Substituted derivatives of norbornylamine, method for their preparing and medicinal agent

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

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

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

21 cl, 70 ex

 

The invention relates to substituted derivatives of norbornylene with asocolflores nitrogen and antoinelawana five-, six - or semifinali cycles of formula I and ectocarpales nitrogen and Antonelliana five-, six - or semifinali cycles of formula Ia,

where denote

And - (C1-C4- alkylen;

S1- free pair of electrons or (C1-C4)-alkyl;

S2- (C1-C4)-alkyl or H;

moreover, if S1 and S2 denote alkyl, X-in the formed group [-N+(S1S2)-X-] matches pharmacologically acceptable anion or triptoreline;

In - saturated or unsaturated carbon of the five-, six - or semiline ring, which independently of each other may be single - or multi-oxo-, hydroxy-, (C1-C4-alkoxygroup and (C1-C4)-alkyl;

and R1, R2, R3, R4 and R5 independently from each other H, HE, F, Cl, Br, I, CN, NO2amidinopropane, -CO2R(11), -CONR(11)R(12), -SOrR(11), -SOsNR (11) R (12), (C1-C4) -alkyl, (C1-C4) -alkoxygroup, (C1-C4) -alkoxy(C1-C4) -alkyl, (C1-C4) -alkoxy(C1-C4) -alkyloxy, hydroxy-(C1-C4)-alkyl, (C3-C7)-cycloalkane or fenoxaprop,

moreover, the phenyl is not substituted or C is substituted by up to three substituents, independently from each other selected from the group consisting of F, Cl, Br and metoxygroup;

amino, (C1-C4) -alkylamino-, di(C1-C4) -alkylamino, amino(C1-C4) -alkyl, di(C1-C4) -alkylamino(C1-C4) -alkyl, (C1-C4)-alkylamino-(C1-C4)-alkyl, and hydrogen atoms in the alkyl residues are fully or partly can be replaced by fluorine;

R11 and R12 independently from each other H or (C1-C4)-alkyl,

moreover, the hydrogen atoms in the alkyl residues are fully or partly can be replaced by fluorine;

r is 0, 1 or 2;

s is 1 or 2;

or each of R1 and R2, R2 and R3, R3 and R4 or R4 and R5 together with the group-O-(CH2)n-O-;

n is 1 or 2;

and each of the remaining residues R1, R2, R3, R4 or R5 independently from each other H, HE, F, Cl, Br, I, CN, NO2amidinopropane, -CO2R(11), -CONR(11)R(12); -SOrR(11), -SOsNR(11)R(12), (C1-C4)-alkyl, (C1-C4)-alkoxygroup, (C1-C4)-alkoxy(C1-C4)-alkyl, (C3-C7) -cycloalkanes, hydroxy-(C1-C4) -alkyl, amino, (C1-C4) -alkylamino-, di(C1-C4) -alkyl-amino, amino(C1-C4) -alkyl, di(C1-C4) -alkylamino-(C1-C4)-alkyl, (C1-C4)-alkylamino-(C1-C4)-alkyl,

moreover, the hydrogen atoms in the alkyl residues of the totally is Yu or in part may be substituted by fluorine;

R11 and R12 independently from each other H or (C1-C4)-alkyl,

moreover, the hydrogen atoms in the alkyl residues are fully or partly can be replaced by fluorine;

r is 0, 1 or 2;

s is 1 or 2;

however benzyl-(octahydro-4,7-methane-inden-5-yl)-amine is excluded, as well as their pharmaceutically acceptable salts or triptoreline.

The preferred connection with asocolflores nitrogen and antoinelawana five - or six-membered ring of formula I and ectocarpales nitrogen and Antonelliana five - or six-membered ring of the formula Ia, which represent

And - (C1-C2-alkylen;

S1 - free pair of electrons or methyl;

S2 - N;

In - saturated or unsaturated carbon of the five - or six-membered ring;

R1, R2, R3, R4 and R5 independently from each other H, amino, hydroxymethyl, HE, a methoxy group, F, Cl, Br or iodine;

or R2 and R3 together are-O-CH2-O-;

and the remaining residues R1, R4 and R5 independently from each other H, HE, F, Cl, Br, I, CN, NO2, (C1-C2)-alkoxy, amino, (C1-C2)-alkylamino - or di- (C1-C2)-alkylamino,

moreover, the hydrogen atoms in the alkyl residues are fully or partly can be replaced by fluorine;

this eliminates benzyl-(octahydro-4,7-methane-inden-5-yl)-amine, as well as their pharmaceutically acceptable salts and triptoreline.

Especially PR is pactically connection with asocolflores nitrogen and antoinelawana five - or six-membered ring of formula I and ectocarpales nitrogen and Antonelliana five - or six-membered ring of the formula Ia, which mean:

And - (C1-C2-alkylen;

S1- free pair of electrons;

S2 - N;

In - saturated or unsaturated carbon of the five - or six-membered ring;

R1, R3 and R5 is hydrogen;

and R2 and R4 independently from each other H, a methoxy group, F or Cl;

or R2 and R3 together are-O-CH2-O-;

and R1, R4 and R5 is hydrogen;

this eliminates benzyl-(octahydro-4,7-methane-inden-5-yl)-amine, as well as their pharmaceutically acceptable salts or triptoreline.

Most preferred are the following compounds with asocolflores nitrogen and antoinelawana five - or six-membered ring of formula I and ectocarpales nitrogen and Antonelliana the five-membered ring of the formula Ia:

Exo/endo-(3-Chlorobenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(3-terbisil)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-benzo[1,3]dioxol-5-ylmethyl(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(rat)-(3-methoxybenzyl)-(octahydro-4,7-methane - inden-5-yl)amine,

Exo/endo-(+)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(-)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-[1-(3-methoxyphenyl)-ethyl]-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(3-terbisil)-(3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)amine,

Exo/endo-(3-terbisil)-(3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-yl)amine,

Exo/endo-(3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)-(3-methoxybenzyl)amine,

Exo/endo-(3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-yl)-(3-methoxybenzyl)amine,

Exo/endo-(decahydro-1,4-methane-naphthalene-2-yl)-(3-methoxybenzyl)amine,

Exo/endo-(3,5-diferensial)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(3-terbisil)-(octahydro-4,7-methane-inden-5-yl)Amin

and

Exo/endo-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

and their pharmaceutically acceptable salts or triptoreline.

Especially preferred are the following compounds with asocolflores nitrogen and antoinelawana five - or six-membered cycles of the formula I:

Exo/endo-(3-Chlorobenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(3-terbisil)-(octahydro-4,7-methane-inden-5-yl)Amin

Exo/endo-(3-terbisil)-(3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)amine,

Exo/endo-(3-terbisil)-(3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-yl)amine,

Exo/endo-benzo[1,3]dioxol-5-ylmethyl(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(rat)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(+)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(decahydro-1,4-methane-naphthalene-2-yl)-(3-methoxybenzyl)amine,

Exo/endo-(-)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine and

Exo/endo-(3,5-diferensial)-(oktay the ro-4,7-methane-inden-5-yl)-amine,

and their pharmaceutically acceptable salts or triptoreline.

As additive salts of the acids take into account all pharmacologically acceptable salts, such as halides, in particular chlorides, lactates, sulfates, citrates, tartratami, acetates, phosphates, methylsulfonate, para-toluensulfonate, adipinate, fumarate, gluconate, glutamate, glycerophosphate, maleate and pamoate. This group is also pharmacologically acceptable anions. But it is also about trifenatate.

If the compound of formula I or Ia contains one or more centers of asymmetry, they can have both S-and R-configuration. The compounds may be presented in the form of optical isomers, diastereomers, racemates or mixtures thereof. Of course, aminosalicylic must be anthopology and the ring to be endo - or oceanseleven.

Named alkyl or alkylene residues may be both linear and branched.

Additionally, the invention relates to a method for producing compounds of the formula I or Ia, wherein a) a compound of the formula II or IIa

subjected to interaction with the compound of the formula III in the presence of a suitable reductant, and may also Lewis acid directly with the formation of compounds of the formula I or Ia,

where S1, S2, R1, R2, R3, R4 and R5 have the above values, while independently from each other a' corresponds to the communication or (C1-C3)-alkyl and A" corresponds to N or (C1-C3)-alkyl and A' and A" together with the carbon atom of the carbonyl group contain as many carbon atoms as described above for A;

or

b) formed from compounds of formula II or IIa and III of the intermediate compound of formula IV or IVa,

where if S1 denotes a (C1-C4)-alkyl, formed viewy nitrogen, which corresponds to the counterion, such as, for example, chloride or tosylate,

allocate and then a suitable reducing agent is transferred to the compounds of formula I or Ia,

or

C) the compound of formula II or IIa turn with an alkylating agent of formula V,

where U denotes nucleophile substituted group, such as chlorine, bromine and iodine, as well as mesilate, toilet, triplet or other well delete the group, and the other residues are defined as described above, but here the carbon atom of the carbonyl group corresponds to the carbon atom that is associated with U,

preferably in the presence of dinucleophiles base, such as diisopropylethylamine,

or

a) amides of carboxylic acids of formula VI or VIa

where And hereafter which includes communication or (C 1-C3)-alkyl and other

residues determined as described above, reduced to the corresponding amines;

or

e) compounds of the formula I or Ia where S1 denotes a free pair of electrons, and S2 denotes hydrogen, one or dalkilic alkylating agent of formula VII

where S* denotes a (C1-C4)-alkyl and U is the above value, so the result of this interaction is formed tertiary amine or Quaternary ammonium salt;

or

f) dicyclopentadienyltitanium complex of formula VIII

subjected to interaction with amines of the type of formula IX

where S1, S2, R1, R2, R3, R4 and R5 have the above values, while independently from each other And' means a connection or (C1-C3)-alkyl and A" represents H or (C1-C3)-alkyl and A' and A" together with the carbon atom linked to the nitrogen atom, contain as many carbon atoms as described above for A,

and then the resulting intermediate compound reduced to obtain the compounds of formula I (J.K. Stille, D.B. Fox JACS 1970 (92), 1974),

and if necessary translate into pharmaceutically acceptable salt or triptorelin.

In the description of the patent US 4024274 (Noah 74/F018) described norbornanamine such structure is s, but unknown spatial structure, with a good diuretic and salureticheskoe activity.

In the analysis of many described in the patent examples should highlight some of the connections of the specified type as a strong inhibitor of sodium-hydrogen exchange, subtype 3 (NHE3). Compounds were based on this tested on their solidarities action and suddenly was not confirmed any solidarities action, so that the relationship between N3-activity and solidarism could not be shown.

Since the spatial structure of the tricycle was unknown, there was a choice between four possible pairs of enantiomers, for a total of eight different spatial structures. For these pairs of enantiomers is shown that only two pairs show strong NHE3-inhibitory effect, whereas the other two pairs of enantiomers barely show N3-blocking properties. Search the most active structures by x-ray analysis showed that in the case of the most powerful N3-active pairs of enantiomers talking about connections with a certain ectocarpales for nitrogen, as well as with certain antoinelawana five-membered ring. Somewhat less active pair of enantiomers has a certain ectocarpales nitrogen, and definitely Antonelliana articlenum ring. The two remaining pairs of enantiomers with specific endo/Exo - or endo/andconfiguration barely show N3-ingibiruet action.

Then suddenly it was shown that certain separated enantiomers of the compound of example, which had a certain ectocervical nitrogen atom, and definitely indoamericano five-membered ring, both were equally active against NHE3. Because of their mirror spatial location was expecting a clear distinction activities.

In contrast to known inhibitors of sodium-hydrogen exchange, subtype 3 in patent EP-OS 825178 {NOAH 96/F226), which presents a relatively polar structures and correspond arylguanidines type (J.-R. Schwark and other Eur. J. Physiol (1998) 436:797), in the case of the proposed connections we are talking about unexpectedly lipophilic substances that do not belong to allhoneyboo type and represent a completely new structure for the inhibition of NHE3. After just called arylguanidines and confidently current squalamine (M.Donowitz and other Am. J. Physiol. 276 (Cell Physiol. 45): C136-C144) activity was observed after one hour, we are talking about the third class of substances N3 inhibitors, which were previously known. In contrast to the above NHE3 inhibitors they have shown an increased permeability through the membrane and immediately tune the attack action.

NHE3 was discovered in various parts of the body, preferably in the gall bladder, intestine and kidney (Larry Fliegel and others, Biochem. Cell. Biol. 76: 735-741, 1998), as well as in the brain (E. MA and other Neuroscience 79:591-603).

Proposed under the;the invention of the compounds of formula I or Ia are suitable for use as antihypertensive agents for the treatment of primary and secondary hypertension.

In addition, the compounds individually or in combination with NHE inhibitors, other subtypes can protect from acute or chronic oxygen deficiency of the body by reducing or difficulties induced by ischemia disorders. They apply so as medicines, for example, in surgical interventions (for example, transplantation of organs, kidneys and liver, and these compounds may be used to protect the organ from the donor before or during the separation, for the protection of separated body, for example, processing or storage in physiological fluids and transplantation in the recipient's organism) or acute and chronic renal failure. Special benefits can reduce induced ischemia disorders in the intestine.

In accordance with their protective effect against induced ischemia violations of compounds potentially applicable also in the quality of medicines on the I treatment of ischemia of the nervous system, in particular the Central nervous system, and they are, for example, applicable for the treatment of acute attacks or swelling of the brain. In addition, the compounds of formula I or Ia are equally applicable to the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

Further compounds induce improvement in respiratory pulse and therefore are involved in the treatment of shortness of breath under the following clinical conditions and diseases: poor Central respiratory pulse (for example, the Central syndrome temporary stopping of breathing during sleep, sudden infant death, postoperative hypoxia)caused by muscles respiratory disorders, respiratory disorders after long-term mechanical ventilation, respiratory disorders during adaptation to the highlands, obstructive and mixed forms of temporary stopping of breathing during sleep, acute and chronic lung disease with hypoxia and hypercapnia.

Additional connection improves muscle tone of the upper respiratory tract, so suppressed snoring.

The combination of an NHE inhibitor with a carbonic anhydrase inhibitor (eg, acetazolamide), the latter leads to metabolic acidosis and thus increases resistance to breathing is useful due to the increased activity and reduced CC is the origin of the active substance.

It is shown that the compounds according to the invention have a mild laxative effect and therefore can usefully be used as laxatives or threatening constipation, and reducing congestion in the gut is particularly useful in ischemic disorders.

Additionally there is a possibility of inhibiting the formation of gallstones.

In addition, proposed according to the invention the compounds of formula I or Ia may have inhibitory effect on the proliferation of cells, such as proliferation fibroblastic cells and cell proliferation of smooth muscles of vessels. Therefore, in the case of compounds of the formula I or Ia it comes to valuable therapeutic tools for diseases in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotic funds funds against late diabetic complications, cancer, fibrocycstic diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney, endothelial dysfunction, hypertrophy and hyperplasia of the authorities, in particular in prostate hyperplasia or hypertrophy of the prostate.

Proposed according to the invention compounds are active inhibitors of the cellular sodium-proton exchange, which in many Zab is the diseases (essential hypertension, atherosclerosis, diabetes etc) increased in these cells, which are easily accessible to measurements, such as, for example, in erythrocytes, platelets or leukocytes. Compounds according to the invention is therefore suitable as a simple scientific tools, for example in their use as diagnostic tools for the detection and identification of certain forms of hypertension, but also of atherosclerosis, diabetes, proliferative diseases, etc. moreover, the compounds of formula I or Ia are applicable for prophylactic therapy to prevent the Genesis of blood pressure, for example of essential hypertension.

In addition, we discovered that NHE inhibitors have a favorable effect on serum lipoproteins. Generally recognized that the emergence arteriosclerotic changes of vessels, such as coronary heart disease, too high content of fat in the blood, the so-called hyperlipoproteinemia, represents a significant risk factor. Therefore, for the prevention and regression of atherosclerotic changes in the reduction of elevated serum lipoprotein has an exceptional value. The proposed connection can therefore be employed for the prevention and regression of atherosclerotic changes, while they exclude a causal risk factor. Thanks to this protection of the vessels in which the compared syndrome of endothelial dysfunction of the compounds of formula I or Ia are valuable drugs for the prevention and treatment of coronary artery spasm, atherogenesis and atherosclerosis, levobetaxolol hypertension and dilated cardiomyopathy, and thrombotic diseases.

These compounds therefore are used for getting medicines for the prevention and treatment of temporary stopping of breathing during sleep and muscle due to breathing disorders; to obtain drugs for prevention and treatment of snoring; to get medicines to reduce blood pressure; to obtain medicines with purgative action for the prevention and treatment of intestinal constipation; to obtain drugs for prevention and treatment of diseases caused by ischemia and reperfusion of the Central and peripheral organs, such as acute renal failure, acute attack, the endogenous state of shock, intestinal diseases, etc.; to obtain medicines for treatment of hypercholesterolemia; to obtain drugs for the prevention of atherogenesis and atherosclerosis; to obtain drugs for prevention and treatment of diseases caused by the increased level of cholesterine; to obtain a medicine for preventing and treating diseases caused by endothelial dysfunction; to obtain medicinal means is for the treatment of lesions of ectoparasites; to obtain drugs for the treatment of the mentioned diseases, combined with lower blood pressure substances, preferably with angiotensin converting enzyme inhibitors (ACE) and antagonists of the angiotensin receptor. The combination of an NHE inhibitor of the formula I or Ia with a decreasing fat levels in the blood of active substance, preferably an inhibitor of HMG-CoA-REDUCTIE (for example, lovastatin or pravastatin), the latter leads to lipid-lowering effect and, thus, increases the hypolipidemic properties of the NHE inhibitor of the formula I or Ia, is a favorable combination with intensified action and reduced by the introduction of the active substance.

As a drug of a new type for lowering high blood pressure levels is proposed introduction of inhibitors of the sodium-proton exchange of formula I or Ia, or a combination of inhibitors of the sodium-proton exchange with lower blood pressure and/or gipolipidemiceski existing drugs.

Medicinal product, which contains a compound I or Ia can thus be administered orally, parenterally, intravenously, rectally or by inhalation, preferably the introduction depends on the corresponding picture of the disease. The compounds I or Ia may be used and dividuals or together with galenovye auxiliary substances as in veterinary medicine, and in medicine.

What excipients are applicable for the desired finished formulations of medicines known specialist on the basis of his special knowledge. Along with solvents, geleobrazovanie, the basics of suppositories, auxiliary means for tableting and other carriers of active substances can be used, for example, antioxidants, dispersing agents, emulsifying agents, blowing agents, flavorings, preservatives, soljubilizatory or dyes.

For oral forms of application of active compound is mixed with suitable additives, such as carriers, stabilizers or inert diluents, and translate customary methods into suitable forms of applications, such as tablets, coated tablets, capsules, aqueous, alcoholic or oily solutions. As the inert carrier can be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. This new form can be obtained both as dry and as wet granules. As an oil carrier or solvent can be used, for example, vegetable or animal oils, such as sunflower little or fish oil.

For subcutaneous or intravenous administration AK is active compounds if desired, conventional substances such as soljubilizatory, emulsifiers or other auxiliaries, contribute to the solution, suspension or emulsion. As a solvent it is, for example, water, physiological salt solution, or alcohol, for example ethanol, propanol, glycerin, in addition, solutions of sugars, such as glucose or mannitol, or a mixture of the mentioned solvents.

As pharmaceutical forms ready for use in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of the active compound of formula I or Ia in a pharmaceutically acceptable solvent, in particular in such as ethanol or water, or in mixtures of such solvents.

Ready preparative form may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and the carrier gas. This ready preparative form contains the active substance is usually in a concentration of from about 0.1 to 10, in particular from about 0.3 to 3 wt.%.

Dosage enter the active substance of the formula I or Ia and frequency of introduction depends on the strength and duration of action of the compounds used; additionally, on the type and severity of treatable diseases, and also from sex, age, weight, and the individual features of the treated mammal.

The average daily dose of the compounds of formula I or Ia with the weight of the patient of approximately 75 kg is at least 0.001 mg/kg, preferably 1-10 mg/kg, at most 100 mg/kg body weight. In acute attacks of the disease may also be the need for more and especially more frequent dosing, for example up to 4 individual doses per day. In particular, when administered intravenously, for example, in the case of infarction patent in the intensive care unit may be necessary up to 200 mg per day.

Experimental part:

Used abbreviations:

CH2Cl2- dichloromethane

CI chemical ionization

DIP - diisopropyl ether

EA - ethyl acetate

ES - elektrorazpredelenie

SPLA - acetic acid

H2O - water

H2O2- hydrogen peroxide

BP. - boiling point

Meon - methanol

MgSO4- magnesium sulfate

TPL - melting point

MS - mass spectrum

MTV - tert-butyl ether

NaBH4- sodium borohydride

NaHCO3- sodium bicarbonate

NaOH - sodium hydroxide

RT - bedroom temperature

THF - tetrahydrofuran

TFA - triperoxonane acid

HCl - hydrochloric acid

Description of the synthesis of some amines

Amin 1)

Synthesis of Exo/endo-octahydro-4,7-methane-inden-5-ylamine

a1) N,N'-dioxide b is s-(6-chloro-3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)-diazene and isomers

In a mixture of 167 g of Dicyclopentadiene, 160 ml of glacial acetic acid and 160 ml of ethanol was added 167 g isoamylamine and then dropwise with stirring at -10°C 420 ml of 15%aqueous solution of hydrogen chloride in ethanol. Was stirred 3 hours at room temperature. After addition of 500 ml of diisopropyl ether was stirred for another 10 minutes and was filtered crystals. Almost colourless crystals, TPL 177-178°C.

b1) octahydro-4,7-methane-inden-5-ylamine

A suspension of 10 g of N,N'-dioxide bis-(6-chloro-3A,4,5,6,7, 7a-hexahydro-1H-4,7-methane-inden-5-yl)-diazene, 60 ml of methanol and Raney Nickel was first made 10 hours at 100°With pressure H2100 at. The catalyst was filtered, the solvent was evaporated on a rotary evaporator under reduced pressure, mixed semi-crystalline residue with water and was very podslushivaet by adding 10 n NaOH. After a 3 - to 4-fold extraction of methyl tert-butyl ether and drying the organic phase over sodium sulfate the solvent is kept off and the oil was distilled in a vacuum. BP.5mm86-91°C., or

A2) 3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-ylamine and 3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-ylamine

20 g of Exo-5-isothiocyanato-5,6-dihydroergocryptine (Maybridge international) rastvoriteli in 60 ml is aravinou acid and 27 hours boiled under reflux. Volatile components were removed under vacuum, was added 50 ml of 20%aqueous NaOH solution and was extracted three times 100 ml of CH2Cl2. Dried over MgSO4and the solvent was removed in vacuum. Got a 13.4 g of a pale yellow oil.

Rf(CH2Cl2/MeOH/HOAc/H2O 32:8:1:1)=0,57; MS(ES+):150 (M+N)+

b2) tert-butyl ether (3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl) carbamino acid tert-butyl ester (3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)carbamino acid

12.8 g of a mixture of 3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-ylamine and 3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-ylamine was dissolved in 200 ml of THF and at RT was mixed with a solution of 18.7 g of di-tert-BUTYLCARBAMATE in 200 ml of THF. Then was added dropwise 12 ml of triethylamine and stirred 2 hours at RT. Volatile components were removed in vacuum and the residue was chromatographically on silica gel with DIP. Received 15 g of colorless oil, which was led from n-heptane; TPL 94°C.

Rf(DIP) = 0,68 MS (CI+):250 (M+H)+

C2) tert-butyl ether (octahydro-4,7-methane-inden-5-yl)-

carbamino acid

500 mg of a mixture of tert-butyl ester (3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)carbamino acid tert-butyl ester (3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-yl)-carbamino acid was dissolved in 20 ml of methanol and 2 ml of acetic acid and was first made with 200 mg 10%-n is th Pd/C (50% water) under an atmosphere of hydrogen (1 bar) for 6 hours. The catalyst was filtered and the volatile components were removed in vacuum. Received 470 mg resinous amorphous solid.

Rf(DIP)=0,70 MS (CI+):252 (M+N)+

d2) triptorelin octahydro-4,7-methane-inden-5-ylamine

460 mg of tert-butyl methyl ether (octahydro-4,7-methane-inden-5-yl)-carbamino acid was dissolved in 5 ml triperoxonane acid and 24 hours was stirred at RT. Then volatile components were removed in vacuum and got 390 mg of a pale yellow foamy product.

Rf(EA/NER/Meon/CH2Cl2/saturated aqueous solution of NH310:5:5:5:1)=0,30

MS (CI+):152 (M+H)+

or

A3) octahydro-4,7-methane-inden-5-ylamine

3,3 g of a mixture of 3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-ylamine and 3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-ylamine (amine example 1, A2) was dissolved in 30 ml of methanol and was restored under the atmosphere of hydrogen in the presence of 0.5 g of Pd/C (10%). After 4 hours the catalyst was filtered and washed with methanol. The filtrate was evaporated in vacuum and received 3 g of the desired product as oil. MS(ES+):152 (M+N)+

Amin 2) Synthesis of endo/acao-octahydro-4,7-methane-inden-5-ylamine

Pre-saturated with a 10° MNCa solution of 15 g tricyclo[5,2,1,02,6]decane-8-she's in 60 ml of methanol after the addition of Raney Nickel was first made in an autoclave at 90°and the pressure at which Orada 100 bar over 10 hours. After filtration of the catalyst and distillation of the solvent at reduced pressure using 10 n NaOH was very podslushivaet and were extracted 2-3 times with ethyl acetate or diisopropyl ether. The combined organic phases were dried and fractionally in vacuum. So Kip.6-7mm86-88°C.

Amin 3)

Synthesis of endo/anthochaera-4,7-methane-inden-5-ylamine

a) the oxime 1,3A,4,6,7 there,7a-hexahydro-4,7-methane-inden-5-she

10 g of N,N'-dioxide bis-(6-chloro-3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)diazene from amine 1, A1) suspended in 75 ml of isoamyl alcohol and stirring was slowly heated to boiling. After complete dissolution was cooled in an ice bath to room temperature and was added 25 ml of dried ethanol, 12.5 ml of glacial acetic acid and 6 g of zinc dust. Boil for one hour, cooled, zinc was filtered and the ethanol drove away. The residue was stirred in 300 ml of simple ether and kept over night. Then the ether decantation from the precipitate and washed three times with sodium carbonate solution and twice with water. After drying over magnesium sulfate was filtered and then the filtrate was evaporated. Subsequent distillation in vacuum is obtained 3,3 g of oil which was immediately used further.

b) octahydro-4,7-methane-inden-5-ylamine

2.2 g of the oxime of 1,3A,4,6,7 there,7a-hexahydro-4,7-methane-inden-5-it dissolve the Yali in 50 ml of methanol and added about 10% of Raney Nickel, dissolved in 50% water. After 20 hours was first made at 100 bars and 100°C, the catalyst was filtered and the solvent drove away. The residue was extracted by a simple ether and 6 n sodium hydroxide, the phases were separated, the aqueous phase was extracted three times with ether, the combined organic phases were dried with magnesium sulfate, filtered and the filtrate was evaporated. Remained 1.8 g of colorless oil, which was purified by distillation with ball reflux. Received 0.96 g of the desired amine in the form of oil.

MS (CI+):152,2 (M+N)+

Amin 4)

Synthesis of Exo/actionthere-4,7-methane-inden-5-ylamine

a) octahydro-4,7-methane-inden-5-ol

25 g tricyclo[5.2.1.0(2,6)]decane-8-she (Aldrich) was dissolved in 100 ml of methanol and, at room temperature with mild cooling and stirring portions over 2 h was added 6.3 g of solid sodium borohydride. Then stirred for another 2 h and kept overnight. When cooled then added dropwise 40 ml of 2 n HCl and then 20 ml of water. The mixture was evaporated, the residue was mixed with ethyl acetate and an ethyl acetate phase was washed once with water and once with sodium hydrogen carbonate solution. After drying with magnesium sulfate an ethyl acetate phase was filtered and evaporated. Remained 26 g of oil, which was purified by distillation in vacuum. Received 20.7 g oily liquid (BP.0.576°C).

b) 2-(who kagero-4,7-methane-inden-5-yl)isoindole-1,3-dione

To a solution of 1.66 g 11 octahydro-4,7-methane-inden-5-ol, 1.47 g of phthalimide and 2,62 g of triphenylphosphine in 15 ml of THF with stirring was added 1.7 g of diethylazodicarboxylate, diluted with 5 ml THF. After standing overnight the reaction mixture was evaporated, the residue was mixed with simple ether, the precipitate was sucked out and the filtrate was evaporated. The residue was purified through silica gel/toluene. Received of 1.36 g of yellow oil.

MS (CI+):282,2 (M+N)+

C) Exo/actionthere-4,7-methane-inden-5-ylamine

To a solution of 1.12 g of 2-(octahydro-4,7-methane-inden-5-yl)isoindole-1,3-dione in 15 ml of ethanol was added dropwise 0.4 g of hydrazine hydrate is added and stirred 2 h at 65°C. Then using conc. HCl has established a pH of 1-2 was mixed with 10 ml of ethanol, the precipitate was filtered and the filtrate was evaporated. The residue was purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). After freeze-drying has received 567 mg of the product as trifenatate. Treatment with sodium hydroxide and ethyl acetate obtained 322 mg of the free amine.

MS (CI+):to 152.0 (M+N)+

Examples

Unless otherwise indicated, in the examples we are talking about the racemates.

Example 1: (Exo/endo)-(3-chlorbenzyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

A solution of 0.54 g of Exo/anthochaera-4,7-methane-inden-5-ylamine (amine 1) and 0,562 g 3-chlorobenzaldehyde the 20 ml of toluene after addition of a small catalytic amount of p-toluenesulfonic acid was heated to boiling for 5 hours and after keeping overnight at room temperature drove the solvent. The residue was dissolved in methanol and added to ice yellow solution with stirring in small portions 0,181 g boronate sodium. Was stirred several hours at room temperature and was acidified with saturated methanolic solution of hydrogen chloride. After briefly stirring the precipitate was filtered and drove away the solvent from the filtrate. The remainder forms a colorless to slightly yellow crystalline substance, TPL 241°C.

Example 2: (Exo/endo)-(3-terbisil)-(3A,4,5,6,7,7a-hexa-hydro-1H-4,7-methane-inden-5-yl)amine and (Exo/endo)-(3-fluoro-benzyl)-(3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-yl)Amin

300 mg of the mixture of 3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-ylamine and 3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-ylamine (see Amin 1, A2), 315 μl of 3-forventelige, and 10 mg p-toluenesulfonic acid was dissolved in 5 ml of toluene (anhydrous) and 5 hours boiled under reflux. Then volatile components were removed in vacuo, the residue was extracted with 20 ml Meon, was added 152 mg NaBH4and was kept for 15 hours at RT. The reaction mixture was then diluted with 200 ml of EA and washed twice with 50 ml saturated aqueous solution of NaHCO3. Dried over MgSO4and the solvent was removed in vacuum. Preparative HPLC on RP-18 with acetonitrile/water (gradient 5:95-95:5) Paul is constrained to 150 mg of colorless oil.

Rf(EA)=0,40; MS (CI+):258 (M+H)+

Example 3: (Exo/endo)-(3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)-(3-methoxybenzyl)amine and (Exo/endo)-(3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-yl)(3-methoxybenzyl)Amin

Connection example 3 were synthesized analogously to example 2).

Rf(EA)=0,35; MS (CI+):270 (M+N)+

Example 4: (Exo/endo)-5-(3-methoxybenzylamine)-octahydro-4,7-methane-inden-2-ol

a) tert-butyl ether (3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)carbamino acid tert-butyl ester (3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-yl)carbamino acid, 12.8 g of a mixture of 3A, 4,5,6,7,7a-hexahydro-1H-4,7-methane - inden-5-ylamine and 3A,4,5,6,7,7a-hexahydro-3H-4,7-methane - inden-5-ylamine was dissolved in 200 ml of THF and at RT was mixed with a solution of 18.7 g of di-tert-BUTYLCARBAMATE in 200 ml of THF. Then was added dropwise 12 ml of triethylamine and stirred 2 hours at RT. Volatile components were removed in vacuum. Chromatography on silica gel with DIP obtained 15 g of a colorless oil. Crystallization from n-heptane obtained 4.9 g of colorless crystals, TPL 94°C.

Rf(DIP)=0,68; MS(ES+):250 (M+H)+

b) tert-butyl ether (2-hydroxy-octahydro-4,7-methane - inden-5-yl)carbamino acid

to 4.87 g of a mixture of tert-butyl ester (3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)carbamino is islote and tert-butyl ester (3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-yl)carbamino acid was dissolved in 30 ml of toluene (anhydrous) and RT syringe was added 20 ml of 2 M solution of borane-dimethylsulfide complex in toluene. 24 hours was stirred at RT, was added by syringe 10 ml of 2 M solution of borane-dimethylsulfide complex in toluene and again stirred 6 hours at RT. Volatile components were removed under vacuum, was added 200 ml of CH2Cl2and 33 ml of 3 n aqueous NaOH solution and slowly mixed with 7 ml of 30%aqueous solution of H2O2. Was stirred for 10 minutes at RT and added the following 100 ml of 3 n native NaOH solution and 20 ml of 30%aqueous solution of H2O2. The next 10 minutes was stirred at RT and then the reaction mixture was extracted three times with 200 ml of CH2Cl2. Dried over MgSO4and the solvent was removed in vacuum. Chromatography on silica gel with MTB obtained 2.9 g of an amorphous solid, which was still contaminated with regioisomers.

Rf(MTV) = 0,47; MS(CI+): 268 (M+H)+

c) 5-amino-octahydro-4,7-methane-inden-2-ol-triptorelin

300 mg of tert-butyl methyl ether (2-hydroxy-octahydro-4,7-methane-inden-5-yl)carbamino acid was dissolved in 3 ml triperoxonane acid and stirred for 30 minutes at RT. Then volatile components were removed in vacuum. Received 340 mg resinous solid, which was used further.

Rf(EA/NER/Meon/CH2Cl2/saturated aqueous solution of NH310:5:5:5:1) = 0,28;

MS(ES+): 168 (M+N)+

d) 5-(3-methoxybenzylamine)-octahydro-4,7-methane-inden-2-ol

309 mg of 5-amino-octahydro-4,7-methane-inden-2-ol-Cryptor-acetate and 225 mg of 3-methoxybenzaldehyde was dissolved in 10 ml of toluene (anhydrous) and 5 hours boiled under reflux. Then volatile components were removed in vacuum. The residue was made in 10 ml Meon, mixed with 208 mg NaBH4and was stirred 16 hours at RT. Then was diluted with 100 ml of EA and washed twice in 30 ml of 10%aqueous solution of NaHCO3. Dried over MgSO4and the solvent was removed in vacuum. Chromatography on silica gel with EA/Meon 2:1 received 100 mg of an amorphous solid.

Rf(EA/MeOH 2:1) = 0,20;

MS(ES+): 288 (M+N)+

Example 5: the rat-(Exo/endo)-(3-methoxybenzyl)-(octahydro-4,7-

methane-inden-5-yl)amine hydrochloride

A mixture of 1.08 g of 3-methoxybenzaldehyde, 1.1 g of (Exo/endo)-octahydro-4,7-methane-inden-5-ylamine (amine 1), a catalytic amount of p-toluenesulfonic acid and 20 ml of anhydrous toluene was heated for 3 hours under reflux, toluene drove under reduced pressure and the residue was dissolved in 20 ml of methanol. To the specified methanol solution was added in small portions while cooling 0.36 g sodium borohydride and stirred 18 hours at room temperature. After addition of a solution of hydrogen chloride in methanol was filtered from the precipitate and drove away the solvent under reduced pressure. The residue was boiled in ethanol, was filtered and was added to the filtrate with stirring, 150 ml of diethyl ether. Kept for several hours in the refrigerator and was filtered Crist is licence substance. Colourless crystals, TPL 190-194°C.

Example 6: (+)-(Exo/endo)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride and (-)-(Exo/endo)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

500 mg rat-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine-hydrochloride from example 5) was divided in several attempts on preparative column (Diacel Chemicals (CSP Chiralpak-AS 250×25, 10 μm). Conditions were as follows: flow: 3 ml/min, temperature: 24°With a mixture allentow: n-hexane/ethanol/isopropanol/TFA 10/1/1/0,1, wavelength: 230 nm.

After freeze-drying was received

(+)-enantiomer: 198 mg, purity according to HPLC: 98%

(-)-enantiomer: 218 mg, purity according to HPLC: 99%

For conversion into the hydrochloride 75 mg of each enantiomer was mixed with potassium carbonate solution and ethyl acetate and was well shaken. After separation of the phases the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were dried with magnesium sulfate, filtered and evaporated in vacuum. The residue was filtered through 5 g of silica gel, the filtrate was evaporated, the residue was mixed with 2 n hydrochloric acid and dried by freezing.

After freeze-drying was received:

(+)-enantiomer: 53 mg, the value of the rotation: +33° (Na, 589 nm), MS(ES+): 272,2 [H+H)+

(-)-enantiomer: 51 mg, the value of rotation: -32°, (Na 589 nm), MS(ES+:272,2 (M+N) +

Example 7: (endo/Exo)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

A mixture of 2.2 g of 3-methoxybenzaldehyde, 40 ml of methanol, and 3.3 g (endo/Exo)-octahydro-4,7-methane-inden-5-ylamine (amine 2) and the catalyst of the Raney Nickel was first made in an autoclave at 80°and 60 bars of hydrogen pressure for 6 hours. The residue was dissolved in ethyl acetate, was filtered from the catalyst, drove away the solvent under reduced pressure, dried over sodium sulfate and again passed through the rotary evaporator. After dissolving the residue in a small amount of ethyl acetate was mixed with excess ethereal hydrochloric acid, from which under stirring fell sediment. A colorless crystalline substance (from diisopropyl ether/methanol) with TPL 206-208°C.

Example 8: (endo/endo)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

190 mg of 3-methoxybenzaldehyde, 211 mg (endo/endo)-octahydro-4,7-methane-inden-5-ylamine (amine 3) and 423 mg of triethylamine were placed under exclusion of moisture in 5 ml of dry CH2Cl2. Through the membrane under stirring was added dropwise 0.7 ml of 1 molar solution of titanium tetrachloride in toluene. After 18 hours at room temperature was added 887 mg triacetoxyborohydride and stirred another hour. Then added the 3 ml of 5 n sodium hydroxide solution and 10 ml of water, next was extracted three times with 20 ml of ethyl acetate, dried, filtered and evaporated in vacuum. The residue was dissolved in 2 n hydrochloric acid and was extracted with simple ether. The aqueous phase was evaporated and purified preparative HPLC on RP-18 with acetonitrile/water. Pure fractions were combined, the acetonitrile was removed on a rotary evaporator, the potassium carbonate was established pH 11, was extracted with CH2Cl2combined phase was dried and evaporated. The residue was extracted with 2 n hydrochloric acid and a small amount of acetonitrile and dried by freezing. Received 10 mg of the hydrochloride as a white solid.

MS(ES+):272,2 (M+N)+

Example 9: (Exo/Exo)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

A mixture of 150 mg of 3-methoxybenzaldehyde, 167 mg (Exo/Exo)-octahydro-4,7-methane-inden-5-ylamine (amine 4), catalytic amount of p-toluenesulfonic acid and 15 ml of anhydrous toluene was heated for 3 hours under reflux, toluene drove under reduced pressure and the residue was dissolved in 10 ml of methanol. To the specified methanol solution under ice cooling was added in small portions 50 mg sodium borohydride and kept at room temperature. After addition of a solution of hydrogen chloride in methanol was filtered from the precipitate and drove away the solvent under reduced the military pressure. The residue was purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). Obtained after freeze-drying triptorelin transformed by the action of sodium hydroxide/ethyl acetate in the free amine and then 2 n HCl was converted into the hydrochloride. Received 125 mg of a white product.

MS(CI+): 272,2 (M+N)+

Example 10: (Exo/endo)-(3-terbisil)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

124 mg of 3-tabunselected, 151 mg (Exo/endo)-(octahydro-4,7-methane-inden-5-ylamine (amine 1) and 303 mg of triethylamine in excluding moisture brought in 10 ml of dry CH2Cl2. Through the membrane under stirring was added dropwise 0.5 ml odnopolyarnogo solution of titanium tetrachloride in toluene. After 18 hours at room temperature was added 3 ml odnopolyarnogo solution cyanoborohydride sodium in THF and stirred for another 15 minutes and Then was added 5 ml of 5 n sodium hydroxide solution and 15 ml of water, then was extracted three times with 25 ml ethyl acetate, dried, filtered and evaporated in vacuum. The residue was filtered through silica gel (CH2Cl2/methanol 97:3), again dried and the crude product was purified preparative HPLC on RP-18 with acetonitrile/water. Pure fractions were combined, the acetonitrile was removed on a rotary evaporator, the potassium carbonate was established pH 11, was extracted three times with ethyl acetate and the United phase was dried and evaporated. The residue was extracted with 2 n hydrochloric acid and a small amount of acetonitrile and dried by freezing. Received 144 mg of a white solid.

MS(CI+):260 [M+N)+

Example 11: (Exo/endo)-(3,5-diferensial)-(octahydro-4,7-

methane-inden-5-yl)amine hydrochloride

200 mg of 3,5-diferentialglea and 151 mg (Exo/endo)-(octahydro-4,7-methane-inden-5-ylamine (amine 1) was dissolved in 15 ml of toluene (anhydrous), was mixed with 11 mg p-toluenesulfonic acid and boiled for 3 hours under reflux. Then volatile components were removed in vacuum. The residue was extracted with 10 ml of methanol under ice cooling and stirring, mixed with 64 mg NaBH4and kept during the night.

A solution of methanolic HCl was brought to pH 1-2, precipitated solid was filtered and the solution was evaporated. The residue was dissolved in hot ethanol, filtered and with stirring, cooled. Addition of diethyl ether the product was besieged, was aspirated, washed with ether and dried. Received 212 mg of a white solid.

MS(CI+):278,3 (M+H)+

Example 12: (Exo/endo)-[1-(3-methoxyphenyl)-ethyl]-(octahydro-

4,7-methane-inden-5-yl)amine hydrochloride

To a solution of 0.75 g of 3-methoxyacetophenone and 2.7 g of (Exo/endo)-octahydro-4,7-methane-inden-5-ylamine (amine 1) in 15 ml of n-pentane was added dropwise at 5-10°With just 10 minutes a mixture of 0.73 g of titanium tetrachloride and 3 ml of n-pentane. Was stirred another hour at 5-10°and was kept over night at room temperature. After filtration of the precipitate drove the solvent on a rotary evaporator. Now the residue was dissolved in 20 ml of methanol and portions while cooling with 5-10°mixed with 0.96 g of sodium borohydride. The mixture was stirred for 15-20 hours at room temperature and the solvent is then drove away. The residue was mixed with water, acidified with hydrochloric acid and was extracted with ethyl acetate, and the precipitated crystals, which were filtered and recrystallized from a small amount of water (TPL 257-259°). The aqueous filtrate was strongly podslushivaet with 2 n NaOH, extracted with ethyl acetate and drove the solvent after drying the organic solution over sodium sulfate. After dissolving the residue in a small amount of ethyl acetate solution was strongly acidified with a solution of hydrogen chloride in diethyl ether, the crystals were filtered off and recrystallized from a small amount of water (TPL 257-259°).

Example 13: (ICAO/endo)-(3-bromobenzyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

to 1.9 g of 3-bromobenzaldehyde, 1.5 g of (Exo/endo)-octahydro-4,7-methane-inden-5-ylamine (amine 1) and 60 mg p-toluenesulfonic acid was dissolved in 180 ml of anhydrous toluene and boiled for 5 hours with the reverse you can see what these lamps. Volatile components were removed in vacuum and the residue was dissolved in 120 ml of methanol. Was added 530 mg NaBH4and was stirred 2 hours at RT. Kept for 18 hours at RT and then volatile components were removed in vacuum. Was extracted with 200 ml of a saturated aqueous solution of NaHCO3and was extracted three times with 200 ml of EA. Dried over MgSO4and the solvent was removed in vacuum. The residue was extracted 12 ml of 10%aqueous HCl solution and the volatile components were removed in vacuum. The residue was stirred with 50 ml of EA and received 3.0 g of crystalline hydrochloride, TPL 248°C.

Rf(EA)=0,44; MS(CI+):320(M+H)+

Example 14: (Exo/endo)-3-[(octahydro-4,7-methane-inden-5-yl-amino)methyl]benzoic acid

a) butyl ester 3-[(octahydro-4,7-methane-inden-5-ylamino)-methyl]benzoic acid

1 g (3-bromobenzyl)-(octahydro-4,7-methane-inden-5-yl)-amine-hydrochloride from example 13), 115 mg of 1,3-bis(diphenylphosphino)propane, 63 mg acetate Pd(II)and 4 ml of tri-n - butylamine were dissolved in 10 ml of 1-butanol and 2 ml of DMF and stirred under an atmosphere (normal pressure) for 8 hours at 110°C. Then was added 115 mg of 1,3-bis(diphenylphosphino)propane and 63 mg acetate Pd(II) and stirred for another 7 hours at 110°C. After cooling, there was added 100 ml of a saturated aqueous solution of Na2CO3and thrice was extracted with 100 ml of EA. Dried over MgSO4and rest rytel was removed in vacuum. Chromatography on silica gel with DIP/2% triethylamine received 600 mg of colorless oil.

Rf(DIP/2% triethylamine)=0,42; MS(ES+):342(M+H)+

b) 3-[(octahydro-4,7-methane-inden-5-ylamino)methyl]benzoic acid

600 mg butyl ester 3-[(octahydro-4,7-methane-inden-5-ylamino)methyl]benzoic acid was dissolved in 1 ml n-butanol was added to 2.1 ml of 1 n aqueous NaOH solution. Was stirred 18 hours at RT, then 4 hours at 60°C. Then volatile components were removed in vacuum and twice with 5 ml of water h-butanolic residue was subjected to azeotropic distillation under reduced pressure. The residue was extracted with 5 ml of 10%aqueous HCl solution, the volatile components were removed in vacuum and the residue twice azeotropic drove water with 5 ml of toluene. The product still contained a considerable amount of substance, so it was again dissolved in 6 ml of methanol and mixed with 1 ml of 2 n aqueous NaOH solution. Was stirred 3 hours at RT and then added 5 ml of 2 n aqueous NaOH and boiled for 4 hours under reflux. Volatile components were removed in vacuo, extracted with 20 ml water and brought to pH 7 with diluted aqueous HCl solution. Again stirred for 1 hour at RT, the product was pumped out and dried in vacuum. Got 260 mg of crystalline solids, TPL 258-261°C.

MS(CI+): 286 (M+N)+

Example 15: (Exo/endo)-[3-(2-methoxyethoxy)benzyl]-(about the TA-hydro-4,7-methane-inden-5-yl)amine hydrochloride

a) 3-(2-methoxyethoxy)benzaldehyde

1.0 g of 3-hydroxybenzaldehyde, 1.1 g of 1-bromo-2-methoxyethane and 10.7 g Cs2COCwas stirred in 10 ml of DMF (anhydrous) 4 hours at 40°C. is Diluted with 100 ml of water and was extracted twice with 50 ml. Dried over MgSO4and the solvent was removed in vacuum. Obtained 1.3 g of colorless oil.

Rf(DIP)=0,24; MS(CI+):181 (M+N)+

b) [3-(2-methoxyethoxy)benzyl]-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride;

300 mg of 3-(2-methoxyethoxy)benzaldehyde, 253 mg (Exo/endo)-octahydro-4,7-methane-inden-5-ylamine (amine 1) and 10 mg p-toluenesulfonic acid was dissolved in 30 ml of anhydrous toluene and boiled for 5 hours under reflux. Volatile components were removed in vacuum and the residue was dissolved in 20 ml of methanol. Was added 90 mg of NaBH4and was stirred 2 hours at RT. Kept for 18 hours at RT and then volatile components were removed in vacuum. Was extracted with 50 ml of saturated aqueous NaHCO3and was extracted three times with 50 ml of EA. Dried over MgSO4and the solvent was removed in vacuum. The residue was extracted with 2 ml of 10%aqueous HCl solution and the volatile components were removed in vacuum. The residue was stirred with 10 ml of diethyl ether and received 163 mg of the crystalline hydrochloride, TPL 134°C.

Rf(EA)=0,30; MS(CI+):316 (M+H)+

Example 16: (Exo/endo)-(3-iodobenzyl)˜ (octahydro-4,7-methane-inden-5-yl)amine hydrochloride

a) 1-methyl bromide-C-odeneal

4,4 D.3-iodotoluene was dissolved in 10 ml of chlorobenzene and 132°portions were mixed with a mixture of 3.6 g of N-bromosuccinimide and 100 mg dibenzoylperoxide. Was stirred another hour at 132°C, after cooling, diluted with 100 ml of EA and washed first with 100 ml saturated aqueous solution of Na2SO4and then 100 ml of a saturated aqueous solution of Na2CO3. Dried over MgSO4and the solvent was removed in vacuum. Got to 5.3 g of a pale yellow oil.

Rf(EA/HEP 1:8)=0,44; MS(ES+):298 (M+H)+

b) (3-iodobenzyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

755 mg (Exo/endo)-(octahydro-4,7-methane-inden-5-ylamine (amine 1) and 830 μl of triethylamine were dissolved in 20 ml of anhydrous THF and at 0°slowly mixed with 2.8 g of 1-bromo-methyl-3-iodobenzoyl. Was stirred for 30 minutes at 0°and then 5 days at RT. Then there was added 100 ml of a saturated aqueous solution of Na2CO3and was twice extracted with 100 ml of EA. Dried over MgSO4and the solvent was removed in vacuum. The residue was dissolved in 20 ml of methanol and established pH <2 10%aqueous HCl solution. Volatile components were removed in vacuo, the residue was mixed with 10 ml of EA and dried in vacuum. Got 1,74 g of colorless crystals, TPL 220-224°C (decomposition).

MS(CI+):368 (M+H)sup> +

Example 17: (Exo/endo)-3-[ (octahydro-4,7-methane-inden-5-yl-amino)methyl]benzonitrile hydrochloride

750 mg of 3-cyanobenzaldehyde, 865 mg (Exo/endo)-octahydro-4,7-methane-inden-5-ylamine (amine 1) and of 1.74 g of triethylamine were placed under exclusion of moisture in 30 ml of dry CH2Cl2. Through the membrane was added dropwise 2,86 ml odnopolyarnogo solution of titanium tetrachloride in toluene under stirring. After 18 hours at room temperature was added to 17.2 ml odnopolyarnogo solution cyanoborohydride sodium in THF and stirred for another 15 minutes Then added 20 ml of 5 n sodium hydroxide solution and 60 ml of water, then was extracted three times with 50 ml of ethyl acetate, dried, filtered and evaporated in vacuum. The residue was filtered through silica gel (CH2Cl2/methanol 97/3), again dried and the crude product was purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). After freeze-drying was obtained 1.1 g of the desired product as a white powder in the form of triptoreline.

250 mg of the specified powder was transferred into the hydrochloride as described in example 9). Received 175 mg of a white solid.

MS(CI+):267,3 (M+H)+

Example 18: hydrochloride methyl ester (Exo/endo)-3- [(octahydro-4,7-methane-inden-5-ylamino)methyl]benzoic acid hydrochloride ethyl ester (Exo/endo)-3-({OK is ahydro-4,7-methane-inden-5-ylamino)methyl]benzoic acid

a) dihydrochloride ethyl ester (Exo/endo)-3-[(octahydro-4,7-methane-inden-5-ylamino)methyl]benzimidazole acid

500 mg trifenatate 3-[(octahydro-4,7-methane-inden-5-ylamino)methyl]benzonitrile from example 17) was dissolved in 20 ml dry ethanol (contaminated with 5% methanol and 5 isopropanol) and under stirring and ice cooling after the solution had to miss 3 hours of gaseous hydrogen chloride. Kept over night at room temperature and the next day nitrogen to remove excess gaseous hydrogen chloride and the residue was evaporated. Received 587 mg of ethyl ether benzamidenafil acid as a white powder, which is contaminated with a minor amount of methyl ester benzamidenafil acid.

The crude product is directly used further.

(b) hydrochloride methyl ester (Exo/endo)-3-[(octahydro-4,7-methane-inden-5-ylamino)methyl]benzoic acid hydrochloride ethyl ester (Exo/endo)-3-[(octahydro-4,7-methane-inden-5-ylamino)methyl]benzoic acid

100 mg of the product from (a) was dissolved in 6 ml of a mixture of water and triperoxonane acid (5:1) and 3 hours and stirred at room temperature. After standing overnight the solvent was removed and the residue was purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). Drop down when thrift razetti ethyl and methyl esters were extracted with a solution of potassium carbonate and was extracted with ethyl ester of acetic acid. After drying and distillation, ethyl ester acetic acid, the residue was mixed with 2 n hydrochloric acid and dried by freezing. Received 28 mg of ethyl ether and 7 mg methyl ester.

Methyl ester: MS(ES+):to 300.2 (M+H)+

Ethyl ester: MS(ES+):314,3 (M+H)+

Example 19: (Exo/endo)-{3-[(octahydro-4,7-methane-inden-5-yl-amino)methyl]phenyl}methanol hydrochloride:

To 0,43 ml odnopolyarnogo solution of lithium aluminum hydride in THF under stirring and exclusion of moisture was added dropwise 50 mg dissolved in 5 ml of THF mixture of methyl/ethyl ester, obtained as described in example 18b). After stirring at room temperature and keeping the rest of the week while cooling with ice was slowly added dropwise water, the precipitate was sucked out and the well was washed with ethyl ether, acetic acid. The aqueous phase was extracted with ethyl ester of acetic acid and the combined organic phases were dried with magnesium sulfate. After filtering off the desiccant, the solvent is kept off and the residue was purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). Then, as described in example 10), was converted into the hydrochloride.

After freeze-drying has received 7 mg of product.

MS(ES+): 272,2 (M+N)+

Example 20: (Exo/endo)-3-[(octahydro-4,7-methane-inden-5-yl-amino)METI is]benzamid-triptorelin

45 mg of the dihydrochloride of ethyl ester of 3-[(octahydro-4,7-methane-inden-5-ylamino)methyl]benzimidazole acid from example 18a) was heated for 8 hours at 60°and then kept for three weeks at room temperature. The solid was then purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). After freeze-drying were allocated to 4 mg of the desired product.

MS(ES+):RUB 285.2 [N+N)+

Example 21: (Exo/endo)-(3-aminomethyl-benzyl)-(octahydro-4,7-methane-inden-5-yl)amine bis-triptorelin

To 5 ml odnopolyarnogo solution of lithium aluminum hydride in THF was added dropwise 100 mg 3-[(octahydro-4,7-methane-inden-5-ylamino)methyl]benzonitrile-trifenatate from example 17)dissolved in 5 ml of dry THF. Then was heated for 5 hours at 80°C. Then, while cooling with ice was slowly added dropwise water and was mixed with sodium hydroxide. The precipitate was filtered and washed with simple ether. After extraction of the aqueous phase combined organic phases were dried and then was filtered from the drying agent. After evaporation the residue was purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). After freeze-drying was allocated 26 mg of product.

MS(ES+):271,2 (M+H)+

Example 22: (Exo/endo)-3-[(octahydro-4,7-methane-inden-yl-amino)methyl]benzamide-bis-triptorelin

200 mg of the dihydrochloride of ethyl ester of 3-[(octahydro-4,7-methane-inden-5-ylamino)methyl]benzimidazole acid from example 18a) was dissolved in 15 ml of dry ethanol and slowly are condensed with about 20 ml of ammonia. After 3 hours boiling under reflux in ammonia was kept in overnight for evaporation of ammonia. The residue was evaporated and then purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). After freeze-drying was 89 mg of the desired product.

MS(CI+): at 284.3 (M+N)+

Example 23: (Exo/endo)-(3-nitrobenzyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

750 mg of 3-nitrobenzaldehyde, 751 mg (Exo/endo)-octahydro-4,7-methane-inden-5-ylamine (amine 1) and 1.5 g of triethylamine were placed under exclusion of moisture in 30 ml of dry CH2Cl2. Through the membrane was added dropwise 2,48 ml odnopolyarnogo solution of titanium tetrachloride in toluene under stirring. After 18 hours at room temperature was added 14,89 ml odnopolyarnogo solution cyanoborohydride sodium in THF and stirred for another 15 minutes Then added 20 ml of 5 n sodium hydroxide solution and 60 ml of water, then was extracted three times with 50 ml of ethyl acetate, dried, filtered and evaporated in vacuum. The residue was filtered through silica gel (CH2Cl2/methanol 95:5), the Nova was dried and the crude product was purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). Part of the thus obtained (3-nitrobenzyl)-(octahydro-4,7-methane-inden-5-yl)- Amin-trifenatate was distributed between ethyl ether, acetic acid and a solution of potassium carbonate (pH 11). The aqueous phase is again three times were extracted with ethyl acetate and the combined organic phase was dried and evaporated. The residue was extracted with 2 n hydrochloric acid and a small amount of acetonitrile and dried by freezing. Received 300 mg of a white solid.

MS(ES+):287,2 (M+H)+

Example 24: (Exo/endo)-(3-aminobenzyl)-(octahydro-4,7-methane-inden-5-yl)amine bis-triptorelin

100 mg (3-nitrobenzyl)-(octahydro-4,7-methane-inden-5-yl)Amin-trifenatate from example 23) was dissolved in a mixture of 5 ml of ethanol and ethyl ester of acetic acid. Then there was added 57 mg of zinc dust and stirred for 4 hours at 60°C. Then was added 25 g of zinc dust and stirred for another two hours at 60°C. the Reaction mixture was evaporated, the residue was extracted with ethyl ether, acetic acid and the organic phase was thrice washed with potassium carbonate solution, dried, filtered and evaporated. The residue was purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). After freezing received 23 mg of the desired product.

MS(ES+):257,2 (M+H)+

Example 25: (Exo/endo)-(3-methoxybenzyl)-methyl-(octahydro-4,7-methane-is-inden-5-yl)amine hydrochloride

50 mg (Exo/endo)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine from example 5) were placed in 5 ml of dry acetone, was added 20 mg of potassium carbonate, stirred 30 min and then was added dropwise 9 µl under the conditions. After keeping the end of the week, the reaction mixture was evaporated, the residue was extracted with water and ethyl acetate, the phases were separated, the aqueous phase was twice extracted with ethyl acetate and the combined organic phases were dried, filtered and evaporated. The residue was chromatographically on silica gel with ethyl ether acetic acid/heptane. The obtained amine was extracted with 2 n hydrochloric acid and dried by freezing. Received 14 mg of the desired product.

MS(CI+):286,4 (M+N)+

Example 26: (Exo/endo)-(3-methoxybenzyl)-dimethyl-(octahydro-4,7-methane-inden-5-yl)ammonium-triptorelin

53 mg (Exo/endo)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine from example 5 were placed in 5 ml of dry acetone and then was added dropwise 61 μl under the conditions. After keeping the rest of the week was added 50 μl under the conditions. After standing overnight was added three drops of N-ethyldiethanolamine and stirred for another 5 hours. Then the reaction mixture was evaporated and purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). the donkey freeze-drying has received 53 mg of the desired product.

MS(ES+):300,3 (M+)

Example 27: (Exo/Exo)-(3-terbisil)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

A mixture of 80 mg of 3-forventelige, 97 mg (Exo/Exo)-octahydro-4,7-methane-inden-5-ylamine (amine 4), catalytic amount of p-toluenesulfonic acid and 7.5 ml of anhydrous toluene was heated for 3 hours under reflux, toluene drove under reduced pressure and the residue was dissolved in 5 ml of methanol. To the specified methanol solution was added under cooling with ice in small portions 29 mg of sodium borohydride and left to warm to room temperature. After addition of 2 n HCl precipitate was filtered, dissolved in hot ethanol and poured into cold simple ether. Thus obtained precipitate was extracted with 2 n NaOH and dichloromethane, the aqueous phase was separated and the organic phase is washed with 2 n NaOH. Then the organic phase was dried MgSO4, was filtered and was evaporated. The residue was transferred into the hydrochloride using 2 n HCl. Received 35 mg of a white product.

MS(CI+):260,0 (M+H)+

Example 28: (Exo/endo)-(2-trifloromethyl)-(octahydro-4,7-

methane-inden-5-yl)amine hydrochloride

To a mixture of 98 mg (Exo/endo)-octahydro-4,7-methane-inden-5-ylamine (amine 1), 103 mg of diisopropylethylamine and 2 ml of dichloromethane is slowly under stirring was added dropwise 158 mg-(trifluoromethyl)benzylbromide, dissolved in 2 ml of dichloromethane. After standing overnight the solvent is kept off and the residue was purified preparative HPLC on RP-18 with acetonitrile/water (0.05% of triperoxonane acid). The fractions containing the product were combined, the acetonitrile was removed on a rotary evaporator, was established pH 11 with potassium carbonate was added ethyl acetate. The aqueous phase was extracted three times with ethyl acetate, the combined phase was dried and evaporated. The residue was extracted with 2 n hydrochloric acid and a small amount of acetonitrile and dried by freezing. After freeze-drying has received 127 mg of the desired product.

MS(CI+): 310,2 (M+N)+

Example 29: (Exo/endo)-(3-dimethylaminobenzoyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

a) (Exo/endo)-3-dimethylamino-N-(octahydro-4,7-methane-inden-5-yl)benzamid

After you have added 1.78 g (to 0.011 mole) N,N-carbonyldiimidazole to a solution of 1.65 g (0,01 mol) 3-N,N-diethylaminobenzoic acid in 40 ml of anhydrous THF was stirred 3 hours at room temperature under argon atmosphere and then mixed with 1,82 g (0,012 mol) (Exo/endo)-octahydro-4,7-methane-inden-5-ylamine (amine 1). Was stirred one hour at room temperature and drove the solvent after curing over night. The residue was mixed with water and set 2 n HCl pH 3-4. After stirring with a magnetic stirrer eye is about 30 minutes and was filtered colorless crystal (Exo/endo)-N-dimethylamino-N-(octahydro-4,7-methane-inden-5-yl)benzamid, washed the solid with water and dried in air stream, TPL 152-156°C;

MS(CI+): 299,4 (M+N)+

b) (Exo/endo)-(3-dimethylaminobenzoyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

To a solution of 2 g (0,0067 mole) of (Exo/endo)-3-dimethylamino-N-(octahydro-4,7-methane-inden-5-yl)benzamide in 100 ml of anhydrous 1,2-dimethoxyethane was added first to 1.38 g (0,0097 mole) of epirate of nortryptaline and then 10-15°With portions of 1.13 g (0,03 mole) boronate sodium. After gradual heating up to 70°and later up to 90°and after standing overnight the solvent is kept off, the residue was mixed with water and was very podslushivaet using 2 n NaOH. Was extracted 4 times with ethyl acetate, the organic phase is washed with water, dried and the solvent was evaporated. After further column chromatography on silica gel with a mixture of 1 part of ethyl acetate and 3 parts of toluene was mixed with a saturated solution of hydrogen chloride. The precipitate (Exo/endo)-(3-dimethylaminobenzoyl)-(octahydro-4,7-methane-inden-5-yl)amine-hydrochloride was filtered and dried. Colorless crystalline solid, TPL: 166-170°C (decomposition).

MS(CI+):RUB 285.2 (M+H)+

Example 30: (Exo/endo)-[2-(3-methoxyphenyl)-ethyl]-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

a) (Exo/endo)-2-(3-methoxyphenyl)-N-(octahydro-4,7-methane-inden-5-yl)acetone is

(Exo/endo)-2-(3-methoxyphenyl)-N-(octahydro-4,7-methane-inden-5-yl)ndimethylacetamide was obtained similarly to example 29A) method of the 3-methoxyphenylacetic acid, N,N'-carbonyldiimidazole and (Exo/endo)-octahydro-4,7-methane-inden-5-ylamine (amine 1). Yellow viscous oil.

MS(CI+): 300,4 (M+H)+

b) (Exo/endo)-[2-(3-methoxyphenyl)ethyl]-(octahydro-4,7 - methane-inden-5-yl)amine hydrochloride

(Exo/endo)-[2-(3-methoxyphenyl)ethyl]-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride was obtained similarly to example 29b) method recovery (Exo/endo)-2-(3-methoxyphenyl)-N-(octahydro-4,7-methane-inden-5-yl)ndimethylacetamide. Colorless crystalline solid, TPL: 222-225°C;

MS(ES+): 286,3 (M+H)+

Example 31: (Exo/endo)-[3-(3-methoxyphenyl)-propyl]-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

a) (Exo/Exo)-3-(3-methoxyphenyl)-N-(octahydro-4,7-methane-inden-5-yl)propionamide

(Exo/Exo)-3-(3-methoxyphenyl)-N-(octahydro-4,7-methane-inden-5-yl)propionamide was obtained similarly to example 29A) method of the 3-methoxytryptophol acid, N,N'-carbonyldiimidazole and (Exo/endo)-octahydro-4,7-methane-inden-5-ylamine (amine 1). Light yellow oily product.

MS(CI+): 314,0 (M+H)+

b) (Exo/endo)-[3-(3-methoxyphenyl)propyl]-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

(Exo/endo)-3-(3-methoxyphenyl)propyl]-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride was obtained similarly to example 29b) method recovery (Exo/ICAO)-3-(3-methoxyphenyl)-N-(octahydro-4,7-methane-inden - 5-yl)propionamide. Colorless crystalline solid, TPL 186-188°C.

MS(ES+):300,3 (M+N)+

Example 32: (Exo/endo)-(decahydro-1,4-methane-naphthalene-2-yl)-(3-methoxybenzyl)amine hydrochloride

a) N,N'-dioxide bis-(3-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene-2-yl)diazene

To a solution of 3.56 g of benzonorbornadiene [L. Friedman and F.M. Logullo, J. Org. Chem. 34: 3089-3092 (1969)] in 6 ml of glacial acetic acid and 6 ml of ethanol was added to 3.34 g isoamylamine and then dropwise to 8.5 ml of 15%aqueous solution of gaseous hydrogen chloride in ethanol. The resulting suspension was stirred for further 2.5 hours at room temperature and then mixed with 20 mg of diisopropyl ether. After further stirring for 30 minutes was filtered solid. Bright crystalline solid; TPL 187-188°C.

MS (FAB (mass spectrometry with the bombardment of accelerated atoms)): 415,1 (M+N)+

b) (Exo)-1,2,3,4-tetrahydro-1,4-methane-naphthalene-2-ylamine

3 g of N,N'-dioxide bis-(3-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene-2-yl)diazene suspended in 150 ml of methanol and was first made with the catalyst of Raney Nickel in an autoclave under hydrogen pressure of 100 bar At 100°20 hours. After filtering off the catalyst, the solvent was evaporated, the residue was mixed with water, was very podslushivaet using NaOH and was repeatedly extracted with methyl tert-butyl EF the rum. After drying the organic phase obtained the desired amine as a pale yellow liquid.

MS(ES+):160,0 (M+H)+

c) (Exo/endo)-decahydro-1,4-methane-naphthalene-2-ylamine

A solution of 1 g of Exo-1,2,3,4-tetrahydro-1,4-methane-naphthalene-2-ylamine in 10 ml of methanol and 30 ml of 2 n hydrochloric acid was first made into the autoclave over 0.4 g RUO Li2hydrogen at 100 bar and 90°10 hours. After separation of the catalyst was evaporated in half, the resulting aqueous solution was strongly podslushivaet using 10 n NaOH and was repeatedly extracted with methyl tert-butyl ether. After drying and evaporation of solvent received Exo-decahydro-naphthalene-2-ylamine as colorless oil, which is preferably stored under argon.

MS(CI+):to 166.2 (M+N)+

d) (Exo/endo)-(decahydro-1,4-methane-naphthalene-2-yl)-(3-methoxybenzyl)amine hydrochloride

0.97 g of (Exo/endo)-decahydro-1,4-methane-naphthalene-2-ylamine was dissolved in 25 ml of anhydrous toluene and, after addition of 0.8 g of 3-methoxybenzaldehyde and small catalytic amount of p-toluenesulfonic acid was heated under reflux for 3 hours. After evaporation of the solvent the residue was dissolved in 50 ml of methanol, portions were added with stirring 0.26 g sodium borohydride and the mixture was stirred at room temperature for about 20 hours. Acidified solution with a solution of gaseous hydrogen chloride in methanol, per massively 30 minutes and was filtered precipitated salt. The filtrate was evaporated and the residue was recrystallized from a mixture of diisopropyl ether and ethanol. A colorless crystalline substance; TPL 234-236°C;

MS(ES+): 286,3 (M+N)+

Subsequently described compounds were obtained, respectively, as shown in the examples

-N
ExampleA similar exampleR1R2R3R4R5HXMS
335-N-N-Och3-N-NHClCl+(M+N)+272,3
345-Och3-N-N-N-NHClCl+(M+N)+272,3
355-N-Och3-N-N-Och3HClES+(M+N)+< / br>
302,2
365-N-Och2O--N-nHClES+ (M+N)+of 286.2
375-N-Och3-Och3-N-Cl+ (M+N)+302,4
385-Och3-N-Och3-N-NHClES+

(M+N)+302,3
395-N-Och3-F-N-NHClCl+

(M+N)+< / br>
290,3
405-N-HE-N-N-NHClCl+ (M+N)+258.2
4110-N-OCF3-N-N-NTFAES+ (M+N)+326,2
4210-N-OEt-N-N-NHClCl+ (M+N)+286,3
4310-N-OCF2CF2H-N-N-HTFAES+ (M+N)+358,2
4410-N-OPri-N-N-NHClCl+

(M+N)+300,3
45 10-N-OEt-Och3-N-NTFAES+

(M+N)+316,3
465-N-CH3-N-N-NHClCl+(M+N)+256,3
4710-N-CF3-N-N-NHClCl+(M+N)+310,3
485-Och3-CO2CH3-Och3-N-NHClES+(M+N)+360,2
4911-N-F-F-F-NHClCl+(M+N)+< / br>
296,3
505-N-CI-N-N-NHClCl+(M+N)+276,2
515-N-SO2NH2-Cl-N-NHClCl+(M+N)+355,1
525-N-H -H-HHClCl+(M+N)+326,2
535-N-N-N-NHClCl+(M+N)+312,2
545-N-N-N-NHClCl+(M+N)+340,2
5528-N-F-F-N-NHClES+

(M+N)+278,2
5628-N-Och3-N-Och3-NHClES+ (M+N)+< / br>
302,3
575-N-CH2CH3-N-N-HHClCl+ (M+N)+270,1
5828-F-N-N-N-NHClCl+ (M+N)+of 260.2
5928-SCF3-N-N-N-NHClCl+ (M+N)+342,0
6028-N-N-OCF3-N-HHClES+ (M+N)+326,2
615-H-SCH3-N-N-HHClES+ (M+N)+288,2
6228-N-N-CF3-N-HHClES+ (M+N)+310,2
639-HE-Och3-N-NO2-HTFAES+

(M+N)+333,2
649-N-N-N-NTFAES+ (M+N)+402,2 (34Cl)

ExampleA similar exampleMS
6512ES+ (M+N)+290,1
6612ES+(M+N)+270,2
67 12ES+ (M+N)+364,2
6812ES+ (M+H)+369,1
6912ES+ (M+N)+368,2

Example 70: (Exo/endo)-(3-methanesulfonyl-benzyl)-(octahydro-4,7-methane-inden-5-yl)amine hydrochloride

65 mg of the product from example 61 was dissolved in 3 ml of methanol. Then were added 4 ml nitroacetate buffer solution and the mixture was cooled to 0°C. After slow addition of 617 mg Oxone®was stirred for three hours at room temperature. The precipitate was filtered and the filtrate was concentrated in vacuum. The residue was mixed with a solution of sodium bicarbonate and was extracted with ethyl acetate. After drying and filtration was concentrated in vacuum. Received 60 mg of the crude product was purified preparative HPLC over RP-18 with acetonitrile/water (0.05% of triperoxonane acid). Containing the product fractions were combined, the acetonitrile was removed on a rotary evaporator, the potassium carbonate was established pH 11 was added ethyl acetate. The aqueous phase was extracted three times with etecetera combined phase was dried and evaporated. The residue was extracted with 2 n hydrochloric acid and a small amount of acetonitrile and sushi and freezing. After freeze-drying received 8 mg of the desired product.

MS(CI+):320,1 (M+N)+

Pharmacological data

Description test diuresis

Test salidores were performed on male Wistar rats weighing from 155 to 175, For 16 hours before testing, animals were deprived of food but not drinking water. Rats were planted without selecting diurese cells. The substance from example 5) was dissolved in water and injected at a dose of 20 mg/kg body weight orally in a volume of 10 ml/kg Control group were treated orally with the appropriate volume of drinking water as a carrier. The urine of each group was measured in the first 5 hours and within 6-24 hours. Electrolytes urine sodium and potassium were determined by flame photometry (Flammen-Photometer Eppendorf, Hamburg) and the potentiometric chloride (Chloridmeter Eppendorf). Osmolarity urine was determined by the method of lowering the freezing point (osmometer Vogel, Giessen). Urine output and electrolyte, as well as osmotolerant are given in ml/kg, mmol/kg or mosmol/kg body weight. The ratio of Na+/K+enables you to recognize a quality diuretic activity. The results in the table represent average arithmetic values with standard errors.

Results

UrineNaTo ClOsmotolerantNa/K
ml/kgmmol/kgmosmol/kg
control media drinking water 10 ml/kg KG r.o. n=5Average1-5 hours9,730,260,480,386,480,61
SD3,690,140,200,231,330,36
Average6-24 hours26,841,753,95the 1.4432,320,45
SD6,440,470,930,407,170,12
&x0200A;
AverageAmount36,572,014,421,8238,810,47
SD1-24 hoursthe remaining 9.080,370,970,267,000,11
Example 5 50 mg in 10 ml of drinking water/kg KG r.o. n=5Average1-5 hoursKZT 12.390,310,750,607,820,47
SD8,030,270,430,37is 3.080,31
Average6-24 hours22,571,293,57of 1.57At 30.51 0,37
SD6,000,660,600,54of 5.060,18
AverageAmount34,961,60or 4.312,1738,330,38
SD1-24 hours9,140,640,610,413,470,16

Assessment: the Substance from example 5) at a dose of 50 mg/kg does not show when administered orally to rats solidarities steps compared to control.

Model description SASO 2

Cell line SASO 2 were purchased from American Type Culture Collection (ATCC) and Dulbecco's Modified Eagle (high glucose), supplemented with nonessential amino acids, L-glutamine, penicillin/streptomycin and 10%fetal calf serum, was kept in the incubator under 10%atmosphere of CO2at 95%relative humidity and 37°C. the Cells was transferred into a flask with cell cultures (175 cm2).

To study the transport of SASO-2 cells were sown on a polycarbonate layers of cell cultures (Costar Transwells®the pore size of 3 microns is, square 4,71 cm2with cellular density of 6.5×104cells/cm2and incubated in sectionone tablets with cultures with a change of environment after four and eight days, and then every two days. For the experiment used the monolayers age from 21 to 25 days.

In each series of samples monolayers age 21 days experienced with3H-dextran as a marker of permeability. The value of the transfer rate (cumulative) after 120 min was supposed to be in the range of 2%.

After removing the medium growth with apical and basolateral sides monolayers were washed transport buffer (solution a balanced salt Hank's 7,8; glucose 2.8 g/l) and the cells were balanced 15 min at 37°With under 10%atmosphere of CO2. Then the specified buffer solution (HBSS) was again removed.

Test compounds were dissolved in a mixture of HBSS buffer and DMSO and was added to apollinea buffer, so that received 1% (vol./about.) solution in DMSO. Test concentration in the first experiment was 1 mm, the second 100 μm. Experiments were performed at 37°and was started by adding 1.5 ml of the test solution on the donor (apical) side. Transport buffer without compounds were applied on the receiving side (basolateral, 2.5 ml). Through various time intervals samples were taken with basolateral side (1 ml) and was replaced by a fresh, warm, 37°who, the buffer solution. Apical samples were taken at the beginning and end (120 min), to determine according to the indicated concentrations and cumulative basolateral concentrations the rate of re-finding connections.

Compounds were analyzed by HPLC.

The apparent permeability coefficient (Parr) was calculated by the following equation:

where denote dc/dt is the flux across the monolayer (mcg or connection/ml x s), V is the volume of fluid in the catching chamber (ml), And - the value of the surface monolayer (cm2) and C0- initial concentration (µg or connection/ml) in the donor chamber. Flow through the monolayer was calculated from the cumulative basolateral concentration to the appropriate point in time using the first linear curve (linear up to 60 min). Each measurement was made three times, so that the calculated value of Parrrepresented the average of three measurements. Values of Parrselected compounds were correlated with known literature values of absorption and was represented by a sigmoidal standard curve. After studies Artursson'a (Artursson p, Karlsson J.; Biochem. Biophys. Res. Comm. 1991; 175/3: 880-885) we can conclude that this curve gives an idea of the absorbed amount of connections. Results

td align="left">  
the absorbed fraction [%]
Example 5100
Example 10100
S 3226<5
S 2120<l

Compared with the known in the literature MNES-active compounds arylguanidines type (J.-R. Schwark and other Eur. J. Physiol. (1998) 436:797) the compounds of formula I or la show significantly greater permeability through the membrane.

Description dimensions NHE activity

Most molecular biological technologies follows the protocols of the works in "Current Protocols in Molecular Biology (ed. Ausubel, F.M., Brent, R., Kingston, R.E., Moore, D.D., Seidman, J.G., Smith, J.A. and Struhl, K.; John Wiley & Sons)" or "Molecular Cloning: A Laboratory Manual (Sambrock, J., Fritsch, E.F. and Maniatis, T.; Cold Spring Harbor Laboratory Press (1989))".

As part of the authors have obtained stable cell lines, each of which expressed one of the following NHE-subtypes: human NHE1 (Sardet and others (1989) Cell 56, 271-280), rabbit NHE2 (Tse and others (1993) J. Biol. Chem. 268, 11917-11924), NHE3 person (Brant and others (1995) Am. J. Physiol. 269 (Cell Physiol. 38), C198-C206) or rat NHE3 (Orlowski and others; J. Biol. Chem. 267, 9331-9339 (1992)).

Received professional Pouyssegur cDNA clones corresponding NHE-subtype after PR is connection to a suitable linker sequences cloned thus in the expression plasmid rampao (received for example, through CLONTECH, Heidelberg), to recognition sequence for the restriction endonuclease NheI plasmids gave about 20 to 100 base pairs to the start codon of each NHE-subtype and General coding sequence was in construction. For obtained via RT-PCR from human kidney NHE3 containing mRNA were selected RT-PCR primers so that the obtained cDNA sequence contained in all sites, passive to rmania.

With the help of the so-called "calcium phosphate method (described in Chapter 9.1 "Current Protocols in Molecular Biology") NHE-deficient cell lines LAP1 (Franchi and others; Proc. Natl. Acad. Sci. USA 83, 9388-9392 (1986)) were transliterowany plasmids that contained the appropriate coding sequences NHE-subtypes. After the selection of transfected cells by growth in medium containing G418 (only cells obtained by transfection of the neo gene can survive in these conditions) were selected for functional NHE-expressions. Was used for this are described Sardet technology "acid load" (Sardet and others; Cell 56, 271-280 (1989)). Cells that Express a functional NHE-subtype, can also in the absence of CO2and the HCO3-to compensate for what is happening at the specified sample acidification, whereas nitrostilbene LAP1-cell opposite can't. After multiple p is torenia selection "acid load" surviving cells were sown in tablets for micrometrology thus, that statistically one well had one cell. Through the microscope after about 10 days, watched as each hole to grow many of the colony. The population of cells from individual colonies were then tested the breakdown of HTT-proliferation (Boehringer Mannheim) in respect of resistance to the survival of the "acid load". The best cell lines were used for further samples and cultivated to reduce losses transtitional sequence at a constant pressure of selection in medium containing G418. To determine the values IC50for inhibition individual NHE-subtype specific substances had been slightly modified test, developed S.Faber (Faber and others; Cell. Physiol. Biochem. 6, 39-49 (1996)), which is based on the technology of "acid load".

In this sample was observed recovery of intracellular pH (pHiafter acidification, which occurs in the case of functional NHE also free from bicarbonate conditions. For this pHiidentified sensitive to pH fluorescent dye BCECF (Calbiochem, included as a preliminary stage BCECF-AM). Cells were first loaded BCECF. The BCECF fluorescence was determined in the "Ratio Fluorescence Spectrometer" (Photon Technology International, South Brunswick, N.J., USA) at excitation wavelengths of 505 and 440 nm and the wavelength of emission of 535 nm and by means of the calibration curve were transferred to pHi. In otst the attack from the described Protocol, cells were incubated with BCECF loading in NH 4Cl-buffer (pH 7.4) (NH4Cl-buffer: 115 mm NaCl, 20 mm NH4Cl, 5 mm KCl, 1 mm CaCl2, 1 mm MgSO4, 20 mm Hepes (4-(2-hydroxyethyl)-1-piperazine-econsultancy), 5 mm glucose, 1 mg/ml BSA (N,O-bis(trimethyl-silyl)ndimethylacetamide), using 1 M NaOH has a pH of 7.4). Intracellular acidification induced by addition of 975 µl containing NH4Cl buffer 25 ál aliquot of the cells incubated in NH4Cl-buffer. The subsequent rate of recovery of pH were recorded at NHE1 2 minutes, when NHE2 5 minutes and NHE3 3 minutes. To calculate the inhibitory potential of the tested substances, the cells were first tested in the buffer, which was full or there was no recovery of pH. For full recovery of pH (100%) cells were incubated in Na+-containing buffer (133,8 mm NaCl, of 4.7 mm KCl, 1.25 mm CaCl2, 1.25 mm MgCl2, 0,97 mm Na2HPO4, 0.23 mm NaH2PO4, 5 mm Hepes, 5 mm glucose, using 1M NaOH was established pH 7.0). To determine the 0%values of cells incubated in a free of Na+buffer (133,8 mm holdingarea, of 4.7 mm KCl, 1.25 mm CaCl2, 1.25 mm MgCl2, 0,97 mm K2HPO4, 0.23 mm KH2PO4, 5 mm Hepes, 5 mm glucose, using 1M NaOH was established pH 7.0). Subjects substances made in Na+-containing buffer. Recovery of intracellular pH at each tested concentration of a substance expressed in% of the tax to the maximum recovery. The percentage recovery values of pH through the program SigmaPlot the calculated values of the IC50each substance for the individual NHE-subtypes.

N3-activity

ExampleNHE3 rats IC50[µm]
50,81
(+)-60,5
(-)-61
100,9
95
870
731

Thomasenia derivatives norbornylene with asocolflores nitrogen and an endo-annulated five or six-membered cycles of formula I and ectocarpales nitrogen and Antonelliana five or six-membered cycles of formula Ia,

where

And means (C1-C4-alkylen;

S1 denotes absent or denotes (C1-C4)-alkyl;

S2 denotes (C1-C4)-alkyl or H;

moreover, if S1 and S2 denote alkyl, X-in the formed group [-N+(S1S2)-X-] matches pharmacologically acceptable anion or triptoreline;

In denotes a saturated or unsaturated carbon of the five - or six-membered cycle which may be substituted by a hydroxy-group;

R11 and R12 independently of one another denote H or (C1-C4)-alkyl,

while the hydrogen atoms in the alkyl residues are fully or partly can be replaced by fluorine;

r denotes 0, 1 or 2;

s denotes 1 or 2;

or R1 and R2, R2 and R3, R3 and R4 or R4 and R5

every together represent a group-O-(CH2)n-O-;

n denotes 1 or 2;

and each of the remaining residues R1, R2, R3, R4 or R5 represent independently from each other H, HE, F, Cl, Br, I, CN, NO2amidinopropane,-CO2 R(11),-CONR(11)R(12), -SOrR(11), -SOsNR(11)R(12), (C1-C4)-alkyl, (C1-C4)-alkoxygroup, (C1-C4)-alkoxy(C1-C4)-alkyl, with hydrogen atoms in the alkyl residues are fully or partly can be replaced by fluorine;

R11 and R12 independently of one another denote H or (C1-C4)-alkyl,

while the hydrogen atoms in the alkyl residues are fully or partly can be replaced by fluorine;

r denotes 0, 1 or 2;

s denotes 1 or 2;

this eliminates benzyl(octahydro-4,7-methane-inden-5-yl)amine, as well as their pharmaceutically acceptable salts or triptoreline.

2. The compounds of formula I or Ia according to claim 1 with asocolflores nitrogen and an endo-fused five - or six-membered cycle formula I and ectocarpales nitrogen and Antonelliana five - or six-membered cycle formula Ia in which a represents (C1-C2-alkylen; S1 denotes hydrogen or methyl; S2 denotes N; denotes a saturated or unsaturated carbon of the five - or six-membered cycle; R1, R2, R3, R4 and R5 independently of one another denote H, amino, hydroxymethyl, HE, a methoxy group, F, Cl, Br or iodine; or R2 and R3 together represent-O-CH2-O-; and the remaining residues R1, R4 and R5 denote independently from each other H, HE, F, Cl, Br, I, CN, NO2, (C1-C2)-alkoxy, in this and the ohms of hydrogen in the alkyl residues are fully or partly can be replaced by fluorine; this eliminates benzyl(octahydro-4,7-methane-inden-5-yl)amine, as well as their pharmaceutically acceptable salts or triptoreline.

3. The compounds of formula I or Ia according to claims 1 and 2 ectocarpales nitrogen and an endo-annulated five - or six-membered cycle formula I and ectocarpales nitrogen and Antonelliana five - or six-membered cycle formula Ia, where a denotes (C1-C2-alkylen; S1; S2 denotes N; denotes a saturated or unsaturated carbon of the five - or six-membered cycle; and R1, R3 and R5 represent hydrogen; and R2 and R4 represent independently from each other H, a methoxy group, F or Cl; or R2 and R3 together represent-O-CH2-O-; and R1, R4 and R5 represent hydrogen; this eliminates benzyl(octahydro-4,7-methane-inden-5-yl)amine, as well as their pharmaceutically acceptable salts.

4. The compounds of formula I or Ia according to one of claims 1 to 3 ectocarpales nitrogen and antoinelawana five - or six-membered cycle formula I and Exo-configuration of nitrogen and Antonelliana five-membered cycle formula Ia, which represent:

Exo/endo-(3-Chlorobenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(3-terbisil)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-benzo[1,3]dioxol-5-ylmethyl(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(rat)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)the min,

Exo/endo-(+)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(-)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-[1-(3-methoxyphenyl)ethyl]-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(3-terbisil)-(3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)amine,

Exo/endo-(3-terbisil)-(3A,4,5,6,7,7a-hexahydro-3H-4,7-methane-inden-5-yl)amine,

Exo/endo-(3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)-(3-methoxybenzyl)amine,

Exo/endo-(3A,4,5,6,7,7a-hexahydro-ZN-4,7-methane-inden-5-yl)-(3-methoxybenzyl)amine,

Exo/endo-(decahydro-1,4-methane-naphthalene-2-yl)-(3-methoxybenzyl)amine,

Exo/endo-(3,5-diferensial)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/Exo-(3-terbisil)-(octahydro-4,7-methane-inden-5-yl)-amine,

Exo/Exo-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

and their pharmaceutically acceptable salts or triptoreline.

5. The compounds of formula I according to one of claims 1 to 4 extrapolating Amin and antoinelawana five - or six-membered cycle, representing;

Exo/endo-(3-Chlorobenzyl)-(octahydro-4,7-methane-inden-5-yl)-amine,

Exo/endo-(3-terbisil)-(octahydro-4,7-methane-inden-5-yl)-amine;

Exo/endo-(3-terbisil)-(3A,4,5,6,7,7a-hexahydro-1H-4,7-methane-inden-5-yl)amine,

Exo/endo-(3-forb nil)-(3A,4,5,6,7,7a-hexahydro-ZN-4,7-methane-inden-5-yl)amine,

Exo/endo-benzo[1,3]dioxol-5-ylmethyl(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(rat)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(+)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine,

Exo/endo-(decahydro-1,4-methane-naphthalene-2-yl)-(3-methoxybenzyl)amine,

Exo/endo-(-)-(3-methoxybenzyl)-(octahydro-4,7-methane-inden-5-yl)amine and

Exo/endo-(3,5-diferensial)-(octahydro-4,7-methane-inden-5-yl)amine,

and their pharmaceutically acceptable salts or triptoreline.

6. Method of producing compounds of the formula I or Ia according to clause 1, characterized in that the compound of formula II or IIa

subjected to interaction with the compound of the formula III in the presence of a suitable reductant, and may also Lewis acid directly with the formation of compounds of the formula I or Ia,

where S1, S2, R1, R2, R3, R4 and R5 have the above values, while independently from each other And' means a connection or (C1-C3)-alkyl and A" represents H or (C1-C3)-alkyl and A' and A" together with the carbon atom of the carbonyl group contain as many carbon atoms as described above for A.

7. The compounds of formula I or Ia according to claim 1, suitable for medicinal among the STW for treatment or prevention of respiratory disorders of impulse.

8. The compounds of formula I or Ia according to claim 1, suitable for the production of pharmaceuticals for the treatment or prophylaxis of respiratory disorders, in particular caused by sleep breathing disorders, as a temporary cessation of breathing during sleep.

9. The compounds of formula I or Ia according to claim 1, suitable for the production of pharmaceuticals for the treatment or prevention of snoring.

10. The compounds of formula I or Ia according to claim 1, suitable for the production of pharmaceuticals for the treatment or prevention of acute and chronic renal diseases, in particular acute renal failure and chronic renal failure.

11. The compounds of formula I or Ia according to claim 1, suitable for the production of pharmaceuticals for the treatment or prevention of disorders of bowel function.

12. The compounds of formula I or Ia according to claim 1, suitable for the production of pharmaceuticals for the treatment or prevention of disorders of gallbladder function.

13. The compounds of formula I or Ia according to claim 1, suitable for the production of pharmaceuticals for the treatment or prophylaxis of ischemic conditions of the peripheral and Central nervous system and acute attacks.

14. The compounds of formula I or Ia according to claim 1, suitable for the production of pharmaceuticals for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs.

15. Connection is ormula I or Ia according to claim 1, suitable for the production of medicines for the treatment of shock.

16. The compounds of formula I or Ia according to claim 1, suitable for medicinal products for introduction in surgical operations and organ transplants.

17. The compounds of formula I or Ia according to claim 1, suitable for medicinal products for preservation and storage of transplants for surgical procedures.

18. The compounds of formula I or Ia according to claim 1, suitable for the production of medicines for the treatment of diseases in which cell proliferation represents a primary or secondary cause.

19. The compounds of formula I or Ia according to claim 1, suitable for the production of pharmaceuticals for the treatment or prevention of disorders of lipid metabolism.

20. The compounds of formula I or 1A according to claim 1, suitable for the production of pharmaceuticals for the treatment or prevention of damage by parasites.

21. Medicinal product containing an effective amount of the compounds of formula I or Ia according to one of claims 1 to 5, with solidarities activity and NHE3-inhibiting action.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing 1-amino-3,5-dimethyladamantane hydrochloride (the preparation memantin or acatinol) used in medicinal practice as agent for treatment of such diseases as Parkinson's disease, neurodegenerative disorders, glaucoma. Method for preparing 1-amino-3,5-dimethyladamantane hydrochloride involves addition of nitric acid to preliminary prepared 1,3-dimethyladamantane emulsion in acetic acid at 10-30oC followed by addition of 30-55% urea solution in water in the mole ratio 1,3-dimethyladamantane : acetic acid : nitric acid : urea = (1:3)-(4:9)-(12:2.5)-5.0, respectively followed by neutralization of obtained reaction mass with alkali an aqueous solution, extraction and the following isolation of product as hydrochloride and its crystallization from water. Method provides preparing product of the high quality that satisfies requirements of Pharmacopoeia.

EFFECT: improved preparing method, enhanced quality of product.

5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

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

13 cl, 3 tbl, 35 ex

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method of obtaining amino adamantane General formula AdR, where R=NH2, NHBu-t,

< / BR>
< / BR>
< / BR>
which are biologically active substances and can find application in pharmacology and adamant-1-ylamine is the basis of the drug midantana"

FIELD: medicine.

SUBSTANCE: vaccine is high molecular weight protein conjugate with angiotensine II taken in high molecular weight protein : angiotensine II proportion of 1:12-55 in % by weight. The conjugate is modified with equilibrium quantity of immunocompetent polyelectrolyte like polyoxydonium.

EFFECT: stable physiological response within prolonged period of 6-12 months.

3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: medicine, cardiology, gastroenterology.

SUBSTANCE: invention relates to a method for treatment of ulcer-erosion injures in gastroduodenal region in patients with arterial hypertension. Method involves detection of immune disturbances and carrying out the combined immunomodulating therapy and hypotensive therapy. Immunocorrecting complex consists of licopide, cortexinum, vetoronum TK in arterial hypertension of I-II degree and comprises superlymph additionally in arterial hypertension of III degree. Method provides attaining optimal results in treatment for relatively short time due to adequate immunocorrection in such patients.

EFFECT: improved method for treatment.

5 cl, 6 tbl, 2 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: medicine.

SUBSTANCE: method involves administering Noliprelum in postoperative period for reducing left ventricle hypertrophy.

EFFECT: enhanced effectiveness of treatment in early postoperative period.

FIELD: medicine, endocrinology, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical combined composition used for treatment or prophylaxis of hypertension in patients suffering with diabetes mellitus. The composition comprises AT1-antagonist valsartan or its pharmaceutically acceptable salt and calcium channel blocking agent or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier. The composition elicits synergistic effect and expanded spectrum effect.

EFFECT: improved and valuable medicinal properties of composition.

10 cl, 3 tbl

The invention relates to pharmaceutical industry and relates to pharmaceutical compositions containing 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate, to prevent, treatment or inhibition of the development of a simple retinopathy or preproliferative retinopathy; the method of preventing, treating or inhibiting the development of a simple retinopathy or preproliferative retinopathy; and applying the 2-ethoxy-1-[[2'-(1 N-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]the benzimidazole-7-carboxylate

The invention relates to medicine, in particular to pharmaceutical compositions containing the blocker of calcium and pharmacologically acceptable alkaline material, which is added in an amount such that the aqueous solution or dispersion solution of a specified pharmaceutical compositions containing a blocker of calcium, would have a pH of at least 8

The invention relates to new 1-(N-(2-(diethylamino)ethyl)-N-(4-(4-triptoreline)-benzyl)aminocarbonylmethyl)-2-(4-terbisil)thio-5,6-trimethylene-pyrimidine-4-ONU formula (I):

or its pharmaceutically acceptable salts, which have the properties of inhibitors of the enzyme Lp-PLA2and can be used to treat or prevent a painful condition associated with the activity of the specified enzyme

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a medicinal formulation consisting of a core and the stomach-dissolving envelope. The core comprises trimetazidine dihydrochloride as an active component, and starch, mannitol, povidone, magnesium stearate, croscarmelose and microcrystalline cellulose as accessory substances. The envelope comprises hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, magnesium stearate and acid red as a dye. Also, invention describes a method for making the trimetazidine medicinal formulation. Trimetazidine tablets show high mechanical strength in the low pressing strength (3.5-5 kH). The composition of the medicinal formulation provides releasing 80% of trimetazidine for 30 min.

EFFECT: improved and valuable properties of formulation.

3 cl, 1 tbl, 1 ex

FIELD: organic chemistry, chemical technology, biochemistry.

SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):

eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):

wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):

and (1.3):

wherein R1, R2 and R4 have above given values.

EFFECT: valuable medicinal and biochemical properties of compounds.

6 cl, 4 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: pharmaceutics.

SUBSTANCE: the suggested pharmaceutical composition at delayed release contains fluvastatin or its pharmaceutically acceptable salt hydroxypropylmethylcellulose and nonionic hydrophilic polymer. The latter is being hydroxyethylcellulose at average molecular weight ranged 90000-1300000 or hydroxypropylcellulose at average molecular weight ranged 370000-1500000 or polyethylenoxide at average molecular weight ranged 100000-500000. The suggested pharmaceutical composition is necessary to obtain peroral medicinal remedy for decreasing cholesterol level in plasma, it, also, provides the supply of fluvastatin into the body during prolonged period of time, for example, for more than 6 h and enables to minimize the possibility for premature release or "discharge" of considerable fluvastatin quantities.

EFFECT: higher efficiency.

21 cl, 6 dwg, 5 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: means has lipid fraction obtained from Berryteuthis Magister Comandor squid liver containing 10% of polyunsaturated fatty acids and 50% of alkyl-diacylglycerides showing marked lipid-correcting and immunomodulating properties.

EFFECT: enhanced effectiveness in treating lipid metabolism disorders and immunity system disorders.

4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

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