Pyranoindazoles, pharmaceutical composition based on thereof and their using in glaucoma treatment

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new pyranoindazoles of the formula (1): wherein R1 and R2 are chosen independently from hydrogen atom or alkyl group; R3 and R4 represent independently hydrogen atom or alkyl group; R5, R6 and R7 mean hydrogen atom; R8 and R9 mean hydrogen atom, hydroxyl, alkoxy-group, -NR10R11, -OC(=O)NR1R2, -OC(=O)-(C1-C4)-alkyl or alkylthiol; R10 and R11 mean hydrogen atom; A means -(CH2)n, C=O; B means a simple or double bond; n = 0-2; Y means nitrogen atom (N); X means carbon atom C; dotted line means the corresponding simple or double bond. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), to a method for regulating normal or enhanced intraocular pressure, method for treatment of glaucoma and method for blocking or binding serotonine receptors. Invention provides preparing new pyranoindazoles possessing the valuable pharmaceutical effect.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 4 tbl, 22 ex

 

This application will require priority based on provisional application for U.S. patent No. 60/295 429, filed June 1, 2001, and is incorporated fully by reference.

Background of invention

The present invention relates to various pyrenoidosa. These new compounds are useful for the reduction and control (regulation) normal or elevated intraocular pressure (IOP) and glaucoma treatment.

A painful condition related to glaucoma, is characterized by the presence of a permanent loss of visual function due to irreversible changes of the optic nerve. Several morphologically or functionally different types of glaucoma are typically characterized by elevated IOP, which is considered as the cause, associated with the pathological progression of the disease. Ocular hypertension is a condition in which the intraocular pressure is elevated, but without obvious loss of visual function, and such patients are considered as having a high risk potential for the development of vision loss associated with glaucoma. If glaucoma or intraocular hypertension to identify at an early stage and be subjected to appropriate treatment drugs that can effectively reduce elevated intraocular pressure, loss of visual function or aprogressive deterioration can be largely reduced. Drug therapy, which is effective to reduce intraocular pressure, includes tools that reduce the formation of ocular fluids, and tools that increase the outflow (the ability to excretion of fluid). This therapy is carried out mainly through the introduction of drugs in one of two possible ways, namely, by local injection (direct injection into the eye), or by oral administration.

However, there are some individuals who are unable to respond adequately to treatment carried out in the framework of the existing methods of treatment of glaucoma. In this context, there is a need to develop other local therapeutic agents that would be able to control IOP.

There are reports that serotonergic agonists 5-HT1Ahave on animal models, neuroprotective, and many of these funds have been tested, among other indications for their use, for the treatment of acute disorders of cerebral circulation. This class of compounds was noted as a means for the treatment of glaucoma (lowering and controlling IOP), in particular in WO 98/18458 (DeSantis, et al.) and EP 0771563 A2 (Mano, et al.), in the work of Osborne et al. (Osborne, et al., Ophthalmologica, Vol.210:308-314, 1996), which reveals that 8-hydroxydiphenylamine (8-OH-DP IS T) (agonist 5-HT 1A) reduces IOP in rabbits. Wang et al. (Wang, et al., Current Eye Research, Vol. 16(8):769-775, August 1997 and IVOS, Vol. 39(4), S488, March 1998) indicate that 5-methylpropenyl, α1Aantagonist and 5-HT1Aagonist reduces IOP in monkeys, but due to their activity against α1Athe receptor. Also indicates that antagonists of 5-HT1Auseful for the treatment of glaucoma (increased intraocular pressure) (for example, WO 92/0338, McLees)). In addition, Desai et al. (DeSai et al., WO 97/35579) and Makor et al. (Macor et al., US 5 578 612) consider the use of 5-HT1and 5-HT1-like agonists for the treatment of glaucoma (increased intraocular pressure). These connections with protivomigrenoznoe activity, such as sumatriptan and naratriptan, as and related compounds are agonists of 5-HT1B,D,E,F.

It was shown that serotonergic compounds that have agonist activity against 5-HT2receptors, effectively reduce and control normal and elevated IOP and useful in the treatment of glaucoma, look simultaneously considering an application PCT/US99/19888 included in this description fully by reference. Compounds that act as agonists of 5-HT2receptor, a well-known and demonstrated many useful properties, especially in the case of diseases or conditions associated with Central nervous system (CNS). Paten the U.S. No. 5 494 928 relates to certain derivatives of 2-(indol-1-yl)ethylamine, which are agonists of 5-HT2Cfor the treatment of neurosis obsessive-compulsive disorder and other personality disorders of Central origin. U.S. patent No. 5571833 relates to the derivatives of tryptamine, which are agonists of 5-HT2for the treatment of portal hypertension and migraine. U.S. patent No. 5874477 relates to a method of treating malaria with the use of agonists of 5-HT2A/2C. U.S. patent No. 5902815 refers to the use of agonists of 5-HT2Ato prevent adverse (side) effects associated with hypofunction of the NMDA receptor. WO 98/31354 relates to agonists of 5-HT2Bused to treat depression and other conditions of the Central nervous system. WO 00/12475 refers to a derivative of indoline, WO 00/12510 and WO 00/44753 belong to some derivative of indole, which are agonists of 5-HT2Band5-HT2Creceptor used for the treatment of various disorders of the Central nervous system, in particular for the treatment of obesity. WO 00/35922 relates to certain derivatives pyrazino[1,2-a]finokalia, which are agonists of 5-HT2Cused for the treatment of neuroses and obsessions, depression, disorders of appetite and other disorders that involve the Central nervous system. WO 00/77002 and WO 00/77010 refer to certain substituted tetracyclic pyrido[4,3-b]indoles, which are agonists of 5-HT2Cfrom the point of view of their application DL the treatment of disorders of the Central nervous system, including, among others, obesity, anxiety, depression, sleep disorders, headache, and social phobia. Specifies that the response of the agonist on the 5-HT2Athe receptor is the main activity responsible for the hallucinogenic effect, with the participation of 5-HT2Creceptor plays a smaller role [Psychopharmacology, Vol. 121:357, 1995].

Describes several condensed indazols containing furan or Piran. Chemical synthesis of 7-methyl - 1,7-dimethyl-1H-furo[2,3-g]indazole [Gazz. Chim. Ital. 106, 1083 (1976)], and 3-methyl - 1-(4-AMINOPHENYL)-3-methyl-1H-benzo[b]furo[2,3-g]indazole ['an. Asoc. Quim. Argent. 59, 69 (1971)] described without discussion of their application potential. The application for the European patent EP 990650 (international publication Number WO 98/56768) relates to substituted 2-(furo[2,3-g]indazol-1-yl)ethylamine, such as (S)-2-(furo[2,3-g]indazol-1-yl)-1-methylethylamine, which, according to the authors, have high selectivity and affinity in relation to 5-HT2Creceptors and are potentially useful for the treatment of various disorders of the Central nervous system. Chemical synthesis of 9-methyl-1H-pyrano[2,3-g]indazol-7-she and the corresponding demetilirovannogo compounds described in the literature [Indian J. Chem. 26B, (1987)], without indications of the possibilities of its application.

U.S. patent No. 5561150 and 5646173 are related to certain derivative compounds tricyclic pyrazole, which is s identified as agonists of 5-HT 2Csuitable for treating diseases of the Central nervous system and is primarily focused on their lipophilic analogues with high probability of entering into the brain. Similarly, WO 98/56768 relates to tricyclic antagonists of 5-HT2Cfor the treatment of diseases of the Central nervous system. All of the above, as well as the following patents and publications is incorporated into this description in full as references.

5-Hydroxytryptamine (serotonin) does not pass through the blood-brain barrier and enters the brain. However, to increase serotonin levels in the brain, you can enter 5-hydroxy-tryptophane. Transportation 5-hydroxytryptophan in the brain is easily accomplished and in brain 5-hydroxy-tryptophane easily decarboxylated with the formation of serotonin.

Accordingly, there is a need to develop new compounds that would be free from the above disadvantages and which would provide increased chemical stability and the desired duration of therapeutic activity in the case, for example, use them to reduce intraocular pressure and treating glaucoma.

A brief description of the invention

The object of the present invention is to develop new compounds that are agonists of 5-HT2.

Another object of the present invention is to develop compounds that about adut high chemical stability and which are useful from the point of view of reduction or control (regulation) normal or elevated intraocular pressure and/or glaucoma treatment.

Another object of the present invention is to develop compounds that provide the desired level of therapeutic activity for reducing or controlling normal or elevated intraocular pressure and/or glaucoma treatment.

Additional objects and advantages of the present invention will be indicated in part in the description below, and they will be partially apparent from the above description, or they may be identified in practice in the implementation of the present invention. The objectives and other advantages of the present invention can be assessed and achieved by means of the elements and their combinations specified in the description and in the accompanying claims.

To achieve these and other advantages and in accordance with the purposes of the present invention, which constitute its essence and is widely represented in the present description, this invention relates to a compound having the formula I:

or its pharmaceutically acceptable salt or solvate or proletarienne form compounds of formula I. In the formula

R1and R2independently selected from hydrogen or alkyl groups, such as1-4alkyl;

R3and R4independently selected from hydrogen or alkyl groups, such as1-4alkyl, or R 3and R4and the carbon atom to which they are attached, may form cycloalkyl ring or forth,

R2and R3together may represent (CH2)mwith the formation of saturated heterocycle;

R5selected from hydrogen, halogen, alkyl group, such as1-6alkyl or C1-4alkyl substituted by halogen;

R6and R7independently selected from hydrogen, halogen, cyano, alkylthio, such as1-4alkylthio, alkyl, such as1-4alkyl, or substituted alkyl, such as1-4alkyl substituted by halogen;

R8and R9independently selected from hydrogen, hydroxyl, alkyl, such as1-6alkyl, alkoxy, such as1-6alkoxy, =O, NR10R11, OC(=O)NR1R2, OC(=O)1-4of alkyl, alkylthiol, such as1-6alkylthiol, substituted alkyl, such as1-6alkyl, substituted with halogen, hydroxyl or NR10R11;

R10and R11independently selected from hydrogen, alkyl groups, such as1-4alkyl, C(=O)1-4alkyl, C(=O)OC1-4alkyl, C(=O)NR1R2or substituted alkyl, such as1-6alkyl, substituted with halogen, hydroxyl, NR1R2or R10and R11together can form a saturated 5 - or 6-membered heterocyclic ring, which is th can include an additional heteroatom, selected from N, O or S, in the case of a 6-membered ring;

And means (CH)n, C=O or CHC1-4alkyl;

B denotes a single or double bond, in the case when B is a double bond, R8and R9selected from hydrogen or a saturated or unsaturated alkyl group;

m=2-4;

n=0-2;

X and Y represent N or C, with X and Y differ from each other; and

the dotted line indicates the corresponding single or double bond.

The present invention also relates to pharmaceutical compositions containing at least one compound of formula I.

The present invention also relates to methods of reducing or controlling normal or elevated intraocular pressure by introducing an effective amount of a composition containing the compound having the above formula I.

The present invention also relates to a method for treatment of glaucoma, which includes the introduction of an effective amount of a composition containing the compound having the above formula I.

It should be understood that the following as a General description and the detailed description of the invention are merely illustrative and are intended to illustrate the invention under examination, the essence of which is expressed in the accompanying claims.

Detailed description of the present invention

The present invention relates to a multitude of compounds, useful when used in accordance with the present invention. These connections are mainly described by formula I

In the formula

R1and R2independently selected from hydrogen or alkyl groups, such as1-4alkyl;

R3and R4independently selected from hydrogen or alkyl groups, such as1-4alkyl, or R3and R4and the carbon atom to which they are attached, may form cycloalkyl ring (for example, cyclopropyl ring) or later,

R2and R3together may represent (CH2)mwith the formation of saturated heterocycle;

R5selected from hydrogen, halogen, substituted or unsubstituted alkyl group, such as1-6alkyl or C1-4alkyl substituted by halogen;

R6and R7independently selected from hydrogen, halogen, cyano, alkylthio, such as1-4alkylthio, alkyl, such as1-4alkyl, or substituted alkyl, such as1-4alkyl substituted by halogen;

R8and R9independently selected from hydrogen, hydroxyl, alkyl, such as1-6alkyl, alkoxy, such as1-6alkoxy, =O, NR10R11, OC(=O)NR1R2, OC(=O)1-4the alkyl and kiltie, such as1-6alkylthiol, substituted alkyl, such as1-6alkyl, substituted with halogen, hydroxyl or NR10R11;

R10and R11independently selected from hydrogen, alkyl groups, such as1-4alkyl, C(=O)1-4alkyl, C(=O)OC1-4alkyl, C(=O)NR1R2or substituted alkyl group, such as1-6alkyl, substituted with halogen, hydroxyl, NR1R2or R10and R11together can form a saturated 5 - or 6-membered heterocyclic ring which can contain an additional heteroatom selected from N, O or S, in the case of a 6-membered ring;

And means (CH2)nor CHC1-4alkyl;

B denotes a single or double bond, in the case when B is a double bond, R8and R9selected from hydrogen, alkyl groups, such as1-4alkyl, or substituted alkyl groups, such as1-4alkyl, substituted with halogen, hydroxyl or NR10R11;

m=2-4;

n=0-2;

X and Y represent N or C, with X and Y differ from each other; and the dotted line indicates the corresponding single or double bond.

Pharmaceutically acceptable salt and solvate and proletarienne forms of the compounds of formula I also form part of the present invention.

The preferred compounds are:

Those in which R1and R2independently selected from hydrogen or C1-4of alkyl;

R3and R4independently selected from hydrogen, C1-4the alkyl or R2and R3together may represent (CH2)mwith the formation of saturated heterocycle;

R5selected from hydrogen, halogen, or C1-6of alkyl;

R6and R7independently selected from hydrogen, halogen, cyano, C1-4alkylthio,1-4the alkyl or C1-4of alkyl, substituted with halogen;

R8and R9independently selected from hydrogen, hydroxyl, C1-6of alkyl, C1-6alkoxy, NR10R11or1-6of alkyl, substituted with halogen, hydroxyl or NR10R11;

R10and R11independently selected from hydrogen, C1-4of alkyl, C(=O)1-4of alkyl, C(=O)OC1-4of alkyl, C(=O)NR1R2or R10and R11together can form a saturated 6-membered heterocyclic ring which can contain an additional heteroatom selected from N, O or S;

And means (CH2)nor CHC1-4alkyl;

B denotes a single or double bond, in the case when B is a double bond, R8and R9selected from hydrogen, C1-4the alkyl or C1-4of alkyl, substituted with halogen, hydroxy or NR10R11;

m=3-4;

n=1-2;

p> X and Y represent N or C, with X and Y differ from each other; and

the dotted line indicates the corresponding single or double bond.

The most preferred compounds are:

Those in which R1and R2independently selected from hydrogen or C1-4of alkyl;

R3stands With1-2alkyl, or R2and R3together may represent (CH2)3with the formation of pyrrolidine;

R4denotes hydrogen;

R5selected from hydrogen or C1-6of alkyl;

R6and R7independently selected from hydrogen, halogen, or C1-4of alkyl;

R8and R9independently selected from hydrogen, hydroxyl, C1-6alkoxy, NR10R11or1-6of alkyl, substituted by hydroxyl or NR10R11;

R10and R11independently selected from hydrogen, C1-4of alkyl, C(=O)1-4the alkyl or R10and R11together can form a saturated 6-membered heterocyclic ring which can contain an additional heteroatom selected from N, O or S;

And means (CH2)n;

B denotes a single bond;

n=1;

X is C and Y represents N; and

the dotted line indicates the corresponding single or double bond.

Representative examples of preferred compounds of formula I in which luchot:

1-(2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

(R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

(S)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S)-2-aminopropyl)-3-methyl-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-(S)-1-pyrrolidin-2-ylmethyl-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S)-2-aminopropyl)-5-fluoro-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

(R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ylamine;

[1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-yl]dimethylamine;

[1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-yl]methanol;

1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8,9-diol;

1-((S)-2-aminopropyl)-9-methoxy-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-(2-aminopropyl)-3,7,8,9-tetrahydropyrido[3,2-e]indazol-8-ol;

1-(pyrrolidin-2-ylmethyl)-3,7,8,9-tetrahydropyrido[3,2-e]indazol-8-ol;

1-((S)-2-aminopropyl)-3,7,8,9-tetrahydropyrido[3,2-e]indazol-8-ol;

1-((S)-2-aminopropyl)-3-methyl-3,7,8,9-tetrahydropyrido[3,2-e]indazol-8-ol;

or combinations thereof.

Some compounds of formula I can contain one or more chiral centers. The present invention includes all enantiomers, diastereomers and mixtures thereof.

In the above definitions, the total number of carbon atoms in substitutional groups is indicated by the prefix C i-jwhere numbers i and j denote the number of carbon atoms. This definition covers a linear chain, branched chain and cyclic or (cycloalkyl) alkyl groups. The Deputy can be represented in a single or plural, when it is included in the specified unit. For example, in the case of the halogen substituent, which represents fluorine, chlorine, bromine or iodine, meaning that the structure to which it is attached may be substituted by one or more halogen atoms, which may be the same or different.

Synthesis

The compounds of formula I can be obtained using one of several synthetic methods. So, for example, 1-(2-aminomethyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-Ola can be obtained from an appropriately protected 1-(6-hydroxyindole-1-yl)propan-2-ol 1, as shown in figure 1. Pg denotes a suitable protective group which is introduced to ensure that a particular atom will not be modified during the review of the chemical reaction.

Other compounds of formula I can be obtained from compound 12 by means known in the art transformations of selected functional groups. E.g., by first protecting the primary amino group and subsequent asset what their hydroxyl groups during the formation of sulfate ester, for example methanesulfonyl, and subsequent reaction with the desired nucleophile, such as alkylamines followed, dialkylamino, aryl - or alkylthiol, etc. will result in a connection 14 of the formula I. in Addition, the direct oxidation of 13 with a suitable oxidant, for example hypervalent iodine reagent, such as O-iodoxybenzoic acid [J.Org. Chem.60, 7272 (1995)], gives the ketone 16, which can be functionalized with other compounds of formula I, such as 17, via reductive alkylation, and 15 through the reactions of addition of the Grignard reagent.

Alternatively, the compounds of formula I can be obtained from an appropriately substituted 5-propargylamines (19) through the original rearrangement reaction of Clausena [Tetrahedron Lett. 33, 2179 (1992), ibid. 35, 45 (1994) ibid. 41, 3541 (2000)] with the formation of the intermediate substituted pyrano[2,3-g]indazols 20 (scheme 3). Other procedures of synthesis using 20 as shown, for example, in schemes 3-5, using well-known transformations of functional groups give other desired compounds of formula I.

1-(Hydroxyalkyl)indazols of interest to obtain the compounds of formula I can be synthesized, as shown in nashama 6, and in co-pending application for U.S. patent 60/295 427 included in this description fully by reference. The reaction of activated terfenol 30 with the corresponding aminosterol 31, in the case where And denotes nitrile, leads to the restoration with the formation of the corresponding aldehyde 32. The nitrosation of network connection 33, which after reductive cyclization leads to the production of 1-(hydroxyalkyl)indazols 34.

Intermediate pyrenoidosa 34 can be obtained by alkylation of the corresponding O-protected 6-hydroxyindole (35), in which the corresponding O-protective groups are, for example, methyl or benzyl, using methods known in the prior art and illustrated in scheme 7 [U.S. patent 5494928 (1997), WO 98/30548 (1998)], using the desired epoxide, such as propylene oxide. Alternatively, for purposes of receiving certain compounds may be convenient to conduct the reaction alkylate 35 using chloroacetone and subsequent reduction, for example, using NaBH4intermediate ketone, receiving intermediate 34.

May also be useful to obtain some compounds of formula I to use it appropriately substituted 1,7,8,9-tetrahydropyrido[2,3-g]indazol, t is coy as 36, shown in scheme 8. So, for example, alkylation of compound 36 in the conditions described above in scheme 4, followed by the appropriate activation of the hydroxyl group to achieve nucleophilic amination through the formation of sulfate ester [J.Chem. Soc., Perkins Vol. 1:1479, 1981], for example methanesulfonyl, toluensulfonyl, brompheniramine or nitrophenyloctyl, and subsequent reaction with the desired amine yield compound 38 of formula I.

Next, the reaction indazols 36 carbon alaninol 39 network connection 40, unprotect which gives the connection 38 of the formula I as shown in scheme 9. Replacement 39 figure 9, for example, activated sulphonate ester or the corresponding halide or N-protected (e.g., using tert-butyloxycarbonyl, benzyloxycarbonyl) pyrrolidin-3-methanol leads, after removal aminosidine group, to obtain other compounds of formula I. Further, the substitution of 39 figure 9 activated sulfate ester of N-(2-hydroxy-1,1-dimethyl-ethyl)phthalimide [J. Amer. Chem. Soc., Vol. 108:3811, 1986], 2-[(t-butyloxycarbonyl)amino]-2-methylpropanal [J. Amer. Chem. Soc., Vol. 113:8879, 1991], 1-[(t-butyloxycarbonyl)amino]cyclopropyl-1-methanol [J. Med. Chem., Vol. 31:1694, 1988] or 2-methyl-2-nitro-propane-1-ol [J. Amer. Chem. Soc., Vol. 68:12, 1946] leads, after removal of the N-protective groups pervyh three cases or after nitrogroup reduction, in the latter case, other options for obtaining compounds 38 of formula I.

Some desirable substituted 1,7,8,9-tetrahydropyrido[2,3-g]indazols can be obtained from an appropriately substituted 1H-indazol-6-ol (41), as described in the methods of synthesis described in scheme 10. Alkylation of indazols 41 allyliodide with subsequent processing in the conditions of the rearrangement reaction of Clausena network connection 43. Protection of the hydroxyl group from the other reactions by transformation, for example, ester, such as acetyl, and the like, enabling the protective group on the nitrogen atom, for example, by reaction with the corresponding isocyanide with the formation of ureide, gives the desired alisondusa 45. Epoxidation of olefin using, for example, 3-chloro-perbenzoic acid and subsequent cyclization under alkaline conditions lead to paranoidalnami intermediate 47. The transformation of the hydroxyl group of pyrenoidosa 47 in other functional groups corresponding to the formula I, can be carried out using known in the art transformations of functional groups.

Desirable pyrano[3,2-e]indazol-3-ethylamine 49 (scheme 11) of the formula I can be obtained from an appropriately substituted 3-(2-hydroxypropyl)1H-indazol-5-ol is 48 using, illustrated in schemes 1 and 3 and described in the application for international patent number PCT/US00/31143 included in this description fully by reference.

Compounds according to the present invention can be used to reduce IOP control, including IOP associated with glaucoma, growing at normal pressure, ocular hypertension, and glaucoma in warm-blooded animals, including humans. Because glaucoma treatment is preferably carried out using compounds that are not in the Central nervous system, relatively polar compounds that are agonists of 5-HT2are of special interest. The connection is preferably introduced in the form of pharmaceutical compositions, which are preferably suitable for local delivery in the patient's eye.

Compounds according to the present invention of formula I can be incorporated into pharmaceutical compositions of various types, such as ophthalmic preparations for introduction into the eye (e.g., for local administration, the inside chamber of the eye or by implantation). Compounds preferably include local ophthalmic composition for introduction into the eye. Connections can be combined with ophthalmologist acceptable preservatives, enhancers viscosity, amplifiers pronica is on, buffers, sodium chloride and water to form a water sterile ophthalmic suspensions or solutions. The composition of the solution for ophthalmic applications can be obtained by dissolving the compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include ophthalmologist acceptable surfactant to facilitate the dissolution of the connection. In addition, the ophthalmic solution may contain a means to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hypromellose, methylcellulose, polyvinylpyrrolidone and the like, to improve retention of the composition in the conjunctival SAC. Can also be used gelling tools that include, but are not limited to the above means, gellan and xanthan gum. To obtain sterile ophthalmic compositions ointment active ingredient combined with a preservative in an appropriate medium such as mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel composition can be obtained by suspendirovanie active ingredient in a hydrophilic base, obtained by combination of, for example, carbopol-974 or similar connection in accordance with published Dan is advised to obtain analogous ophthalmic preparations may also include preservatives and means to enhance the tone.

The compounds are preferably prepared in the form of local ophthalmic suspensions or solutions, with a pH of about 5-8. OK these connections are part of the considered compositions in amounts of from 0.01 wt.% up to 5 wt.%, preferably in quantities of from 0.25 wt.% up to 2 wt.% by weight. Thus, in the case of local forms of composition (1-2 drops of the above compositions) to impose on the eye surface from 1 to 4 times a day, as prescribed by the treating physician.

Connections can also be used in combination with other agents used to treat glaucoma, such as, but not ogranichivayas them, β-blockers (such as timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), antagonists α1(for example, nipradilol), antagonists α2(for example, iopidine, brimonidine), mitotic tools (e.g., pilocarpine and epinephrine), analogs of prostaglandins (e.g., latanoprost, travoprost, unoprostone and compounds mentioned in U.S. patent No. 5889052, 5296504, 5422368 and 5151444, "hypotensive lipids (e.g., lumigan and connections specified in the patent No. 5352708) and neuroprotection (for example, the compounds mentioned in U.S. patent No. 6690931, in particular eliprodil and R-elip the Odil, specified in conjunction pending application, U.S.S.N. 06/203350, and the corresponding compounds of WO 94/13275, including memantine.

In the above formulas, the alkyl group can be linear-chain, branched or cyclic, etc. Halogen includes Cl, Br, F or I. Alkoxy denotes an alkyl group that is connected by linkage through an oxygen atom.

Compounds according to the present invention preferably function as 5-HT2agonists and preferably does not take place in the CNS. In more detail, specific compounds according to the present invention includes in its structure a phenolic hydroxyl, which is thought to be comparable with those of the serotonin and, thus, the compounds according to the present invention preferably do not cross the blood-brain barrier and enter the brain. Compounds with the ability to act as 5-HT2agonists that are useful for control of IOP, as well as for the treatment of glaucoma, as was shown in the publication of the application for international patent # WO 00/16761 included in this description fully by reference. Compounds according to the present invention preferably have a high chemical stability and preferably demonstrate the desired level of therapeutic activity, which provides for the reduction or control of IOP.

is soedineniya according to the present invention can be used to control or reduce IOP in warm-blooded animals, including humans. Preferably, the patient is administered an effective amount of the compounds, to achieve the control or reduction of intraocular pressure to acceptable levels. In addition, the compounds according to the present invention can be used for the treatment of glaucoma in warm-blooded animals, including humans, by introducing the patient is effective for the treatment of glaucoma number of connections when the need for such treatment. Examples of suitable quantities of pharmaceutically acceptable compounds according to the present invention include those quantities that are given in the examples.

Another variant of implementation of the present invention is the method of activation or binding to serotonin receptors, including the introduction to the patient an effective amount of at least one compound according to the present invention using amounts that are effective for the activation or binding to serotonin receptors, such as, not limited to the values given in the present description dosage.

Below examples are given to illustrate methods of producing compounds which are the object of the present invention, but they should not be construed as including any limitations of the claims. Preferred compounds of formula I described in point is imarah 4 and 5. The most preferred compound described in example 4. Range of proton magnetic resonance of each of the compounds shown in the examples corresponds to the expected structure.

Method 1

Test for binding to 5-HT2receptor

To assess epinasty serotonergic compounds to the 5-HT2receptors determine their ability to compete with the agonist radioligand [125I]DOI for binding to 5-HT2receptors in the brain, as described below, according to the literature method, including minor modifications (Neuropharmology, 26, 1803 (1987)]. Aliquots of homogenates of cerebral cortex of the rat or human, taken after death (400 μl), was dispersed in 50 mm Tris-HCl buffer (pH of 7.4) and incubated with [125I]DOI (final concentration 80 PM) in the absence or in the presence of methiothepin (final concentration 10 μm) in a total volume of 0.5 ml, to determine total and nonspecific binding, respectively. Mixture for analysis incubated for 1 hour at 23°in polypropylene tubes and the reaction is stopped by rapid filtration under vacuum on glass-fiber filters, Whatman GF/B, pre-soaked in 0.3% polyethylenimine using ice-cold buffer. Instead methiothepin enter the compounds (at various concentrations). Associated with the filter radioactively shall be determined by the method of scintillation spectrometry on a beta counter. To determine indicators of epinasty connection of the received data is analyzed using nonlinear iterative graph built using computer programs [Trends Pharmacol. Sci., 16, 413 (1995)]. The concentration required for inhibition of binding of [125I]DOI 50% of the maximum value, is designated as the value of IR50ori.

Method 2

Functional test at the 5-HT2: mobilization of [Ca2+]I

Study receptor-mediated mobilization of intracellular calcium ([Ca2+]I) using fluorescent tablet reader (counter plates) (FLIPR). Vascular smooth muscle cells rat AG grown in normal DMEM/10% FTS and 10 μg /ml gentamicin. Monolayers fused cells treated with trypsin, receive sediment and resuspending in a normal environment. Cells were seeded in a volume of 50 µl with a density of 20,000 cells/cell in a 96-cell tablets for tissue culture with a black wall and grown for 2 days.

On the day of experiment one ampoule with dye from a set to determine the FLIPR calcium resuspended in 50 ml of FLIPR buffer, consisting of a balanced salt solution Hanks (HBSS), 20 mm HEPES and 2.5 mm probenecid, pH of 7.4. Cells treated with sensitive calcium dye by adding an equal volume (50 ál) to each cell of the 96-lunochod the tablet and incubated with the dye for 1 hour at 23° C.

In the typical case of the investigated compound is stored at a concentration of 25 μm in a solvent comprising 50% DMSO/50% ethanol. The compound is diluted in the ratio 1:50 mixture of 20% DMSO/20% ethanol. For "hit-screening" connection further diluted in the ratio 1:10 in FLIPR buffer and examined at a final concentration of 10 μm. For the experiments on the dose-response connection is diluted in the ratio of 1:50 in FLIPR buffer and make the serially diluted 1:10 with obtaining curves dose-response with 5 or 8 points.

The tablet with the connection and the tablet with the cells is placed in the analyzer FLIPR. In the beginning of the experiment conducted test signal to determine the basal fluorescence signals from cells containing the dye, and to confirm the homogeneity of the signal passing through the tablet. Basal fluorescence is brought to a value 8000-12000 pulses by changing the exposure time, F-stop the camera or the laser power. Set the following parameters of the device for carrying out typical analysis: laser power of 0.3-0.6 W, camera F-stop of F/2 and the exposure time is 0.4 seconds. Add an aliquot (25 μl) of the studied compounds to 100 μl of the cells with the dye with the speed of a spill of 50 μl/sec. The data of fluorescence is collected in real time at intervals of 1.0 second for the first 60 seconds with intervals of 6.0 seconds for 120 secundatum reaction is measured by peak fluorescence intensity minus basal fluorescence and there, where appropriate, expressed as a percentage of the maximum value of the 5-HT-induced response. In the case when connections are examined as agonists versus 10 μm 5-HT, incubated with cells for 15 minutes before adding 5-HT.

Used the above method has resulted in obtaining the data shown in Tables 1-2.

Table 1

Data binding to 5-HT2Areceptor and functional characteristics
ExampleIR50nmEC50nmEfficiency

(Emax%)
32,1914585
42,2565,392
53,4422670
66,5617587
7to 3.7319485
8China 0,6869085
90,27441,491
5-HT0,94164,2101
Table 2

IOP was the reaction in the minds of Cynomolgus monkeys
ExampleDose, mcgThe base value IOP (MND)The percentage reduction in IOP±RMS

Hours after dose
123
430035,17,68±2,9125,8±3,5330,2±4,48
530034,37,9±4,0617,3±a 3.8725,1±4,76
(R)-DOI10031,911,0±to 4.9825,3±2,9734,4±to 4.98

The method of obtaining 1

1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

Stage A: 6 allyloxy-1H-indazol

To a solution of 1H-indazol-6-o is a (20,0 g, 150 mmol) in acetone (450 ml) is added powdered potassium carbonate (22,4 g, 162 mmol), cesium carbonate (2.00 g, 5.7 mmol) and allibiotic (14,63 ml, 160 mmol) and the mixture is stirred for 18 hours at ambient temperature. Add a further quantity of potassium carbonate (5,00 g, 36 mmol) and alreadyd (1.4 ml, 15 mmol) and the mixture is stirred for further 2 hours and then filtered. To the filtrate add water (200 ml) and the volume of the mixture reduced in vacuo to half (twice) and extracted with dichloromethane (I ml). The combined extracts dried (MgSO4) and evaporated to obtain the residue, which is purified by chromatography (silica gel, 20% to 50% EtOAc/hexane) to give yellow solid (14,7 g, 56%): TPL- 110-112°C; LC/MS (+APCI) m/z 175 (M+H). Unreacted starting material cast (4.71 g).

Stage: 7-allyl-1H-indazol-6-ol

A solution of the product obtained at stage A (14.2 g, 82 mmol)in 1,2-dichlorobenzene (90 ml) is refluxed for 6 hours and the reaction mixture is evaporated to obtain the residue, which is purified by chromatography (silica gel, EtOAc) to give a reddish brown solid (8,59 g, 60%), which is used in the next stage: LC/MS (+APCI) m/z 175 (M+H).

Stage C: 7-allyl-1H-indazol-6-silt ether acetic acid

A solution of the product obtained in stage (6,35 g, 37 mmol) in THF (100 ml), containing triethylene the (7,6 ml, 55 mmol), stirred for 5 minutes at ambient temperature, cooled to 0°C (ice bath) and add acetylchloride (2,63 ml, 37 mmol). The mixture was stirred at 0°C for 2 hours, pay an additional amount of acetylchloride (of 0.26 ml, 3.7 mmol) and the mixture is stirred for 10 minutes, then make another batch of acetylchloride (of 0.26 ml, 3.7 mmol) and stirring is continued for 15 minutes. The reaction is quenched by adding triethylamine (1 l) and saturated aqueous sodium bicarbonate solution (100 ml) and the extraction is carried out with ethyl acetate (100 ml). The extracts are dried (MgSO4) and evaporated to obtain an oil (9,27 g)which is purified by chromatography (silica gel, 10% - 50% EtOAc/hexane) to give white solid (3.5 g, 44%): LC/MS (+APCI) m/z 217 (M+H).

Stage D: 7-allyl-1-ethylcarbamate-1H-indazol-6-silt ether acetic acid

To a solution of the product obtained in stage C (2.5 g, 11.6 mmol)in THF (10 ml) add utilizationa (1,01 ml, 13 mmol) and the mixture is heated at 70°C for 18 hours. The reaction mixture is evaporated to obtain a residue, which was purified by chromatography (silica gel, 10% - 50% EtOAc/hexane) to give colorless oil (2.7 g, 81%): LC/MS (+APCI) m/z 288 (M+H).

Stage E: 1-ethylcarbamate-7-oxiranylmethyl-1H-indazol-6-silt ether acetic acid

To a solution of the product obtained in stage D (2.70 g, 9.4 mmol)in dichloro is not (15 ml) is added 3-chloro-perventing acid (2,31 g, of 10.3 mmol, 77% purity) and the mixture was stirred at ambient temperature for 1 hour. Pay an additional amount of 3-chloro-perbenzoic acid (0.2 g, 0.9 mmol) and the reaction is carried out for 3 hours. Then the reaction quenched by adding saturated aqueous sodium bicarbonate solution (100 ml) and the extraction is carried out with dichloromethane (50 ml). The extract is dried (MgSO4) and evaporated to obtain white solids (1,59 g, 56%): Tpl.- 110-111°C; LC/MS (+APCI) m/z 304 (M+H).

Stage F: 1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

To a solution of the product obtained in stage E (1,g, 4,mol), in methanol (100 ml) is added a saturated aqueous solution of potassium carbonate (10 ml) and the mixture is stirred for 18 hours at ambient temperature. To the reaction mixture are added water (200 ml) and the pH adjusted to 7 using concentrated HCl, followed by extraction with ethyl acetate (CH ml). The combined extracts dried (MgSO4) and evaporated to obtain a reddish brown solid (0.84 g, 93%):1H NMR(DMSO-d6) δ 12,77 (s, 1H), 7,94 (s, 1H), 7,49 (d, J =6.0 Hz, 1H), 6,66 (d, J = 6.0 Hz, 1H) 5,02 (t, J=6.0 Hz, 1H), 4,85-of 4.95 (m, 1H), 3,62 (m, 2H), 2,9-3,4 (m, 2H); LC/MS(+APCI) m/z 191 (M+H).

The method of obtaining 2

1-(6-benzyloxyindole-1-yl-propan-2-ol)

Stage A: (6-benzyloxyindole-1-yl-propan-2-ol)

To a stirred cooled (10° (C) suspension hydride NAT the Oia (80,7 g 60% dispersion in mineral oil, 2.02 mol) in anhydrous THF (1.9 l) add a solution of 6-benzyloxyindole (375 g, 1,68 mol) in anhydrous THF (1.9 l), keeping the temperature below 25°C. After 2 hours at 10°With added dropwise a propylene oxide (140 ml, 2.0 mol), keeping the temperature below 25°C. After 48 hours at 10°With added propylene oxide (71 ml, 1.0 mol). After 96 hours at 10°carefully add saturated aqueous solution of potassium dihydrophosphate (3.8 l) and ethyl acetate (3.8 l), the layers separated and the aqueous layer was extracted with 3.8 l of ethyl acetate. The combined organic extracts dried over sodium sulfate and concentrated in vacuo to obtain a solid (520 g, 110%, with the content of mineral oil).

Stage b: N-(5-benzyloxy-2-formylphenyl)-N-(2-hydroxypropyl)formamid

A solution of the product obtained at stage A (172 g)in 1.5 l of dichloromethane is cooled to -78°and ozoniruyut (4% ozone in oxygen). Excess ozone replace oxygen for 5 minutes and then add the dimethyl sulfide (78 ml) and heated to 25°C. the Solution is concentrated to half volume, hold elution through Florisil (Florisil), washed with a mixture of ethyl ether - ethyl acetate, and concentrated in vacuo. The procedure is repeated four times: once using portions 172 g and three times portions 58, the combined products are passed through silica gel (2.5 kg) with a gradient of 0%-80% acetate-hexane, getting after concentration in vacuum oil (351 g, 70%).

Stage C: 4-benzyloxy-2-(2-hydroxypropylamino)benzaldehyde

Chilled with ice a solution of the product obtained in stage (298 g, 0.95 mol)in THF (3 l) was treated with 1 M aqueous sodium hydroxide solution (1,95 l, 1.9 mol), keeping the temperature below 8°C. After consumption of the starting material mixture is diluted with saturated salt solution and extracted twice with ethyl ether. The organic solution is washed with water until neutral and then with saturated salt solution, dried over sodium sulfate, treated with charcoal and passed through silica gel (1 kg) using ether and a mixture of ethyl acetate-hexane (1:1) to give after concentration under vacuum, a yellow solid (207 g, 76%).

Stage D: 1-(6-benzyloxyindole-1-yl)propan-2-ol

The product obtained in stage (202,7 g, 0.71 mol), treated as described for stages C and D in the way of getting 3. After transformation nitrosamino intermediate product in the mixture is desirable indazol product and unreacted source material (5:1) add sodium nitrite (29.5 g, 0.43 mol) to re-nitrosation of the source material. Then portions while cooling, as described above, add zinc dust (84 g, 1.28 mol). After consumption of starting material the reaction secobarbital, as described above, combined with the product from another party, the receipt of which was conducted with 176 g of the product from step C. the combined crude products purified by chromatography (Biotage Kiloprep-250) to obtain a solid (226 g, 60%): 99% purity according to HPLC.

The method of obtaining 3

(R)-1-(6-benzyloxyindole-1-yl)propan-2-ol

Stage A: 4-benzyloxy-2-perbenzoate

To a solution of 2-fluoro-4-hydroxybenzonitrile (490 g of 3.57 mol) in acetone (3.4 l) add benzylbromide (467 ml, 3.93 mol) and potassium carbonate (1.4 kg, 10.1 mol). The stirred mixture is heated at 60°C for 20 hours, then cooled and filtered. The filtrate is concentrated and the resulting solid triturated with a mixture of 10% ethyl acetate/hexane (5 l) and dried in vacuum at 35°obtaining the target product (787 g, 97%).

Stage b: 4-benzyloxy 2-((R)-2-hydroxypropylamino)benzonitrile

A solution of (R)-(-)-1-aminopropan-2-ol (389 g, 5,19 mol) in dimethylsulfoxide (600 ml) are added to a solution of product from step A (786 g, 3.46 mol), basic alumina (786 g) and molecular sieves 4A (131 g). The stirred mixture is heated at 110-140°within 24 hours, cooled and filtered, the filter (device) washed with 10 l of a mixture of ether-ethyl acetate (4:1) and then 4 l of a mixture of ethyl acetate-hexane (3:2). Organic washing liquid is extracted with water (5 l) and the aqueous phase is extracted with a mixture of 25% ethyl acetate-hexane 4 x 2 l). The combined organic phases are washed with water and saturated salt solution, dried over anhydrous sodium sulfate, concentrated to approximately 3 l and leave for 48 hours. The precipitated solid material is collected by filtration, washed with hexane and dried in vacuum to obtain the desired product in the form of two parties (619 g 86 g). The concentrated supernatant is applied on the layer 5 kg of silica gel and elute with a gradient of 10-50% ethyl acetate-hexane to obtain after concentration in vacuo additional quantity of the product (119 g): total output 791 g (81%).

Stage C: 4-benzyloxy-2-((R)-2-hydroxypropylamino)benzaldehyde

To a solution of the product obtained at stage (790 g, 2.8 mol)in a mixture of pyridine-acetic acid-water (2:1:1) (7 l) add a hydrate hypophosphite sodium (986 g, and 11.2 mol) and Nickel catalyst Raney (500 g 50% aqueous suspension). The mixture was stirred at 45°C for 7 hours, then cooled to 25°during the night and filtered through filter device, rinsing it with water and ethyl acetate. The filtrate is washed with saturated sodium phosphate to pH 5, then with water and saturated salt solution, dried over sodium sulfate and concentrated. During the preconcentration add 4 l of heptane for azeotropic removal of pyridine. After removal of 8 l of a solvent, the product hardens. Add heptane (5 l) and Rast is play solid, separating it by filtration and dried in vacuum at 35°obtaining the target product (722 g, 90%).

Stage D: (R)-1-(6-benzyloxyindole-1-yl)propan-2-ol

Within 25 minutes, add sodium nitrite (209 g, 3.03 mol) to a stirred solution of the product obtained at stage (720 g of 2.53 mol)in acetic acid (5.6 l) and water (1.4 l), keeping the temperature below 25°C. the resulting solution nitrosamino intermediate is cooled in an ice bath and add zinc dust (595 g, 9,10 mol) in portions of 25 g for 3.5 hours, keeping the temperature below 35°C. Add ethyl acetate (7 l) and heavy suspension filtered through a funnel with a sintered glass by washing it with ethyl acetate (7.5 l). To the filtrate containing a mixture of desirable indazol product and recovered starting material (5:1)add reagent Tons of Girard (Girard''s Reagent T) (98 G. of 0.58 mol). After stirring at 25°C for 1 day, add another portion of the reagent Tons of Girard 150 g (0.90 mol). After 3 days all the source material is consumed. The mixture is extracted twice with water, an aqueous solution of sodium hydrogen phosphate to remove acetic acid, water and saturated salt solution, dried over sodium sulfate, filtered through Florisil and concentrate. The residue is passed through 5 kg of silica gel using a mixture of ethyl acetate-hexane (1:1). The appropriate fractions thing in common is t and concentrate and add heptane (4 l) to precipitate indazol product. The solid is collected by filtration, washed with a mixture of ethyl acetate-hexane (1:1) and dried in vacuum at 35°obtaining yellow solid (417 g, 58%): HPLC analysis: (R) - 96,7%; (S) - 0,3%, the initial material - 3%. Concentration of the supernatant results in additional 141 g (20%) of the target product.

The method of obtaining 4

(S)-1-(6-benzyloxyindole-1-yl)propan-2-ol

Method 1. The specified S stereoisomer receive, as described above in the method of obtaining racemic 1-(6-benzyloxyindole-1-yl)propan-2-ol, but using (S)-1-amino-2-propanol instead of racemic amerosport.

Method 2. Stage A: 4-benzyloxy-2-perbenzoate

A mixture of 2-fluoro-4-hydroxybenzonitrile (15.0 g, 109 mmol), potassium carbonate (21,0 g, 152 mmol) and benzylbromide (19.6 g, 115 mmol) in acetone (150 ml) under nitrogen atmosphere is heated overnight at 50°C. the Solid material is removed by filtration and the filtrate is evaporated to obtain a residue that was mixed with ethyl acetate (500 ml). This solution was washed with saturated salt solution, dried and evaporated to obtain amorphous solids (24,9 g, 100%).

Stage b: 4-benzyloxy-2-((S)-2-hydroxypropylamino)benzonitrile

A mixture of the product from step A (24.8 g, 109 mmol), (S)-1-amino-2-propanol (12.3 g, 164 mmol), molecular sieves 4A (4.0 g) and basic alumina (32 g) in anhydrous dimethyl sulfoxide (100 ml) in the atmosphere is e nitrogen heated at 95° With over 40 hours. The suspension is cooled to ambient temperature, filtered through a filter device which is washed with ethyl acetate (2 x 300 ml) and water (300 ml). The aqueous layer of the filtrate is extracted with ethyl acetate (2 x 300 ml) and the combined organic material was washed with a saturated salt solution (200 ml), dried (MgSO4) and purified by chromatography (silica gel, EtOAc/hexane) to give a viscous oil (24,9 g, 81%).

Stage C: 4-benzyloxy-2-((S)-2-hydroxypropylamino)benzaldehyde

To a solution of the product obtained at stage (19.3 g, to 68.3 mmol)in a mixture of anhydrous cyclohexane and THF (200 ml, 40 ml) at 0°C in nitrogen atmosphere for 30 minutes add the hydride of diisobutylamine (1 M solution in hexane, 239 ml, 239 mmol). The mixture is stirred for 18 hours at ambient temperature, contribute an additional amount of hydride of diisobutylamine (40 ml, 40 mmol) and the mixture is stirred for 24 hours. The reaction mixture was cooled in an ice bath and the reaction quenched by adding MeOH (exothermic reaction) and 2 N. HCl to maintain a pH of 1. The mixture is extracted with EtOAc (3 x 300 ml) and the extracts dried and concentrated to a brown oil (18.5 g). Crude oil rubbed using EtOAc/hexane and filtered to obtain oil (16.1 g, 83% yield of crude material). A small portion of this material is cleaned chromium is ografia (silica gel, 20%-50% EtOAc/hexane) to obtain the solid material, Tpl.68-69°C.

Stage D: (S)-1-(6-benzyloxyindole-1-yl)propan-2-ol (4)

To a mixture of the product obtained at stage (16.0 g, or 56.1 mmol)in a mixture of acetic acid/water (150 ml/30 ml) at 0°With portions over 40 minutes add sodium nitrite (of 7.75 g, 112 mmol). The mixture is stirred for 50 minutes, cooled (ice bath) and add portions zinc (14,7 g, 224 mmol). After 1 hour, the suspension is warmed to room temperature and add more zinc (14,7 g, 224 mmol). The mixture is stirred for 1 hour, concentrated and extracted with EtOAc (2 x 300 ml). The extracts are filtered through the filtration device, the filtrate washed with saturated aqueous disodium hydrogen phosphate (to pH 8) and saturated salt solution, dried and purified by chromatography (silicagel, 25% EtOAc/hexane) to give oil (7.01 g, 44%).

Example 1

1-(2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

Stage A: 6-benzyloxy-1-[2-(tert-butyldimethylsilyloxy)propyl]-1H-indazol

To a mixture of 1-(6-benzyloxyindole-1-yl)propan-2-ol (10 g, 35.5 mmol) in THF (100 ml) and imidazole (3.4 g, 50 mmol) is added tert-BUTYLCARBAMATE-silane (6.42 per g of 42.6 mmol) and the mixture is stirred for 15 minutes at ambient temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium acetate (300 ml) and extracted with ethyl acetate (2 x ml). Purification by chromatography (silica gel, EtOAc/hexane) gives a yellow solid material (10.6 g, 76%): Tpl.56-58°C; LC/MS (+APCI) m/z 397 (M+H).

Stage b: 1-[2-(tert-butyldimethylsilyloxy)propyl]-1H-indazol-6-ol

A mixture of the product obtained at stage A (10.6 g, 27 mmol), and palladium on coal (10% g, 0.26 g) in methanol (250 ml) is stirred under hydrogen atmosphere for 6 hours, add dichloromethane (100 ml) and the mixture filtered. Evaporation of the filtrate gives a yellowish-white solid (7.0 g, 85%): Tpl.169-174°C; LC/MS (+APCI) m/z 307 (M+H).

Stage C: 7-bromo-1-[2-(tert-butyldimethylsilyloxy)propyl]-1H-indazol-6-ol

To a solution of the product obtained at stage (6,00 g and 19.6 mmol)in anhydrous THF (300 ml) at 0°add N-bromosuccinimide (3,49 g and 19.6 mmol) in 10 portions over 20 minutes. The mixture is poured into a saturated aqueous solution of sodium bisulfite (300 ml) and extracted with EtOAc (3 x 100 ml). The combined extracts dried (MgSO4) and evaporated to obtain the residue (6,39 g). Chromatography (silica gel, 10% EtOAc/hexane) gives the solid material (4,95 g, 66%): LC/MS (+APCI) m/z 385, 387 (M+H).

Stage D: 7-bromo-1-[2-(tert-butyldimethylsilyloxy)propyl]-6-oxiranylmethyl-1H-indazol

A suspension of the product obtained at stage (4,47 g, 11.6 mmol), potassium carbonate (2.25 g, 16 mmol) and epibromohydrin (1,59 ml, 19 mmol) in acetone (230 ml) is heated to the boiling point under reflux in ECENA 20 hours. Make more epibromohydrin (1.5 ml, of 17.9 mmol) and the mixture is heated at boiling temperature under reflux for 18 hours. The solid material is removed by filtration and the filtrate concentrated to obtain oil, which was dissolved in EtOAc (150 ml). This solution was washed with a saturated aqueous solution of ammonium acetate (150 ml), dried (MgSO4) and evaporated to obtain the residue, which is purified by chromatography (silica gel, 2%-10% EtOAc/hexane) to give oil (3.77 g, 74%): LC/MS (+APCI) m/z 441, 443 (M+H).

Stage E: 1-bromo-3-[7-bromo-1-[2-(tert-butyldimethylsilyloxy)propyl]-1H-indazol-6-yloxy]propan-2-ol

To a suspension of magnesium powder (0,81 g of 33.5 mmol) in anhydrous THF (150 ml) under nitrogen atmosphere is added dropwise dibromethane (1,09 ml, 12.6 mmol). During this process the mixture is heated to about 50°to release gas and then allow to cool to 40°C. Make more dibromoethane (0.05 ml) and the mixture is heated at boiling temperature under reflux for 20 minutes and placed in an ice bath. To the cooled mixture is added a solution of the product obtained in stage D (3,70 g scored 8.38 mmol)in THF (50 ml). After stirring the mixture for 20 minutes at ambient temperature the reaction is quenched by adding saturated aqueous solution of ammonium chloride (200 ml) and the mixture extracted with EtOAc (2 the 150 ml). Evaporation of the extracts gives the crude oil (of 3.78 g, 86%): LC/MS (+APCI) m/z 521, 523, 525 (M+H).

Stage F: 7-bromo-6-[3-bromo-2-(1-ethoxyethoxy)propoxy]-1-[2-(tert-butyldimethylsilyloxy)propyl]-1H-indazol

To a solution of the product obtained in stage E (of 3.78 g, 7.2 mmol), and p-toluensulfonate acid (0.14 g) in dichloromethane (50 ml) at 0°add ethylenically ether (2,75 ml, 28.8 mmol). After 30 minutes the reaction is quenched by adding a saturated solution of sodium bicarbonate (50 ml) and the mixture extracted with dichloromethane (3 x 80 ml). Evaporation and purification by chromatography (silica gel, 1%-8% EtOAc/hexane) to give a viscous oil (3,30 g, 77%): LC/MS (+APCI) m/z 593, 595, 597 (M+H).

Stage G: 1-[8-(1-ethoxyethoxy)8.9bn-dihydro-7H-pyrano[2,3-g]indazol-1-yl]propane-2-ol

To a solution of the product obtained in stage F (3,3 g, 5.5 mmol)in anhydrous THF (100 ml) at -78°C in an atmosphere of nitrogen is added n-utility (2 M in hexane, 2.76 ml of 6.90 mmol). After 30 minutes the reaction is quenched by adding a saturated solution of sodium bicarbonate (200 ml) and the mixture extracted with EtOAc (2 x 150 ml). The combined extracts dried (MgSO4) and evaporated to obtain the residue, which chromatographic (silica gel, 10% EtOAc/hexane) to give oil (1.06 g)which was dissolved in THF (50 ml) and then to the specified solution was added tetrabutylammonium fluoride (1 M in THF, 3,84 ml of 13.8 mmol). The mixture is stirred overnight at ambient temperature the Reda, poured into a saturated solution of sodium bicarbonate (200 ml) and extracted with EtOAc (2 x 100 ml). The combined extracts dried (MgSO4), evaporated and chromatographic (silica gel, 20%-50% EtOAc/hexane) to give oil (0.52 g, 29%): LC/MS (+APCI) m/z 321 (M+H).

Stage H: 1-(2-azithromy)-8-(1-ethoxyethoxy)-1,7,8,9-tetrahydropyrido[2,3-g]indazol

To a solution of the product obtained in stage G (0.52 g, 1.6 mmol), and triethylamine (1,12 ml, 8.1 mmol) in anhydrous THF (75 ml) at 0°add methanesulfonyl anhydride (0.71 g, of 4.05 mmol). The mixture is stirred for 20 minutes and add sodium azide (2,11 g, 32,4 mmol) with DMSO (20 ml). Remove THF (in vacuum) and the reaction mixture is heated at 90°C for 3 hours. The mixture is cooled, poured into saturated sodium bicarbonate solution (150 ml) and the mixture extracted with EtOAc (3 x 100 ml). The combined extracts washed with saturated salt solution (100 ml), dried (MgSO4) and evaporated to obtain the residue, which is purified by chromatography (silica gel, 10% EtOAc/hexane) to give oil (0.40 g, 72%): LC/MS (+APCI) m/z 346 (M+H).

Stage I: 1-(2-azithromy)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

To a mixture of the product obtained at stage N (0,40g, 1.1 mmol)in THF (60 ml) was added 1 N. HCl (26 ml). After stirring for 40 minutes, add a saturated solution of sodium bicarbonate (150 ml) and the mixture extracted with EtOAc (3 x 100 ml). The combined extracts are dried vypaivajut to obtain a residue, which is purified by chromatography (silica gel, 50% EtOAc/hexane) to give oil (0.29 grams, 92%): LC/MS (+APCI) m/z 374 (M+H).

Stage J: Hydrochloride 1-(2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

A mixture of the product obtained at stage I (0,27G, 0,99 mmol), and palladium on coal (10%, 0.03 g) in EtOHc (20 ml) is stirred under hydrogen atmosphere for 18 hours at ambient temperature. The mixture is filtered and the filtrate is evaporated to obtain the residue, which is dissolved in a mixture of EtOAc/hexane (1:1) (10 ml). After maturation for 18 hours, harvested formed in the form of a colorless solid residue (0.14 g, 57%): TPL124-125°S: LC/MS (+APCI) m/z 248 (M+H). Analytical data for C13H17N3O2x 0,33 H2O: Calculated: C - 61,64: H - 7,03; N - 16,59. Found: 61,62; N - 6,83; N - 16,43.

Example 2

Hydrochloride of 1-((R)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

Stage A: 6-benzyloxy-1-[(S)-2-(tert-butyldimethylsilyloxy)propyl]-1H-indazol

To a mixture of (S)-1-(6-benzyloxyindole-1-yl)propan-2-ol (2,03 g, 7.20 mmol) in anhydrous THF/DMF (100 ml/35 ml) in an atmosphere of nitrogen was added sodium hydride (60% in mineral oil, 0.40 g, 10.0 mmol). After 30 minutes add tert-BUTYLCARBAMATE (1.52 g, 10 mmol) and a catalytic amount of NaH (5 mmol) and the mixture is stirred overnight at ambient temperature. Pay an additional amount of NaH (5 mm is l) and tert-BUTYLCARBAMATE (5 mmol) and the reaction mixture is stirred for 6 hours. Next, the reaction mixture is evaporated to obtain a residue that was mixed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2 x 200 ml). Purification by chromatography (silica gel, EtOAc/hexane) gives the oil (2,81 g, 99%).

Stage b: 1-[(S)-2-(tert-butyldimethylsilyloxy)propyl]-1H-indazol-6-ol

A mixture of the product obtained at stage A (5,44 g, 13.7 mmol), and palladium on coal (10% g, 0.50 g) in methanol (200 ml) is stirred under hydrogen atmosphere for 18 hours, filtered and evaporated to obtain a yellowish-white solid (3.80 g, 90%): Tpl.171-172°C.

Stage C: 7-bromo-1-[(S)-2-(tert-butyldimethylsilyloxy)propyl]-1H-indazol-6-ol

To a solution of the product obtained at stage (3,79 g, 12.4 mmol)in anhydrous THF (100 ml) at 0°add N-bromosuccinimide (2.20 g, 12.4 mmol) in 3 portions over 10 minutes. After 20 minutes the mixture is poured into a saturated aqueous solution of sodium bisulfite (100 ml) and extracted with EtOAc (3 x 100 ml). The combined extracts dried (MgSO4), and evaporated to obtain the residue (4,79 g). Chromatography (silica gel, 10% EtOAc/hexane) gives the solid material (3,66 g, 77%): Tpl.103-105°C.

Stage D: 7-bromo-1-[(S)-2-(tert-butyldimethylsilyloxy)propyl]-6-oxiranylmethyl-1H-indazol

A suspension of the product obtained at stage (3,66 g of 9.51 mmol), potassium carbonate (1.92 g, of 1.46 mmol) and epibromohydrin (1,32 g, 160 mmol) in acetone (200 g) is heated at boiling temperature under reflux for 30 hours. The solid material is removed by filtration and the filtrate concentrated to obtain oil, which is purified by chromatography (silica gel, 2%-10% EtOAc/hexane) to give oil (3.33 g, 79%): LC/MS (+APCI) m/z 441, 443 (M+H).

Stage E: 1-bromo-3-[7-bromo-1-[(S)-2-(tert-butyldimethylsilyloxy)propyl]-1H-indazol-6-yloxy]propan-2-ol

To a suspension of magnesium powder (0.73 g, 30.2 mmol) in anhydrous THF (50 ml) under nitrogen atmosphere add dibromethane (2,13 g and 0.98 ml, 11.3 mmol) in portions over about 30 minutes. During this process the mixture is heated to a temperature of about 50°until gas evolution. Next, the mixture is stirred for 1 hour, placed in an ice bath and add a solution of the product obtained in stage D (3.33 g, at 7.55 mmol)in THF (10 ml). After stirring for 1 hour at ambient temperature the mixture was quenched by adding saturated aqueous solution of ammonium chloride (100 ml) and extracted with EtOAc (3 x 100 ml). Evaporation of the extracts gives the crude oil (3,76 g, 95%): LC/MS (+APCI) m/z 441, 443 (M+H-HBr).

Stage F: 7-bromo-6-[3-bromo-2-(1-ethoxyethoxy)propoxy]-1-[(S)-2-(tert-butyldimethylsilyloxy)propyl]-1H-indazol

To a solution of the product obtained in stage E (1.85 g, 3.54 mmol), and p-toluensulfonate acid (0.01 g) in dichloromethane (50 ml) at 0°add ethylenically ether (1 ml, 10.5 mmol). After 30 minutes the reaction is quenched by adding a saturated solution of bi is carbonate sodium (50 ml) and extracted with EtOAc (3 x 80 ml). Evaporation and purification of the residue by chromatography (silica gel, 1%-8% EtOAc/hexane) gives the oil (1,79 g, 81%): LC/MS (+APCI) m/z 595 (M+H).

Stage G: (S)-1-[8-(1-ethoxyethoxy)8.9bn-dihydro-7H-pyrano[2,3-g]indazol-1-yl]propane-2-ol

To a solution of the product obtained in stage F (0,90 g 2,07 mmol)in anhydrous THF (50 ml) at -78°C in nitrogen atmosphere for 3 minutes, add n-utility (2.5 M in hexano, and 1.56 ml, 3.90 mmol). After 30 minutes the reaction is quenched by adding a saturated solution of sodium bicarbonate (80 ml) and the mixture extracted with EtOAc (3 x 100 ml). The combined extracts dried (MgSO4) and evaporated to obtain an oil (1.30 grams), which was dissolved in THF (50 ml), and then to the specified solution was added tetrabutylammonium fluoride (1 M solution in THF). The mixture is stirred over night at ambient temperature, add portions of sodium bicarbonate (80 ml) and extracted with EtOAc (3 x 100 ml). The combined extracts evaporated and purified by chromatography (silica gel, 10%-40% EtOAc/hexane) to give oil (0.35 g, 53 %): LC/MS (+ES) m/z 321 (M+H).

Stage H: 1-((R)-2-azithromy)-8-(1-ethoxyethoxy)-1,7,8,9-tetrahydropyrido[2,3-g]indazol

To a solution of the product obtained in stage G (0.35 g, of 1.09 mmol), and triethylamine (0.55 g, vs. 5.47 mmol) in anhydrous THF (50 ml) at 0°add methanesulfonyl anhydride (0,47 g, 2,73 mmol). The mixture is stirred for 1 hour and add sodium azide (0.71 g, 10.9 mmol). Reaction the second mixture is evaporated and the resulting residue is dissolved in anhydrous DMF (80 ml) and heated at 95° C for 3 hours. The mixture is cooled, poured into saturated sodium bicarbonate solution (80 ml) and extracted with EtOAc (3 x 80 ml). The combined extracts dried (MgSO4) and evaporated to obtain the residue, which is purified by chromatography (silica gel, 10% EtOAc/hexane) to give oil (0,30 g, 80%): LC/MS (+APCI) m/z 346 (M+H).

Stage I: 1-((R)-2-azithromy)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

To a mixture of the product obtained at stage N (0,30 g, 0.87 mmol)in THF (50 ml) was added 1 N. HCl (20 ml). After stirring for 40 minutes, add a saturated solution of sodium bicarbonate (80 ml) and the mixture extracted with EtOAc (3 x 50 ml). The combined extracts are dried and evaporated to obtain the residue, which is purified by chromatography (silica gel, 20%-50% EtOAc/hexane) to give oil (0,22 g, 92%).

Stage J: Hydrochloride 1-((R)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

A mixture of the product obtained at stage I (0,21 g, 0.77 mmol), and palladium on coal (10%, 0.02 g) in MeOH (30 ml) is stirred under hydrogen atmosphere for 18 hours at ambient temperature. The mixture is filtered and the filtrate is combined with a solution of hydrogen chloride in ethanol (2 N, 1 ml), then this solution is evaporated at 60°in high vacuum to obtain a solid substance (0,13 g, 59%): TPL82-86°S: LC/MS (+APCI) m/z 248 (M+H). Analytical data for C13H17N3O2x HCl x 0.1 H2x 0,4 3H7NO: Calculation: C - 54,17: H - 6,72; N - 15,12. Found: 54,06; N - 6,76; N - 14,98.

Example 3

1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

Stage A: 1-((S)-2-azithromy)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

This compound is synthesized following the procedure described in example 2, step I, but using 1-((S)-2-azithromy)-8-(1-ethoxyethoxy)-1,7,8,9-tetrahydropyrido[2,3-g]indazole, which is obtained from (S)-1-(6-benzyloxyindole-1-yl)propan-2-ol instead of (R)-1-6-benzyloxyindole-1-yl)propan-2-ol, above: you get an oil (0.45 g, 79%); LC/MS (+APCI) m/z 274 (M+H).

Stage b: 1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

A solution of the product obtained at stage A, in methanol is treated as described in example 2, stage J, to obtain the free base in the form of an amorphous solid (0.36 g, 88%): TPL46-51°; GCMS(Cl+) m/z 248 (M+H). Analytical data for C13H17N3O2x 0.1 H2O: Calculated: C - 62,68: H - Of 6.96; N - 16,97. Found: C - 62,55; N - 7,03; N - 16,64.

Example 4

(R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

Stage A: 1-[2-(R)-(tert-butyldimethylsilyloxy)propyl]-6-prop-2-ynyloxy-1H-indazol

To a solution of 1-[(R)-2-tert-butyldimethylsilyloxy)propyl]-1H-indazol-6-ol (of 10.93 g, 35,7 mmol), obtained from (R)-1-(6-benzyloxyindole-1-yl)propan-2-ol by the method of example 2, stage is, in acetone (250 ml) is added potassium carbonate (6.90 to g, to 35.7 mmol) and propargylamine (5,19 ml of 46.4 mmol) and the mixture is heated at boiling temperature under reflux for 18 hours. Pay an additional amount of potassium carbonate (1.97 g, 14 mmol) and propargylamine (1.2 ml, about 10.7 mmol) and the mixture is heated at boiling temperature under reflux for 2 hours. Remove solid material by filtration and the filtrate concentrated to an oil, which was purified by chromatography (silica gel, 5% ethyl acetate in hexane) to give oil (1.40 g, 96%): LC/MS (+APCI) m/z 345 (M+H).

Stage b: 1-[(R) -2-(tert-butyldimethylsilyloxy)propyl]-1,7-dihydro-pyrano[2,3-g]indazol

A solution of the product obtained at stage A (10,9 g of 31.8 mmol), mesitylene (60 ml) was placed in a test tube under pressure, and Tegaserod in vacuum. Next, the tube sealed and heated at 190°for 20 hours. The solution is cooled and purified by chromatography (silica gel, 10% ethyl acetate in hexane) to give a solid (at 9.53 g, 87%): Tpl.58-59°C; LC/MS (+APCI) m/z 345 (M+H).

Stage C: (R)-1-[(R)-2-(tert-butyldimethylsilyloxy)propyl]-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8 ol

To the product obtained in stage (1,00 g, only 2.91 mmol), added under stirring in nitrogen atmosphere 9-BBN (0.5 M in THF, 13 ml, 6.4 mmol). The solution is heated at 70°C for 2 hours, cooled to ambient temperature the market environment and the reaction quenched by adding methanol (5 ml) and hydrogen peroxide (30%, 5 ml). After stirring for 30 minutes, the mixture is evaporated to obtain a residue, which was combined with a saturated solution of sodium bicarbonate (50 ml), after which this mixture is extracted with ethyl acetate (3 x 50 ml). The combined extracts evaporated to obtain the residue, which is purified by chromatography (silica gel, 10%-30% ethyl acetate in hexane) to give the desired diastereoisomer in the form of a viscous oil (0.56 g, 75%) and a mixture (0,22 g) nonshared diastereomers. LC/MS (+APCI) m/z 363 (M+H).

Stage D: (R)-1-((S)-2-azithromy)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8 ol

A solution of the product obtained in stage C (0.56 g, 1.55 mmol), p-toluensulfonate pyridinium (50 mg) and etilenovogo ether (1 ml) in anhydrous dichloromethane (50 ml) is stirred under nitrogen atmosphere at 0°C for 1 hour. Remove the cooling bath, the mixture is stirred for 1 hour and add triethylamine (1 ml). This mixture is evaporated to obtain a residue, which was combined with THF (10 ml) and tetrabutylammonium fluoride (1 M solution in THF, 3.1 ml, 3.1 mmol) and stirred for 1 hour. The reaction mixture is evaporated to obtain the residue, which is purified by chromatography (silica gel, 10%-30% ethyl acetate in hexane) to give hydroxyamino intermediate is in the form of oil (0,47 g, 96%). To a solution of the specified oil (0,46 g, 1.44 mmol) in anhydrous THF (50 ml) at 0°add triethyl is min (0,726 g, 7.19 mmol) and methanesulfonyl anhydride (0.50 g, is 2.88 mmol) and the mixture is stirred for 30 minutes. Add sodium azide (0,936 g, 14.4 mmol) and the solvent is removed by evaporation. Then add DMF (50 ml) and the suspension heated at 100°C for 4 hours, cooled and extracted with ethyl acetate (3 x 80 ml). The combined extracts washed with water, dried and purified by chromatography (1%-10% ethyl acetate in hexane) to produce asidefor in the form of oil (0,38 g, 77%). The oil is dissolved in methanol, add p-toluensulfonate acid (50 mg) and the resulting solution was stirred for 1 hour. Add triethylamine (0.1 ml) and the mixture is evaporated to obtain the residue, which is purified by chromatography (10%-35% ethyl acetate in hexane) to give the desired aspidosperma in the form of a solid (0.27 g, 99%). LC/MS (+APCI) m/z 274 (M+H).

Stage E: (R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8 ol

The product obtained in stage D, is treated as described in example 2, stage J, to obtain the desired compound as a yellowish solid (0.26 g, 65%): TPL126-128°; [α]D=+47,7° (0,352, CH3OH); [α]405=+115° (0,352, CH3OH); LC/MS (+APCI) m/z 248 (M+H); Analytical data for C13H17N3O2: Calculate: C - 63,14: H - 6,93; N - 16,99. Found: C - 63,37; N - 6,79; N - 16,93.

Example 5

(S)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahed operano[2,3-g]indazol-8-ol

Stage A: (S)-1-((S)-2-azithromy)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

The product obtained in example 3 on stage And (1.35 g), applied to a chromatographic column Packed with a chiral adsorbent (Chiracel OJ). The elution is conducted with a mixture of hexane and 2-propanol (9:1), which allows to divide the mixture into two diastereoisomer: S,8S-diastereoisomer (0.68 g) and S,8R-diastereomer (0.65 g).

Stage b: (S)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8 ol

The solution S,8S-diastereoisomer (0,23 g)obtained in stage A, in methanol is treated as described in example 3, step B, to obtain oil (0.18 g, 87%); [α]D=-6,21° (0,467, CH3OH); [α]405=is 3.5° (0,467, CH3OH). Analytical data for C13H17N3O2x 0.2 H2O: Calculated: C - 62,22: H - 7,03; N - 16,74. Found: C - 62,36; N - 7,06; N - 16,93.

Example 6

Trihydrochloride (R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ylamine

Stage A: (S)-8-azido-1-((R)-2-azithromy)-1,7,8,9-tetrahydropyrido[2,3-g]indazol

To a solution of S,8S-diastereoisomer obtained in example 5, stage And (0,44 g of 1.61 mmol), and triethylamine (0,90 ml 6,44 mmol) in anhydrous THF (50 ml) at 0°add methanesulfonyl anhydride (0.56 g, up 3.22 mmol) and this mixture is stirred for 30 minutes, then remove the ice bath and the mixture is stirred for another 20 minutes. The reaction mixture Lipari who try to obtain a residue, to which is added DMSO (50 ml) and sodium azide (1,05 g, 16,1 mmol) and then heated the mixture at 90°C for 5 hours. Next, the mixture is cooled, poured into water and extracted with ethyl acetate (3 x 60 ml). The combined extracts dried, filtered and evaporated to dryness. Purification by chromatography (silica gel, 5%-25% ethyl acetate in hexane) gives an oil (0,19 g of 16.1 mmol): LC/MS (+APCI) m/z 299 (M+H).

Stage: Trihydrochloride (R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ylamine

A solution of the product obtained at stage A, in methanol is treated as described for stage J in example 2, to obtain a yellowish solid (0.16 g, 78%); Tpl.>300°C; LC/MS (+APCI) m/z 247 (M+H). Analytical data for C13H21Cl3N4O x 0,33 C2H5OH x 0.5 H2O: Calculated: C - 43,14: H - 6,35; N - 14,72. Found: 43,52; N - 6,39; N - 14,51.

Example 7

(8R*,9S*)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8,9-diol

Stage A: Benzyl (S)-2-(6-hydroxy-1H-indazol-1-yl)methylethylketone

To a suspension of 1-((S)-2-aminopropyl)-1H-indazol-6-ol (2.00 g, 10.5 mmol) in THF (20 ml) is added a saturated aqueous solution of sodium bicarbonate (10 ml) and benzylchloride (1,50 ml, 1.5 mmol). The mixture is stirred until dissolution of all solid amine source. After stirring at ambient temperature for 45 minutes, add a saturated solution of sodium bicarbonate (150 ml) and the mixture extracted with ethyl acetate (3 x 150 ml). The combined extracts dried (MgSO4) and evaporated to obtain reddish-brown foam (2.65 g 78%): LC/MS (+APCI) m/z 326 (M+H).

Stage b: Benzyl (S)-1-methyl-2-(6-prop-2-injectiondate-1-yl)ethylcarbamate

A solution of the product obtained at stage A (2,88 g, 8,86 mmol)in acetone (100 ml) Tegaserod under reduced pressure in a nitrogen atmosphere. Add powdered potassium carbonate (1.35 g of 9.75 mmol) and propargylamine (80 wt.% in toluene, of 0.99 ml, 8,86 mmol) and the mixture refluxed for 24 hours. The cooled reaction mixture is filtered and the filtrate evaporated to a yellow oil (3.15 g), which is purified by chromatography (silica gel, 20%-50% ethyl acetate in hexane) to give white solid (2.37 g, 74%): TPL104-106°C; LC/MS (+APCI) m/z 364 (M+H).

Stage C: Benzyl (S)-1-methyl-2-(7H-pyrano[2,3-g]indazol-1-yl)ethylcarbamate

The product obtained in stage (2.37 g, 6,53 mmol), heated at mesitylene (40 ml) by a procedure similar to that described in example 4, step B, to obtain after purification (silica gel, 20%-50% ethyl acetate in hexane) oil (1.01 g, 43%): LC/MS (+APCI) m/z 364 (M+H).

Stage D: Benzyl (S)-2-((8R*,9S*) - 8.9bn-dihydroxy-8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl)-1-methylethylketone

A solution of the product obtained in stage (1.01 g, 2,78 mmol)in a mixture of tert-butyl alcohol (20 ml) and water (20 ml) is added at room temperature to a mixture of tert-butyl alcohol (25 ml), water (25 ml), AD-mix-α (4,2 g) and methanesulfonamide (0.26 g, 2.8 mmol). The reaction mixture is stirred for 24 hours and then add the powder of sodium sulfite (5 g) and the mixture is stirred for another hour. Then to the mixture is added saturated aqueous sodium bicarbonate solution (150 ml) and extracted it with ethyl acetate (3 x 150 ml). The combined extracts dried (MgSO4) and evaporated to an oil (1,03 g)which is purified by chromatography (silica gel, 50% ethyl acetate in hexane - ethyl acetate) to give two products. Product And receive in the form of a white foam (0.16 g, 15%): the ratio of diastereomers 4:1; LC/MS (+APCI) m/z 398 (M+H). The product is a colorless amorphous solid (0.18 g, 16%): Tpl.64-67°C; ratio of diastereoisomers 1:4; LC/MS (+APCI) m/z 398 (M+H).

Stage E: (8R*,9S*)-1-[(2S)-2-aminopropyl]-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8,9-diol

A solution of the product As obtained in stage D (0.14 g, 0,354 mmol)in THF (20 ml) is treated by the method of stage J of example 2 to obtain the free base as a colourless solid (50 mg, 54%): Tpl.115-117°; [α]D=-79,3°With (from 0.27, THF), the ratio of diastereomers 4:1; LC/MS (+APCI) m/z 264 (M+H) and 264 (M+H-H2O).

Example 8

The dihydrochloride (S)-2-(8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl)-1-methylethylamine

Stage A: (R)-1-(7H-pyrano[2,3-g]indazol-1-yl)propan-2-ol

A mixture of the product obtained at stud and In example 4,(0.26 g, 0,76 mmol), and tetrabutylammonium fluoride (1 M of 1.52 mmol) in THF (3 ml) was stirred at ambient temperature for 4 hours. The reaction mixture was added to saturated aqueous sodium bicarbonate solution (10 ml) and this mixture is extracted with ethyl acetate (3 x 5 ml). The combined extracts are dried and evaporated to a residue which is purified by chromatography (silica gel, 10%-40% ethyl acetate in hexane) to give the alcohol as an oil (0.14 g, 81%): LC/MS (+APCI) m/z 231 (M+H).

Stage b: 1-((S)-2-azithromy)-1,7-dihydropyrano[2,3-g]indazol

To a solution of the product obtained at stage A (0.14 g, 0.61 mmol), and triethylamine (of 0.18 ml, 1.8 mmol) in anhydrous THF (50 ml) at 0°add methanesulfonyl anhydride (0.16 g, to 0.92 mmol). The mixture is stirred for 10 minutes and add sodium azide (0.40 g, 6.1 mmol), the solvent is evaporated and add anhydrous DMF (50 ml) and then heated at 110°C for 3 hours. The mixture is cooled, poured into saturated sodium bicarbonate solution (80 ml) and extracted with ethyl acetate (3 x 60 ml). The combined extracts dried, filtered and evaporated to a residue which is purified by chromatography (silica gel, 10% ethyl acetate in hexane) to give oil (0.06 g, 39%): LC/MS (+APCI) m/z 256 (M+H).

Stage C: Dihydrochloride (S)-2-(8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl)-1-methylethylamine

A solution of the product obtained at stage b, the methanol treatment is indicate by the method of stage J of example 2 to obtain a yellowish solid (0.07 g, 77%): Tpl.>120°C; LC/MS (+APCI) m/z 232 (M+H). The product in the form of a free base is a colorless solid: Tpl.95-98°; [α]D=-66,7° (0,445, THF). Analytical data for C13H17N3O: Calculated: C - 67,51: H - 7,41; N - 18,17. Found: C - 67,47; N - 7,51; N - 17,91.

Example 9

(S)-1-methyl-2-(7H-pyrano[2,3-g]indazol-1-yl)ethylamine

To a solution of the product obtained in example 8 at a stage In (0.10 g, 0,39 mmol)in dry THF (20 ml) at 0°add a solution of lithium aluminum hydride (of 0.39 ml, 1.56 mmol, 1M solution in THF) and the mixture was allowed to warm to room temperature (1 hour) with stirring. To the reaction mixture an aqueous solution of potassium hydroxide (2 M, 0,02 ml) and the resulting solid material removed by filtration. The filtrate is evaporated to yellow oil (0.05 g, 56%): LC/MS (+APCI) m/z 230. Analytical data for C13H15N3O x 0,17 H2O: Calculated: C - 67,26: H - 6,60; N - 18,10. Found: C - 67,35; N - 6,45; N - 17,76.

Example 10

Triptorelin 1-(S)-2-aminopropyl)-1H-pyrano[2,3-g]indazol-7-it

A suspension of 1-((S)-2-aminomethyl)-1H-indazol-6-ol (1,00 g, 5,23 mmol) and malic acid (0.74 g, 5.5 mmol) in concentrated sulfuric acid (3 ml) is heated at 80°C for 48 hours and at 90°C for 24 hours. The reaction mixture is neutralized with sodium phosphate (dwuhosnovny, to pH 7) and add a saturated salt solution (100 ml), PEFC is why the extraction is carried out indicated a mixture of THF (3 x 100 ml). The combined extracts dried (MgSO4) and evaporated to a yellow residue (0.54 g)which is purified by chromatography treatment phase (C-18, water/acetonitrile, 0.1% of triperoxonane acid) to give a yellow oil (70 mg): LC/MS (+APCI) m/z 244 (M+H).

Example 11

9-amino-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

Stage A: Benzyl (S)-2-(8-bromo-9-hydroxy-8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl)-1-methylethylketone

To a solution of the product obtained in example 7 in stage C (1.35 g, 3,71 mmol)in a mixture of dimethyl sulfoxide and water (20 ml:2 ml) at 0°add N-bromosuccinimide (0,g, to 3.89 mmol). The resulting mixture is stirred for 2 hours, combined with water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined extracts are dried and concentrated to a residue, which was purified by chromatography (silica gel, 20% ethyl acetate in hexane) to give oil (1.18 g, 69%): LC/MS m/z 460, 462 (M+H).

Stage b: Benzyl (S)-2-(9-azido-8-bromo-8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl)-1-methylethylketone

A mixture of the product obtained at stage A (0.31 g, 0.67 mmol), and sodium azide (0.65 g, 10 mmol) in dimethylsulfoxide (20 ml) is heated at 80°C for 3 hours, cooled to room temperature and extracted with ethyl acetate. The combined extracts are dried and concentrated to a residue, which was purified by chromatography (silica gel, 30% ethyl acetate in hexane) to obtain the oil (0.26 g, 68%): LC/MS (+APCI) m/z 423 (M+H).

Stage C: 9-amino-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

The product obtained at stage B (0.26 g, 0.30 mmol), and Pd/C (10%, was 0.026 g) is mixed with methanol (5 ml) and placed in an atmosphere of hydrogen for 18 hours. The mixture is filtered and evaporated to obtain yellow solids (0,155 g, 96%): Tpl.84-88°C; LC/MS (+APCI) m/z 263 (M+H).

Example 12

1-((S)-2-aminopropyl)-9-methoxy-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

Stage A: Benzyl (S)-2-(8-hydroxy-9-methoxy-8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl)-1-methylethylketone

To a solution of the product obtained in example 11 on stage And (0,46 g, 1.12 mmol)in tetrahydrofuran (50 ml) is added 2 n sodium hydroxide (6 ml). After stirring for 10 minutes, add methanol (10 ml) and the mixture is stirred for 1 hour, then evaporated to a residue that was mixed with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulfate and evaporated to a residue which is purified by chromatography (silica gel, 20%-35% ethyl acetate in hexane) to give oil (0.45 g); LC/MS (+APCI) m/z 378 (M+H).

Stage b: 1-((S)-2-aminopropyl)-9-methoxy-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol

To a solution of the product obtained at stage A (0,22 g, of 0.58 mmol)in methanol (5 ml) is added triperoxonane acid (5 ml) and the mixture is stirred at the temperature of the environment within 2 days. Next, the mixture is evaporated to a residue which is stirred with 2 N. a solution of hydrogen chloride in ethanol (5 ml) and evaporated to obtain a solid (0.21 g): Tpl.105-108°C; LC/MS (+APCI) m/z 278 (M+H). Below local ophthalmic compositions applicable in accordance with the present invention with the introduction of 1-4 times a day, on the recommendation of the treating physician.

Example 13

IngredientsAmount (wt.%)
The compound of example 30.01 to 2%
The hypromellose0,5%
Dwuosobowy sodium phosphate (anhydrous)0,2%
Sodium chloride0,5%
EDTA disodium (edetate disodium)0,01%
Polysorbate 800,05%
The benzalkonium chloride0,01%
The sodium hydroxide/hydrochloric acidTo bring the pH to 7.3 to 7.4
Purified waterq.s. up to 100%

Example 14

IngredientsAmount (wt.%)
The compound of example 30.01 to 2%
The methylcellulose4,0%
Duenow the OI sodium phosphate (anhydrous) 0,2%
Sodium chloride0,5%
EDTA disodium (edetate disodium)0,01%
Polysorbate 800,05%
The benzalkonium chloride0,01%
The sodium hydroxide/hydrochloric acidTo bring the pH to 7.3 to 7.4
Purified waterq.s. up to 100%

Example 15

IngredientsAmount (wt.%)
The compound of example 30.01 to 2%
Guar gum0,4%-6,0%
Dwuosobowy sodium phosphate (anhydrous)0,2%
Sodium chloride0,5%
EDTA disodium (edetate disodium)0,01%
Polysorbate 800,05%
The benzalkonium chloride0,01%
The sodium hydroxide/hydrochloric acidTo bring the pH to 7.3 to 7.4
Purified waterq.s. up to 100%

Example 16

IngredientsAmount (wt.%)
The compound of example 30.01 to 2%
White is aselin and mineral oil and lanolin Consistency ointment
Dwuosobowy sodium phosphate (anhydrous)0,2%
Sodium chloride0,5%
EDTA disodium (edetate disodium)0,01%
Polysorbate 800,05%
The benzalkonium chloride0,01%
The sodium hydroxide/hydrochloric acidTo bring the pH to 7.3 to 7.4

Other embodiments of the present invention will be clear to the person skilled in the art based on the description and practice of the present invention discussed herein. It should be borne in mind that the present description and examples should be considered only as illustrative, because the nature and scope of the present invention defined by the claims and its equivalents.

Example 17

(S)-1-methyl-2-(3,7,8,9-tetrahydropyran-[3,2-e]-indazol-1-yl)ethylamine

Stage A: 3-((R)-2-hydroxypropyl)-1H-indazol-5-ol

To a solution of (R)-1-(5-methoxy-1H-indazol-3-yl)propan-2-ol (2,31 g, and 11.2 mmol) in anhydrous dichloromethane (50 ml), cooled at -78°add 1 to N. the solution tribromide boron in dichloromethane (33.6 ml, 33.6 mmol). After introduction of the mixture was allowed to warm to ambient temperature and stirred 2 hours The mixture is cooled (in a bath with ice and quenched with 20 ml of water. Dichloromethane is evaporated and the residue is mixed with ethyl acetate (100 ml). To this solution was added in small portions potassium carbonate until then, until there is no further gas evolution, and the pH becomes about 8. The mixture is extracted with ethyl acetate (3×100 ml) and the combined extracts dried and evaporated to dryness. Chromatography on silica (gradient, 50-90% ethyl acetate in hexane) receive oil (1.50 g, 70%): LC/MS (+APCI) m/z 193 (M+H).

Stage b: (R)-1-(5-prop-2-ynyloxy-1H-indazol-3-yl)-propan-2-ol

To a stirred mixture of the product from step A (1.50 g, 7,81 mmol) in a mixture of ethanol in water (50 ml/10 ml) is added potassium carbonate (of 1.62 g, 11.7 mmol) and propargylamine (80% in toluene, 1,74 g, 11.7 mmol). The mixture is heated at 75°C for 2 h in nitrogen atmosphere, evaporated to dryness, mixed with saturated aqueous sodium bicarbonate (50 ml) and extracted with ethyl acetate. Chromatography on silica (gradient, 25-95% ethyl acetate in hexane) receive oil (1.25 g, 69%): LC/MS (+APCI) m/z 231 (M+H).

Stage C: 3-[(R)-2-(tert-butyldimethylsilyloxy)propyl]-5-prop-2-ynyloxy-1H-indazol

To a stirred solution of the product from step B (1.25 g, 5.43 mmol) in anhydrous THF (tetrahydrofuran) (50 ml) is added tert-butyldimethylsilyl (1,23 g, 8,15 mmol), imidazole (0.74 g, 10.9 mmol) and catalytic amount of DMAP (0.1 g). The mixture is stirred for 6 h and introduce an additional quantity of each of the reagents. The mixture is stirred until the morning and unite with saturated aqueous sodium bicarbonate (100 ml) and extracted with ethyl acetate. Chromatography on silica (gradient, 2-30% ethyl acetate in hexane) receive oil (0,98 g, 52%). This product slowly decomposes during curing in wet conditions to give the desired product. Chromatography of the mixture get additional desired product as an oil (0.68 g, 36%of total 88%): LC/MS (+APCI) m/z 345 (M+H).

Stage D: 1-[(R)-2-(tert-butyldimethylsilyloxy)propyl]was 3.7-dihydropyrano-[3,2-e]-indazol

A mixture of the product from step C (1.66 g, 4,82 mmol) in mesitylene (8 ml) is placed in the reaction vessel, purge nitrogen gas for 5 min and sealed. The vessel is heated at 210°C for 1 h, cooled to ambient temperature and chromatographic on silica (gradient, 2-15% ethyl acetate in hexane) to give oil (1.31 g, 79%): LC/MS (+APCI) m/z 345 (M+H).

Stage E: (R)-1-(3,7-dihydropyrano-[3,2-e]-indazol-1-yl)propan-2-ol

A mixture of the product from step D (0,30 g, 0.87 mmol) and tetrabutylammonium (0.5 M, 2,62 ml of 1.31 mmol) in THF (30 ml) was stirred at ambient temperature overnight and evaporated to dryness. Chromatography on silica (gradient, 30-100% ethyl acetate in hexane) receive oil (0,165 g, 83%).

Stage F: (S)-1-(2-azithromy)was 3.7-dihydropyrano-[3,2-e]-indazol

To peremeshivaemogo solution of the product from step E (0.16 g, 0.70 mmol) and triethylamine (0.28 g, of 0.39 ml, 7,51 mmol) in anhydrous THF (50 ml) at 0°add the anhydride of methansulfonate (0.24 g, 1.4 mmol). The mixture is stirred for about 30 min and introduce additional 1 EQ. anhydride of methansulfonate. After 30 min to the reaction mixture is added sodium azide (1.10 g, 7.0 mmol). THF is evaporated and anhydrous dimethylsulfoxide (20 ml) is added to the residue, which was heated at 90°C for 1 h, the Reaction mixture is cooled, poured into saturated sodium bicarbonate solution (80 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts are dried over MgSO4), filtered and evaporated to an oil. Chromatography on silica (gradient of 10-20% ethyl acetate in hexane) receive oil (0.09 g, 51%): LC/MS (+APCI) m/z 256 (M+H).

Stage G: (S)-1-methyl-2-(3,7,8,9-tetrahydropyran-[3,2-e]-indazol-1-yl)ethylenedichloride

A mixture of the product from step F (0.09 g) and palladium-on-carbon (10%, 0.01 g) in methanol (20 ml) is placed in an atmosphere of hydrogen and stirred overnight. The mixture is purified HPLC (HPLC) (high-performance liquid chromatography with reversed phase (gradient, acetonitrile/water, 0-55% 0.1% triperoxonane acid). The main factions unite, evaporated, treated with 2 N. HCl in ethanol (5 ml) and evaporated to dryness to obtain amorphous solids (0,053 g, 58%): melting point 235-240°C; LC/MS (+APCI) mz 232 (M+H).

Example 18

[1-((S)-2-aminopropyl)-7,8-dihydro-1H-furo-[2,3-g]-indazol-7-yl]methanol

Stage A: Tert-butyl ether [1-[(R)-2-(tert-butyldimethylsilyloxy)propyl]-7-hydroxymethyl-1H-indazol-6-yl-oxy]acetic acid

To a mixture of 1-[(R)-2-(tert-butyldimethylsilyloxy)propyl]-1H-indazol-6-ol (a 3.06 g, 10 mmol) in DMF DMF (dimethylformamide) (60 ml) was added formaldehyde (37%, 2,43 ml, 30 mmol) and 2 N. NaOH (10 mmol). The mixture is stirred until the morning and add tert-butylbromide (2,42 ml of 2.93 g, 15 mmol). After 1 h the mixture is mixed with saturated aqueous sodium bicarbonate (100 ml) and extracted with ethyl acetate.

Chromatography on silica (gradient of 5-25% ethyl acetate in hexane) receive oil (2,87 g, 64%): LC/MS (+APCI) m/z 451 (M+H).

Stage b: Tert-butyl ether [1-(R)-2-(tert-butyldimethylsilyloxy)propyl]-7-chloromethyl-1H-indazol-6-yloxy]-acetic acid

To a stirred solution of the product from step A (2,78 g, 6,18 mmol) in anhydrous dichloromethane (100 ml) is added thionyl chloride (0.68 g, 9,27 mmol). After 1.5 h, then add an excess of thionyl chloride (0,23 ml) and stirring is continued for 20 minutes

Evaporation of the mixture under high vacuum gives the oil (2,90 g), which is used in subsequent reactions without further purification.

Stage C: Tert-butyl ether [1-(R)-2-(tert-butyldimethylsilyloxy)propyl]-7,8-dihydro-1H-furo-[2,3-g]-indazole-7-carboxylic to the slots

To a solution of product from step B (2,90 g, 6,18 mmol) in anhydrous 1-methyl-2-pyrrolidone (30 ml) is added sodium hydride (60%, 0,371 g, 9,27 mmol). The mixture is heated at 50°C overnight and incubated at ambient temperature for 2 days, cooled and poured into saturated aqueous sodium bicarbonate solution (100 ml) and extracted with ethyl acetate.

Chromatography on silica (gradient of 2-25% ethyl acetate in hexane) receive oil (0,48 g, 18%): LC/MS (+APCI) m/z 433 (M+H).

Stage D: Tert-butyl ester 1-[(R)-2-hydroxypropyl]-7,8-dihydro-1H-furo-[2,3-g]-indazole-7-carboxylic acid

To a mixture of the product from step C (0,46 g, 1.06 mmol) in THF (50 ml) add tetrabutylammonium (1 N. in THF, 2,13 ml, 2,13 mmol). The mixture was combined with saturated aqueous sodium bicarbonate (100 ml) and extracted with ethyl acetate.

Chromatography on silica (gradient 20-70% ethyl acetate in hexane) receive oil (0.39 g): LC/MS (+ESI) m/z 319 (M+H).

Stage E: Tert-butyl ester 1-[(S)-2-azithromy]-7,8-dihydro-1H-furo-[2,3-g]-indazole-7-carboxylic acid

To a solution of product from step D (0.39 g, of 1.23 mmol) and triethylamine (0,49 g of 4.90 mmol) in anhydrous THF (30 ml) at 0°add the anhydride of methansulfonate (0.34 g, to 3.38 mmol). The mixture is stirred for 30 min and introduce additional anhydride of methansulfonate (0.17 g). After 30 min the volatile components of viparita is fast and to the residue added sodium azide (1.22 g, for 18.8 mmol, 10 EQ.) and anhydrous dimethyl sulfoxide (50 ml). The mixture is heated at 80°C for 4 h, cooled, poured into saturated aqueous sodium bicarbonate solution (80 ml) and extracted with ethyl acetate (3×60 ml). The combined extracts are dried over MgSO4), filtered and evaporated to obtain oil.

Chromatography on silica (gradient, 0-10% ethyl acetate in hexane) receive oil (0,22 g, 52%): LC/MS (+ESI) m/z 344 (M+H).

Stage F: [1-((S)-2-aminopropyl)-7,8-dihydro-1H-furo-[2,3-g]-indazol-7-yl]metamorphically

To a mixture of the product from step E (0.21 g, 0.61 mmol) in anhydrous THF (50 ml) was added 1 M solution of sociallyengaged in THF (3.0 ml, 3.0 mmol) with stirring in a nitrogen atmosphere. The mixture is stirred for 3 h, cooled in ice and quenched by adding methanol and then 2 N. HCl. Evaporation of this mixture gives a residue which is purified HPLC with reversed phase (gradient of acetonitrile and water, 0-50% 0.1% triperoxonane acid). The desired fractions unite, concentrate, process 2 N. HCl in ethanol (10 ml) and evaporated to obtain not quite white solid (0,13 g, 59%), which is dried in high vacuum at 78°till morning: LC/MS (+APCI) m/z 248 (M+H).

Analysis: Calculated for C13H19Cl2N3O2·0.5 C2H5OH·H2O: C, 46,92; N, 6,72; N, 11,73. Defined: C, 47,25; N, 6,41; N, 11,50.

Scheme 11

Some desired substituted 7,8-dihydro-furano-[2,3-g]-indazols formula I can be obtained from the correspondingly substituted 1H-indazol-6-ol (53), as described in the sequence of the synthesis presented in figure 12. In addition, the use of standard transformations of functional groups is well known in the art, for example, by modifications of the connections 60, can give other compounds of formula I.

Scheme 12

Using the techniques described in the above schemes, examples, and well-known techniques specialist in the art can obtain the compounds discussed here.

AL-39695A: Example 20

AL-40105A: Example 21

AL-38035: Example 22

Example 20

(8R)-1-[(2S)-2-aminopropyl]-1,7,8,9-tetrahydropyrido-[2,3-g]-indazol-8-ylacetic

Stage A: (8R)-1-[(2S)-2-azithromy]-1,7,8,9-tetrahydropyrido-[2,3-g]-indazol-8-illecillewaet

To a stirred solution of the product from example 4, step D (0,22 g, 0.81 mmol) and triethylamine (0,224 ml, 1.6 mmol) in anhydrous dichloromethane (30 ml) under nitrogen atmosphere at 0°With added using syringe acetylchloride (0,069 ml, 0.97 mmol, 1.2 EQ.). After 30 min bath with ice is removed and the reaction mixture stirred at ambient temperature for 18 hours Volatile products is evaporated and the residue is dissolved in ethyl acetate, filtered and concentrate the obtaining oil (0.12 g, 55%), which turns into a dull-white solid when maturation: the melting point of 88-89°; data1H-NMR correspond to the desired acetate.

Stage b: (8R)-1-[(2S)-2-aminopropyl]-1,7,8,9-tetrahydropyrido-[2,3-g]-indazol-8-ylacetic

A mixture of the product from step A (0.12 g, 0.38 mmol) and Pd/C (10%, 0,012 g) in methanol (10 ml) is stirred under nitrogen atmosphere for 18 h, filtered and evaporated to dryness to obtain oil. The oil is dissolved in dichloromethane and treated with 2 N. HCl in ethanol. Evaporation of the mixture gives a yellowish powder (0.12 g): LC/MS (+APCI) m/z 290 (M+H). Analysis. Calculated for C15H19N3About3·HCl·1,2 N2O: N 6,50; 51,86; N 12,21.

Defined: N 6,58; 51,88; N, 11,93.

Example 21

(8R)-1-[(2S)-2-aminopropyl]-1,7,8,9-tetrahydropyrido-[2,3-g]-indazol-8-illecillewaet

Stage A: Benzyl ester [(S)-2-((R)-8-hydroxy-8,9-dihydro-7H-pyrano-[2,3-g]-indazol-1-yl)-1-methylethyl]carbamino acid

To stir, to a solution of the product from example 4 (16.2 g, 65,6 mmol) in ethyl acetate (100 ml) at 0°add saturated aqueous sodium bicarbonate solution (150 ml) and benzylchloride (95%, to 9.32 ml, 65,6 mmol). The mixture was stirred at ambient temperature for 3 h and the organic layer is separated, dried and concentrated to obtain oil. Thin-layer chromatography (gradient, 30-50% ethyl acetate in hexane) get a solid prophetic the TWT (16.2 g, 65%): LC/MS (+APCI) m/z 382 (M+H).

Stage b: (R)-1-((S)-2-benzyloxycarbonylamino)-1,7,8,9-tetrahydropyrido-[2,3-g]-indazol-8-yl-new air imidazole-1-carboxylic acid

To a stirred solution of the product from step A (2.0 g, 5.2 mmol) in anhydrous dichloromethane (100 ml) add carbonyldiimidazole (1.1 g, 6.8 mmol, 1.3 EQ.) when the ambient temperature. After 1 h, add aqueous sodium bicarbonate solution, the organic part is evaporated, and the aqueous portion extracted with ethyl acetate. The extract is evaporated to obtain white solids: (2.4 g, 98%): LC/MS (+ESI) m/z 476 (M+H).

Stage C: Benzyl ester [(S)-1-methyl-2-((R)-8-methylcarbamoyl-8,9-dihydro-7H-pyrano-[2,3-g]-indazol-1-yl)-ethyl]carbamino acid

To a solution of compound from step B (0,30 g to 0.63 mmol) in anhydrous tetrahydrofuran (10 ml) is added methylamine (2 M in Meon, of 0.47 ml, 0.95 mmol) and the mixture is heated at 40°C for 1 h, the Reaction mixture was concentrated and purified by thin-layer chromatography (gradient, 20-80% ethyl acetate/hexane) to obtain a solid substance made (0.13 g, 47%): melting point 186-188°C; LC/MS (+APCI) m/z 439 (M+H).

Stage D: (8R)-1-[(2S)-2-aminopropyl]-1,7,8,9-tetrahydropyrido-[2,3-g]-indazol-8-illecillewaet

A mixture of the product from step C (0,13 g, 0.30 mmol) and Pd/C (10%, 0.02 g) in a mixture of methanol (20 ml) and ethyl acetate (20 ml) is stirred under nitrogen atmosphere for 3 h, filtered and evaporated to what rucenim oil. The oil is dissolved in ethanol and treated with 2 N. HCl in ethanol. Evaporation of this mixture gives a crude solid. The solid is dissolved in methanol (1 ml) and add ethyl acetate (about 10 ml); this solution is allowed to stand until the morning when the ambient temperature. The solid is collected by filtration and dried to give the desired product (0,089 g, 88%): LC/MS (+APCI) m/z 305 (M+H). Analysis. Calculated for C15H19N4O3·HCl: 52,86; N 6,21; N 16,44. Defined: 52,77; N. Of 6.25; N 16,21.

Example 22

1-[(2S)-2-aminopropyl]-1,7,8,9-tetrahydropyrido-[2,3-g]-indazol-8-ylcarbamate

Stage A: 1-[(2S)-2-azithromy]-1,7,8,9-tetrahydropyrido-[2,3-g]-indazol-8-ylcarbamate

The solution chlorosulfonylisocyanate (0,064 ml, 0.73 mmol) in diethyl ether (3 ml) at room temperature is treated with a solution of the product from example 3, step A (100 mg, 0.35 mmol) in diethyl ether (4 ml). The reaction mixture was stirred at ambient temperature for one hour and the reaction quenched with water (10 ml), stirred for 10 min and neutralized in an aqueous solution of NaH2PO4. The mixture is extracted with ethyl acetate (3×10 ml) and the combined organic layers dried (over magnesium sulfate) and evaporated to a yellow solid (110 mg). After purification by thin-layer chromatography (gradient, silica, hexane/ethyl acetate) get bestv is the based solid (60 mg, 52%): melting point 141-145°C; LC/MS m/z 317.

Stage b: 1-[(2S)-2-aminopropyl]-1,7,8,9-tetrahydropyrido-[2,3-g]-indazol-8-ylcarbamate

A solution of product from step A (90 mg, 0.28 mmol) in methanol (10 ml) and THF (2 ml) is treated with 10% palladium on carbon (10 mg) and hydrogen (1 MPa) under stirring at room temperature for 18 hours, the Reaction mixture was filtered and evaporated to obtain a yellow oil (70 mg, 86%): LC/MS m/z 291. Data1H-NMR consistent with the structure.

Table 3

5-HT2Areceptor binding and functional data
ExampleIC50nmEC50nmThe efficiency (Emax, %)
170,7915488

1. Pyrenoidosa formula 1

where R1and R2independently selected from hydrogen or alkyl groups;

R3and R4are independently hydrogen or alkyl group, or

R5, R6and R7represent hydrogen;

R8and R9represent hydrogen, hydroxyl, alkoxy, NR10R11OS(=O)NR1R2OS(=O)1-4alkyl or alkylthio, where R10and R11represent hydrogen;

And means (CH2)nor C=O;

B denotes either a single or double bond;

n=0-2;

Y denotes N, X is C; the dotted line indicates the corresponding single or double bond.

2. The compound according to claim 1, in which R1and R2chosen independently from hydrogen or C1-4of alkyl;

R3and R4chosen independently from hydrogen or C1-4of alkyl;

R8and R9selected from hydrogen, hydroxyl, C1-6alkoxy or NR10R11,

And means (CH2)n.

3. The compound according to claim 1, in which R1and R2chosen independently from hydrogen or C1-4of alkyl;

R3represents C1-2alkyl;

R4denotes hydrogen;

R8and R9chosen independently from hydrogen, hydroxyl, C1-6alkoxy or NR10R11;

And means (CH2)n,

In denotes a single bond;

n=1.

4. The compound according to claim 1, in which the connection specified is a

1-(2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

(R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

(S)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S-2-aminopropyl)-3-methyl-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-(S)-1-pyrrolidin-2-ylmethyl-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S)-2-aminopropyl)-5-fluoro-1,7,8,9-thecoalition[2,3-g]indazol-8-ol;

(R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ylamine;

[1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-yl]dimethylamine;

1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8,9-diol;

or combinations thereof.

5. The way the regulation of normal or elevated intraocular pressure, including the introduction of a pharmaceutically effective amount of a composition comprising at least one compound according to claim 1.

6. The method according to claim 5, wherein R1and R2independently selected from hydrogen or C1-4of alkyl;

R3and R4chosen independently from hydrogen or C1-4of alkyl;

R8and R9selected from hydrogen, hydroxyl, C1-6alkoxy or NR10R11;

And means (CH2)n.

7. The method according to claim 5, wherein R1and R2independently selected from hydrogen or C1-4of alkyl; R3represents C1-2alkyl; R4denotes hydrogen; R8and R9chosen independently from hydrogen, hydroxyl, C1-6alkoxy or NR10R11; And means (CH2)nIn denotes a single bond; n=1.

8. The method according to claim 5, the tives such as those the specified connection is a

1-(2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

(R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

(S)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S)-2-aminopropyl)-3-methyl-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-(S)-1-pyrrolidin-2-ylmethyl-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S)-2-aminopropyl)-5-fluoro-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

(R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ylamine;

[1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-yl]dimethylamine;

1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8,9-diol;

or combinations thereof.

9. A method of treating glaucoma, comprising the introduction of a pharmaceutically effective amount of a composition comprising at least one compound according to claim 1.

10. The method according to claim 9, wherein R1and R2chosen independently from hydrogen or C1-4of alkyl; R3and R4chosen independently from hydrogen or C1-4of alkyl; R8and R9selected from hydrogen, hydroxyl, C1-6alkoxy or NR10R11And indicates (CH2)n.

11. The method according to claim 9, wherein R1and R2ybiraut independently from hydrogen or C 1-4of alkyl; R3stands With1-2alkyl; R4denotes hydrogen; R8and R9chosen independently from hydrogen, hydroxyl, C1-6alkoxy or NR10R11; And means (CH2)nIn denotes a single bond; n=1.

12. The method according to claim 9, characterized in that the connection specified is a

1-(2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

(R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

(S)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S)-2-aminopropyl)-3-methyl-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-(S)-1-pyrrolidin-2-ylmethyl-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

1-((S)-2-aminopropyl)-5-fluoro-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ol;

(R)-1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-ylamine;

[1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8-yl]dimethylamine;

1-((S)-2-aminopropyl)-1,7,8,9-tetrahydropyrido[2,3-g]indazol-8,9-diol;

or combinations thereof.

13. Pharmaceutical composition suitable for the regulation of intraocular pressure, glaucoma and/or activation or binding of serotonin receptors, comprising the compound according to claim 1 and at least one media device.

14. The way was blocked and the and the binding of serotonin receptors, including the introduction of an effective amount of at least one compound according to claim 1 to a patient.



 

Same patents:

FIELD: organic chemistry, pharmacy, biochemistry.

SUBSTANCE: invention relates to new substituted 2H-pyrano[2,3-c] of the general formula (1) eliciting ability to inhibit activity of protein kinase. In the general formula (1) X represents oxygen atom or group NR3; R1 represents group -C(O)R4, optionally substituted and optionally condensed azaheterocycle; R2 represents optionally substituted hydroxyl group or optionally substituted amino-group; R3 represents hydrogen atom or inert substitute meaning optionally substituted low- or non-reactive radical including such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, (C2-C12)-alkoxyalkyl, (C2-C10)-alkylsulfinyl, (C2-C10)-alkylsulfonyl, -(CH2)-O-(C1-C7-alkyl), -(CH2)m-N(C1-C7-alkyl)n, aryloxyalkyl, heterocyclyl wherein m and n have value from 1 to 7; R4 represents optionally substituted amino-group or hydrogenated optionally substituted azaheterocycle. Also, invention relates to combinatory and focused libraries consisting of compounds of the present invention and designated for the search of compound-hits and compound-leaders prepared by screening of these libraries for using in preparing medicinal agents.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 6 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention proposes applying derivatives of benzopyranoimidazole and benzothiopyranoimidazole as inhibitors of activity of phosphodiesterase VII, new derivatives of benzopyranoimidazole of the general formula (I)

with radical values given in the invention claim that elicit the above said activity and a pharmaceutical preparation based on thereof. Claimed derivatives elicit specific inhibition of rolipram-insensitive cAMP-phosphodiesterase (phosphodiesterase VII) in combination with good tolerance that allows their applying in asthma treatment. Indicated compounds show activity with respect to inhibition of tumor necrosis factor (TNF) producing that allows their applying for treatment of some autoimmune diseases.

EFFECT: valuable medicinal and biochemical properties of compounds.

3 cl, 2 tbl, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims

The invention relates to derivatives of 1-arylsulfonyl, arylcarbamoyl or aristoteleion General formula I where L is selected from the group consisting of Co, CS and SO2; R1and R2independently selected from the group consisting of hydrogen, halogen, alkyl (C1-C6), haloalkyl (C1-C6), provided that when L - SO2, R1and R2at the same time do not represent hydrogen; R3independently represents 1 to 3 groups consisting of hydrogen, halogen, alkyl (C1-C6), haloalkyl (C1-C6); X is chosen from (CH2)nor Y(CH2)n-1where Y Is O or S, and n = 1, 2, 3

The invention relates to new coumadinhydrochloride acids, in which the system of pyridone condensed in the 3,4-, 6,7 - and 7,8-positions coumarin system, the General formula I

< / BR>
where R1R2= NHCH=C(CO2R6)CO., R3= NO2or NH2, R4= R5= H, R6= H or C2H5; R1R2= NHCH=C(CO2R6)CO., R3= R4= H, R5= F, R6= H or C2H5; R1R2= CO(CO2R6) = СНNH, R3= R4= R5= H, R6= H or C2H5; R1R2= R3R4= NHCH= C(CO2R6)CO., R5= H, R6= H or C2H5; R1= H or HE, R2= R5= N, R3R4= -NHCH=C(CO2R6)CO., R6= H or C2H5; R1= HE, R2= R3= N, R4R5= -CO(CO2R6) = СНNH, R6= H or C2H5; R1= R5= N, R2- CH3or CF3, R3R4= CO(CO2R6)C = CHNH, R6= H or C2H5and their pharmaceutically acceptable salts

The invention relates to new substituted dihydropyrimidines, methods for their preparation, pharmaceutical compositions containing them and their use as pharmaceuticals, in particular for the prevention or treatment of disorders characterized by excessive expansion of vessels, in particular migraine

The invention relates to tricyclic derivatives of pyrrole General formula (I), where R1-R4denote hydrogen, halogen, lower alkyl, phenyl, cycloalkyl or lower alkoxy, a R2indicates additional lower alkoxycarbonyl, acyloxy or mesilate; R5denotes lower alkyl; R6, R7represent hydrogen or lower alkyl; X represents-CH2CH(C6H5), -CH= C(C6H5)-, -YCH2-, -CH=CH - (CR11R12)n; R11and R12denote hydrogen, phenyl, lower alkyl; h denotes 1-3 and Y denotes O or S, and pharmaceutically acceptable acid additive salts

The invention relates to a new diisobutylaluminum connection, which has an excellent activity, which increases potassium exchange by opening potassium channels and therapeutic agents for the treatment of hypertension, angina pectoris and asthma, which contain diazabicyclo connection as the active agent

FIELD: medicine, pharmacy.

SUBSTANCE: invention represents a pharmaceutical tablet comprising a core and bound envelope wherein (a) core comprises solid particles of water-soluble dye dispersed in matrix, and (b) envelope comprises hellanic gum. Due to the presence of water-soluble dye in the tablet core it shows spotted shape that provides easy recognition of the tablet. The tablet is useful for peroral and intraoral administration.

EFFECT: improved and valuable properties of tablet.

30 cl, 6 ex

Muscarinic agonists // 2269523

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein Z1 represents -CR1 or nitrogen atom (N); Z2 represents -CR2; Z3 represents -CR3 or N; Z4 represents -CR4; W1 represents oxygen (O), sulfur (S) atom or -NR5; one of W2 and W3 represents N or -CR6 and another among W2 and W3 represents CG; W1 represents NG; W2 represents -CR5 or N; W3 represents -CR6 or N; or W1 and W3 represent N and W2 represents NG; G represents compound of the formula (II): wherein Y represents oxygen atom (O), -C(O)- or absent; p = 1, 2, 3, 4 or 5; Z is absent; each t = 2. Also, invention describes a method for enhancing activity of the muscarinic cholinergic receptor and a method for treatment of morbid states when modification of cholinergic and, especially, muscarinic receptors m1, m4 or both m1 and m4 offers the favorable effect.

EFFECT: valuable medicinal properties of agonists.

14 cl, 2 tbl, 101 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: the present innovation deals with introducing medicinal preparation onto scleral bottom and episclerally at the end of operation. As medicinal preparation one should apply 50%-glycerol solution, onto scleral bottom and episclerally introduced per 1 drop of solution. Exposure of glycerol solution corresponds to 1-2 min. The innovation enables to decrease the quantity of complications in post-operational period.

EFFECT: higher efficiency of therapy.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves per os introducing lipoic acid concurrently with beta-carotene at a dose of 0.05 and 10 mg 3 times a day during 1 month, respectively.

EFFECT: enhanced effectiveness of treatment; improved antioxidation activity in eye tissues; improved vision function.

3 dwg, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to 1-ethanolamide PGF of formula I useful in relaxation of mammalian intraocular pressure. Claimed substance unlike majority of ocular hypotensive prostaglandins doesn't effect through FP-receptor.

EFFECT: new effective compound for relaxation of mammalian intraocular pressure.

4 cl, 1 ex, 16 dwg, 16 tbl

The invention relates to the creation of homeopathic remedies and can be used in the conservative treatment of glaucoma with medication or surgically normalized and normal intraocular pressure

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to the field of medicine and relates to a composition for topical application, reducing intraocular pressure, comprising the antagonist of angiotensin II, boric acid and ethylenediaminetetraacetic acid

The invention relates to the field of medicine and organic chemistry and relates to new derivatives of prostaglandin F-type used as an ocular hypotensive drugs, as well as to a method of treatment of glaucoma with their help, ophthalmic solutions and kits comprising these solutions

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds able to prevent the extracellular release of inflammatory cytokines. Proposed compounds including their diastereomeric forms and their pharmaceutically acceptable salts correspond to the formula: wherein R means: (a) -O[CH2]kR3 or (b) -NR4aR4b; R3 means a substituted or unsubstituted (C1-C4)-alkyl, a substituted or unsubstituted phenyl wherein substitutes are taken among halogen atom, cyano-group, trihalidemethyl, (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein R3 means hydrogen atom each among R4a and R4b means independently hydrogen atom or (C1-C4)-alkyl-CO- or benzo(1,3)dioxol; index k has a value from 0 to 5; each among R4a and R4b means independently: (a) hydrogen atom or (b) -[C(R5aR5b)2]mR6 wherein each Ra means hydrogen atom, and R5b means hydrogen atom, linear or branched (C1-C)-alkyl; R6 means vinyl, the group -OR7, -CO2R7, cyclic (C3-C)-alkyl, unsubstituted phenyl or phenyl substituted with (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein each among R3, R4a and R4b means independently hydrogen atom, or unsubstituted 6-membered nitrogen-containing heteroaryl; R7 means hydrogen atom, water-soluble cation or (C1-C4)-alkyl; index m has a value from 0 to 5. Also, invention relates to a pharmaceutical composition comprising the effective dose of compounds corresponding to abovementioned formula, and to a method for inhibition of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 sch, 6 tbl, 3 ex

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