylcyclohexenones of the general formula (I) that possess the herbicide activity.

EFFECT: valuable property of compounds.

2 cl, 10 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes derivatives of tetrazole of the general formula (I): wherein R1 means independently halogen atom, methyl, methoxyl, (C1-C3)-alkylsulfonyl, nitro- or cyano-group; R2 means (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C4)-halogenalkyl or (C2-C6)-alkenyl; m = 0, 1 or 2; n = 1 or 2; Q means one of the following groups: (Q-1) (Q-2) (Q-3) or (Q-6) wherein R9 means hydrogen, halogen atom or (C1-C4)-alkyl; k = 1; R11 means halogen atom. Also, invention relates to a fungicide composition based on their base and an intermediate compound of the formula: wherein R1, R2, m and n are given in claim 1; W means hydroxyl, (C1-C4)-alkoxyl or group of the formula:

EFFECT: valuable properties of compounds and composition.

7 cl, 6 tbl, 6 ex

FIELD: organic chemistry, chemical technology, pharmacy.

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EFFECT: improved preparing method.

10 cl, 2 tbl, 5 ex

FIELD: inorganic synthesis and explosives.

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EFFECT: increased preparation safety due to less sensitive starting material and reduced sensitivity of product to friction.

3 cl, 2 tbl, 10 ex

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