2-aminobenzothiazols as invers agonist of cb1 receptors

FIELD: chemistry.

SUBSTANCE: this invention refers to new compounds of formula (Ia) and to their pharmaceutically acceptable salts. Compounds of this invention are characterised by CB1 receptor antagonist properties. In formula (Ia) , R1 means phenyl independently mono-, di- or tri-substituted with haloid, (lower)alkoxy, (lower)alkyl, halogenated (lower)alkoxy or di(lower)alkylamino; R2 means phenyl, independently mono-, di- or tri-substituted with haloid, halogenated (lower)alkyl, nitro or cyano; R3 means hydrogen, nitro, amino, -NHSO2-R3a or -NHCO-R3b; R3a means (lower)alkyl, di(lower)alkylamino, benzyl, phenyl or phenyl monosubstituted with (lower)alkyl; R3b means benzyl or phenyl monosubstituted with (lower)alkyl.

EFFECT: application of compounds thereof as therapeutically active substance with CB1 receptor agonist properties and to relevant pharmaceutical composition.

18 cl, 1 dwg, 5 tbl, 70 ex

 

The present invention relates to benzothiazole derivatives for use as therapeutically active substances and pharmaceutical compositions containing them. Derivatives of benzothiazole according to the present invention are useful in the treatment of obesity and other disorders.

In particular, the present invention relates to compounds of formula (I)

where R1means phenyl or phenyl mono-, di - or tizamidine independently by halogen, (ness.)alkoxy, (ness.)the alkyl, halogenated (ness.)alkoxy or di(ness.)alkylamino;

R2means phenyl or phenyl mono-, di - or tizamidine independently halogen, halogenated (ness.)by alkyl, nitro or cyano;

R3means hydrogen, (ness.)alkyl, benzyl, (ness.)alkoxy, halogen, cyano, nitro, amino, -NHSO2-R3aor-NHCO-R3b;

R3Ameans (ness.)alkyl, di(ness.)alkylamino, benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)by alkyl;

R3bmeans benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)by alkyl;

or their pharmaceutically acceptable salts for use as therapeutically active substances.

Two different subtypes of cannabinoid receptors (CB1and CB2), and both belong to the superfamily of receptors, opragen the x with a G-protein.

Alternative splicing form CB1, CB1Aalso described, but it has no non-CB1properties of ligand binding and activation of the receptor (D.Shire, .Carrillon, M.Kaghad, .Calandra, .Rinaldi-Carmona, G.LeFur, Caput, P. Ferrara, J. Biol. Chem., 270 (8) (1995) s-3731). Receptor CB1found primarily in the brain, whereas the receptor SV2mainly distributed on the periphery and is mainly localized in the spleen and cells of the immune system (S.Munro, K.L.Thomas, M.Abu-Shaar, Nature, 365 (1993) pp.61-65).

Therefore, in order to avoid side effects, it is desirable to have selective to CB1connection.

Δ9-Tetrahydrocannabinol (Δ9-THC) is the main psychoactive compound in Indian hemp (Y.Gaoni, R.Mechoulam, J. Am. Chem. Soc., 86 (1964) s), Canabis savita (marijuana), which have long been used in medicine (R.Mechoulam (as amended) in "Cannabinoids as therapeutic Agents", 1986, SS-20, CRC Press). Δ9-THC is a non-selective agonist of receptors SV1/2and available in the US as dronabinol (Marinol®) for edema vomiting induced by anticancer chemotherapy (CIE), and through stimulating the appetite for reversibility experienced by patients with acquired immunodeficiency syndrome (AIDS) loss of body weight. In the UK for CIE is applied nablidon (LY-109514, cesamet®), a synthetic analogue Δ 9-TNS (R.G.Pertwee, Pharmaceut. Sci., 3 (11) (1997) c.c.539-545, E.M.Williamson, F.J.Evans, Drugs, 60 (6) (2000) c.c.1303-1314).

Anandamide (arachidonoylethanolamide) was identified as the endogenous ligand (agonist) to the receptor CB1(R.G.Pertwee, Curr. Med. Chem., 6 (8) (1999) c.c.635-664; W.A.Devane, L.Hanus, A.Breuer, R.G.Pertwee, L.A.Stevenson, G.Griffin, D.Gibson, .Mielbaum, A.Etinger, R.Mechoulam, Science, 258 (1992) c.c.1946-1949). Anandamide and 2-arachidonoylglycerol (2-AG) negatively modulate into the presynaptic nerve ending adenylate cyclase and sensitive to the voltage of CA2+channels, and activate inwardly To straighten+channel (V.Di Marzo, D.Meick, T.Bisogno, L.De Petrocellis, Trends in Neuroscience, 21 (12) (1998) c.c.521-528), thereby affecting the release of neurotransmitter and/or action, which reduces the release of neurotransmitter (..Porter, C.C.Felder, Pharmacol. Ther., 90 (1) (2001) c.c.45-60).

Anandamide, as Δ9-THC, also increases the power by a mechanism mediated by the receptor CB1. Selective antagonists of the receptor CB1block increased food intake associated with the introduction of anandamide (..Williams, ..Kirkham, Psychopharmacology, 143 (3) (1999) c.c.315-317; C.C.Felder, E.M.Briley, J.Axelrod, J.T.Simpson, K.Mackie, W.A.Devane, Proc. Natl. Acad. Sci. USA, 90 (16) (1993) c.c.7656-7660) and cause appetite suppression and weight loss (G.Colombo, R.Agabio, G.Diaz, .Lobina, R.Reali, G.L.Gessa, Life Sci., 63 (8) (1998) c.c.L113-PL117).

Leptin is the primary signal by which the hypothalamus senses the state of food and m is delerue food intake and energy balance. After the time limit feed the mouse with broken receptor CB1eat less than their wild-type counterparts from the same litter, and SR141716A, receptor antagonist CB1reduces feed intake in wild-type mice but not in mice with embossed receptor. In addition, defective signaling of leptin is associated with reduced hypothalamic, but not cerebellar levels endocannabinoids in mice with obesity, obtained by crossing refractory to insulin individuals (db/db) and by crossing individuals with obesity (ob/ob), and rats Zucker. Intensive treatment with leptin in normal rats and mice ob/ob reduces the levels of anandamide and 2-arachidonoylglycerol in the hypothalamus. These findings indicate that endocannabinoids in the hypothalamus can toniceski to activate the receptor CB1to support the consumption of food and form part of the neural circuit, adjustable leptin (V.Di Marzo, S..Goparaju, L.Wang, J.Liu, S.Bitkai, Z.Jarai, F.Fezza, G.I.Miura, R.D.Palmiter, T.Sugiura, G.Kunos, Nature, 410 (6830) c.c.822-825).

The drug SR141716A, a selective antagonist/inverse agonist of the receptor CB1, is currently undergoing phase III clinical trials for the treatment of obesity. In a double-blind controlled placebo study at daily doses of 5, 10 and 20 mg drug SR141716A significantly reduces body weight when compared with placebo (F.Barth, .Rinaldi-Carmona, Merope, .Heshmati, G.Le Fur, "cannabinoid chemistry antagonists: rom research tools to potential new drugs. Abstracts of Papers, 222nd ACS National Meeting, Chicago, IL, United States, August 26-30, 2001).

Other compounds that have been proposed as antagonists respectively inverse agonists of the receptor CB1are aminoalkylindole (AAI; .Pacheco, S.R.Childers, R.Arnold, F.Casiano, S.J.Ward, J.Pharmacol. Exp. Ther., 257 (1) (1991) c.c.170-183), as 6-ponravelis (WIN54661; F..Casiano, R.Arnold, D.Haycock, J.Kuster, S.J.Ward, NIDA Res. Monogr., 105 (1991) c.c.295-296) or 6-improvathon (AM, .Hosohata, R..Quock, R.M.Hosohata, Tnwiki, A.Makriyannis, P.Consroe, W.R.Roeske, Way, Life ScL, 61 (1997) c.c.115-118; R.Pertwee, G.Griffin, S.Fernio, X.Li, A.Hill, A.Makriyannis, Life Sci., 56 (23-24) (1995) c.c.1949-1955). It is known that ailment[b]thiophene and benzo[b]furan (LY320135, ..Felder, ..Joyce, ..Briley, .Glass, Cremaschi, .J.Fahey. G.J.Cullinan, D..Hunden, D.W.Johnson, M.O.Chaney, G.A.Koppel, M.Brownstein, J.Pharmacol. Exp. Ther., 284 (1) (1998) c.c.291-297), which are disclosed in the application WO 9602248 or patent US 5596106, 3-alkyl-(5,5-diphenyl)imidazolidinedione (M.Kanyonyo, S.J.Govaerts, E.Hermans, J.H.Poupaert, D.M.Lambert, Bioorg. Med. Chem. Lett., 9 (15) (1999) c.c.2233-2236), and 3-alkyl-5-aryleneethynylene (F.Ooms, J.Wouters, O.Oscaro. .Happaerts, G.Bouchard, P.A.Carrupt, B.Testa, D.M.Lambert, J. Med. Chem., 45 (9) (2002) c.c.1748-1756), which are antagonists of the receptor CB1accordingly act as inverse agonists of the receptor hCB1. Substituted derivatives of 1-bis(aryl)methylaziridine as antagonists CB1open application WO 0015609 (FR 2783246-A1), WO 0164634 (FR 2805817-A1), WO 0228346, WO 0164632 (FR 2805818-A1), WO 0164633 (FR 2805810-A1). In the application WO 0170700 derivatives of 4,5-dihydro-1H-pyrazole described as Anta is honesty CB 1. A few patents derivative of 1,5-diphenyl-3-pyrazolecarboxylate, with the bridge and without, are disclosed as antagonists/inverse agonists of the receptor CB1(WO 0132663, WO 0046209, WO 9719063, EP-658546, EP 656354, US 5624941, EP 576357, US 3940418).

The purpose of this invention is to provide selective, directly acting antagonists of the receptor CB1respectively inverse agonists. Such antagonists/inverse agonists useful in drug therapy, especially in the treatment and/or prevention of diseases associated with modulation of receptor CB1.

Unless otherwise specified, formulated the following definitions to illustrate and establish the value and limits of different terms used to describe the context of the invention.

In this description, the term "lower" is used to represent the group consisting of 1-8, preferably 1-6, and preferably 1-4 carbon atoms.

The term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably by chlorine and fluorine.

The term "alkyl", alone or in combination with other groups, refers to a branched or linear monovalent saturated aliphatic hydrocarbon radical of 1-20 carbon atoms, preferably from 1 to 16 carbon atoms, more preferably from 1-10 carbon atoms.

The term "(ness.)Alki the", alone or in combination with other groups, refers to a branched or linear monovalent alkyl, the radical of 1-8 carbon atoms, preferably from 1-4 carbon atoms. In addition, this term is confirmed by the examples of radicals such as methyl, ethyl, N-propyl, isopropyl, N-butyl, sec-butyl, isobutyl, tert-butyl, N-pentyl, 3-methylbutyl, N-hexyl, 2-ethylbutyl and the like.

The term "alkoxy" refers to the group R'-O-in which R' is alkyl. The term "(ness.)alkoxy" refers to the group R'-O-in which R' means (ness.)alkyl. Examples (ness.)alkoxygroup are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, hexyloxy, and a methoxy group is particularly preferred.

The term "di(ness.)alkylamino" refers to the group-N(R')R", where R' and R" denote each independently (ness.)the alkyl residue.

The term "halogenated (ness.)alkyl" refers to (ness.)alkyl group in which at least one of the hydrogens (ness.)alkyl groups substituted by halogen, such as fluorine and chlorine, preferably fluorine. Among the preferred halogenated (ness.)alkyl groups triptoreline, deformational, permetrina and chlormethine, and triptorelin is especially preferred.

The term "halogenated (ness.)alkoxy" refers to (ness.)and is maksigrupp, in which at least one of the hydrogens (ness.)alkoxygroup replaced by halogen, such as fluorine or chlorine, preferably fluorine. Among the preferred halogenated (ness.)alkoxygroup - fluorinated alkoxygroup, such as triptoreline, deformedarse, formatosi, and tripterocarpa is especially preferred.

The term "pharmaceutically acceptable salt" includes salts of compounds of formula (I) with inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonate acid, salicylic acid, p-toluensulfonate acid and the like, which are not toxic to living organisms. The preferred salts with acids are the formate, maleate, citrates, hydrochloride, hydrobromide and salt methanesulfonic acid, and hydrochloride are particularly preferred.

In one variant embodiment of the present invention relates to the compound of formula (I) for use as therapeutically active substances, as defined above, where R1means phenyl or phenyl mono-, di - or tizamidine nez the performance of halogen, such as chlorine, (ness.)alkoxygroup, such as methoxy, ethoxy, isopropoxy, (ness.)the alkyl, such as methyl, halogenated (ness.)alkoxygroup, such as triptoreline, or di(ness.)alkylamino, such as dimethylamino, diethylamino. In a preferred variant embodiment of the invention R1means phenyl, mono - or disubstituted independently with halogen, such as chlorine, or (ness.)alkoxygroup, such as methoxy. The most preferred substituents R1are 4-chlorophenyl, 4-chloro-3-methoxyphenyl and 3,4-acid.

In another variant embodiment of the present invention relates to the compound of formula (I) for use as therapeutically active substances, as defined above, where R2means phenyl or phenyl mono-, di - or tizamidine independently by halogen, such as chlorine and fluorine, halogenated (ness.)alkyl group such as trifluoromethyl, nitro or cyano. In a preferred variant embodiment of the invention R2means phenyl, monosubstituted by halogen. The most preferred substituent R2is ortho-chlorophenyl or 2,4-dichlorophenyl.

In another variant embodiment of the present invention relates to the compound of formula (I), where R3means hydrogen, (ness.)alkyl, benzyl, (ness.)alkoxy, halogen, cyano, nitro, amino, -NHSO2-R3 is or-NHCO-R3b. In a preferred variant embodiment of the invention, the substituent R3means hydrogen, nitro, amino, -NHSO2-R3Aor-NHCO-R3b. The most preferred substituent R3is hydrogen.

Deputy R3may be in positions 4, 5, 6 or 7 benzothiazole rings. Preferably the substituent R3is in position 6 benzothiazole rings.

In another variant embodiment of the present invention relates to the compound of formula (I) for use as therapeutically active substances, as defined above, where R3Ameans (ness.)alkyl, such as methyl or N-butyl, di(ness.)alkylamino, such as dimethylamino, benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)the alkyl, such as methyl.

In another variant embodiment of the present invention relates to the compound of formula (I) for use as therapeutically active substances, as defined above, where R3bmeans (ness.)alkyl, di(ness.)alkylamino, benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)the alkyl, such as methyl. In a preferred variant embodiment, the substituent R3bmeans benzyl or phenyl, monosubstituted (ness.)the alkyl, such as methyl.

In another variant embodiment of the present invention relates to the uedineniyu formula (Ia)

or its pharmaceutically acceptable salt,

where R1means phenyl or phenyl mono-, di - or tizamidine independently by halogen, (ness.)alkoxy, (ness.)the alkyl, halogenated (ness.)alkoxy or di(ness.)alkylamino;

R2means phenyl or phenyl mono-, di - or tizamidine independently halogen, halogenated (ness.)by alkyl, nitro or cyano;

R3means hydrogen, (ness.)alkyl, benzyl, (ness.)alkoxy, cyano, nitro, amino, -NHSO2-R3aor-NHCO-R3b;

R3ameans (ness.)alkyl, di(ness.)alkylamino, benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)by alkyl;

R3bmeans benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)by alkyl;

provided that when R3means hydrogen, R1selected from the group consisting of 2-haloethanol, 4-(ness.)the alkoxyphenyl, 3-(ness.)alkylphenyl, 4-halogen-2-(ness.)alkylphenyl, 3-halogen-2-(ness.)alkylphenyl, 4-halogen-3-(ness.)alkylphenyl, 2-halogen-4-(ness.)alkylphenyl, 3-halogen-4-(ness.)alkylphenyl, 2-(ness.)alkoxy-4-(ness.)alkylphenyl, 3-(ness.)alkoxy-4-(ness.)alkylphenyl, 4-(ness.)alkoxy-2-(ness.)alkylphenyl, 4-(ness.)alkoxy-3-(ness.)alkylphenyl, 3-(ness.)alkoxy-2-(ness.)alkylphenyl, phenyl, substituted halogenated (ness.)alkoxy or di(ness.)alkylamino, phenyl, Sames who spent two or three groups independently selected from halogen, (ness.)alkoxy, halogenated alkoxy, and di(ness.)alkylamino, phenyl, substituted (ness.)alkyl group or one or two groups selected from halogenated alkoxy and di(ness.)alkylamino, and phenyl substituted with two (ness.)alkyl group and a group selected from halogen, (ness.)alkoxy, halogenated alkoxy, and di(ness.)alkylamino.

In a preferred variant embodiment of the invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts,

where R1means phenyl or phenyl mono-, di - or tizamidine independently by halogen, (ness.)alkoxy, (ness.)the alkyl, halogenated (ness.)alkoxy or di(ness.)alkylamino;

R2means phenyl or phenyl mono-, di - or tizamidine independently halogen, halogenated (ness.)by alkyl, nitro or cyano;

R3means (ness.)alkyl, benzyl, (ness.)alkoxy, cyano, nitro, amino, -NHSO2-R3aor-NHCO-R3b;

R3ameans (ness.)alkyl, di(ness.)alkylamino, benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)by alkyl;

R3bmeans benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)the alkyl.

The following compounds of formula (1A) are examples:

2-chloro-N-(4-ethoxyphenyl)-4-fluoro-N-(6-nitrobenzothiazole-2-yl)benzamid,

2-chloro-N-(4-this is xifei)-N-(6-nitrobenzothiazole-2-yl)benzamid,

2,4-dichloro-N-(4-ethoxyphenyl)-N-(6-nitrobenzothiazole-2-yl)benzamid,

2,4-dichloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)benzamid,

N-(6-aminobenzothiazole-2-yl)-2,4-dichloro-N-(3,4-acid)benzamid,

2,4-dichloro-N-(3,4-acid)-N-(6-methanesulfonylaminoethyl-2-yl)-benzamid,

N-[6-(butane-1-sulfonylamino)benzothiazol-2-yl]-2,4-dichloro-N-(3,4-dimethoxy-phenyl)benzamide,

N-[6-(dimethylamino-1-sulfonylamino)benzothiazol-2-yl]-2,4-dichloro-N-(3,4-acid)benzamid,

N-(6-benzensulfonamidelor-2-yl)-2,4-dichloro-N-(3,4-acid)-benzamid,

2,4-dichloro-N-(3,4-acid)-N-(6-phenylmethanesulfonyl-2-yl)benzamid,

2,4-dichloro-N-(3,4-acid)-N-[6-(toluene-2-sulfonylamino)benzothiazol-2-yl]benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-phenylacetylamino-2-yl)-benzamid,

2-chloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)benzamid,

N-(6-aminobenzothiazole-2-yl)-2-chloro-N-(3,4-acid)benzamid,

2-chloro-N-(3,4-acid)-N-(6-methanesulfonylaminoethyl-2-yl)-benzamid,

N-[6-(butane-1-sulfonylamino)benzothiazol-2-yl]-2-chloro-N-(3,4-acid)-benzamid,

N-[6-(dimethylamino-1-sulfonylamino)benzothiazol-2-yl]-2-chloro-N-(3,4-dimethoxy-phenyl)benzamide,

N-(6-benzensulfonamidelor-2-yl)-2-chloro-N-(3,4-acid)-benzamid,

2-chloro-N-(3,4-acid)-N-(6-Hairdryer shall metasulphobenzoate-2-yl)-benzamid,

2-chloro-N-(3,4-acid)-N-[6-(toluene-2-sulfonylamino)benzothiazol-2-yl]-benzamide,

N-(6-(2-methylbenzylamino)benzothiazol-2-yl)-2-chloro-N-(3,4-acid)-benzamide

or their pharmaceutically acceptable salts.

In an additional preferred variant of embodiment of the invention relates to compounds of formula (Ia)as defined above, where R3means hydrogen, and R1choose from 3,5-dichlorophenyl, 3,4-dichlorophenyl, 4-chloro-2-methylphenyl and 4-chloro-3-methoxyphenyl.

In another preferred variant of embodiment of the invention relates to compounds of formula (Ia)as defined above, where R3means hydrogen, and R1choose from 4-(ness.)the alkoxyphenyl, 3,4-di(ness.)the alkoxyphenyl, 3,4,5-three(ness.)the alkoxyphenyl and 3-(ness.)alkoxy-4-(ness.)alkylphenyl.

In another preferred variant of embodiment of the invention relates to compounds of formula (Ia)as defined above, where R3means hydrogen, and R1means phenyl, substituted halogenated (ness.)alkoxy or di(ness.)alkylamino.

Preferred compounds of formula (Ia)in which R3means hydrogen, are the following:

N-benzothiazol-2-yl-2-chloro-N-(3,5-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-methoxime the Il)benzamid,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-2-were)benzamid,

N-benzothiazol-2-yl-2-fluoro-N-(4-methoxyphenyl)-4-cryptomelane,

N-benzothiazol-2-yl-N-(4-methoxyphenyl)-2,4-bistrifluormethylbenzene,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-methoxyphenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-4-cyano-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-N-(4-ethoxyphenyl)-2-fluoro-4-cryptomelane,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)-4-perbenzoic,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-4-cyano-N-(4-ethoxyphenyl)benzamid,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)benzamid,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-ethoxyphenyl)benzamid,

N-benzothiazol-2-yl-N-(3,4-acid)-2-fluoro-4-cryptomelane,

N-benzothiazol-2-yl-N-(3,4-acid)-2,4-bistrifluormethylbenzene,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)-4-perbenzoic,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)-4-nitrobenzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)benzamid,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-acid)benzamid,

N-benzothiazol-2-yl-2-chloro-N-(4-dimethylaminophenyl)-4-perbenzoic,

N-benzothiazol-2-yl-2-chloro-N-(4-dimethylaminophenyl)benzamid,

N-benzothiazol-Il-2-chloro-N-(4-diethylaminophenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-diethylaminophenyl)benzamid,

N-benzothiazol-2-yl-2-chloro-N-(3-methoxy-4-were)benzamid,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dioxyphenyl)benzamid,

N-benzothiazol-2-yl-2-chloro-N-(3,4,5-trimethoxyphenyl)benzamid,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dioxyphenyl)benzamid,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4,5-trimethoxyphenyl)benzamid,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(3-methoxy-4-were)benzamid,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dioxyphenyl)-4-perbenzoic,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-isopropoxyphenyl)benzamid,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(3,4,5-trimethoxyphenyl)benzamid,

N-benzothiazol-2-yl-2-chloro-N-(4-trifloromethyl)benzamid,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-trifloromethyl)benzamid,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-trifloromethyl)benzamid,

N-benzothiazol-2-yl-2-chloro-N-(4-chloro-3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-chloro-3-methoxyphenyl)benzamide

and their pharmaceutically acceptable salts.

Preferred compounds of General formula (I) are compounds selected from the group consisting of:

N-benzothiazol-2-yl-2-chloro-N-(4-chlorophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,5-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dichlorophenyl)benzo the foreign Ministry,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-2-were)benzamide,

N-benzothiazol-2-yl-2-fluoro-N-(4-methoxyphenyl)-4-cryptomelane,

N-benzothiazol-2-yl-N-(4-methoxyphenyl)-2,4-bitreversed,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-methoxyphenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-4-cyano-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-N-(4-ethoxyphenyl)-2-fluoro-4-cryptomelane,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-4-cyano-N-(4-ethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-ethoxyphenyl)benzamide,

N-benzothiazol-2-yl-N-(3,4-acid)-2-fluoro-4-cryptomelane,

N-benzothiazol-2-yl-N-(3,4-acid)-2,4-bitreversed,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-4-fluoro-benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)-4-nitrobenzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-acid)benzamide,

N be societal-2-yl-2-chloro-N-(4-dimethylaminophenyl)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-N-(4-dimethylaminophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-diethylaminophenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-diethylaminophenyl)benzamide,

2-chloro-N-(4-ethoxyphenyl)-4-fluoro-N-(6-nitrobenzothiazole-2-yl)benzamide,

2-chloro-N-(4-ethoxyphenyl)-N-(6-nitrobenzothiazole-2-yl)benzamide,

2,4-dichloro-N-(4-ethoxyphenyl)-N-(6-nitrobenzothiazole-2-yl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3-methoxy-4-were)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dioxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4,5-trimethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dioxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4,5-trimethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(3-methoxy-4-were)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dioxyphenyl)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-isopropoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(3,4,5-trimethoxyphenyl)benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)-benzamide,

N-(6-aminobenzothiazole-2-yl)-2,4-dichloro-N-(3,4-acid)benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-methanesulfonylaminoethyl-2-yl)-benzamide,

N-[6-(butane-1-sulfo is ylamino)benzothiazol-2-yl]-2,4-ALOR-N-(3,4-acid)benzamide,

N-[6-(dimethylamino-1-sulfonylamino)benzothiazol-2-yl]-2,4-dichloro-N-(3,4-acid)benzamide,

N-(6-benzensulfonamidelor-2-yl)-2,4-dichloro-N-(3,4-acid)-benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-phenylmethanesulfonyl-2-yl)benzamide,

2,4-dichloro-N-(3,4-acid)-N-[6-(toluene-2-sulfonylamino)benzothiazol-2-yl]benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-phenylacetylamino-2-yl)-benzamide,

2-chloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)benzamide,

N-(6-aminobenzothiazole-2-yl)-2-chloro-N-(3,4-acid)benzamide,

2-chloro-N-(3,4-acid)-N-(6-methanesulfonylaminoethyl-2-yl)-benzamide,

N-[6-(butane-1-sulfonylamino)benzothiazol-2-yl]-2-chloro-N-(3,4-acid)-benzamide,

N-[6-(dimethylamino-1-sulfonylamino)benzothiazol-2-yl]-2-chloro-N-(3,4-dimethoxy-phenyl)benzamide,

N-(6-benzensulfonamidelor-2-yl)-2-chloro-N-(3,4-acid)-benzamide,

2-chloro-N-(3,4-acid)-N-(6-phenylmethanesulfonyl-2-yl)-benzamide,

2-chloro-N-(3,4-acid)-N-[6-(toluene-2-sulfonylamino)benzothiazol-2-yl]-benzamide,

N-(6-(2-methylbenzylamino)benzothiazol-2-yl)-2-chloro-N-(3,4-acid)-benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-trifloromethyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-trifloromethyl)benzamide,

N-besot the azole-2-yl-2-chloro-4-fluoro-N-(4-trifloromethyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-chloro-3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-chloro-3-methoxyphenyl)benzamide

and their pharmaceutically acceptable salts.

The most preferred compounds of General formula (I) are compounds selected from the group consisting of:

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)-4-nitrobenzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-acid)benzamide,

2,4-dichloro-N-(4-ethoxyphenyl)-N-(6-nitrobenzothiazole-2-yl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dioxyphenyl)benzamide,

N-[6-(butane-1-sulfonylamino)benzothiazol-2-yl]-2,4-dichloro-N-(3,4-dimethoxy-phenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-chloro-3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-3-methoxyphenyl)benzamide

and their pharmaceutically acceptable salts.

The compounds of formula (I) can be obtained using the General methods described below.

Obtaining compounds of formula (I) or formula (1A) this is the overarching invention (compounds of formula IB, IC and ID, respectively, in scheme 1 below) can be implemented in sequential or convergent synthetic routes. The syntheses of the compounds of the present invention are illustrated by the following scheme 1. Qualification required for the implementation of the reaction and purification of the resulting products, well-known specialists in this field of technology. The substituents and indices used in the following description of the method, have the meanings given above unless otherwise specified.

Scheme 1

The compounds of formula IB (compounds of formula I in which the substituent R3means hydrogen, (ness.)alkyl, benzyl, alkoxy, halogen, nitro or cyano) can be obtained according to scheme 1 as follows.

a) Derivatives of N-aryl-1,3-benzothiazol-2-amine IV or commercially available, or can be obtained by methods known in the art, preferably from the corresponding 1,3-benzothiazole II, which is either commercially available or synthetically achievable using the General techniques described, for example, in patent EP 0043013 (X is an appropriate leaving group, which does not cause adverse reactions in the course of procedures for the receipt, usually chlorine or other halogen, and the like), and aniline III (commercially available) by mixing substances with a solvent or without him in Pris is accordance or in the absence of acid. There are no particular limitations concerning the nature of the solvent to be used, provided that it does not exert undesirable influence on the reaction or the reagents involved and that he should dissolve the reagents, at least to some extent. Examples of appropriate solvents include ethanol, methanol, dioxane and the like. There are no special restrictions regarding the nature of the acid used at this stage, and any acid commonly used in reactions of this type may equally be used in this reaction. Examples of such acids include hydrochloric, acetic and the like, in the presence of a solvent or without him. The reaction may take place under a wide range of temperatures, and the temperature is not decisive for the invention. Applicants have found that it is convenient to carry out the reaction by heating to a temperature in the range from ambient temperature to boiling point. The time required for the reaction may also vary widely, depending on many factors, to a large extent on the reaction temperature and the nature of the reagents. However, time from 0.5 h to several days will usually be enough to get the corresponding derivatives of N-aryl-1,3-benzothiazol-2-amine IV. This describes the transformation can be implemented is prohibited ways, described in the literature (see, for example, application WO 97/49704 or publication S.N.Sawhney, S.K.Akora, J.V.Singh, O.P.Bansal, S.P.Singh, Indian J. Chem., 16, 1978, c.c.605-609).

b) Transformation of the corresponding derivatives of N-aryl-1,3-benzothiazol-2-amine IV to obtain the corresponding derivatives of 1,3-benzothiazol-2-yl-N-riverslide IB may be made from suitable starting compounds according to methods known in the art. For example, to obtain the corresponding amides IB, the conversion of aniline part of the compounds of formula IV can be carried out by the interaction of the compound IV with the corresponding anhydrides of the acids of the V in the presence or in the absence of solvent and in the presence or in the absence of base. There are no special restrictions regarding the nature of the solvent, which should be used, provided that it does not exert undesirable influence on the reaction or the participating reactants and that it can dissolve the reagents, at least to some extent. Examples of appropriate solvents include dichloromethane, tetrahydrofuran, dioxane and the like. There are no special restrictions regarding the nature of the base used at this stage, and any base commonly used in reactions of this type may equally be used in this case. Examples of such bases include triethylamine, aminobutiramida is tillin, tert-butyl potassium (KOtBu), and the like. The reaction may take place under a wide range of temperatures, and the temperature is not decisive for the invention. Applicants have found that it is convenient to carry out the reaction with heating from ambient temperature to boiling point. The time required for the reaction may also vary widely, depending on many factors, to a large extent on the reaction temperature and the nature of the reagents. However, time from 0.5 h to several days will usually be enough to get the required derivatives of 1,3-benzothiazol-2-yl-N-riverslide IA. The transformation of this type can be carried out by methods described in the literature (see, for example. Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C.Larock. John Wiley & Sons, New York, NY. 1999). The compounds of formula IB (compounds of formula I in which the substituent R3means hydrogen, (ness.)alkyl, benzyl, alkoxy, halogen, nitro or cyano) are the compounds of the present invention and may be the desired product; alternatively, they may be subjected to subsequent reactions.

The compounds of formula 1C (compounds of formula I in which the substituent R3means an amino group) can be obtained according to scheme 1 as follows.

C) the compounds of formula IB, in which the substituent R3 means the nitrogroup, can be converted into their corresponding amino derivatives IC recovery methods, which are widely described in literature and known to experts in this field. For example, the restoration of the nitro group of compounds of formula IB (R3means the nitrogroup, preferably in position 6) can be carried out by reaction of the compound IB (R3means the nitrogroup, preferably in position 6) with regenerating agent in the presence or in the absence of solvent and in the presence or in the absence of acid. There is no particular restriction on the nature of the reducing agent used at this stage, and any reducing agent commonly used in reactions of this type may equally be used in this reaction. Examples of such reducing agents include tin chloride, hydrogen and the like. There are no special restrictions regarding the nature of the acid used at this stage, and any acid commonly used in reactions of this type, equally can be used in this reaction. Examples of such acids include hydrochloric acid, acetic acid and the like, in the presence of a solvent or without him. There are no special restrictions regarding the nature of the solvent, which should be used, provided that it is N. who has an unwanted effect on the reaction or the participating reactants and that it can dissolve the reagents, at least to some extent. Examples of appropriate solvents include dimethylformamide (DMF), tetrahydrofuran (THF), dioxane and the like. The reaction may take place under a wide range of temperatures, and the temperature is not decisive for the invention. Applicants have found that it is convenient to carry out the reaction with heating from ambient temperature to boiling point. The time required for the reaction may also vary widely, depending on many factors, to a large extent on the reaction temperature and the nature of the reagents. However, time from 0.5 h to several days will usually be enough to get the required connection ID. The resulting compounds of formula ID are compounds according to the present invention and may be the desired product; alternatively, they may be subjected to subsequent reactions.

The compounds of formula ID (compounds of formula I in which the substituent R3means-NHSO2-R3aor-NHCO-R3b) can be obtained according to scheme 1 as follows.

The compounds of formula ID can be obtained from the corresponding starting compounds according to methods known in the art. The transformation of the amide part in the compounds IC, to gain access to sulfonamides or Amida ID (R3means NHSO2-R3aor-NHCO-R3bpreferably Polo is attachment 6), may be effected by methods described in the literature. For example, the conversion of amino IC or their respective salts, to gain access to compounds of the formula ID, by the reaction of compounds IC with the corresponding anhydrides of the acids VI or sulphonylchloride VII (known compounds or compounds obtained by known methods), respectively, in the presence or in the absence of solvent and in the presence or in the absence of base. There are no special restrictions regarding the nature of the solvent, which should be used, provided that it does not exert undesirable influence on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of appropriate solvents include dichloromethane (DHM), dioxane, tetrahydrofuran (THF) and the like. There are no special restrictions regarding the nature of the base used at this stage, and any base commonly used in reactions of this type may equally be used in this reaction. Examples of such bases include triethylamine, diisopropylethylamine and the like. The reaction may take place under a wide range of temperatures, and the temperature is not decisive for the invention. Applicants have found that it is convenient to perform R is share with heating from ambient temperature to boiling point. The time required for the reaction may also vary widely, depending on many factors, to a large extent on the reaction temperature and the nature of the reagents. However, time from 0.5 h to several days will usually be enough to get amide or sulfonamidnuyu derivative ID (R3means NHSO2-R3aor-NHCO-R3b, preferably in position 6). Described in the literature, the reaction conditions affecting such reactions see for example, the manual Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C.Larock. John Wiley & Sons, New York, NY, 1999.

It will be recognized that compounds of General formula (I) according to this invention can undergo transformations of functional groups to provide derivatives which are capable of reverse conversion in vivo to the parent compound.

As described above, the compounds of formula (I) or their pharmaceutically acceptable salts can be used as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prevention of diseases associated with modulation of receptor CB1. Therefore, in one variant embodiment of the invention relates to compounds as defined above for use as therapeutically active substances, especially as therapeutic the ski active substances for the treatment and/or prevention of diseases, which is associated with modulation of receptor CB1.

The invention also relates to pharmaceutical compositions comprising a compound of formula (I)

where R1means phenyl or phenyl mono-, di - or tizamidine independently by halogen, (ness.)alkoxy, (ness.)the alkyl, halogenated (ness.)alkoxy or di(ness.)alkylamino;

R2means phenyl or phenyl mono-, di - or tizamidine independently halogen, halogenated (ness.)by alkyl, nitro or cyano;

R3means hydrogen, (ness.)alkyl, benzyl, (ness.)alkoxy, halogen, cyano, nitro, amino, -NHSO2-R3aor-NHCO-R3b

R3ameans (ness.)alkyl, di(ness.)alkylamino, benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)by alkyl;

R3bmeans benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)by alkyl;

or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and/or excipient.

In another variant embodiment of the invention relates to a method of treatment and/or prevention of diseases associated with modulation of receptor CB1to the way, which includes the introduction of the compounds of formula (I)

where R1means phenyl or phenyl mono-, di - or triamese the hydrated independently halogen, (ness.)alkoxy, (ness.)the alkyl, halogenated (ness.)alkoxy or di(ness.)alkylamino;

R2means phenyl or phenyl mono-, di - or tizamidine independently halogen, halogenated (ness.)by alkyl, nitro or cyano;

R3means hydrogen, (ness.)alkyl, benzyl, (ness.)alkoxy, halogen, cyano, nitro, amino, -NHSO2-R3aor-NHCO-R3b;

R3ameans (ness.)alkyl, di(ness.)alkylamino, benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)by alkyl;

R3bmeans benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)by alkyl;

or its pharmaceutically acceptable salt for human or animal.

The invention also relates to the use of compounds as defined above for the treatment and/or prevention of diseases associated with modulation of receptor CB1.

In addition the invention relates to the use of compounds of formula (I)

where R1means phenyl or phenyl mono-, di - or tizamidine independently by halogen, (ness.)alkoxy, (ness.)the alkyl, halogenated (ness.)alkoxy or di(ness.)alkylamino;

R2means phenyl or phenyl mono-, di - or tizamidine independently halogen, halogenated (ness.)by alkyl, nitro or cyano;

R3means hydrogen, (ness.)alkyl, b is nil, (ness.)alkoxy, halogen, cyano, nitro, amino, -NHSO2-R3aor-NHCO-R3b;

R3ameans (ness.)alkyl, di(ness.)alkylamino, benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)by alkyl;

R3bmeans benzyl, phenyl or phenyl mono-, di - or tizamidine independently (ness.)by alkyl;

or their pharmaceutically acceptable salts in the preparation of medicines for the treatment and/or prevention of diseases associated with modulation of receptor CB1. Such medicines include compound, as defined above.

In this context, the expression ' diseases associated with modulation of receptor CB1"means diseases that can be treated and/or prevented by modulation of receptor CB1. Such diseases include, but without limitation, mental disorders, especially anxiety and disorders associated with anxiety, psychosis, schizophrenia, depression, disturbances associated with the misuse of substances, including the abuse of psychotropic drugs, such as abuse and/or dependence on substances, including alcohol dependence and nicotine dependence, neuropathy, migraine, stress, epilepsy, dyskinesia, Parkinson's disease, amnesia, memory disorders and cognitive abilities, the old one is a mini dementia, Alzheimer's disease, eating disorders, obesity, diabetes type II or non-insulin dependent diabetes (NIDD), gastrointestinal diseases, vomiting, diarrhea, related to urinary disorders, cardiovascular disorders associated with infertility disorders, inflammation, infection, malignant tumors, disorders associated with the destruction of the myelin layer, neurospine, especially atherosclerosis, or Guillain-Barre syndrome, viral encephalitis, incidents with vessels of the brain and cranial trauma.

In a preferred aspect, the expression ' diseases associated with modulation of receptor CB1"refers to eating disorders, obesity, diabetes type II or non-insulin dependent diabetes (NIDD), neuronophagia, diarrhea, misuse and/or dependence on substances, including alcohol dependence and nicotine dependence. In a more preferred aspect, the above term refers to eating disorders, obesity, diabetes type II or non-insulin dependent diabetes (NIDD), misuse and/or dependence on substances, including alcohol dependence and nicotine addiction, and obesity is especially preferred.

Further preferred object of the invention is to provide a method for the treatment or prevention of type II diabetes (non-insulin dependent diabetes what about diabetes (NIDDM)) the person, which includes the introduction of a therapeutically effective amount of a compound according to formula (I) in combination or Association with a therapeutically effective amount of a lipase inhibitor, particularly, when the lipase inhibitor is orlistat. The object of the invention is the method as described above, simultaneous, separate or sequential introduction of the compound according to formula (I) and lipase inhibitor, particularly, tetrahydrolipstatin.

Additional preferred object of the invention is to provide a method of treating or preventing obesity and obesity-related disorders, which includes the introduction of a therapeutically effective amount of a compound according to formula (I) in combination or Association with a therapeutically effective amount of another drug for the treatment of obesity or eating disorders, so that together they produce an effective weakening of the disease. Appropriate other drugs include, but without limitation, reduces appetite agents, lipase inhibitors and selective inhibitors of reuptake of serotonin (SSRI). Combinations or associations of the above-mentioned agents can include separate, sequential or simultaneous administration.

A preferred lipase inhibitor is tetrahydrolipstatin.

Relevant to the respective reduces appetite agents, used in combination with the compound of the present invention, include, but are not limited to, Aminorex, amphora, amphetamine, benzphetamine, chlorphentermine, clobenzorex, klotrix, glominerals, clortermine, cyclodextrin, dexfenfluramin, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, penetrex, fenproporex, fluorex, luminares, furfurylmercaptan, levamfetamine, levorotatory, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, phenterex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, pillories, sibutramine and their pharmaceutically acceptable salts.

The most preferred agents that reduce appetite are sibutramine and phentermine.

Appropriate selective inhibitors of reuptake of serotonin, used in combination with the compound of the present invention, include fluoxetine, fluvoxamine, paroxetine, sertraline, and their pharmaceutically acceptable salts.

The following tests were conducted to determine the activity of the compounds of formula (I).

The affinity of the compounds according to the invention for cannabinoid receptors CB1was determined using membrane preparations of cells of the human embryonic kidney (SOME), in which a human receptor CB1cannabis temporarily mansfeldova using virus Semliki forest in combination with the compound [ 3H]-CP-55940 as radioligand. After incubation of freshly prepared drug cell membranes with [3H]-ligand, with or without compounds according to the invention the separation of bound and free ligand was carried out by filtration on glass fiber filters. The radioactivity on the filter was measured by liquid-scintillation counting.

The affinity of the compounds according to the invention for cannabinoid receptors SV2was determined using membrane preparations of cells of the human embryonic kidney (SOME), in which a human receptor SV2cannabis temporarily transfirieran using virus Semliki forest in combination with the compound [3H]-CP-55940 as radioligand. After incubation of freshly prepared drug cell membranes with [3N]-ligand, with or without compounds according to the invention the separation of bound and free ligand was carried out by filtration on glass fiber filters. The radioactivity on the filter was measured by liquid-scintillation counting.

Antagonistic activity against cannabinoid receptors CB1compounds according to the invention was determined by functional studies using cells of Chinese hamster ovary (Cho), in which the human cannabinoid receptor CB1steadily expr sirawan (see .Rinaldi-Carmona and others, J. Pharmacol. Exp. Ther., 278 (1996) s). Stable expression of the human cannabinoid receptor in cellular systems was first described in Nature, 346, 1990, s-564 (CB1and Nature, 365, 1993, SS-65 (ST2) respectively. Adenylylcyclase stimulated using Forskolin, and was measured by determining the amount of accumulated cyclic AMP. Concomitant activation of receptors CB1agonists of receptors CB1(for example, CP-55940, or (R)-WIN-55212-2) can weaken induced Forskolin accumulation of cyclic AMP-dependent concentration of the way. This is mediated by receptors CB1the answer may be provided with a counter-receptor antagonists CB1such as compounds according to the invention.

The compounds of formula (I) exhibit an excellent affinity to the receptor CB1defined in the experimental conditions described by Devane and others, Mol. Pharmacol., 34 (1988) SS-613. Compounds of the present invention or their pharmaceutically acceptable salt or solvate are antagonists and selective in relation to receptor CB1with lower affinity IC50=5 μm, preferably below the IC50=2 μm. They have at least 10-fold selectivity for receptor SV2.

The compound of exampleIC50[The KMS]
80,73
91,96
122,48
281,38
450,83
521,59
571,42

The compounds of formula (I) and/or their pharmaceutically acceptable salts can be used as medicines, for example in the form of pharmaceutical preparations for enteral, parenteral or local administration. They can be introduced, for example, orally, for example in the form of tablets, pills, coated, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.

Obtaining pharmaceutical preparations can be carried out in a manner that will be familiar to any qualified specialist in this field, by bringing the described compounds of formula (I) and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, Galanova the form of the introduction together with the corresponding non-toxic, inert and, therapeutically compatible solid or liquid substances-carriers and, if desired, usual pharmaceutical excipients.

The relevant matter-the media are not only inorganic substances-media, but also organic substances-carriers. So, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used as substances-carriers for tablets, coated tablets coated tablets and hard gelatin capsules. The relevant substances-carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active ingredient no carriers may not be required in the case of soft gelatin capsules). The relevant substances-carriers for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like. The relevant substances-carriers for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. The relevant substances-carriers for suppositories are, for example, natural or solidified oils, waxes, fats and semi-liquid or liquid polyols. The relevant substances is native to drugs local actions are for example, glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

Conventional stabilizers, preservatives, wetting and emulsifying agents, improving consistency agents, flavoring agents, salts for modifying the osmotic pressure, buffer substances, contributing to the dissolved substances, dyes, masking agents and antioxidants are considered as pharmaceutical excipients.

The dose of the compounds of formula (I) can vary within wide limits depending on the disease, which should be controlled, the age and the individual condition of the patient and the type of injection and, of course, be adapted to the individual requirements in each particular case. For adult patients whereas a daily dose of about 1 to 1,000 mg, particularly from about 1-100 mg depending on the severity of the disease and the precise pharmacokinetic profile of the compound may be introduced into one or more basic daily doses, for example in 1-3 standard doses.

The pharmaceutical preparations normally contain about 1-500 mg, preferably 1-100 mg of the compounds of formula (I).

The following examples serve to further illustrate us Otsego invention. However, they in no way claim to be limiting of its scope.

Examples

MS - mass spectrometry; ISP - ion sputtering (positive ion) corresponds to the ESI (electrospray ionization with the formation of positive ions); tPL- melting point; aq. water; THF - tetrahydrofuran; DMF is dimethylformamide; DHM - dichloromethane; KOtBu - tert-butyl potassium; NMR spectroscopy nuclear magnetic resonance.

Example 1 (educt)

a) Benzothiazol-2-yl-(4-chlorophenyl)amine

A mixture of 1.7 g (10 mmol) of 2-chloro-1,3-benzothiazole and 2.6 g (10 mmol) 4-Chloroaniline in 20 ml of acetic acid was heated at 110°C for 3 hours, the Reaction mixture was diluted with 200 ml of water and the resulting mixture was extracted with ethyl acetate (3×150 ml). The combined organic phases were washed with water (2×100 ml), dried over magnesium sulfate, filtered and evaporated to dryness. The residue was recrystallized from a mixture of hexane/ethyl acetate, gaining 1.4 g (54%) specified in the connection header.

1H-NMR (300 MHz, CDCl3that δ): 10,6 (s ears., 1H, NH), 7,82 (m, 3H, (Ar-H-3/H-5)/(H-7), a 7.62 (d, J=7.8 Hz, 1H, H-4), 7,42 (d, J=6,8 Hz, 2H, Ar-H-2/H-6), 7,35 (t, J=8,1 Hz, 1H, H-6), 7,18 (t, J=7.5 Hz, 1H, H-5). MS (m/e): 261,2 (MN+, 100%).

b) Benzothiazol-2-yl-(3,5-dichlorophenyl)amine

The connection specified in the header, was synthesized from 2-chlorobenzothiazole (commercially available) and 3,5-dichloraniline (commercially available is Phnom) in accordance with the methodology described above for example 1A.

1H-NMR (300 MHz, CDCl3that δ): to 7.68 (d, J=7.9 Hz, 1H, H-7), 7,63 (d, J=8,1 Hz, 1H, H-4), 7,37 (m, 3H, H-5, (Ar-H-2/H-6/H-6), 7,22 (t, J=7.9 Hz, 1H, H-5), 7,18 (d, J=1.7 Hz, 1H, Ar H-4). MS (m/e): 295,2 (MH+, 0%).

in) Benzothiazol-2-yl-(3,4-dichlorophenyl)amine

The connection specified in the header, was synthesized from 2-chlorobenzothiazole (commercially available) and 3,4-dichloraniline (commercially available) in accordance with the procedure described above for example 1A.

1H-NMR (300 MHz, DMSO-d6that δ): 10,81 s ears., 1H, NH), 8,24 (d, J=2.3 Hz, 1H,Ar-N-2), 7,86 (d, J=7.8 Hz, 1H, H-7), 7,63 (m, 3H, (Ar-H-5/H-6/H-4), of 7.36 (t, J=7.8 Hz, 1H, H-6), 7,21 (t, J=7.7 Hz, 1H, H-5). MS (m/e): 295,2 (MN+, 100%).

g) Benzothiazol-2-yl-(4-methoxyphenyl)amine

The connection specified in the header, was synthesized from 2-chlorobenzothiazole (commercially available) and 4-methoxyaniline (commercially available) in accordance with the procedure described above for example 1A.

1H-NMR (300 MHz, DMSO-d6that δ): 11.75 (s, ush., 1H, NH), 7,76 (d, J=7.7 Hz, 1H, H-7), to 7.68 (d, J=8,9 Hz, 2H, (Ar-H-2/Ar H-6), of 7.55 (d, J=7.9 Hz, 1H, H-4), 7,29 (t, J=7.7 Hz, 1H, H-6), to 7.09 (t, J=7.9 Hz, 1H, H-5), of 6.96 (d, J=a 8.9 Hz, 2H, (Ar-H-3/Ar-H-5)in), 3.75 (s, 3H, och3). MS (m/e): 257,1 (MN+, 100%).

d) Benzothiazol-2-yl-(4-chloro-2-were)Amin

The connection specified in the header, was synthesized from 2-chlorobenzothiazole (commercially available) and 2-chloro-4-methylaniline (commercially available) in accordance with the methodology described above for approx the RA 1A.

1H-NMR (300 MHz, DMSO-d6, 5): 9,68 (s ears., 1H, NH), 8,01 (d, J=8.5 Hz, 1H, H-7), 7,76 (d, J=7.2 Hz, 1H, Ar H-5), to 7.50 (d, J=7.8 Hz, 1H, H-4), 7,31 (m, 3H, (Ar-H-2/Ar-H-6/H-5), to 7.15 (t, J=8,5 Hz, 1H, H-6), to 2.29 (s, 3H, CH3). MS (m/e): 275,2 (MN+, 100%).

e) Benzothiazol-2-yl-(4-ethoxyphenyl)Amin

The connection specified in the header, was synthesized from 2-chlorobenzothiazole (commercially available) and 4-ethoxyaniline (commercially available) in accordance with the procedure described above for example 1A.

1H-NMR (300 MHz, DMSO-d6that δ): 10,26 (s ears., 1H, NH), 7,76 (d, J=7.5 Hz, 1H, H-7), to 7.68 (d, J=6,9 Hz, 2H, (Ar-H-2/Ar H-6), of 7.55 (d, J=7.9 Hz, 1H, H-4), 7,29 (t, J=7.5 Hz, 1H, H-6), to 7.09 (t, J=7.9 Hz, 1H, H-5), of 6.96 (d, J=6,9 Hz, 2H, (Ar-H-3/Ar-H-5)), to 4.01 (q, J=7,0 Hz, 2H, OCH2), to 1.32 (t, J=7.0 Hz, 3H, CH3). MS (m/e): 271,1 (MH+, 100%).

W) Benzothiazol-2-yl-(3,4-acid)Amin

The connection specified in the header, was synthesized from 2-chlorobenzothiazole (commercially available) and 3,4-dimethoxyaniline (commercially available) in accordance with the procedure described above for example 1A.

1H-NMR (300 MHz, DMSO-d6that δ): 10,26 ('s. ush., 1H, NH), to 7.77 (d, J=7,1 Hz, 1H, H-7), 7,53 (d, J=7,6 Hz, 1H, H-4), 7,40 (s, 1H, Ar-H-2), 7,30 (m, 2H, (Ar-H-6/H-5), to 7.15 (t, J=7,1 Hz, 1H, H-6), 6,97 (d, J=8.7 Hz, 1H, Ar-H-5), of 3.78 (s, 3H, och3), 3,74 (s, 3H, och3). MS (m/e): 287,0 (MR+, 100%).

C) N-Benzothiazol-2-yl-N',N'-xylene-1,4-diamine

The connection specified in the header, was synthesized from 2-chlorobenzothiazole (commercially available) and N,N-dimethyl-pphenylenediamine (commercially available) in accordance with the methodology described above for example 1A.

1H-NMR (300 MHz, DMSO-d6that δ): 10,08 (s ears., 1H, NH), 7,71 (d, J=7,1 Hz, 1H, H-7), to 7.50 (m, 3H, (Ar-H-2/Ar-H-6)/H4), 7,27 (t, J=7,1 Hz, 1H, H-6), 7,10 (t, J=7.8 Hz, 1H, H-5), is 6.78 (d, J=9.0 Hz, 2H, (Ar-H-3/Ar-H-5)), of 2.86 (s, 6H, N(CH3)2). MS (m/e): 270,2 (MH+, 100%).

and) N-Benzothiazol-2-yl-N',N'-diethylbenzene-1,4-diamine

The connection specified in the header, was synthesized from 2-chlorobenzothiazole (commercially available) and N,N-diethyl-p-phenylenediamine (commercially available) in accordance with the procedure described above for example 1A.

MS (m/e): 298,2 (MN+, 100%).

K) Benzothiazol-2-yl-(3-methoxyphenyl)amine

The connection specified in the header, or commercially available or can be synthesized from 2-chlorobenzothiazole (commercially available) and 3-methoxyaniline (commercially available) in accordance with the procedure described above for example 1A.

MS (m/e): 257,0 (MN+, 100%).

l) Benzothiazol-2-yl-(4-chloro-3-methoxyphenyl)amine

The connection specified in the header, was synthesized from 2-chlorobenzothiazole (commercially available) and 4-chloro-3-methoxyaniline (commercially available) in accordance with the procedure described above for example 1A.

MS (m/e): 291,3 (MN+, 100%).

m) Benzothiazol-2-yl-(4-trifloromethyl)Amin

The connection specified in the header, was synthesized from 2-chlorobenzothiazole (commercially available) and 3-formicoxenini (comm is Ronski available) in accordance with the methodology described above for example 1A.

MS (m/e): 310,0 (MH+, 100%).

n) (4-Ethoxyphenyl)-(6-nitrobenzothiazole-2-yl)Amin

The connection specified in the header, synthesized from 2-chloro-6-nitrobenzothiazole (commercially available) and 4-ethoxyaniline (commercially available) in accordance with the procedure described above for example 1A.

1H-NMR (300 MHz, DMSO-d6that δ): 10,8 (s ears., 1H, NH), 8,80 (d, J=2.4 Hz, 1H, H-7) is 8.16 (dd, J1=a 8.9 Hz, J2=2.4 Hz, 1H, H-5), the 7.65 (m, 3H, (Ar-H-2/Ar-H-6)/N4), 6,97 (d, J=6,8 Hz, 2H, (Ar-H-3/Ar-H-5)), was 4.02 (q, J=6,9 Hz, 2H, OCH2), of 1.28 (t, J=6.9 Hz, 3H, CH3). MS (m/e): 316,2 (MH+, 100%).

o) (3,4-Acid) (6-nitrobenzothiazole-2-yl)Amin

The connection specified in the header, synthesized from 2-chloro-6-nitrobenzothiazole (commercially available) and 3,4-dimethoxyaniline (commercially available) in accordance with the procedure described above for example 1A.

MS (m/e): 322,2 (MN+, 100%).

Example 2

N-Benzothiazol-2-yl-2-chloro-N-(4-chlorophenyl)benzamide

The mixture is 39.1 mg (0.15 mmole) benzothiazol-2-yl-(4-chlorophenyl)amine in 0.5 ml of tetrahydrofuran, to 45.2 mg (of 0.18 mmole) of the acid chloride of 2-chlorbenzoyl acid 0.18 ml of tetrahydrofuran and 0.17 ml of 1 M solution of potassium tert-butylate in tetrahydrofuran was heated at 50°C for 16 hours After addition of 0.5 ml of formic acid and the mixture was separated using preparative HPLC on reversed phase, luira gradient acetonitrile/water. Evaporation of fractions containing product gave to 40.1 mg (67%) of the connection specified in the header.

MS (m/e): 399,3 (MN+, 100%).

According to the method described in example 2, derivatives of N-benzothiazol-2-yl-N-riverslide were synthesized from derivatives of benzothiazole-2-Yarilin and anhydrides of the acids. The results are shown below in table 1 and include examples 3-34.

Example 35

N-Benzothiazol-2-yl-2-chloro-N-(3-methoxy-4-were)benzamid

The mixture 0,339 g (2 mmole) of 2-chlorobenzothiazole (commercially available) and 0,275 g (2 mmole) of 3-methoxy-4-methylaniline (commercially available) in 4 ml of acetic acid was heated at 115°C for 4 h After cooling to room temperature the mixture was separated using preparative HPLC on reversed phase elwira gradient acetonitrile/water. The fractions containing the product, benzothiazol-2-yl-(3-methoxy-4-were)amine was evaporated to dryness and subjected to the interaction with the acid chloride of 2-chlorbenzoyl acid according to the procedure described for example 2, obtaining specified in the header of the connection.

MS (m/e): 409,3 (MN+, 100%).

In accordance with the procedure described for example 35, additional the ones derived N-benzothiazol-2-yl-N-(aryl)benzamide was synthesized by the reaction of 2-chlorobenzothiazole with the appropriate aniline (commercially available) and then with the appropriate acid chloride acid. The results are shown below in table 2 and include examples 36-43.

Example 44

2,4-Dichloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)benzamid

The connection specified in the header, was synthesized from (3,4-acid) (6-nitrobenzothiazole-2-yl)amine and acid chloride 2,4-dichlorobenzoyl acid (commercially available) according to the procedure described in example 2.

MS (m/e): 504,1 (MN+, 100%).

Example 45

N-(6-Aminobenzothiazole-2-yl)-2,4-dichloro-N-(3,4-acid)benzamid

A mixture of 2 g (of 3.97 mmole) of 2,4-dichloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)benzamide in 25 ml of dimethylformamide and 4 ml of 1 N. hydrochloric acid was treated with 2.24 g of dihydrate dvuhgolosnogo tin and heated at 80°C for 4 h After cooling to room temperature was added 50 ml of saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic phase was treated with dealitem and filtered. The organic phase of the filtrate was washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified preparative HPLC on reversed phase elwira gradient acetonitrile/water to obtain 536 mg (29%) specified in C is the coupling head in the form of amorphous solids yellowish color.

MS (m/e): 474,0 (MN+, 100%).

Example 46

2,4-Dichloro-N-(3,4-acid)-N-(6-methanesulfonylaminoethyl-2-yl)benzamid

A mixture of the 33.2 mg (0.07 mmole) of N-(6-aminobenzothiazole-2-yl)-2,4-dichloro-N-(3,4-acid)benzamide in 0.7 ml of dichloromethane, and 18.2 mg (of 0.18 mmole) of triethylamine and 10.3 mg (0,091 mmole) of methanesulfonamide in 0.2 ml of dichloromethane was reacted for 16 h at room temperature. After evaporation of all volatiles the residue was dissolved in a mixture of dimethylformamide/acetonitrile and was shared by preparative HPLC on reversed phase elwira gradient acetonitrile/water to obtain 9.6 mg (25%) specified in the connection header.

MS (m/e): 552,1 (MN+, 100%).

In accordance with the procedure described for the synthesis of example 46, derivatives of 2,4-dichloro-N-(3,4-acid)-6-aminobenzothiazole-2-yl)benzamide or 2,4-dichloro-N-(3,4-acid)-6-sulfhemoglobinemia-2-yl)benzamide was synthesized from N-(6-aminobenzothiazole-2-yl)-2,4-dichloro-N-(3,4-acid)benzamide and sulphonylchloride or acid chlorides acid (commercially available). The results are shown below in table 3 and include examples 47-52.

Example 53

2-Chloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)benzamid

Connect the tion, named in the title, was synthesized from (3,4-acid) (6-nitrobenzothiazole-2-yl)amine and acid chloride of 2-chlorbenzoyl acid (commercially available) according to the procedure described for example 2.

MS (m/e): 469,7 (MN+, 100%).

Example 54

N-(6-Aminobenzothiazole-2-yl)-2-chloro-N-(3,4-acid)benzamid

The compound named in the heading, synthesized from 2-chloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)benzamide according to the procedure described for example 45.

MC (m/e): 440,1 (MN+, 100%).

According to the procedure described for the synthesis of example 46, derivatives of 2-chloro-N-(3,4-acid)-6-aminobenzothiazole-2-yl)benzamide or 2-chloro-N-(3,4-acid)-6-sulfhemoglobinemia-2-yl)benzamide was synthesized from N-(6-aminobenzothiazole-2-yl)-2-chloro-N-(3,4-acid)benzamide and sulphonylchloride or acid chlorides acid (commercially available). The results are shown below in table 4 and include examples 55-61.

Example 62

N-Benzothiazol-2-yl-2-chloro-N-(4-trifloromethyl)benzamid

To 0.2 g (0.6 mmole) benzothiazol-2-yl-(4-trifloromethyl)amine dissolved in tetrahydrofuran (5 ml), was added tert-butyl potassium (0.11 g, 1.0 mmol) and acid chloride 2-Harb what Noynoy acid (0,13 g, 0.7 mmole). The mixture was stirred for 3 h at room temperature. Was added water (10 ml) and the mixture was extracted with ethyl acetate (2×20 ml). The organic phases were combined, dried over magnesium sulfate and after evaporation and chromatography (silica gel, n-hexane/ethyl acetate) has been specified in the title compound (0.26 g, 89%).

MS (m/z): 449,4 (MN+, 100%).

In accordance with the procedure described for the synthesis of example 61, derivatives of benzothiazole-2-ilasamaja synthesized from derivatives of benzothiazole-2-ilfenomeno and anhydrides of the acids. The results are shown below in table 5 and include examples 63-67.

Glenavy examples

Example

Film-coated tablets containing the following ingredients can be prepared in the usual way.

IngredientsPills
Core
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Water lactose60,0 mg70.0 mg
Povidone K12.5 mg15,0 mg
Sodium salt Carbo is dimetilovogo ether 12.5 mg17,0 mg
starch
Magnesium stearate1.5 mg4.5 mg
(Earth core)120,0 mg350,0 mg
Film coating
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredient was sieved, mixed with microcrystalline cellulose and the mixture was granulated with a solution of polyvinylpyrrolidone in water. The granulate was mixed with the sodium salt carboxymethylated ether of starch and magnesium stearate and subjected to compression, receiving core weight of 120 or 350 mg, respectively. The core was covered with glaze with an aqueous solution/suspension of the above-mentioned film coating.

Example B

Capsules containing the following ingredients can be prepared in the usual way.

td align="center"> On capsule
Ingredients
The compound of formula (I)25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

The components were screened, mixed and loaded into capsules of size 2.

The example In

Injectable solutions may have the following structure.

The compound of formula (I)3.0 mg
The polyethylene glycol 400150,0 mg
Acetic acidenough to pH 5.0
Water for injection solutionsto 1.0 ml

The active ingredient was dissolved in a mixture of polyethylene glycol 400 and water for injection (part). Brought the pH to 5.0 by addition of acetic acid. The volume was made up to 1.0 ml by adding the remaining amount of water. The solution was filtered, loaded into vials using the appropriate excess, and sterilized.

1. The use of compounds of formula (I)

where R1means phenyl, mono-, di - or tizamidine independently by halogen, (ness.)alkoxy, (ness.)the alkyl, halogenated (ness.)alkoxy or di(ness.)alkylamino;

R2means phenyl, mono - or disubstituted is independently halogen, halogenated (ness.)by alkyl, nitro or cyano;

R3means hydrogen, nitro, amino, -NHSO2-R3aor-NHCO-R3b;

R3ameans (ness.)alkyl, di(ness.)alkylamino, benzyl, phenyl or phenyl, monosubstituted (ness.)by alkyl;

R3bmeans benzyl or phenyl, monosubstituted (ness.)by alkyl;

or their pharmaceutically acceptable salts as therapeutically active substances having the properties of agonist CB1the receptor.

2. The use according to claim 1, where R1means phenyl, mono - or disubstituted independently with halogen or (ness.)alkoxy.

3. The use according to claim 1, where R1means 4-chlorophenyl, 4-chloro-3-methoxyphenyl or 3,4 - acid.

4. The use according to claim 1, where R2means phenyl, monosubstituted by halogen.

5. The use according to claim 1, where R2mean 2-chlorophenyl or 2,4-dichlorophenyl.

6. The use according to claim 1, where R3means hydrogen.

7. The use according to claim 1, where R3is in position 6 bestiales rings.

8. The use according to claim 1, where R3ameans methyl, n-butyl, dimethylamino, benzyl, phenyl or phenyl, monosubstituted the stands.

9. The use according to claim 1, where the compounds of formula (I) according to claim 1 selected from the group consisting of

N-benzothiazol-2-yl-2-chloro-N-(4-chlorophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,5-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-2-were)benzamide,

N-benzothiazol-2-yl-2-fluoro-N-(4-methoxyphenyl)-4-cryptomelane,

N-benzothiazol-2-yl-N-(4-methoxyphenyl)-2,4-bitreversed,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-methoxyphenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-4-cyano-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-N-(4-ethoxyphenyl)-2-fluoro-4-cryptomelane,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-4-cyano-N-(4-ethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-ethoxyphenyl)benzamide,

N-benzothiazol-2-yl-N-(3,4-acid)-2-fluoro-4-cryptomelane,

N-benzothiazol-2-yl-N-(3,4-acid)-2,4-bitreversed,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-N-(3,-acid)-4-nitrobenzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-acid)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-dimethylaminophenyl)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-N-(4-dimethylaminophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-diethylaminophenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-diethylaminophenyl)benzamide,

2-chloro-N-(4-ethoxyphenyl)-4-fluoro-N-(6-nitrobenzothiazole-2-yl)benzamide,

2-chloro-N-(4-ethoxyphenyl)-N-(6-nitrobenzothiazole-2-yl)benzamide,

2,4-dichloro-N-(4-ethoxyphenyl)-N-(6-nitrobenzothiazole-2-yl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3-methoxy-4-were)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dioxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4,5-trimethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dioxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4,5-trimethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(3-methoxy-4-were)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dioxyphenyl)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-isopropoxyphenyl)benzamide,

N-benzothiazol the-2-yl-2-chloro-4-fluoro-N-(3,4,5-trimethoxyphenyl)benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)benzamide,

N-(6-aminobenzothiazole-2-yl)-2,4-dichloro-N-(3,4-acid)benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-methanesulfonylaminoethyl-2-yl)-benzamide,

N-[6-(butane-1-sulfonylamino)benzothiazol-2-yl]-2,4-dichloro-N-(3,4-dimethoxy-phenyl)benzamide,

N-[6-(dimethylamino-1-sulfonylamino)benzothiazol-2-yl]-2,4-dichloro-N-(3,4-acid)benzamide,

N-(6-benzensulfonamidelor-2-yl)-2,4-dichloro-N-(3,4-acid)-benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-phenylmethanesulfonyl-2-yl)benzamide,

2,4-dichloro-N-(3,4-acid)-N-[6-(toluene-2-sulfonylamino)benzothiazol-2-yl]benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-phenylacetylamino-2-yl)benzamide,

2-chloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)benzamide,

N-(6-aminobenzothiazole-2-yl)-2-chloro-N-(3,4-acid)benzamide,

2-chloro-N-(3,4-acid)-N-(6-methanesulfonylaminoethyl-2-yl)benzamide,

N-[6-(butane-1-sulfonylamino)benzothiazol-2-yl]-2-chloro-N-(3,4-acid)-benzamide,

N-[6-(dimethylamino-1-sulfonylamino)benzothiazol-2-yl]-2-chloro-N-(3,4-dimethoxy-phenyl)benzamide,

N-(6-benzensulfonamidelor-2-yl)-2-chloro-N-(3,4-acid)benzamide,

2-chloro-N-(3,4-acid)-N-(6-phenylmethanesulfonyl-2-yl)-benzamide,

2-chloro-N-(3,4-acid)-N-[6-(toluene-2-sulfonylamino)benzothiazol-2-yl]-benzamide,

N-(6-(2-methylbenzylamino)benzothiazol-2-yl)-2-chloro-N-(3,4-acid)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-trifloromethyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-trifloromethyl)benzamide,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-trifloromethyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-chloro-3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-chloro-3-methoxyphenyl)benzamide,

and their pharmaceutically acceptable salts.

10. The compounds of formula (Ia)

or their pharmaceutically acceptable salt,

where R1means phenyl, mono-, di - or tizamidine independently by halogen, (ness.)alkoxy, (ness.)the alkyl, halogenated (ness.)alkoxy or di(ness.)alkylamino;

R2means phenyl, mono - or disubstituted independently with halogen, halogenated (ness.)by alkyl, nitro or cyano;

R3means hydrogen, nitro, amino, -NHSO2-R3aor-NHCO-R3b;

R3ameans (ness.)alkyl, di(ness.)alkylamino, benzyl, Hairdryer is l or phenyl, monosubstituted (ness.)by alkyl;

R3bmeans benzyl or phenyl, monosubstituted (ness.)by alkyl;

provided that when R3means hydrogen, R1selected from the group consisting of 2-haloethanol, 4-(ness.)the alkoxyphenyl, 3-(ness.)alkylphenyl, 4-halogen-2-(ness.)alkylphenyl, 3-halogen-2-(ness.)alkylphenyl, 4-halogen-3-(ness.)alkylphenyl, 2-halogen-4-(ness.)alkylphenyl, 3-halogen-4-(ness.)alkylphenyl, 2-(ness.)alkoxy-4-(ness.)alkylphenyl, 3-(ness.)alkoxy-4-(ness.)alkylphenyl, 4-(ness.)alkoxy-2-(ness.)alkylphenyl, 4-(ness.)alkoxy-3-(ness.)alkylphenyl, 3-(ness.)alkoxy-2-(ness.)alkylphenyl, phenyl, substituted halogenated (ness.)alkoxy or di(ness.)alkylamino, phenyl, substituted by two or three groups independently selected from halogen, (ness.)alkoxy, halogenated alkoxy, and di(ness.)alkylamino, phenyl, substituted (ness.)alkyl group or one or two groups selected from halogenated alkoxy and di(ness.)alkylamino, and phenyl substituted with two (ness.)alkyl group and a group selected from halogen, (ness.)alkoxy, halogenated alkoxy, and di(ness.)alkylamino.

11. The compounds of formula (Ia) of claim 10 or their pharmaceutically acceptable salt,

where R1means phenyl, mono-, di - or tizamidine independently by halogen, (ness.)alkoxy, (ness.)the alkyl, halogenated (ness.)Alcock and go di(ness.)alkylamino;

R2means phenyl, mono - or disubstituted independently with halogen, halogenated (ness.)by alkyl, nitro or cyano;

R3means nitro, amino, -NHSO2-R3aor-NHCO-R3b;

R3ameans (ness.)alkyl, di(ness.)alkylamino, benzyl, phenyl or phenyl, monosubstituted independently (ness.)by alkyl; and

R3bmeans benzyl, phenyl, monosubstituted (ness.)the alkyl.

12. The compounds of formula (Ia) according to claim 11, selected from the group consisting of

2-chloro-N-(4-ethoxyphenyl)-4-fluoro-N-(6-nitrobenzothiazole-2-yl)benzamide,

2-chloro-N-(4-ethoxyphenyl)-N-(6-nitrobenzothiazole-2-yl)benzamide,

2,4-dichloro-N-(4-ethoxyphenyl)-N-(6-nitrobenzothiazole-2-yl)benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)benzamide,

N-(6-aminobenzothiazole-2-yl)-2,4-dichloro-N-(3,4-acid)benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-methanesulfonylaminoethyl-2-yl)-benzamide,

N-[6-(butane-1-sulfonylamino)benzothiazol-2-yl]-2,4-dichloro-N-(3,4-dimethoxy-phenyl)benzamide,

N-[6-(dimethylamino-1-sulfonylamino)benzothiazol-2-yl]-2,4-dichloro-N-(3,4-acid)benzamide,

N-(6-benzensulfonamidelor-2-yl)-2,4-dichloro-N-(3,4-acid)-benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-phenylmethanesulfonyl-2-yl)benzamide,

2,4-dichloro-N-(3,4-acid)-N-[6-(toluene-2-sulfonylamino)benzothiazol-2-yl]benzamide,

2,4-dichloro-N-(3,4-acid)-N-(6-phenylacetylamino-2-yl)benzamide,

2-chloro-N-(3,4-acid)-N-(6-nitrobenzothiazole-2-yl)benzamide,

N-(6-aminobenzothiazole-2-yl)-2-chloro-N-(3,4-acid)benzamide,

2-chloro-N-(3,4-acid)-N-(6-methanesulfonylaminoethyl-2-yl)-benzamide,

N-[6-(butane-1-sulfonylamino)benzothiazol-2-yl]-2-chloro-N-(3,4-acid)-benzamide,

N-[6-(dimethylamino-1-sulfonylamino)benzothiazol-2-yl]-2-chloro-N-(3,4-dimethoxy-phenyl)benzamide,

N-(6-benzensulfonamidelor-2-yl)-2-chloro-N-(3,4-acid)-benzamide,

2-chloro-(3,4-acid)-N-(6-phenylmethanesulfonyl-2-yl)-benzamide,

2-chloro-N-(3,4-acid)-N-[6-(toluene-2-sulfonylamino)benzothiazol-2-yl]-benzamide,

N-(6-(2-methylbenzylamino)benzothiazol-2-yl)-2-chloro-N-(3,4-acid)benzamide,

or their pharmaceutically acceptable salt.

13. The compounds of formula (Ia) of claim 10, where R3means hydrogen, a R1choose from 3,5-dichlorophenyl, 3,4-dichlorophenyl, 4-chloro-2-methylphenyl and 4-chloro-3-methoxyphenyl.

14. The compounds of formula (1A) according to claim 10, where R3means hydrogen, a R1choose from 4-(ness.)the alkoxyphenyl, 3,4-di(ness.)the alkoxyphenyl, 3,4,5-three(nissanmaxima and 3-(ness.)alkoxy-4-(ness.)alkylphenyl.

15. The compounds of formula (1A) according to claim 10, where R3means hydrogen, a R1means phenyl, substituted halogenated (ness.)alkoxy or di(ness.)alkylamino.

16. The compounds of formula (1A) according to claim 10, selected from the group consisting of

N-benzothiazol-2-yl-2-chloro-N-(3,5-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dichlorophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-2-were)benzamide,

N-benzothiazol-2-yl-2-fluoro-N-(4-methoxyphenyl)-4-cryptomelane,

N-benzothiazol-2-yl-N-(4-methoxyphenyl)-2,4-bitreversed,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-methoxyphenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-4-cyano-N-(4-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-N-(4-ethoxyphenyl)-2-fluoro-4-cryptomelane,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-4-cyano-N-(4-ethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-ethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichl the p-N-(4-ethoxyphenyl)benzamide,

N-benzothiazol-2-yl-N-(3,4-acid)-2-fluoro-4-cryptomelane,

N-benzothiazol-2-yl-N-(3,4-acid)-2,4-bitreversed,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)-4-nitrobenzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-acid)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-acid)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-dimethylaminophenyl)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-N-(4-dimethylaminophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-diethylaminophenyl)-4-nitrobenzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-diethylaminophenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3-methoxy-4-were)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dioxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4,5-trimethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dioxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(3,4,5-trimethoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(3-methoxy-4-were)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(3,4-dioxyphenyl)-4-fermentated,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-isopropoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(3,4,5-trimethoxybenzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-trifloromethyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-trifloromethyl)benzamide,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-trifloromethyl)benzamide,

N-benzothiazol-2-yl-2-chloro-N-(4-chloro-3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-3-methoxyphenyl)benzamide,

N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-chloro-3-methoxyphenyl)benzamide,

and their pharmaceutically acceptable salts.

17. Pharmaceutical composition having the properties of a receptor antagonist SV1comprising as active ingredient a compound of the formula (I)

where R1means phenyl, mono-, di - or tizamidine independently by halogen, (ness.)alkoxy, (ness.)the alkyl, halogenated (ness.)alkoxy or di(ness.)alkylamino;

R2means phenyl, mono - or disubstituted independently with halogen, halogenated (ness.)by alkyl, nitro or cyano;

R3means hydrogen, nitro, amino, -NHSO2-R3aor-NHCO-R3b;

R3ameans (ness.)alkyl, di(ness.)alkylamino, benzyl, phenyl or phenyl, monosubstituted independently (ness.)by alkyl;

R3bmeans benzyl or phenyl, monosubstituted (ness.)by alkyl;

or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and/or excipient.

18. The use of compounds of formula (I) according to claim 1 as therapeutically active substances for obtaining a medicinal product having the properties of a receptor antagonist SV1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. Method involves the following successive steps: (i) interaction of bromine with 4-acetamidocyclohexanone an aqueous solution to yield 2-bromo-4-acetamidocyclohexanone; (ii) addition of thiourea to yield 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole; (iii) addition of hydrobromic acid an aqueous solution to yield 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole without isolation of 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole synthesized at stage (ii); (iv) isolation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and if necessary separation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole isolated at stage (iv) for R-(+)- and S-(-)-enantiomers, and isolation of R-(+)- and/or S-(-)-enantiomer. 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole is used for synthesis of pramipexole. Also, invention relates to a method for synthesis of pramipexole by synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole by using the method said and its conversion to pramipexole and if necessary by separation of pramipexole for its R-(+)- and S-(-)-enantiomers and isolation of R-(+)- and/or S-(-)-enantiomer.

EFFECT: improved method of synthesis.

15 cl, 1 sch, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds that possess affinity for adenosine A2A-receptors and represent compounds of the general formula: wherein R1 and R2 represent independently hydrogen atom, lower alkyl, tetrahydropyrane-2,3- or 4-yl, -(CH2)n-O-lower alkyl, -C(O)-lower alkyl, -(CH2)n-C(O)-lower alkyl, -(CH2)n-C(O)-NR'R'', -(CH2)n-phenyl substituted optionally with lower alkyl, lower alkoxy-group or -(CH2)n-pyridinyl, -(CH2)n-tetrahydropyrane-2,3- or 4-yl, -C(O)-piperidine-1-yl; or R1 and R2 in common with nitrogen atom (N) to which they are added form the ring 2-oxa-5-azabicyclo[2,2,1]hept-5-yl; R3 represents lower alkoxy-group, phenyl substituted optionally with halogen atom, -(CH2)n-halogen or -(CH2)n-N(R')-(CH2)n+1-O-lower alkyl, or represents pyridinyl substituted optionally with lower alkyl, halogen atom or morpholinyl; n means 1 or 2; R'/R'' represent independently of one another hydrogen atom or lower alkyl, and their pharmaceutically acceptable acid-additive salt. Except for, invention relates to a medicinal agent showing affinity to adenosine A2A-receptors containing one or some compounds by any claims 1-11, and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds and agents.

13 cl, 38 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

FIELD: medicine, organic chemistry.

SUBSTANCE: the present innovation deals with new benzothiazole derivatives and medicinal preparation containing these derivatives for treating diseases mediated by adenosine receptor A2.A.. The present innovation provides efficient treatment of the above-mentioned diseases.

EFFECT: higher efficiency of therapy.

14 cl, 354 ex

The invention relates to new derivatives of benzothiazole General formula (I) or its salt, where p denotes 1; X1and X2together form =O; R1denotes hydrogen, halogen, alkyl, alkoxy; R2denotes hydrogen; R3denotes a-Z4-R6, -Z13-NR7R8; Z4denotes a-Z11-C(O)-Z12-, -Z11-C(O)-O-Z12-; Z11and Z12represent a simple bond or alkylene; Z13denotes a-Z11-C(O)-Z12-; R4denotes hydrogen; R5denotes phenyl, substituted groups Z1, Z2selected from alkyl, halogen, nitro, -HE, hydroxyalkyl, -C(O)Z6, -C(O)OZ6-Z4-NZ7Z8where Z4represents a simple bond; biphenyl, substituted alkyl; naphthalenyl, which optionally can be substituted-HE; chinoline, substituted alkyl; heterocyclics; Z6denotes alkyl which may be optionally substituted by a group-Z4-NZ7Z8, morpholinium; Z7, Z8each independently represents alkyl; R6denotes alkyl optionally substituted by cyano, methoxy, phenyl, -Z4-NZ7Z8and so on; R7denotes hydrogen, alkyl; R8denotes alkyl, the long is Z4-NZ7Z8; and t

The invention relates to the production of derivatives of 3-amino-2-mercaptobenzoic acid of the formula I, in which X represents fluorine, n = 0 or 1, Z represents CO-a or CS-A1A represents hydrogen, halogen, OR1or SR2, A1denotes hydrogen or or1, R1and R2denote hydrogen, substituted or unsubstituted, saturated or unsaturated hydrocarbon radical with an open chain, containing not more than 8 carbon atoms; the interaction of the compounds of formula II in which T represents hydrogen, C1-C6alkyl, C3-C6alkenyl,3-C6quinil,3-C6cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl; with aqueous strong base

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to organic chemistry, in particular to the synthesis of substituted 6-hydroxybenzothiazole containing labile fragments

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new condensed dicyclic nitrogen-containing heterocycles with the general formula (I), their pharmaceutically accepted salts and stereoisomers, possessing DGAT inhibiting action. In the compound of formula (I): , X is selected from a group, which consists of C(R1) and N; Y is selected from a group, which consists of C(R1), C(R2)(R2), N and N(R2); Z is selected from a group, which consists of O; W1 is selected from cyclo(C3-C6)alkyl, aryl and 5- or 6-member heteroaryl, containing 1-2 heteroatoms, selected from a group, which comprises of nitrogen and sulphur, W2 selected from cyclo(C3-C8)alkyl, (C5-C6)heterocycloalkyl, containing 1 or 2 heteroatoms, selected from groups, consisting of nitrogen or oxygen, benzol and 5-or 6-member heteroaryl, containing 1-2 nitrogen atoms as heteroatoms, L1 is the link; L2 is selected from a group consisting of links, 0, (C1-C4)alkylene and (C1-C4)oxyalkylene; m denotes 0 or 1; its not a must that when m denotes 1 and L2 denotes a link, the substitute for W2 can be integrated with the substitute for W1 forming a 5-or 6-member ring, condensed with c W1 forming a spiro-system or condensed with W2, where specified ring could be saturated or unsaturated and has 0 or 1 atom O, as a member of the ring R1 is H; R2 is H; R3 and R4 are independently selected from groups consisting of H and (C1-C8) alkyl; optionally, R3 and R4 can together form 3-, 4-, 5- or 6-member spirorings, R5 and R6 are independently H; optionally, when Y includes the group R1 or R2, R5 or R6 can be joined with R1 and R2 forming a 5- or 6-member condensate ring, containing a nitrogen atom, to which R5 or R6 are joined, and optionally containing an oxo-group; R7 is selected from a group, composed of H, (C1-C8) alkyl, halogen(C1-C4)alkyl, 0Ra and NRaRb ; Ra selected from groups composed of H and (C1-C8)alkyl; and Rb selected from groups consisting of H and (C1-C8)alkyl; a dotted line indicates a possible bond. The invention also relates to pharmaceutical compositions and applications of the compounds.

EFFECT: obtaining compounds which can be used for getting medicinal agents to treat or prevent diseases or a mediated action state of DGAT, such as obesity, diabetes, syndrome X, resistance of insulin, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, disease of non-alcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, coronary artery disease and myocardial infarction.

33 cl, 17 dwg, 11 tbl, 391 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to agonist of receptor of glucagone-like peptide-1, which can be applied for treatment of diseases, caused by disturbance of glycometabolism, such as type II diabetes, insensibility to insulin or obesity. In structural formula each of Ar1 and Ar2 independently represents substituted phenyl, and group-substituents represent one, two or three groups selected from C1-C6alkoxyl, C1-C6-alkanoylamino, which is substituted with hydroxyl (which contains groups-substituents, including hydroxyl); C3-C6-cyclolkanoylamino, C2-C6-lkenoylamino; banzoylamino, banzyloxy C1-C6-alkanoylamino, thenoyloxy, tret-butoxyformamido, adamantanformamido; and mandeloylamino; X represents O; Y represents O. Invention also relates to method of obtaining agonist, and to its application for obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

EFFECT: obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

8 cl, 4 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: described is obtaining and pharmaceutical application of substituted derivatives of arylalkane acid of formula I , where ring A, ring B, R1, R2, R3, R4, R5, X, Alk1, Alk2, Ar1 and Ar2 are such as determined in said description. Said compounds, as selective agonists activating (RAPPs) receptors, activated by peroximal proliferator, in particular, RXRs/RAPPs-alfa, RXRs/RAPPs-gamma and RXRs/RAPPs-delta heterodimers, are applied in treatment and/or prevention of type 2 diabetes and connected with it metabolic syndrome, such as hypertension, obesity, insulin-resistence, hyperlipidemia, hyperglycemia, hyperolesterinemia, artheriaslerosis, coronary artery disease, and other cardio-vascular disorders, and possess improved profile of side effects, connected with common RAPPs-gamma agonists.

EFFECT: obtaining compunds, which possess improved profile of side effects, connected with common RAPPs-gamma agonists.

22 cl, 38 ex, 2 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

EFFECT: using compounds as biologically active agent and creating pharmaceutical compositions based on said compounds.

124 cl, 52 ex, 17 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: preparations Zonisamide and Bupropion are used in combination.

EFFECT: provides effective weight reduction due to synergetic effect of these preparations on organism.

7 cl, 4 ex, 2 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: nutraceutical composition is intended for treatment or prevention of adiposity or the conditions bound to adiposity, such as achrestic diabetes (AD, type II) and a syndrome X which includes effective amounts of epigallocatechine gallate (EGCG) and 4 (4-hydroxyphenyl)-2-butanone (KM). Also the method of treatment or prevention of adiposity or the conditions bound to adiposity, such as achrestic diabetes (AD, type II) both a syndrome X and application of EGCG and KM in manufacture of nutraceutical composition is revealed.

EFFECT: synergistic effect at adiposity treatment or prophylaxes.

9 cl, 4 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula (I) , where: R and Ri stand for phenyl, which can be substituted with 1, 2, 3 or 4 substitutes, which can be identical or different and chosen from a group consisting of chlorine, iodine, bromine, fluorine, trifluoromethyl and cyano. R2 and R3 can be identical or different and represent C1-5 branched or straight alkyl group. The alkyl group can be substituted with 1-3 fluorine atoms, or R2 and R3 - together with a nitrogen atom, with which they are bonded to, form pyrrolidine or piperidine ring. R7 represents hydrogen, C3-8 cycloalkyl, pyrrolidinyl or piperidinyl. The invention also pertains to salts of these derivatives used in pharmacology, as well as to compounds with general formula (IV), their pharmaceutical compositions, and their use.

EFFECT: obtaining new biologically active compounds which can function as modulators of cannabinoid receptors.

9 cl, 3 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: application of asimadolin or its pharmaceutically acceptable sals is proposed for preparation of pharmaceuticals for indigestion treatment: gastroparesis, gastroatonia, gastroparalysis and the digestive tract stenosis in particular. Medication is effective for tonus modulating of the digestive tract, satiation. Registered, that asimadolin (N-methyl-N-[(1S)-1-phenil-2-((3S)-3-hydroxipyrrolidin-1-il)ethyl]-2,2-dyphenylacetylene (EMD 61753), a selective modulator of the opiate kappa-receptors) depending on the dose, contributes to consumed food volume increase without afterdinner symptoms: bloat, nausea, pain after meal.

EFFECT: creation for effective medication for tonus modulating of digestive tract, satiation.

8 cl, 5 dwg, 4 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

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