Aminocyclohexanol ethers, composition having antiarrhythmic activity and uses thereof

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

 

The technical field

The present invention is directed primarily to aminocyclohexane-ether compounds, pharmaceutical compositions and kits containing aminocyclohexane-ether compounds and their use in therapy.

Background of the invention

Atrial fibrillation is a variation of the normal rhythm of the heartbeat and is usually the result of an abnormality in the structure, number or function of ion channels. Known as Adrianna fibrillation, and ventricular arrhythmia. The main cause of deaths due to cardiac arrhythmias, is a type of ventricular arrhythmia (ventricular arrhythmias), known as ventricular fibrillation (ventricular fibrillation) (FG). By conservative estimates, in the US alone, every year more than one million Americans have a new or repeat coronary attack (defined as myocardial infarction or ischemic heart disease with fatal outcome). About 650,000 of them are the first heart attacks and 450000 repeated attacks. About one-third of people who experience these attacks, die. At least 250,000 people a year die from coronary heart disease within 1 hour after onset of symptoms and before he could get to the hospital. The cause of these sudden deaths are cardiac arrest, originating the I, as a rule, the result of ventricular fibrillation.

Atrial fibrillation or Adrianna fibrillation (AF) is the more common form of arrhythmia observed in clinical practice and which is the cause of pain for many people (Pritchett E.L., N. Engi. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031-2; Kannel and Wolf, Am. Heart J. 123(1):264-7 Jan. 1992). It is very likely that its prevalence increases with increasing age of the population, and in 3-5% of patients aged over 60 years is OP (Kannel W.B., Abot R.D., Savage D.D., P.M. McNamara, N. Engi. J. Med. 306(17):1018-22, 1982; Wolf P.A., Abbot R.D., Kannel W.B. Stroke. 22(8):983-8, 1991). Although the OP rarely causes death, it can worsen the heart activity is the main cause of stroke (Hinton R.C. Kistler JP, Fallon J.T., Friedlich A.L., C.M. Fisher, American Journal of Cardiology 40 (4): 509-13, 1977; Wolf P.A., Abbot R.D., Kannel W.B., Archives of Internal Medicine 147(9):1561-4, 1987; Wolf P.A., Abbot R.D., Kannel W.B. Stroke. 22 (8):983-8, 1991; Cabin H.S., Clubb for K.S., Hall, C., Perlmutter R.A., Feinstein A.R., American Journal of Cardiology 65(16):1112-6, 1990).

Developed tools against arrhythmia in order to prevent or alleviate the condition of cardiac arrhythmias. For example, antiarrhythmic compounds of class I are used for the treatment of supraventricular arrhythmias and ventricular or ventricular arrhythmias. It is very important treatment of ventricular arrhythmias, such as arrhythmia can be fatal. Having severe consequences of ventricular arrhythmia (ventricular tachycardia ventricular fibrillation) most often occur in the presence of myocardial ischemia and/or infarction. Ventricular fibrillation often occurs on the background of acute myocardial ischemia before developing fully infarction. At the present time there is no satisfactory drug therapy for treatment and/or prevention of ventricular fibrillation during acute ischemia. In fact, many antiarrhythmic compounds of class I can actually increase the mortality of patients with myocardial infarction.

Anti-arrhythmic drugs class Ia, IC and III are used to translate an acute attack of AF to sinus rhythm and prevent the recurrence of arrhythmia (Fuch and Podrid, 1992; Nattel, S., Hadjis T., Talajic M., Drugs 48(3):345-71, 1994). However, drug therapy is often limited by side effects, including increased mortality, and inadequate efficiency (Feld G.K., Circulation. 83 (6):2248-50, 1990; Copien SE, Antman E.M., J.A. Berlin, Hewitt p, Chalmers T.C., Circulation 1991; 83(2):714 and Circulation 82 (4):1106-16, 1990; Flaker G.C., Blackshear J.L., R. McBride, R.A. Kronmal, Halperin J.L., Hart, R.G., Journal of the American College of Cardiology 20 (3):527-32, 1992; CAST, N. Engl. J. Med. 321:406, 1989; Nattel, S., Cardiovascular Research. 37 (3):567-77, 1998). Indicators of translation for antiarrhythmic drugs class I range between 50-90% (Nattel S., Hadjis T., Talajic M., Drugs 48 (3):345-71, 1994; Steinbeck G., Remp T., Hoffmann E., Journal of Cardiovascular Electrophysiology. 9(8 Suppi):S104-8, 1998). Antiarrhythmic agent of class III, appears to be more effective for termination of atrial flutter than the OP, and are generally considered to be less EF the objective, than drugs in class I for termination of AF (Nattel S., Hadjis T., Talajic M., Drugs 48 (3):345-71, 1994; Capucci, A., Aschieri d, Villani G.Q., Drugs and Aging, 13 (1):51-70,1988). Examples of such drugs include ibutilide, dofetilide and sotalol. Indicators translate these drugs are between 30-50% for an acute attack of OP (Capucci, A., Aschieri d, Villani G.Q., Drugs and Aging, 13 (1):51-70,1988), and their use is also associated with the risk of induction of ventricular tachyarrhythmias Torsades de Pointes (Pointes de Pointes). If ibutilide the risk of proaramme ventricles is estimated at ~4.4%in ~1.7% of patients required electro-therapy refractory ventricular fibrillation (Kowey .R., VanderLugt J.T., Luderer J.R., American Journal of Cardiology 78(8A):46-52,1996). Such events are particularly tragic in the cases of AF, because the arrhythmia itself is rarely fatal.

Thus, in this area there is a need to identify new anti-arrhythmic treatments for arrhythmias of ventricular and atrial arrhythmias. This invention satisfies this need, and in addition provides other related advantages.

Brief description of the invention

In one embodiment of the present invention are provided by aminocyclohexane-ether compounds having the formula (I), or their solvate, or pharmaceutically acceptable salt:

in which, independently in each case,

X is selected from a direct link, -C (R6, R14) -Y-and-C (R13)=CH-;

Y is selected from a direct link, O, S and C1-C4alkylene;

R13selected from hydrogen, C1-C6of alkyl, C3-C8cycloalkyl, aryl and benzyl;

R1and R2independently selected from hydrogen, C1-C8of alkyl, C3-C8alkoxyalkyl, C1-C8hydroxyalkyl and C7-C12aralkyl; or

R1and R2taken together with the nitrogen atom to which they are directly connected in the formula (I), form a ring denoted by formula (II):

moreover, the ring of formula (II) formed by the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen and sulfur; and any two adjacent atoms of the ring may be linked together by single or double bonds, and any one or more of the ring carbon atoms may be substituted by one or two substituents selected from hydrogen, hydroxy, C1-C3hydroxyalkyl, oxo-, With2-C4acyl, C1-C3of alkyl, C2-C4alkylcarboxylic, C1-C3alkoxy, C1-C20alkanoyloxy, or can be substituted with the formation of five - or six-membered what about the spiroheterocyclic ring, containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional ring of carbon atoms can be condensed with C3-C8carbocyclic ring, and any one or more additional ring nitrogen atoms can be substituted by substituents selected from hydrogen, C1-C6of alkyl, C2-C4acyl, C2-C4hydroxyalkyl and C3-C8alkoxyalkyl; or

R1and R2taken together with the nitrogen atom to which they are directly connected in the formula (I), may form a bicyclic ring system selected from 3-azabicyclo-[3.2-2]nonan-3-yl, 2-azabicyclo[2.2.2]Octan-2-yl, 3-azabi-cyclo[3.1.0]-hexane-3-yl and 3-azabicyclo[3.2.0]heptane-3-yl;

R3and R4independently associated with the cyclohexane ring shown in formula (I), the provisions of the 3-, 4-, 5 -, or 6 independently selected from hydrogen, hydroxy, C1-C6the alkyl and C1-C6alkoxy, and when R3and R4linked to the same atom of the cyclohexane ring, they can form a five - or six-membered spiroheterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur;

R5, R6and R14independently selected from hydrogen, C1-C6of alkyl, aryl and benzyl, or R6and R14taken the e together with the carbon with which they are linked, can form Spyros3-C5cycloalkyl;

A is selected from C5-C12of alkyl, C3-C13carbocyclic ring, and a cyclic system selected from compounds of formula (III), (IV), (V), (VI), (VII) and (VIII):

where R7, R8and R9independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifloromethyl,2-C7alkanoyloxy, C1-C6of alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, aryl and N(R15, R16), where R15and R16independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6of alkyl;

where R10and R11independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifloromethyl,2-C7alkanoyloxy, C1-C6of alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl and N(R15, R16), where R15and R16independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6of alkyl;

where R12selected from bromine, chlorine, fluorine, carb is XI, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifloromethyl,2-C7alkanoyloxy, C1-C6of alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, and N(R15, R16), where R15and R16independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6of alkyl; and Z is selected from CH, CH2, O, N and S, where Z may be directly associated with "X"as shown in the formula (I), when Z is CH or N, or Z may be directly associated with R17when Z represents N, and R17selected from hydrogen, C1-C6of alkyl, C3-C8cycloalkyl, aryl and benzyl;

including their single enantiomeric, diastereomeric and geometric isomers, and mixtures thereof.

In another embodiment, the invention provides a composition or drug, which comprises a compound corresponding to the formula (I), in combination with a pharmaceutically acceptable carrier, diluent or excipient (excipients), and further provides a production method of the composition or the medicinal product, which contains a compound corresponding to the formula (I).

In other embodiments, the invention provides a pharmaceutical is oppozitsii, which contain at least one compound of formula (1) in an amount effective to treat the disease or condition warm-blooded animal subject or is a carrier of the disease or condition, and/or prevention of diseases or conditions warm-blooded animal, which may otherwise occur, and, in addition, contain at least one pharmaceutically acceptable carrier, diluent or excipient. In addition, the invention provides methods of treating diseases or conditions warm-blooded animal subject, or is a carrier of a disease or condition, and/or prevention of a disease or condition in a warm-blooded animal, in which a therapeutically effective amount of the compounds of formula (I) or the compositions containing the compound of formula (I), inserted a warm-blooded animal in need of it. Diseases and conditions that are applicable to the compounds, compositions or methods of this invention are the following: arrhythmia, diseases of the Central nervous system, convulsions, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, gastrointestinal disorders, urinary incontinence, mucous colitis, genial, OEM is cardiovascular disease, cerebral ischemia or myocardial ischemia, hypertension, long QT syndrome, stroke, migraine, eye diseases, diabetes, myopathy, myotonia Becker, male pregnancy, congenital paramythia, malignant hyperthermia, gipercalziemiceski periodic paralysis, myotonia Thomsen, autoimmune diseases, graft rejection in organ transplantation or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease or other mental disorders, and alopecia.

In another embodiment, the invention provides a pharmaceutical composition comprising an amount of the compounds of formula (I), effective for the implementation of local analgesia or anesthesia in a warm-blooded animal that is in need, and a pharmaceutically acceptable carrier, diluent or excipient. In addition, the invention provides a method for making local analgesia or anesthesia in a warm-blooded animal, which includes the introduction of a warm-blooded animal in need, an effective amount of the compounds of formula (1) or pharmaceutical composition containing the compound of formula (I). These compositions and methods can be used to reduce or prevent pain in warm-blooded animals.

In another VA who ianthe this invention provides a pharmaceutical composition, contains a number of compounds of formula (I), effective for enhancing libido in a warm-blooded animal that is in need, and a pharmaceutically acceptable carrier, diluent or excipient. In addition, the invention provides a method of enhancing libido in a warm-blooded animal, which includes the introduction of a warm-blooded animal that is in need, an effective amount of the compounds of formula (I) or pharmaceutical compositions containing a compound of the formula (I). These compositions and methods can be used, for example, for the treatment of sexual dysfunction, e.g. impotence in males, and/or enhancing sexual desire in patients with sexual dysfunction. As another example, a therapeutically effective amount may be the bull (or other domestic animal bred)to promote increased ejaculation of sperm, and traveled by ejaculated sperm is collected and stored for use as needed for insemination of cows for the development of the livestock program.

In another embodiment, the present invention provides a compound of formula (1) or a composition comprising a compound of formula (I), for use in the methods or modulate the activity of ion channels in a warm-blooded animal, or modulate the activity of ion channels in vitro.

These and the other variants of the present invention will be apparent upon reference to the following drawings and detailed description.

Brief description of drawings

Figure 1 illustrates the sequence of reactions for obtaining compounds of aminocyclohexanol ether of the present invention, described below in example 1.

Figure 2 illustrates the procedure, which can be obtained either CIS-or TRANS - aminocyclohexane esters of this invention.

Figure 3 illustrates the method of synthesis, which can be used to obtain either CIS-or TRANS - stereoisomers of the compounds of this invention.

Figa and 4B illustrate the method of synthesis described in example 15.

Detailed description of the invention

As noted above, the present invention is directed to compounds aminocyclohexanone esters, pharmaceutical compositions containing the compounds aminocyclohexanone esters, and various uses of the compounds and compositions. Such applications include the blocking of ion channels in vitro or in vivo, treatment of arrhythmias, conduction anesthesia, and others described herein applications. The understanding of this invention may be facilitated by reference to the following definitions and explanations used here for the legend.

Definitions and explanations

Aminocyclohexane-ether compounds of the invention have an oxygen atom simple ether in position 1 cyclohexane ring and the amine nitrogen atom in position is AI 2 cyclohexane ring numbering of other provisions in the following order, shown below in structure (A):

In the above formula from the cyclohexane ring to atoms 1 oxygen and 2-nitrogen can be located relative to each other or in CIS - or TRANS - configuration. In a preferred embodiment of the present invention, the stereochemistry of the amine and ether substituents cyclohexane ring is either (R,R)-TRANS or (S,S)-TRANS. In another preferred embodiment, the stereochemistry is (R,S)-CIS or (S,R)-CIS.

Shown here are the formulas communication with the Deputy and/or the relationship that connects the fragment of the molecule with the rest of the connections can be specified in the form of crossing one or more bonds in the structure of rings. This indicates that the bond may be formed with any one of the atoms constituting the ring structure, and in another case this atom could be a hydrogen atom. When in a particular position in the structure do not specify any particular Vice, then this provision (provisions) is hydrogen.

For example, it is understood that the compounds of the invention containing A-X-CH (R5)-group in which a represents the formula (III)

encompass compounds having group (In)

in which there is tsya in mind, the group (B) covers a group in which any atom of the ring, which would otherwise have as a substituent of hydrogen, may instead be substituted by a group R7, R8or R9provided that each of R7, R8and R9presented in the ring once and only one. The atoms of rings that are not substituted with any of R7, R8or R9replaced by hydrogen. In those cases where the invention is indicated that the non-aromatic ring is substituted by more than one R group, and it is shown that these R groups are associated with non-aromatic ring bonds, which halve the ring connection, then R groups can be present in different ring atoms, or the same atom in the ring, because otherwise this atom could be replaced by a hydrogen atom.

Similarly, when the invention are compounds containing A-X-CH(R5)-group in which a represents aryl group, (VI)

understood that the invention encompasses compounds in which the group-X-CH(R5)is connected through X with the aryl group, (VI) for any atom that forms an aryl group, (VI), because otherwise the atom group (VI) could be replaced by a hydrogen atom. Thus, there are seven positions (indicated by letters from "a" to "g") in the structure is e (VI), which can be attached to the group-X-CH(R5), and she will join in one of these seven positions. The group R12it will take one and only one of the remaining six positions, and the hydrogen atoms will be present in each of the five remaining provisions. It should be understood that when Z represents a divalent atom such as oxygen or sulfur then Z cannot be directly linked with-X-CH(R5)-.

When the invention indicates the position of the asymmetric bivalent radical, then this divalent organic radical can be located in any possible way, which provides a stable chemical structure. For example, compounds containing A-X-CH (R5)-group, in which X is C(R14,R6)-Y-, the invention provides compounds having A-C(R14,R6)-Y-CH(R5)-group or A-Y-C(R14,R6)-CH(R5) group.

Wavy communication from the Deputy to the Central cyclohexane ring indicates that the group may be located on either side of the Central plane of the ring.

The compounds of this invention contain at least two asymmetric carbon atoms and therefore exist as enantiomers and diastereomers. Unless otherwise stated, this invention includes all enantiomeric and diastereomeric forms is aminocyclohexane-ether compounds of the invention. In this invention included pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of various compounds of the invention. Thus, the compounds of this invention can be in the form of the racemates, racemic mixtures and as individual diastereomers, or enantiomers in all isomeric forms are included in this invention. The racemate or racemic mixture does not mean that it is a mixture of stereoisomers 50:50.

The phrase “independently in each case” means a situation (i)when in the compound of the invention meets any variable more than once, the definition of this variable, regardless of its definition in any other case; and (ii) the identity of any one of two different variables (e.g., R1complete R1and R2selected regardless of the identity of another member of the set. However, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The following terms, in accordance with this invention used herein are defined as follows.

The term “salt accession acids or acid additive salts refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise Nagel the tion, formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and similar, or with organic acids such as acetic, propionic, glycolic, pyruvic, oxalic, maleic, malonic, succinic, fumaric, tartaric, citric, benzoic, cinnamic, almond acid, methanesulfonate acid, econsultancy acid, para-toluensulfonate, salicylic acid and similar.

"Acyl" refers to a branched or unbranched hydrocarbon fragments ending carbonyl(C=O)-group containing the specified number of carbon atoms. Examples include acetyl [CH3C=O, C2-acyl] and propionyl [CH3CH2C=O-, C3acyl].

"Alkanoyloxy" refers to ester Deputy, in which the ether oxygen is the point of connection with the molecule. Examples include propenyloxy [(CH3CH2C=O-O,3alkanoyloxy], ethanolate [CH3C=O-O,2alkanoyloxy].

"Alkoxy” refers to an O-atom, substituted alkyl group, for example methoxy [-och3With1alkoxy].

"Alkoxyalkyl" refers to a group of alkylene, replaced by alkoxygroup. For example, methoxyethyl [CH3Och2CH2-] and ethoxymethyl [CH3CH2Och -] are3alkoxygroup.

“Alkoxycarbonyl” refers to ester Deputy, in which the carbonyl carbon is the point of joining the molecule. Examples include etoxycarbonyl [CH3CH2OC=O,3alkoxycarbonyl] and methoxycarbonyl [CH3OS=O,2alkoxycarbonyl].

“Alkyl” refers to branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms and having at least one attachment point. Examples include n-propyl (C3alkyl), isopropyl (also With3alkyl) and tert-butyl (C4alkyl).

“Alkylene” refers to a bivalent radical which is branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms and having two points of attachment. An example is propylene [-CH2CH2CH2-With3alkylen].

“Alkylcarboxylic” refers to a branched or unbranched hydrocarbon fragment ending with carbon acid group [COOH]. Examples include carboxymethyl [HOOC-CH2-With2alkylcarboxylic] and carboxyethyl [noos-CH2CH2-With3alkylcarboxylic].

“Aryl” refers to aromatic groups which have at least one ring having a conjugated elektronnuyu system, which includes carbocyclic aryl, heterocyclic aryl (also referred to as heteroaryl groups) and burilnye group.

Usually, the preferred groups in the compounds of this invention are carbocyclic aryl groups, and preferred carbocyclic aryl groups are phenyl and naphthyl.

“Aralkyl” refers to a group of alkylene, in which one of the connection points goes to the aryl group. Example aranceles group is a benzyl group [P6H5CH2-With7kalkilya group].

“Cycloalkyl” refers to a ring which may be saturated or unsaturated, and the monocyclic, bicyclic or tricyclic, entirely formed by the carbon atoms. Example cycloalkyl group is cyclopentenone group (C5H7-), which is a five-carbon (C5) unsaturated cycloalkyl group.

“Carbocyclic” refers to a ring which can be either aryl or cycloalkyl ring, both of which are defined above.

“Carbocyclic aryl” refers to aromatic groups containing atoms forming the aromatic ring are carbon atoms. To carbocyclic aryl groups include monocyclic carbocyclic aryl groups such as phenyl, bicyclic carbocyclic the arilje the s group, such as naphthyl.

“Heteroatom” refers to non-carbon atom, preferably the heteroatoms are boron, nitrogen, oxygen, sulfur, and phosphorus, and particularly preferred heteroatoms in the compounds of this invention are nitrogen, oxygen and sulphur.

“Heteroaryl” refers to aryl groups having from 1 to 9 carbon atoms and the remaining atoms are heteroatoms and include heterocyclic systems described in "Handbook of Chemistry and Physics, 49thedition, 1968, R.C.Weast, editor; The Chemical Rubber Co., Cleveland, HE. See, in particular, Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl and similar.

“Hydroxyalkyl” refers to a branched or unbranched hydrocarbon fragment bearing the hydroxy (-OH) group. Examples include hydroxymethyl (CH2HE1hydroxyalkyl) and 1-hydroxyethyl (SNONCE3With2hydroxyalkyl).

“Thioalkyl” refers to a sulfur atom, substituted alkyl group, such as thiomethyl (CH3S-, C1thioalkyl).

The term “modulation or modulation in communication with the ion channel activity means that the activity of the ion channel can either increase or decrease in response to the introduction of the compound or composition, or R is a result of the application of the method of the present invention. Thus, the ion channel can be activated to transport more ions, or can be blocked so that fewer ions are transported or not transported by the channel.

“Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remingtons Pharmaceutical Science, Mack Publishing Co. (A.R.Gennaro edit. 1985). For example, use of sterile physiological saline solution and phosphate buffered saline at physiological pH values. In the pharmaceutical compositions can be provided preservatives, stabilizers, dyes and even flavoring or flavoring agents. For example, as preservatives may be added sodium benzoate, sorbic acid and esters of peroxybenzoyl acid. There, at 1449. In addition, can be used antioxidants and suspendresume agents. Ibid.

“Pharmaceutically acceptable salt” refers to salts of the compounds of the present invention, the resulting combination of such compounds and an organic or inorganic acid (salt accession acids) or organic or inorganic bases (salt accession reason). The compounds of this invention can be used either in free base form or in salt form, both fo which we are covered by the scope of the present invention.

“Therapeutically effective amount” of the compounds of the invention depends on the method of administration, type of warm-blooded animal to be treated, and the physical characteristics of the considered specific warm-blooded animal. These factors and their relationship to determine the number of connections is well known to practitioners in the field of medicine.

This amount and method of administration can be selected in order to achieve optimum efficiency and depend on such factors as weight, diet, concomitant medications and other factors that are known to experts in the field of medicine.

The compositions described herein as containing the compound having the formula (I)encompass compositions that contain more than one compound with formula (I).

The compounds of this invention

The compounds of this invention are amines which can be represented by the formula (I):

The compounds of formula (I) are aminocyclohexanone esters. More specifically, these aminocyclohexanone esters substituted in position 2 tsiklogeksilnogo ring amino group-NR1R2-. Tsiklogeksilnogo ring may also be substituted with additional substituents (denoted R3and R4), described in more detail is correctly below. Examples of specific compounds represented by formula (I)described below.

Depending on the choice of substituents R1and R2the compounds of formula (I) can be tertiary amines (none of R1and R2are not hydrogen). When the amine is tertiary, it can be a cyclic amine. The amine substituents R1and R2can be independently selected from substituents which include CNS group containing from three to eight carbon atoms (i.e.3-C8alkoxyalkyl), alkyl groups containing from one to eight carbon atoms, in which one of the carbon atoms substituted by a hydroxyl group (i.e. C1-C8hydroxyalkyl), and kalkilya group containing from seven to twelve carbon atoms (i.e.7-C12aralkyl).

Alternative R1and R2together with the nitrogen atom to which they are directly connected in the formula (I), may form a ring denoted by formula (II):

moreover, the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen and sulfur, where any two adjacent atoms of the ring may be connected by single or double bonds, and where one or more carbon atoms in the ring could the t to be substituted by one or two substituents, selected from hydrogen, hydroxy, C1-C3hydroxyalkyl, oxo, C2-C4acyl, C1-C3of alkyl, C2-C4alkylcarboxylic, C1-C3alkoxy, C1-C20alkanoyloxy, or can be substituted with the formation of five - or six-membered spiroheterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur (e.g. acetaline, diacetylene, Catalina or ticketline group); and any two adjacent additional carbon atoms of the ring can be condensed with C3-C8carbocyclic ring, and one or more additional nitrogen atom in the ring may be substituted by substituents selected from hydrogen, C1-C6of alkyl, C2-C4acyl, C2-C4hydroxyalkyl and C3-C8alkoxyalkyl. Examples of substituents containing condensed ring system, are peridontal and 1,2,3,4-tetrahydroisoquinoline.

As for the ring of formula (II), any two adjacent atoms of the ring may be linked together by single or double bonds. Thus, the ring of formula (II) may be saturated or unsaturated, or unsaturated ring which can contain one or more sites of unsaturation. In other words, the ring of formula (II) may contain one or more double light is her but have in mind that unsaturated ring of formula (II) is chemically stable.

Alternative R1and R2together with 2-amine nitrogen in formula (I) can complete a bicyclic ring. Bicyclic rings include, for example, 3-azabicyclo[3.2.2]nonan, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.1.0]hexane and 3-azabicyclo [3.2.0]heptane. In these derivatives of 2-substituents cyclohexylamin esters of the formula (I) are the following groups: 3-azabicyclo[3.2.2.]nonan-3-yl, 2-azabicyclo[2.2.2]Octan-2-yl, 3-azabicyclo[3.1.0]hexane-3-yl and 3-azabicyclo[3.2.0]-heptane-3-yl.

Preferably R1and R2taken together, contain only one heteroatom. For your preferred heteroatoms include nitrogen, oxygen and sulfur. An example of a ring in which R1and R2together include a heteroatom of oxygen, is morpholinyl. An example of a ring in which R1and R2together include another heteroatom of nitrogen, is piperazinil.

Deputy cyclohexane R3and R4can be independently connected with the ring in positions 3, 4, 5 or 6 (i.e., R3and R4can be attached in the same position of the ring, or each of them is connected with the ring in different positions). R3and R4independently selected from hydrogen, hydroxy, C1-C6the alkyl and C1-C6alkoxy, and when, and R3and R4 linked to the same atom of the cyclohexane ring, they may together form a five - or six-membered spiroheterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur. Preferred heterocyclic substituents contain either a single ring atom of oxygen, or a single ring atom of sulfur.

Depending on the identity X ether side chain-CH(R5)-X-A in the formula (I) can take several forms. For example, the compound of formula (I) can have X as a group-C(R6,R14)-Y-, where Y may be any of a direct link, an oxygen atom (O), sulfur atom (S) or (C1-C4alkalinous group. R6and R14independently selected from hydrogen, C1-C6of alkyl, aryl and benzyl, or R6and R14taken together with the carbon to which they are bound, may form a Spiro3-C5cycloalkyl. Thus, the compounds of the invention include compounds of formula (I)in which R6and R14represent hydrogen and Y represents a direct link, so that X can represent CH2.

Alternative X can be alkenylamine fragment, such as CIS - or TRANS-alkenylamine fragment C(R13)=CH in which R13may be any of hydrogen, C1-C6of alkyl, C3-C8cycloalkyl, aryl or benzyl. For compounds of formula (I)in which X is the tsya alkenylamine fragment X is preferably a TRANS-alkenylamine fragment.

Alternative X may be a direct link. Regardless of the choice of A, X and other variables R5selected from hydrogen, C1-C6of alkyl, aryl and benzyl.

Component And the ether side chain is usually hydrophobic fragment. In a typical case, the hydrophobic fragment composed of non-polar chemical groups, such as hydrocarbons or hydrocarbons, substituted by halogen, or ethers, or a heterocyclic group containing a ring nitrogen atoms, oxygen or sulfur. Suitable hydrocarbons are5-C12alkyl and C3-C13carbocyclic ring. Particularly preferred cyclic hydrocarbons include selected aromatic groups such as phenyl, 1-naphthyl, 2-naphthyl, indenyl, acenaphthyl and fluorenyl and represented respectively by formulas (III), (IV), (V), (VI), (VII) or (VIII).

Suitable "A" group in the compounds of the present invention is a phenyl ring represented by the formula (III):

in which R7, R8and R9independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifloromethyl,2-C7alkanoyloxy, C1-C6of alkyl, C1-C6alkoxy, C -C7alkoxycarbonyl, C1-C6-thioalkyl, aryl and N(R15,R16), where R15and R16independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6the alkyl.

For compounds of formula (I)in which X is a direct bond or CH2at least one of R7, R8and R9preferably selected from the following: Amin (-NR15R16where R15and R16independently are hydrogen, acetyl, methanesulfonyl and C1-C6the alkyl, bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, nitro, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkylsulphonyl, C1-C6thioalkyl or aryl. For compounds of formula (I)in which X is CH=CH, and R3and R4are hydrogen, at least one of R7, R8and R9preferably Deputy other than hydrogen.

Other suitable "A" groups in compounds of this invention are group 1-naphthyl represented by the formula (IV):

in which R10and R11independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifloromethyl,2-C7alkanoyloxy, C 1-C6of alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6-thioalkyl, and N(R15,R16), where R15and R16independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6the alkyl.

Another suitable group a in the compounds of this invention is the group of 2-naphthyl represented by the formula (V):

in which R10and R11independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifloromethyl,2-C7alkanoyloxy, C1-C6of alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, and N(R15,R16), where R15and R16independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6of alkyl defined above.

Other appropriate groups in the compounds of this invention are the aromatic group represented by the formula (VI):

in which R12selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifloromethyl,2-C7alkanoyloxy, C1-C6of alkyl, C1-C6alkoxy, C2-C7aldoxycarb the Nile, C1-C6thioalkyl, and N(R15,R16), where R15and R16independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6of alkyl; and Z is selected from CH, CH2, O, N and S, where 2 can be directly associated with "X"as shown in the formula (I), when Z is CH or N, or Z may be directly associated with R17when Z represents N, and R17selected from hydrogen, C1-C6of alkyl, C3-C8cycloalkyl, aryl and benzyl.

Aryl group of the formula (VI) are derivatives of indene, indole, benzofuran and tianeptine, when Z is methylene, nitrogen, oxygen and sulfur, respectively. Preferred heterocyclic groups of formula (VI) include indole, in which Z is NH, benzofuran, in which Z is Oh, and tianamen, in which Z is S. As described below, in a preferred embodiment, Z is O, S or N-R17and in a particularly preferred embodiment, Z is O or S.

Other suitable "A" groups in compounds of this invention are acenaphthylene group represented by the formula (VII):

Another suitable "And" group in the compounds of this invention is the group fluorene represented by the formula (VIII):

Preferably, component a of the ether side chain which is acenaphtylene or fluorenyl group, only when X is a direct bond or CH2. In additional preferred embodiments, acenaphthylene group is 1-acenaphthylene group, and fluoroaniline group is 9-fluorenyl group.

As mentioned above, the present invention provides aminocyclohexanone esters represented by the formula (I). In a preferred embodiment, X is (CH2). For these options Y preferably represents a direct link, an oxygen atom or a sulfur atom. In a particularly preferred embodiment, Y represents a direct bond or an oxygen atom. In another preferred embodiment, Y represents a direct bond and X is C(R6,R14), where R6and R14have the values specified above. In another preferred embodiment, in which X is C(R13)=CH, R13represents a hydrogen atom. In these embodiments, R3and R4preferably independently associated with cyclohexanebis ring in positions 4 or 5.

In a preferred embodiment, the invention provides compounds of formula (IX), or their solvate, or pharmaceutically acceptable salt:

in which, independently in each case,

X is selected from a direct link-CH=CH - and-C(R6,R14)-Y-;

Y is selected from a direct link O and S; and

R1, R2, R3, R4, R6 , R7, R8, R9, R10, R11, R12, R14And Z have the meanings given above for compounds of formula (I).

In another preferred embodiment, the invention provides a compound having the formula (X), or MES, or pharmaceutically acceptable salt:

where independently in each case,

X is selected from a direct link-CH=CH - and-C(R6,R14)-Y-;

Y is selected from a direct link O and S; and

R1, R2, R6and R14have the meanings given above for compounds of formula (I);

R3and R4independently associated with cyclohexanebis ring in positions 4 or 5 independently selected from hydrogen and C1-C6alkoxy; and

A is selected from C5-C12of alkyl, C3-C8cycloalkyl and any of formulas (III), (IV), (V) and (VI)as defined above for compounds of formula (I)in which Z, R7, R8, R9, R10, R11and R12shall have the same meaning described above for compounds of formula (I).

In another preferred embodiment, the invention provides compounds having the formula (XI), or their solvate, or pharmaceutically acceptable salt:

where independently in each case,

R1and R2have the values specified above for compounds of formula (I);

R3 and R4independently associated with cyclohexanebis ring in positions 4 or 5 independently selected from hydrogen and metoxygroup; and

A is selected from C5-C12of alkyl, C3-C8cycloalkyl and any of formulas (III), (IV), (V) and (VI)as defined above for compounds of formula (I)in which Z, R7, R8, R9, R10, R11and R12have the same meaning described above for compounds of formula (I).

In another preferred embodiment, the invention provides compounds of formula (XII), or their solvate, or pharmaceutically acceptable salt:

where independently in each case,

R1and R2have the values specified above for compounds of formula (I);

R3and R4independently associated with cyclohexanebis ring in positions 4 or 5 independently selected from hydrogen and methoxy; and

A is selected from C5-C12of alkyl, C3-C8cycloalkyl and any of formulas (III), (IV), (V) and (VI)as defined above for compounds of formula (I)in which Z, R7, R8, R9, R10, R11and R12have the same meaning described above for compounds of formula (I).

In another preferred embodiment, the invention provides compounds of formula (XIII), or a solvate or pharmaceutically acceptable salt:

where, independently in each case,

X is selected from a direct link, and-CH=CH-;

R1and R2have the meanings given above for compounds of formula (I);

R3and R4independently associated with cyclohexanebis ring in positions 4 or 5 independently selected from hydrogen and methoxy; and

A is selected from C3-C8cycloalkyl and any of formulas (III), (IV), (V), (VI), (VII) and (VIII)defined above for compounds of formula (I); where R8and R9have the meanings indicated above for compounds of formula (I); R7, R10, R11and R12are hydrogen, and Z is selected from O, S and N-R17where R17selected from hydrogen and methyl; provided that may be selected from the formulae (VII) and (VIII)only when X is a direct link.

In another preferred embodiment, the invention provides compounds having the formula (XIV), or their solvate, or pharmaceutically acceptable salt:

where independently in each case,

R1and R2have the values specified above for compounds of formula (I);

And selected from any of formula (III), (IV), (V) and (VI)defined above for compounds of formula (I), where R7, R10, R11and R12represent hydrogen, R8and R9independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulfonamido, methanolate, methoxycarbonyl, neither the ro sulfamyl, thiomethyl, trifloromethyl, methyl, ethyl, methoxy, ethoxy and NH2provided that at least one of R8and R9is not hydrogen; and Z is selected from O and S.

In another preferred embodiment, the invention provides compounds having the formula (XV), or their solvate, or pharmaceutically acceptable salt:

where independently in each case,

R1and R2have the values specified above for compounds of formula (I);

And selected from any of formula (III), (IV), (V) and (VI)as defined above for compounds of formula (I), where R7, R10, R11and R12represent hydrogen, R8and R9independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulfonamido, methanolate, methoxycarbonyl, nitro, sulfamyl, thiomethyl, trifloromethyl, methyl, ethyl, methoxy, ethoxy and NH2provided that at least one of R8and R9is not hydrogen; and Z is selected from O and S.

In another preferred embodiment, the invention provides compounds having the formula (XVI), or their solvate, or pharmaceutically acceptable salt:

where independently in each case,

X is selected from a direct link, TRANS-CH=CH-, -CH2-and-CH2-O-;

R1and R2both are methoxyethanol is together with the nitrogen atom, to which they are attached, complete a ring selected from pyrrolidinyl, cloperastine, acetoxypiperidine, hydroxypyrrolidine, thiazolidine, piperidine, Ketobemidone, acetylpiperidine, 1,4-dioxa-7-azaspiro[4.4]non-7-yl, hexahydroazepin, morpholinyl, N-methylpiperazine and 3-azabicyclo[3.2.2]nonanal; and

A is selected from cyclohexyl, monochlorophenol, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2-bromophenyl, 2,4-dibromophenyl, 3-bromophenyl, 4-bromophenyl, 1-naphthyl, 2-naphthyl, 3-benzo(b)-thiophenyl, 4-benzo(b)thiophenyl, (2-trifluoromethyl)phenyl, 2,4-di(trifluoromethyl)phenyl and (4-trifluoromethyl)phenyl.

The following compounds are most preferred compounds of this invention are:

(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(2-naphthenate)]cyclohexane

(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(1-naphthenate)]cyclohexane

(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(4-bromophenetole)]cyclohexane

(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-[2-(2-naphthoxy)ethoxy]]cyclohexane

(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-[2-(4-bromophenoxy)ethoxy]]cyclohexane

(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(3,4-dimethoxyphenoxy)]cyclohexane

(1R,2R)/(1S,2S)-[2-(1-pyrrolidinyl)-1-(1-naphtenate the si)]cyclohexane

(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophene-3-yl)]cyclohexane

(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophene-4-yl)]cyclohexane

(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(3-bromophenetole)]cyclohexane

(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(2-bromophenetole)]cyclohexane

(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(3-(3,4-acid)propoxy)]cyclohexane

(1R,2R)/(1S,2S)-[2-[bis(2-methoxyethyl)aminol]-1-(2-naphthenate)]cyclohexane

(1R,2R)/(1S,2S)-2-(4-morpholinyl)-1-(3,4-dichlorophenoxy)cyclohexane

(1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(1-naphthenate)cyclohexane

(1R,2R)/(1S,2S)-2-(1-acetylpiperidine)-1-(2-naphthenate)cyclohexane

(1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(2,6-dichlorophenoxy)cyclohexane

(1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(1-naphthenate)cyclohexane

monohydrochloride (1R,2S)/(1S,2R)-2-(4-morpholinyl)-1-[(2-trifluoromethyl)venetucci]cyclohexane

monohydrochloride (1R,2R)/(1S,2S)-2-(3-clopyralid is)-1-[3-(cyclohexyl)propoxy]cyclohexane

monohydrochloride (1R,2R)/(1S,2S)-2-(3-acetoxypropionyl)-1-(1-naphthenate)cyclohexane

monohydrochloride (1R,2R)/(1S,2S)-2-(4-morpholinyl)-1-[(2,6-dichlorophenyl)methoxy]cyclohexane

monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-[2,6-dichlorophenyl)methoxy]cyclohexane

monohydrochloride (1R,2R)/(1S,2S)-2-(3-hydroxypyrrolidine)-1-(2,6-dichlorophenoxy)cyclohexane

monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(2,2-diphenylmethoxy)cyclohexane

monohydrochloride (1R,2R)/(1S,2S)-2-(3-thiazolidine)-1-(2,6-dichlorophenoxy)cyclohexane

monohydrochloride (1R,2S)/(1S,2R)-2-(3-ketopropionic)-1-(1-naphthenate)cyclohexane

Description of the method of obtaining compounds of the invention

Aminocyclohexane-ether compounds of this invention contain amino and ether side chains located in positions 1,2 cyclohexane ring. Accordingly, amino and ether side chains relative to each other and relative to the plane of the cyclohexane ring can be either in CIS or in transvaalense. The present invention provides IU is odology synthesis, through which can be obtained CIS and Transmediale.

Transmediale of the present invention can be obtained by analogy with known methods of synthesis (see, for example, Shanklin, Jr. et al., U.S. Patent, 5130309). The figure 1 shows roughly getting Transmediale of the invention, and this more fully described in example 1. As noted in figure 1, receipt of Transmediale invention can be achieved by using the following chetyrehstennoy procedure.

In the first stage (marked "i" on figure 1) cyclohexene epoxide undergoes reaction disclosure ring with an amine. See, for example, Szmuszkovicz, U.S. Patent 4145435. Although the reaction may occur at room temperature, typically preferred is a high temperature to bring the reaction to completion within desirable in an industrial scale period of time. Usually, the reaction is carried out in a solvent such as water, and the temperature of the reflux distilled solvent provides just the right temperature. Satisfactory results are usually provided when using equal molar amounts of amine and epoxide cyclohexene. In any case, the amine nitrogen reacts with the epoxy group with the formation of 1-hydroxy-2 aminocyclohexane, and normal is the mutual translatology hydroxy - and amino-groups.

The overall reaction can be used in a wide variety of amine compounds and substituted cyclohexene oxides, and figure 1 illustrates the response for the case when the amine is morpholine and cyclohexene oxide are not substituted. For other amines or substituted cyclohexene epoxides, which can contain other reactive functional groups before the implementation of stage i) are suitable protective group. Suitable protective groups are described, for example, in Green, Protective Groups in Organic Chemistry, John Wiley and Sons, New York, NY (1991).

In the second stage (labeled "ii)" in figure 1) a hydroxy-group, which is obtained from the epoxide, is converted into an activated form. The term “activated form”, as used here, means that the hydroxy-group becomes easy tsepliaeva group. Tsepliaeva group, shown in figure 1, represents a group nelfinavir, and it is preferred tsepliaeva group. However, the hydroxy-group can turn into other otsepleniya group in accordance with methods well known in the field. In a typical reaction the connection aminocyclohexanol processed by methanesulfonamido in the presence of a base, such as triethylamine, as shown in figure 1. The reaction is satisfactorily carried out at about 0° C. is Usually preferred excess is methanesulfonanilide relatively aminocyclohexanol, in order to make more valuable aminocyclohexanol in activated form.

For some other compounds aminocyclohexanol may be necessary to introduce suitable protective groups before performing stage ii). Suitable protective groups are described, for example, in Green, Protective Groups in Organic Chemistry, John Wiley and Sons, New York, NY (1991).

At the third stage (indicated by "iii" on figure 1) alcohol is subjected to reaction with a strong base to obtain a salt of an alkoxide. The conversion of the alcohol to the alkoxide (also known as the alcoholate) using a strong base, is a common reaction, and it will occur with a wide variety hydroxysteroid compounds. In some cases, the combination of alcohol may have other reactive functional group, which is desirable to protect against contact of the alcohol with a strong base. Suitable protective groups are described, for example, in Green, Protective Groups in Organic Chemistry, John Wiley and Sons, New York, NY (1991). Such alcohols are, or industrial available or can be obtained using the procedures described in this area, or adapted for this case, with suitable procedures can be determined by Chemical Abstracts and indexes (Indices), developed and published by the American chemical society.

In the fourth stage (marked "iv)" in figure 1)alcoholate stage iii)is subjected to reaction with activated aminocyclohexanol stage ii). Thus, generally speaking, the compounds of this invention can be obtained by the reaction of the activated form of the corresponding 1,2-aminocyclohexanol (1 mol) with an alcoholate (1.25 mol), obtained by processing the selected alcohol (1.25 mol), for example, sodium hydride (1.3 mol). 1,2-Aminocyclohexanol (1 mol) can be activated by formation of the corresponding nelfinavir in the presence of methanesulfonamide (1.25 mol) and triethylamine (1.5 mol). Mesilate quickly added to the alcoholate in a suitable solvent, such as dimethylformamide. At the reaction temperature are carefully monitored in order to avoid undesirable side reactions, such as β -elimination. Generally for the formation of compounds of the invention typically is suitable reaction temperature of 80-90° C for 2 hours. When the reaction goes essentially to completion, the desired product stands out from the reaction mixture by conventional techniques of organic chemistry and is cleared mainly by chromatography on columns with subsequent recrystallization. The protective group can be removed at an appropriate stage of the sequence of reactions. Suitable methods are described, for example, in Green, "Protective Groups in Organic Chemistry", John Wiley and Sons, New York, NY (1991).

The sequence of reactions described above (and shown in figure 1), and gives encyclopediaby ether in the form of free base. Using preparative chiral HPLC can be obtained in pure enantiomeric form. The free base can, if desired, using known methods to turn into monohydrochloride salt and subsequently, if desired, other salts accession acid via reaction with inorganic or organic salts. Salt accession acid can also be obtained Metallichesky by the reaction of one salt accession acid with an acid that is stronger than the acid anion source of salt.

CIS - and TRANS-compounds of the invention can be obtained in accordance with the chemical processes shown in figure 2. As shown in figure 2, 1,2-aminocyclohexanone can be obtained by oxidation will Roll (Swern) corresponding compounds TRANS-1,2-aminocyclohexanol (which can be obtained as described above) using oxalicacid/dimethyl sulfoxide (see, for example, Synthesis 1980, 165). Subsequent recovery of aminocyclohexanone with lithium aluminum hydride or sodium borohydride gives a mixture of CIS - and TRANS-aminocyclohexanol. A mixture of aminoalcohols can tarifitsirovatsja the corresponding carboxylic acid with azeotropic distillation in toluene in the presence of catalytic amount of para-toluenesulfonic acid, giving diastereomer a mixture of CIS - and TRANS-esters. Slidestream esters can be separated by using preparative chromatography using techniques well-known experts in this field. Then the obtained racemic CIS - or Transline esters can be recovered by sodium borohydride in the presence of Lewis acid in the corresponding racemic CIS - or TRANS-ethers (see, for example, J. Org. hem. 25, 875, 1960 and Tetrahedron 18, 953, 1962). Racemic simple CIS-ester can be separated using preparative chiral HPLC, as discussed above for the cross-connect.

Alternative CIS - and TRANS-compounds of the invention can be obtained according to the chemical reactions given in figure 3. As shown in figure 3, cyclohexene oxide may react with the alcohol (ROH) in the presence of MD(ClO4)2(see, for example, M. Chini et al., Synlett, 673-676, 1992), giving 1,2-hydroxycyclohexanone esters. The oxidation with pyridinium dichromate (see, for example, R. Oshima et al., J.Org. Chem., 50, 2613-2621, 1985) gives the corresponding 1,2-alkoxysilane. Subsequent reductive amination of (R.F.Borch et al., SoC., 93(12), 2897-2904, 1971) gives a mixture of CIS - and TRANS-aminocyclohexanol esters. The mixture of diastereoisomeric esters can be separated using chromatography specialists in this field. Thus obtained racemic CIS - or TRANS-esters can then be separated using well-known in the field of classical methods recrystallization or by using preparative chiral who ASH, giving individual enantiomers: TRANS-(1R,2R)TRANS-(1S,2S)CIS-(1R,2S) or CIS-(1S,2R)amino esters.

This procedure of synthesis, especially with regard to the General knowledge in this field, provide sufficient guidance to specialists in this field for carrying out the synthesis, isolation and purification of compounds of this invention.

Compositions and methods introduction

In yet another embodiment, the invention provides compositions that include the above-described connection cyclohexylamine in a mixture or other combination with one or more inert carriers, excipients and diluents, and optionally with additional optional ingredients. These compositions are useful, for example, as standards for analysis, a convenient means of delivery in the form of bulk or pharmaceutical compositions. Analyzed the amount of coupling of the invention is an amount that can easily be measured using the procedures of analysis and techniques, well known to specialists in this field. Detectable amounts of the compounds of the invention typically varies approximately from 0.001% by mass to 75% by weight relative to the total weight of the composition. Inert carriers include any material which does not cause degradation or does not interact covalently otherwise with the compound of the invention. Por the measures of suitable inert carriers are water; aqueous buffer systems, such as are commonly used in the analysis of high performance liquid chromatography (HPLC); organic solvents, such as acetonitrile, ethyl acetate, hexane and similar services which are appropriate for the diagnosis or in vitro, but usually not suitable for the introduction of a warm-blooded animal); and pharmaceutically acceptable carriers, such as a physiological salt solution.

Thus, the present invention provides a pharmaceutical or veterinary composition (hereinafter simply referred to as a pharmaceutical composition containing the compound of cyclohexylamine described above, in a mixture with a pharmaceutically acceptable carrier, excipient or diluent. The invention also provides a pharmaceutical composition comprising an effective amount of a compound of cyclohexylamine described above, in combination with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of this invention can be in any form that allows you to enter the composition to the patient. For example, the composition may be in the form of solids, liquids or gas (aerosol). Typical routes of administration include, without limitation, oral, local, parenteral, sublingual, rectal, vaginal, and intranasal. The term “parenteral”, and is used here includes subcutaneous injections, intravenous, intramuscular, epidural, intrasternally (vnutrigrudne) injection or infusion. The pharmaceutical composition of the invention is produced according to a formula which allows it contains active ingredients to be bioavailable upon introduction of the composition to the patient. Compositions that will be administered to the patient, have the form of one or more dosage units or single doses, in which, for example, tablet, capsule or starch wafer may be a single dose, and the container with the compound of cyclohexylamine in aerosol form may hold a number of individual doses.

The materials used to produce pharmaceutical compositions should be pharmaceutically pure and non-toxic in the quantities used. Compositions of the invention can include one or more of the compounds (active ingredients), known for a specific desired effect. For example, epinephrine can be combined with the connection aminocyclohexanol ether of the invention, giving a composition useful for inducing local anesthesia. Specialists in this field it is obvious that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on many factors. Relevant factors include, without limitation the IP of the subject (for example, people), the particular form of the active ingredient, route of administration and the applied composition.

In General, the pharmaceutical composition includes the compound of cyclohexylamine described here, in a mixture with one or more carriers. The carrier(s) may be in the form of particles, so that the composition has the form of, for example, tablets or powder. The carrier(s) can be liquid, and the composition is a syrup for oral administration or injectable liquid. In addition, the carrier(s) may be gaseous, to give an aerosol composition, useful, for example, for administration by inhalation.

When the composition is intended for oral administration, it is preferably represented either in solid or in liquid form, while semi-solid, semi-solid, suspension and gel form included in the forms, which are considered here as a solid or a liquid.

As solid compositions for oral administration, the composition may be prepared in the form of powder, granules, compressed tablets, pills, capsules, starch capsules, chewing gum, wafers, cakes or similar form. Such solid compositions typically contain one or more inert diluent or edible carrier. In addition, you may attend one or more of the following adjuvants: binders prophetic is TBA, such as syrup, gum acacia, sorbitol, polyvinylpyrrolidone, carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, gum tragakant or gelatin, and mixtures thereof; fillers (excipients, such as starch, lactose or dextrins, dezintegriruetsja tools such as alginic acid, sodium alginate, Primogel, corn starch and similar; lubricants such as magnesium stearate or Sterotex; fillers such as lactose, mannite, starch, calcium phosphate, sorbitol, methylcellulose and mixtures thereof; lubricants such as magnesium stearate, polymers with high molecular weight such as polyethylene glycol, fatty acids with high molecular weight, such as stearic acid, silica, humectants such as sodium lauryl sulfate, a substance that helps the slide (swallowing), such as colloidal silicon dioxide; substances imparting a sweet taste, such as sucrose or saccharin, korrigentami smell and taste, such as peppermint oil, methyl salicylate or orange corrigent, and coloring agents.

When the composition has the form of a capsule such as a gelatin capsule, it may contain in addition to materials of the above type, a liquid carrier such as polyethylene glycol or fatty oil.

The composition may be in liquid form, for example in the form of an elixir, Ciro is a, solution, water or oil emulsion or suspension, or even in the form of dry powders, which can rekonstruirovatsya with water and/or other liquid medium before use. As two examples of oral fluids or delivery of fluid by injection. When the composition is intended for oral administration, the preferred composition contains in addition to these compounds, one or more sweeteners, thickeners, preservatives (for example, alkyl para-hydroxybenzoate), dye/tint substances and amplifiers of taste or smell (corrigentov). In a composition intended for administration by injection may be included one or more surfactants, preservatives (for example, alkyl para-hydroxybenzoate), moisturizers, dispersing funds, suspendida agents (e.g. sorbitol, glucose or other sugar syrups), buffer substances, stabilizers and isotonic agents. Emulsifying agent may be selected from lecithin or monooleate sorbitol.

Liquid pharmaceutical compositions of the invention, whether they are solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably a physiologically the ski ringer's solution, isotonic sodium chloride, fatty oils such as synthetic mono or diglycerides which may serve as a solvent or suspendida medium, polyethylene glycols, glycerine, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffering agents such as acetates, citrates or phosphates, and agents for bringing osmotic pressure, such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes or vials with multiple doses of glass or plastic. The preferred adjuvant is a physiological saline solution. Injectable pharmaceutical compositions are preferably sterile.

A liquid composition intended for either parenteral or oral administration should contain a number of compounds of the invention, to achieve the appropriate dosage. Usually this amount in the composition is at least 0.01% of the compound of the invention. When intended for oral administration, this number can vary between 0.1 and about 70% by weight of the composition. Preferred compositions the AI for oral administration contain from about 4% to 50% of the active connection cyclohexylamine. In accordance with this invention, the preferred compositions and preparations are prepared so that a parenteral dosage unit contains between 0.01 and 10% by weight of active compound.

The pharmaceutical composition may be intended for local or topical administration, in this case, acceptable composition is one in which the media may include a solution, emulsion, ointment, cream or gel base. For example, the base may include one or more of the following ingredients: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents, such as water and alcohol, and emulsifiers and stabilizers. In the pharmaceutical compositions for local injection may be present thickeners. If the composition is intended for transdermal administration, it may include a transdermal patch or device for medicinal electrophoresis. Topical forms that may contain the compound of the invention in a concentration of from about 0.1 to 25 wt%./about. (weight per unit volume).

The composition may be intended for rectal administration, for example, in the form of a suppository, which will melt in the rectum and release the drug. Composition for rectal injection may contain, as appropriate does not cause irritation to the floor is of Italia oily base. Such bases include, without limitation lanolin, cocoa butter and polyethylene glycol. For preparing suppositories preferred low-melting waxes, while suitable waxes are mixtures of glycerides of fatty acids and/or cocoa butter. The wax can melt and homogeneous dispersed connection cyclohexylamine by stirring. The molten homogeneous mixture is then poured into molds of suitable size, allow it to cool and thereby solidify.

The composition may include various materials which modify the physical form of a solid or liquid unit dose. For example, the composition may include materials that form the covering shell around the active ingredients. The materials that form the covering shell, usually inert and can be selected, for example, of sugar, shellac and other enterococci covering agents. Alternative active ingredients can be enclosed in a gelatin capsule or starch wafer.

The composition in solid or liquid form may include an agent that binds the connection cyclohexylamine and thus contributes to the delivery of active ingredients. Suitable agents that may have this ability include monoclonal and polyclonal antibodies, proteins or liposomes.

Pharmaceutical to notice of the present invention may consist of gaseous dosage units, for example, it may be in the form of an aerosol. The term aerosol is used to denote multiple systems range from systems of colloidal nature to systems consisting of packaged under pressure. Can be delivered liquefied or compressed gas or delivering by means of a suitable pumping system, which distributes active ingredients. Aerosols compounds of the invention can be delivered in single phase, two phase or three-phase systems for the delivery of the active ingredient(s). The system of delivery of the aerosol includes the necessary container, activators, valves, subcontainers, etc. which can be set. Preferred aerosol can be determined by experts in the field without undue experimentation.

Whether solid, liquid or gaseous form, the pharmaceutical composition of the present invention may contain one or more known pharmacological agents used or the methods of modulating activity of ion channels in a warm-blooded animal, or in methods of modulating activity of ion channels in vitro, or used to treat arrhythmia, diseases of the Central nervous system, convulsive States, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma is, cough, inflammation, arthritis, allergic conditions, gastrointestinal disorders, urinary incontinence, mucous colitis, cardiovascular disease, cerebral ischemia or myocardial ischemia, hypertension, syndrome, prolonged QT, stroke, migraine, eye diseases, diabetes, myopathy, myotonia Becker, infants pregnant, congenital paramythia, malignant hyperthermia, giperglikemicescoa periodic paralysis, myotonia Thomsen, autoimmune diseases, transplant rejection in transplantation of an organ or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease and other mental disorders, and alopecia. With the compounds of this invention can be combined with other tools, known as tools that cause increased libido, funds local analgesia or anesthesia.

The pharmaceutical composition can be obtained according to methods well known in the pharmaceutical field. Aminocyclohexane compounds of the invention can be in the form of a solvate in a pharmaceutically acceptable solvent such as water or physiological salt solution. Alternative compounds may be in free base form or in the form of pharmaceutically acceptable salts such as hydrochloride, sulfate, phosphate, citrate, fumarate, met sulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate and other salts known in this area. The corresponding salt is selected to enhance bioavailability or stability of the compounds with the appropriate application method (e.g., oral or parenteral routes of administration).

Compositions intended for administration by injection can be obtained by combining the compounds of cyclohexylamine with water and preferably with a buffer agents, to obtain the solution. Water preferably is sterile and free from pyrogens water. May be added a surfactant to facilitate the formation of homogeneous solution or suspension. Surfactants are compounds that ecovalence interact with the connection cyclohexylamine, thereby facilitating the dissolution or the homogeneous suspension connection cyclohexylamine in the aqueous delivery system. It is desirable that the surface-active substances are present in the aqueous compositions of the invention, since the connection cyclohexylamine of the present invention are typically hydrophobic. Other carriers for injection include, without limitation sterile free from peroxide etiloleat, digidrirovannye alcohols, propylene glycol, and mixtures thereof.

Suitably the pharmaceutical adjuvants for injection solutions include stabilizing agents, solubilizing agents, buffering agents and viscosity regulators. Examples of such adjuvants include ethanol, ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citrate buffers, and high-molecular polyoxyethylene viscosity regulators. These pharmaceutical compositions can inetservices intramuscularly, epidurally, intraperitoneally or intravenously.

Pharmacological testing

As noted above, the present invention provides compounds described above for use in in vitro and in vivo methods. In one embodiment, the blocked in vitro and in vivo ion channels such as sodium channels in the heart.

Ion channels are ubiquitous membrane proteins in the cells of warm-blooded animals such as mammals. Their essential physiological role is to control the transmembrane electrical potential, the mediating ion and fluid balance, relieving neuromuscular and neuronal transmission, rapid transmembrane signal transduction and regulation of secretion and contractility.

Therefore, compounds that can modulate the activity or functioning of ion channels will be useful for the treatment or prevention of many diseases or disorders caused by defective or inadequate funktsioniroval who eat ion channels. Found that the compounds of the invention have significant activity in modulating the activity of ion channels in vivo and in vitro.

Thus, the invention provides methods of treating diseases or conditions warm-blooded animal suffering from or is a carrier for the disease or condition and/or prevent disease or condition in a warm-blooded animal, in which a therapeutically effective amount of the compounds of formula (I)or the compositions containing the compound of formula (I), inserted a warm-blooded animal that is in need. Compounds, compositions and methods of this invention can be used for the following diseases and conditions: arrhythmia, diseases of the Central nervous system, convulsions, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, gastrointestinal disorders, urinary incontinence, mucous colitis, cardiovascular disease, cerebral ischemia or myocardial ischemia, hypertension, syndrome, prolonged QT, stroke, migraine, eye diseases, diabetes, myopathy, myotonia Becker, male pregnancy, congenital paramythia, malignant hyperthermia, gipercalziemiceski periodic p is relic, myotonia Thomsen, autoimmune diseases, graft rejection in organ transplantation or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease or other mental disorders, and alopecia.

In addition, this invention provides a method of performing local analgesia or anesthesia in a warm-blooded animal, which includes the introduction of a warm-blooded animal that is in need, an effective amount of the compounds of formula (1) or pharmaceutical composition containing the compound of formula (I). These methods can be used to alleviate or prevent pain in a warm-blooded animal.

In addition, this invention provides a method in which a drug containing ion channels, with an effective number of connections aminocyclohexanol ether of the invention, or an effective amount of this compound is introduced warm-blooded animal (e.g. a mammal such as man). Suitable preparations containing cardiac sodium channels include cells isolated from the heart tissue and cultured cell lines. The stage at which the contact includes, for example, incubation of ion channels with the compound under conditions and for p the period of time sufficient to provide modulation of activity of channels this connection.

In another embodiment, the above-described connections are provided for the treatment of arrhythmia. Used herein, the term “arrhythmia” refers to the treatment of arrhythmias and the prevention of arrhythmias that occur in the case of a disposition of the heart to arrhythmias. For the treatment of arrhythmia in a warm-blooded animal, such as man, applies an effective amount of the composition of the present invention. Methods of administration of effective amounts of antiarrhythmic drugs is well known in this area and include the introduction of oral or parenteral dosage forms. Such dosage forms include forms for parenteral administration, but are not limited to. Such forms include, but are not limited to, solutions for parenteral administration, tablets, capsules, slow-release implants and systems for transdermal delivery. In General, it is preferable to oral and intravenous administration. The dosing amount and frequency of injection was selected to create an effective level of funds without the harmful effects. In General, oral or intravenous order antiarrhythmic effects dose will be in the range from about 0.1 to 100 mg/kg/day, and typically from about 0,to 10 mg/kg

The introduction of the compositions of this invention may be combined with the introduction of other means. For example, desirable may be the introduction of the opioid antagonist, such as naloxone, if the connection manifests opioid activity where such activity may be undesirable. Naloxone can counteract opioid activity entered connection without interfering with its antiarrhythmic action. As another example, the connection aminocyclohexanol ester of the invention may be administered in conjunction with epinephrine to induce local anesthesia.

In order to assess whether the connection is desirable for the present invention pharmacological activity, it is subjected to a series of tests. The definition of the test that should be performed depends on the interest of the physiological response. In the published literature there are numerous protocols for testing the efficacy of potential therapeutic agents, and these protocols can be applied to these compounds and compositions.

For example, in connection with the treatment or prevention of arrhythmia can be a series of four tests. In the first of these tests, the compound of the present invention every 8 minutes is given in the form of increasing (double with each dose) intravenous bolus shot by pentobarbital is the lynx. After 30 seconds, 1, 2, 4 and 8 minutes after each dose measure the effect of compounds on blood pressure, heart rate and ECG. Increasing doses give up until the animals will not die. Identified deaths or respiratory or cardiac origin. This test shows that modulates whether the connection activity of sodium channels and/or potassium channels, and, in addition, provides information about acute toxicity. Indicators blocking sodium channels are increased interval P-R and the broadening of the QRS complex on the ECG. The result of the blocking of potassium channels is a lengthening of the interval Q-T ECG.

The second test involves the introduction of a connection in the form of infusion shot by pentobarbital rats, the left ventricle which is subjected to electrical rectangular pulses, performed in accordance with pre-established Protocol, described in more detail below. This Protocol includes determining thresholds for the induction of extrasystoles and ventricular fibrillation. In addition, using the method of introducing a single PVCs estimated impact on the electric refractoriness. In addition, the recorded impact on blood pressure, heart rate and ECG. In this test, blockers of sodium channels give ECG changes expected on the basis of p is pout test. In addition, blockers of sodium channels also increase the thresholds for induction of extrasystoles and ventricular fibrillation. Blocking potassium channels revealed to increase the refractoriness and the broadening of the interval Q-T ECG.

The third test consists of exposure of isolated hearts of rats exposed to compounds at increasing concentrations. In the isolated heart in the presence of varying concentrations of the compounds are recorded intraventricular pressure, heart rate, conduction velocity and ECG. The test provides evidence of a direct toxic effect on the myocardium. In addition, in terms of stimulating ischemia can be installed selectivity, activity and efficiency of the connection. It is assumed that found to be effective in this test concentrations will be effective in electrophysiological studies.

The fourth test is an assessment of the antiarrhythmic activity of the compounds against arrhythmias induced by occlusion of a coronary artery from shot rats. It is expected that a good anti-arrhythmic compound under normal conditions will possess antiarrhythmic activity when using doses that have little or no influence either on the ECG, blood pressure, or heart rate decrease in the s.

All the above tests are performed using tissue of rats. To ensure that the connection has not only a specific tissue of rats effect, further experiments are performed on dogs and primates. In order to assess the possible blocking action on sodium channels and potassium channels in vivo in dogs, the connection test, determining its influence on the ECG, the speed of conduction of the ventricular epicardium and responses to electrical stimulation. Shot the dog open the chest to expose the epicardium of the left ventricle. After removal of the pericardium of the heart in the epicardial layer of the left ventricle into the recording/stimulating electrode. Using this procedure and the appropriate stimulation protocols, we can estimate the conduction velocity of the epicardium, and sensitivity to electrical stimulation. This information in combination with ECG measurements allows you to determine whether blocking sodium and/or potassium channels. As in the first test in rats the compound is given in a series of increasing bolus doses. However, is determined by the possible toxic effect of the compounds on the cardiovascular system of dogs.

The effect of compounds on the ECG and responses to electrical stimulation were evaluated also on intact shot by the halothane gas baboons (Papio anubis). In preparation for this case is e the cannula to determine blood pressure and ECG electrodes are appropriately introduced shot a baboon. In addition, in the right ventricle was placed stimulating electrodes with electrode for the registration of the monophasic action potential. Also as in the test described above, the response to the connection shown on the ECG and electrical stimulation, indicates a possible blocking of the sodium and/or potassium channels. Monophasic action potential also shows whether the connection to the expansion of the action potential, an effect that is expected from an agent that blocks potassium channels.

As another example, in connection with the reduction or prevention of the pain may be carried out following the testing. To determine the effect of the compounds of this invention by the reaction of animals to acute pain was to assess the effect of weak injection syringe 7.5 g, equipped with a 23G needle, which was applied to the shaven spot on the back of the Guinea pig (Cavia porcellus) after subcutaneous injection of saline solution (50 μl, 10 mg/ml), sufficient for swellings visible blister on the skin. Each test was performed in the Central region of the blister, as well as on its periphery, in order to control the diffusion of the test solution from the point of introduction. If the animal trembled in response to a stimulus, it showed the absence of blocking pain. Testing was performed with time intervals up to 4 hours after introduction the Oia. Lots of bubbles formation was examined after 24 hours and observed anomalies of the skin as a result of local injection of test substances or saline, the media used to prepare test solutions.

Other songs

The invention also provides kits containing a pharmaceutical composition that includes one or more compounds of the above formula. The set also includes instructions for using the pharmaceutical compositions for modulating the activity of ion channels for the treatment of arrhythmia or implementation of local analgesia and/or anesthesia, and other applications that are pending. Preferably commercial packaging contains one or more unit doses of the pharmaceutical composition. For example, such a single dose may be sufficient for intravenous injection. Specialists in this field clearly evident that the compounds, which are sensitive to light and/or air, require special packaging and/or cooking techniques. For example, can be used in packaging, no light, and/or sealed, eliminating contact with the ambient air, and/or compounding apply acceptable coatings or fillers.

The following examples are offered to illustrate, but not to the OTF is the limit. In the examples, unless otherwise noted, the source material is procured from the well-known commercial companies suppliers, such as Aldrich Chemical Company (Milwaukee, WI), and were of standard quality and purity. The terms “broadcast” and “ethyl ester” refers to diethyl ether; “h” refers to hours; “min” refers to minutes; “GC” refers to gas chromatography;“./about.” refers to the volume of the volume; and the ratio of ratios are by weight, unless otherwise stated.

Examples

Example 1

Monohydrochloride (± )-TRANS-[2-(4-morpholinyl)-1-(2-naphthenate)]cyclohexane

(Compound No. 1)

(i) Morpholine (5 ml, 57 mmol), cyclohexene oxide (5.8 ml, 57 mmol) and water (3 ml) was heated under reflux for 1.5 hour. GC analysis showed that the reaction was completed. The cooled mixture was distributed between saturated NaOH solution (50 ml) and ether (75 ml). The aqueous layer was repeatedly washed with ether (30 ml) and the combined ether layers were dried over sodium sulfate. The ether was removed in vacuo, leaving a yellow oil (9,83 g). The crude product (± )-TRANS-[2-(4-morpholinyl)]cyclohexanol was purified by vacuum distillation (BP. 75-80° under full vacuum)to give a clear liquid (8.7 g). The yield of 82.5%.

(ii) To a cooled (0° (C) the solution (± )-TRANS-[2-(4-morpholinyl)]cyclohexanol (6.0 g, 32,4 mmol) and triethylamine (6.8 ml, 48 the mol) in dichloromethane (100 ml) via cannula solution was added methanesulfonamide (3,10 ml, 40 mmol) in dichloromethane (50 ml). The addition was completed within 10 min, the reaction mixture was stirred for one hour at 0° and then at room temperature for 4 hours. Dichloromethane and the mixture was washed with water (2× 50 ml) and the combined aqueous washings were extracted with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining 8.5 g (100% yield) of the crude nelfinavir.

(iii) To sodium hydride, 80% oil dispersion, previously washed with hexane (3× 20 ml), (1.24 g, 51.6 mmol) in dry dimethylformamide (50 ml) via cannula was added a solution of 2-naphtenate (6.8 g, 40 mmol) in dry dimethylformamide (50 ml). The addition was accompanied by evolution of gas, and as the reaction mixture was stirred at room temperature, it turned into a gel. Mesilate obtained above in the item (ii), was dissolved in dimethylformamide (50 ml) and the resulting solution was rapidly added via cannula to a suspension of alcoholate. The reaction mixture was heated to 80° and then the temperature was lowered to 40° C. the resulting yellow solution was poured into ice water (1500 ml) and was extracted with ethyl acetate (3× 300 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (500 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo the e gave a 13.4 g of amber oil, which was dissolved in water (150 ml) and the pH of the solution was brought to pH 2 aqueous 1M Hcl. The acidic aqueous solution was extracted with ethyl ether (2× 100 ml) and then was podslushivaet to pH 10 with 50% aqueous sodium hydroxide solution. Basic aqueous solution was extracted with ethyl ether (2× 100 ml), the combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining a remainder 7,16 g of the crude free aminoether. The crude product was purified by chromatography on silica gel 60 (70-230 mesh), using as eluent a mixture of ethyl acetate - chloroform (1:1 vol./vol.), and received 4,37 g purified free base. The product was dissolved in ethyl ether (80 ml) and turned in monohydrochloride salt by adding a saturated solution of Hcl in ethyl ether (80 ml). From the solution were oil, the solvent is evaporated in vacuum and the residue was dissolved in a minimum amount of warm ethanol, adding a large amount of ethyl ether was begun crystallization. The crystals were collected, which gave a 3.83 g (31% yield) specified in the connection header, TPL 158-160°, elemental composition indicated in table 1.

Example 2

Monohydrochloride (± )-TRANS-[2-(4-morpholinyl)-1-(1-naphthenate)]cyclohexane

(Compound No. 2)

(i) the Original TRANS-aminocyclohexanol receive according to example 1.

ii) To a cooled (0° C) the solution (± )-TRANS-[2-(4-morpholinyl)]cyclohexanol (6.0 g, 32 mmol) and triethylamine (6.8 ml, 48 mmol) in dichloromethane (100 ml) via cannula solution was added methanesulfonamide (3,10 ml, 40 mmol) in dichloromethane (50 ml). The addition was completed within 10 min, the reaction mixture was stirred for another hour at 0° and then at room temperature for 4 hours. Dichloromethane and the mixture was washed with water (2× 50 ml) and the combined aqueous wash was extracted again with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining 9.0 g of the crude nelfinavir.

(iii) To sodium hydride, 80% oil suspension, pre-washed hexane (3× 20 ml), (1,30 g, 51.6 mmol) in dry dimethylformamide (50 ml) via cannula solution was added 1-naphtenate (6.8 g, 40 mmol) in dry dimethylformamide (50 ml). The addition was accompanied by evolution of gas, the reaction mixture was stirred at room temperature for 4 hours. Mesilate obtained above in the item (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (3 min) through a cannula to a suspension of alcoholate. The reaction mixture was heated to 80° C for 3 hours, then the temperature was lowered to 35° With over night with stirring. The reaction mixture was poured into ledian the Yu water (1500 ml) and was extracted with ethyl acetate (3× 300 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (500 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 12.0 g of oil which was dissolved in ether (80 ml) and treated with saturated solution of Hcl in ether. From the solution were oil, the solvent is evaporated in vacuum and the resulting crude cleaners containing hydrochloride salt was dissolved in water (200 ml). The acidic aqueous solution was extracted with ethyl ether (2× 100 ml) and then was podslushivaet to pH 10 with 50% aqueous sodium hydroxide solution. Basic aqueous solution was extracted with ethyl ether (2× 100 ml), the combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining a remainder of 7.20 g of the crude free aminoether. The crude product was purified by chromatography on silica gel 60 (70-230 mesh), using as eluent a mixture of ethyl acetate - dichloromethane (1:1 vol./vol.), and received purified free base. The product was dissolved in ethyl ether (80 ml) and turned in monohydrochloride salt by adding a saturated solution of Hcl in ethyl ether (80 ml). Besieged white product and the solid precipitate was collected and dissolved in minimum amount of hot ethyl alcohol, adding a large amount of ethyl ether was begun crystallization. Crystals with Irali, that gave 2.30 g specified in the connection header, TPL 198-200° having the elemental composition indicated in table 1.

Example 3

Monohydrochloride (± )-TRANS-[2-(4-morpholinyl)-1-(4-bromophenetole)]cyclohexane

(Compound No. 3)

(i) the Original TRANS-aminocyclohexanol receive according to example 1.

(ii) To a cooled (0° (C) the solution (± )-TRANS-[2-morpholinyl)]cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (25 ml) via cannula solution was added methanesulfonamide (of 1.55 ml, 20 mmol) in dichloromethane (25 ml). The addition was completed within 5 min, the reaction mixture was stirred for another hour at 0° and then at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (2× 50 ml), the combined aqueous washings were extracted with dichloromethane (25 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining 4.7 g of the crude nelfinavir.

(iii) To sodium hydride, 80% oil suspension, pre-washed hexane (3× 10 ml), (0,62 g for 25.8 mmol) in dry dimethylformamide (25 ml) via cannula was added a solution of 4-bromophenethylamine alcohol (4.0 g, 20 mmol) in dimethylformamide (50 ml). The addition was accompanied by evolution of gas, the reaction mixture was stirred at room temperature in accordance with the s 4 hours. Mesilate obtained above in stage (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (3 min) through a cannula to a suspension of alcoholate. The reaction mixture was heated to 80° C for 2 hours, then the temperature was lowered to 35° and the reaction mixture was stirred over night. The reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (150 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 7.4 g of oil which was dissolved in ether (80 ml) and treated with saturated solution of Hcl in ether. The oil was made from a solution, the solvent is evaporated in vacuum and the residue was dissolved in water (100 ml). The acidic aqueous solution was extracted with ethyl ether (2× 50 ml) and then was podslushivaet to pH 10 with 50% aqueous sodium hydroxide solution. Basic aqueous solution was extracted with ethyl ether (2× 50 ml), the combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining a remainder to 3.67 g of the crude free aminoether. The crude product was purified by chromatography on silica gel 60 (70-230 mesh), using as eluent a mixture of ethyl acetate - dichloromethane (1:1 vol./vol.), and got cleared the free bases of the interview. The product was dissolved in ethyl ether (30 ml) and was turned into monohydrochloride salt by adding a saturated solution of Hcl in ethyl ether (30 ml). The solvent is evaporated, and the residue was dissolved in minimum amount of ethyl alcohol, adding a large amount of ethyl ether was begun crystallization. The crystals were collected, which gave 1.31 g specified in the connection header, TPL 148-151° having the elemental composition indicated in table 1.

Example 4

Monohydrochloride (± )-TRANS-[2-(4-morpholinyl)-1-[2-(2-naphthoxy)ethoxy)]cyclohexane

(Compound No. 4)

(i) the Original TRANS-aminocyclohexanol receive according to example 1.

(ii) To a cooled (0° (C) the solution (± )-TRANS-[2-(4-morpholinyl)]cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (50 ml) via cannula solution was added methanesulfonamide (of 1.55 ml, 20 mmol) in dichloromethane (50 ml). The addition was completed within 10 min, the reaction mixture was stirred for another hour at 0° and then at room temperature for 4 hours. Dichloromethane and the mixture was washed with water (2× 50 ml) and the combined aqueous washings were extracted with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining 4.3 g (100% yield) of the crude nelfinavir.

(iii) hydride NAT the Oia, 80% oil suspension, pre-washed hexane (3× 10 ml), (0.7 g, 29 mmol) in dry dimethylformamide (50 ml) via cannula was added a solution of 2-(2-naphthoxy)ethanol (3,76 g, 20.0 mmol) in dry dimethylformamide (50 ml). The addition was accompanied by evolution of gas, the reaction mixture was stirred at room temperature for 90 minutes Mesilate obtained above in stage (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (3 min) through the cannula to the reaction mixture. The resulting reaction mixture was heated to 90° C overnight and then cooled at room temperature. The reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (300 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 7.8 g of a yellow oil, which was dissolved in ether (100 ml) and treated with saturated solution of Hcl in ether (100 ml). The resulting precipitate was collected, partially dissolved in water (200 ml) and the heterogeneous aqueous solution was extracted with ether (2× 100 ml). The remaining insoluble material was collected and recrystallized in boiling ethanol (75 ml), receiving the first batch of the desired product. The acidic aqueous solution was podlachian what to pH 10 with 50% aqueous NaOH solution and was extracted with ether (2× 50 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuum, obtaining 1.6 g of the crude free aminoether. The product was purified by chromatography on silica gel 60 (70-230 mesh), using as eluent a mixture of ethyl acetate - dichloromethane, and obtained 0.73 g of pale yellow oil. Then the purified free base was dissolved in ether (50 ml) and was turned into monohydrochloride salt by adding a saturated solution of Hcl in ether (50 ml).

A white precipitate was collected and recrystallized in hot ethanol (40 ml), receiving a second party. The merger of the two parties received 1,03 g specified in the connection header, TPL 235-237° having the elemental composition indicated in table 1.

Example 5

Monohydrochloride (± )-TRANS-[2-(4-morpholinyl)-1-[2-(4-bromophenoxy)ethoxy)]]cyclohexane

(Compound No. 5)

(i) the Original TRANS-aminocyclohexanol receive according to example 1.

(ii) To a cooled (0° (C) the solution (± )-TRANS-[2-(4-morpholinyl)]cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (50 ml) via cannula solution was added methanesulfonamide (of 1.55 ml, 20 mmol) in dichloromethane (50 ml). The addition was completed within 10 min, the reaction mixture was stirred for another hour at 0° and then at room temperature for 4 hours. chlormadinone the mixture was washed with water (2× 50 ml) and the combined aqueous wash was extracted again with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining of 3.95 g (92% yield) of the crude nelfinavir.

(iii) To sodium hydride, 80% oil suspension, pre-washed hexane (3× 10 ml), (0,63 g, 26 mmol) in dry dimethylformamide (50 ml) via cannula was added a solution of 2-(4-bromophenoxy)ethanol (4,34 g, 20.0 mmol) in dry dimethylformamide (50 ml). The addition was accompanied by evolution of gas, the reaction mixture was stirred at room temperature for 90 minutes Mesilate obtained above in stage (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (3 min) through the cannula to the reaction mixture. The reaction mixture was heated to 90° C for 90 min and then the temperature was lowered to 40° and the reaction mixture was stirred over night. The reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (300 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 8,35 g of yellow oil, which was dissolved in ether (100 ml) and treated with saturated solution of Hcl in ether (100 ml). The resulting white solid prophetic the TWT was collected and recrystallized in boiling ethanol (150 ml), getting 3.7 g (54% yield) of pure indicated in the title compound, TPL 228-230° having the elemental composition indicated in table 1.

Example 6

Monohydrochloride (± )-TRANS-[2-(4-morpholinyl)-1-(3,4-dimethoxyphenoxy)]cyclohexane

(Compound No. 6)

(i) the Original TRANS-aminocyclohexanol receive according to Example 1.

(ii) To a cooled (0° (C) the solution (± )-TRANS-[2-(4-morpholinyl)]cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (50 ml) via cannula solution was added methanesulfonamide (of 1.55 ml, 20 mmol) in dichloromethane (50 ml). The addition was completed within 10 min, the reaction mixture was stirred for another hour at 0° and then at room temperature for 4 hours. Dichloromethane and the mixture was washed with water (2× 50 ml) and the combined aqueous wash was extracted again with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining 4,18 g of the crude nelfinavir.

(iii) To sodium hydride, 80% oil suspension, pre-washed hexane (3× 10 ml), (0.64 g, 27 mmol) in dry dimethylformamide (50 ml) via cannula solution was added 3,4-dimethoxyphenethyl alcohol (of 3.64 g, 20.0 mmol) in dry dimethylformamide (50 ml). The addition was accompanied by evolution of gas, the reaction mixture was stirred at room is the temperature for 90 minutes Mesilate obtained above in stage (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (3 min) through the cannula to the reaction mixture. The reaction mixture was heated to 80° C for 90 min and then the temperature was lowered to 40° and stirring continued over night. The reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (300 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 7,18 g of the crude product, which was dissolved in ether (100 ml) and treated with saturated solution of Hcl in ether (100 ml). The solvent is evaporated in vacuo, and the residual oil washed with water (100 ml) and was extracted with ether (2× 50 ml). The aqueous layer was podslushivaet to pH 10 with 50% aqueous NaOH solution and was extracted with ether (2× 50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum. The crude product was purified by chromatography on silica gel 60 (70-230 mesh), using as eluent a mixture of ethyl acetate and dichloromethane (1:1 vol./vol.), and got 2.8 g of a pale yellow oil. The free base was dissolved in ether (80 ml) and turned in monohydrochloride salt by adding a saturated solution of Hcl in ether (80 ml). The adhesive on the of ADOC collected, was dissolved in minimum amount of ethanol was added a large excess of ether, initiating crystallization of 2.24 g (36% yield) specified in the connection header, TPL 148-150° having the elemental composition indicated in table 1.

Example 7

Monohydrochloride (± )-TRANS-[2-(1-pyrrolidinyl)-1-(1-naphthenate)]cyclohexane

(Compound No. 7)

(i) Pyrrolidine (25 ml, 300 mmol), cyclohexene oxide (30 ml, 297 mmol) and water (10 ml) was heated under reflux for 3 hours. GC analysis showed that the reaction was completed. The cooled mixture was distributed between saturated NaOH solution (10 ml) and ether (150 ml). The aqueous layer was washed with ether (2× 100 ml) and the combined ether layers were dried over sodium sulfate. The ether was removed in vacuum, obtaining a remainder of a yellow oil. The crude product was purified by vacuum distillation (BP. 66-69° under full vacuum)to give a clear liquid (43,9 g). Yield 87%.

(ii) To a cooled (0° (C) the solution (± )-TRANS-[2-(pyrrolidinyl)]cyclohexanol (2,74 g, 16.2 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (50 ml) via cannula solution was added methanesulfonamide (of 1.55 ml, 20 mmol) in dichloromethane (50 ml). The addition was completed within 10 min, the reaction mixture was washed with water (2× 50 ml) and the combined aqueous washings were extracted again with dichloromethane (50 ml). United organic the ski layers were dried over sodium sulfate and concentrated in vacuum, getting 3,24 g of the crude nelfinavir.

(iii) To sodium hydride, 80% oil suspension, pre-washed hexane (3× 10 ml), (0.64 g, 27 mmol) in dry dimethylformamide (50 ml) via cannula solution was added 1-naphtenate (of 3.64 g, 20.0 mmol) in dry dimethylformamide (50 ml). The addition was accompanied by evolution of gas, the reaction mixture was stirred at room temperature for 90 minutes Mesilate obtained above in stage (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (3 min) through the cannula to the reaction mixture. The reaction mixture was heated to 80° C for 90 min and then the temperature was lowered to 40° and the mixture was stirred over night. The reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (300 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 9.00 g of the crude product, which was dissolved in ether (50 ml) and treated with saturated solution of Hcl in ether (50 ml). The solvent is evaporated in vacuo, and the residual oil washed with water (100 ml) and was extracted with ether (2× 50 ml). The aqueous layer was podslushivaet to pH 10 with 50% aqueous NaOH solution and was extracted with ether (2× 50 ml). The combined organic layers sushi is over sodium sulfate and concentrated in vacuum. The crude product was purified by chromatography on silica gel 60 (70-230 mesh), using as eluent a mixture of atimetool and chloroform (2:8.vol.). Free aminoether was partially dissolved in ether (80 ml), the insoluble material was filtered and then the filtrate was added a saturated solution of Hcl in ether (80 ml). The solvent is evaporated in vacuo, the residue was dissolved in acetone, and adding the aliquot of ether induced slow crystallization. Collected 2 party specified in the title compound (0.88 g), TPL 103-105° having the elemental composition indicated in table 1.

Example 8

Monohydrochloride (± )-TRANS-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophene-3-yl)ethoxy)]cyclohexane

(Compound No. 8)

(i) the Original TRANS-aminocyclohexanol receive according to Example 1.

(ii) To a cooled (0° (C) the solution (± )-TRANS-[2-(4-morpholinyl)]cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (50 ml) via cannula solution was added methanesulfonamide (of 1.55 ml, 20 mmol) in dichloromethane (50 ml). The addition was completed within 5 min, the reaction mixture was stirred for another hour at 0° and then at room temperature for 3 hours. The reaction mixture was washed with water (3× 30 ml) and the combined aqueous washings were extracted with dichloromethane (50 ml). The combined organic layers were dried n the d sodium sulfate and concentrated in vacuum, getting a 5.25 g of the crude nelfinavir.

(iii) To sodium hydride, 80% oil suspension, pre-washed hexane (3× 10 ml), (0,60 g, 25 mmol) in dry dimethylformamide (50 ml) via cannula was added a solution of 2-(benzo[b]thiophene-3-yl)ethanol (of 3.56 g, 20.0 mmol) in dry dimethylformamide (50 ml). The addition was accompanied by evolution of gas, the reaction mixture was stirred at room temperature for 3 hours. Mesilate obtained above in stage (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (2 min) through the cannula to the reaction mixture. The reaction mixture was heated to 75° C for 2 hours, then the temperature was lowered to 65° and stirring continued over night. The reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (300 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 7.7 g of oil which was dissolved in ether (100 ml) and treated with saturated solution of Hcl in ether (100 ml). Oil besieged from the solution, the solvent is evaporated in vacuum and the resulting crude cleaners containing hydrochloride salt was dissolved in water (200 ml). The acidic aqueous solution was extracted with ethyl ether (2× 100 ml) and then Podlachia and to pH 10 with 50% aqueous sodium hydroxide solution. Basic aqueous solution was extracted with ethyl ether (3× 100 ml), the combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining a remainder 3,30 g of the crude free aminoether. The crude product was purified by chromatography on silica gel 60 (70-230 mesh), using as eluent a mixture of ethyl acetate and dichloromethane (1:1 vol./vol.), to obtain the free base. The product was dissolved in ethyl ether (100 ml) and was turned into monohydrochloride salt by adding a saturated solution of Hcl in ethyl ether (100 ml). The solvent is evaporated in vacuum and the residue was dissolved in a minimum amount of boiling methanol, while cooling the first batch (0.7 g) of crystalline product. Adding diethyl ether to methanol filtrate was awarded a second party (0.55 g). Both parties were United, while receiving 1,25 g specified in the connection header, TPL 158-160° having the elemental composition indicated in table 1.

Example 9

Monohydrochloride (± )-TRANS-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophene-4-yl)ethoxy)]cyclohexane

(Compound No. 9)

(i) the Original TRANS-aminocyclohexanol receive according to Example 1.

(ii) To a cooled (0° (C) the solution (± )-TRANS-[2-(4-morpholinyl)]cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (50 ml) via cannula on balali solution methanesulfonanilide (of 1.55 ml, 20 mmol) in dichloromethane (50 ml). The addition was completed within 5 min, the reaction mixture was stirred for another hour at 0° and then at room temperature for 3 hours. The reaction mixture was washed with water (2× 30 ml) and the combined aqueous washings were extracted with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining 4,24 g of the crude nelfinavir.

(iii) To sodium hydride, 80% oil suspension, pre-washed hexane (3× 10 ml), (0,60 g, 25 mmol) in dry dimethylformamide (50 ml) via cannula was added a solution of 2-(benzo[b]thiophene-4-yl)ethanol (of 3.56 g, 20.0 mmol) in dry dimethylformamide (50 ml). The addition was accompanied by evolution of gas, the reaction mixture was stirred at room temperature for 3 hours. Mesilate obtained above in stage (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (2 min) through the cannula to the reaction mixture. The reaction mixture was heated to 85° C for 2 hours, then the temperature was lowered to 40° and the reaction mixture was stirred over night. The reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (300 ml) and dried over with what LifeCam sodium. Evaporation of the solvent in vacuo gave an 8.2 g of oil which was dissolved in ether (100 ml) and treated with saturated solution of Hcl in ether (100 ml). The oil was besieged, and the solvent evaporated in vacuum and the resulting crude cleaners containing hydrochloride salt was dissolved in water (200 ml). The acidic aqueous solution was extracted with ethyl ether (2× 100 ml) and then was podslushivaet to pH 10 with an aqueous solution of sodium hydroxide (50% weight/volume). Basic aqueous solution was extracted with ethyl ether (3× 100 ml), the combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining a remainder of 3.0 g of the crude free aminoether. The crude product was purified by chromatography on silica gel 60 (70-230 mesh), using as eluent a mixture of ethyl acetate - dichloromethane (1:1 vol./vol.), and received the pure free base. The product was dissolved in ethyl ether (50 ml) and transferred to monohydrochloride salt by adding a saturated solution of Hcl in ethyl ether (50 ml). The solvent is evaporated in vacuo, and the residue was dissolved in a minimal amount of cold ethanol, and adding ether initiated the formation of crystals (1,17 g), TPL 178-180° having the elemental composition indicated in table 1.

Example 10

Monohydrochloride (± )-TRANS-[2-(4-morpholinyl)-1-(3-bromophenetole)]cyclohexane

(Compound No. 10)

(i) the Original TRANS-aminocyclohexanol receive according to Example 1.

(ii) To a cooled (0° (C) the solution (± )-TRANS-[2-(4-morpholinyl)]cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (50 ml) via cannula solution was added methanesulfonamide (of 1.55 ml, 20 mmol) in dichloromethane (50 ml). The addition was completed within 5 min, the reaction mixture was stirred for another hour at 0° and then at room temperature for 3 hours. The reaction mixture was washed with water (2× 30 ml) and the combined aqueous washings were extracted with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining of 5.4 g of the crude nelfinavir.

(iii) To sodium hydride, 80% oil suspension, pre-washed hexane (3× 10 ml), (0,60 g, 25 mmol) in dry dimethylformamide (50 ml) via cannula was added a solution of 3-bromination alcohol (4.0 g, 20.0 mmol) in dry dimethylformamide (50 ml). The addition was accompanied by evolution of gas, the reaction mixture was stirred at room temperature for 3 hours. Mesilate obtained above in stage (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (2 min) through the cannula to the reaction mixture. The reaction mixture was heated to 85° C for 2 hours, then the temperature is at reduced up to 45° C, and the reaction mixture was stirred over night. The reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (300 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 8.0 g of oil which was dissolved in ether (100 ml) and treated with saturated solution of Hcl in ether (100 ml). Oil besieged, the solvent is evaporated in vacuum and the resulting crude cleaners containing hydrochloride salt was dissolved in water (200 ml). The acidic aqueous solution was extracted with ethyl ether (2× 100 ml) and then was podslushivaet to pH 10 with an aqueous solution of sodium hydroxide (50% weight/volume). Basic aqueous solution was extracted with ethyl ether (3× 100 ml), the combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining a remainder of 2.9 g of the crude free aminoether. The crude product was purified by chromatography on silica gel 60 (70-230 mesh), using as eluent a mixture of ethyl acetate - dichloromethane (1:1 vol./vol.), and received the pure free base. The product was dissolved in ethyl ether (50 ml) and was turned into monohydrochloride salt by adding a saturated solution of Hcl in ethyl ether (50 ml). The solvent is evaporated in vacuo, and the residue was dissolved in minimum the amount of cold ethanol, and adding ether initiated the formation of crystals (0,53 g), TPL 145-148° having the elemental composition indicated in table 1.

Example 11

Monohydrochloride (± )-TRANS-[2-(4-morpholinyl)-1-(2-bromophenetole)cyclohexane

(Compound No. 11)

(i) the Original TRANS-aminocyclohexanol receive according to Example 1.

(ii) To a cooled (0° (C) the solution (± )-TRANS-[2-(4-morpholinyl)]cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (50 ml) via cannula solution was added methanesulfonamide (of 1.55 ml, 20 mmol) in dichloromethane (50 ml). The addition was completed within 5 min, the reaction mixture was stirred for another hour at 0° and then at room temperature for 3 hours. The reaction mixture was washed with water (2× 30 ml) and the combined aqueous wash was extracted again with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining 5.9 g of the crude nelfinavir.

(iii) To sodium hydride, 80% oil suspension, pre-washed hexane (3× 10 ml), (0,60 g, 25 mmol) in dry dimethylformamide (50 ml) via cannula was added a solution of 2-bromophenethylamine alcohol (4.0 g, 20.0 mmol) in dry dimethylformamide (50 ml). The addition was accompanied by evolution of gas, the reaction mixture was stirred at room temperature during the 3 hours. Mesilate obtained above in stage (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (2 min) through the cannula to the reaction mixture. The reaction mixture was heated to 85° C for 2 hours, then the temperature was lowered to 45° and the reaction mixture was stirred over night. The reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (300 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave a 8.4 g of oil which was dissolved in 1.0 M Hcl aqueous solution (50 ml), the volume was brought to 200 ml water and the pH was brought to pH 2 with 1.0 M aqueous solution of Hcl. The acidic aqueous solution was extracted with ethyl ether (3× 100 ml) and then was podslushivaet to pH 10 with 50% aqueous sodium hydroxide solution. Basic aqueous solution was extracted with ethyl ether (3× 100 ml), the combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining a remainder of 2.8 g of the crude free aminoether. The crude product was purified by chromatography on silica gel 60 (70-230 mesh), using as eluent a mixture of ethyl acetate - dichloromethane (1:1 vol./vol.), and received the pure free base. The product was dissolved in ethyl ether (50 ml) and turned monohydrochloride salt by adding a saturated solution of Hcl in ethyl ether (50 ml). The solvent is evaporated in vacuo, and the residue was dissolved in a minimal amount of cold ethanol, and adding ether initiated the formation of crystals, which were collected in two portions (0.74 g), TPL 140-142° having the elemental composition indicated in table 1.

Example 12

Monohydrochloride (± )-TRANS-[2-(4-morpholinyl)-1-(3-(3,4-acid)-1-propoxy)]cyclohexane

(Compound No. 12)

(i) the Original TRANS-aminocyclohexanol receive according to Example 1.

(ii) To a cooled (0° (C) the solution (± )-TRANS-[2-(4-morpholinyl)]cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (50 ml) via cannula solution was added methanesulfonamide (of 1.55 ml, 20 mmol) in dichloromethane (50 ml). The addition was completed within 10 min, the reaction mixture was stirred for another hour at 0° and then at room temperature for 4 hours. Dichloromethane and the mixture was washed with water (2× 50 ml) and the combined aqueous wash was extracted again with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining the crude mesilate.

(iii) To sodium hydride, 80% oil suspension, pre-washed hexane (3× 10 ml), (0.6 g, 27 mmol) in dry dimethylformamide (50 ml) via cannula was added a solution of 3-(3,4-acid)-1-propanol (3,93 is, 20.0 mmol) in dry dimethylformamide (50 ml). The addition was accompanied by evolution of gas, the reaction mixture was stirred at room temperature for 90 minutes Mesilate obtained above in stage (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (3 min) through the cannula to the reaction mixture. The reaction mixture was heated to 90° C for 90 min and then the temperature was lowered to 45° and stirring continued over night. The reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (300 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 8.5 g of the crude product, which was dissolved in 15% aqueous solution of Hcl (200 ml) and was extracted with ether (2× 100 ml). The aqueous layer was podslushivaet to pH 10 with 50% aqueous NaOH solution and was extracted with ether (2× 100 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum. The crude product was purified by chromatography on silica gel 60 (70-230 mesh), using as eluent a mixture of ethyl acetate and dichloromethane (1:1 vol./vol.), and got free base which was dissolved in ether (80 ml) and turned in monohydrochloride salt by adding a saturated RA the creators Hcl in ether (80 ml). The sticky precipitate was collected, dissolved in a minimum amount of warm ethanol was added a large excess of ether to initiate crystallization specified in the connection header, TPL 175-177° having the elemental composition indicated in table 1.

Example 13

Monohydrochloride (± )-TRANS-[2-[bis(2-methoxyethyl)amino]-1-(2-naphthenate)]cyclohexane

(Compound No. 13)

(i) Bis-(2-methoxyethyl) amine (25 ml, 169 mmol) and cyclohexene oxide (17,2 ml, 170 mmol) were mixed in water (5 ml) and the resulting mixture was heated under reflux for 30 hours. The cooled reaction mixture was distributed between 10% aqueous NaOH solution (200 ml) and diethyl ether (200 ml). The aqueous layer was twice extracted with additional diethyl ether (2× 100 ml), the combined organic layers were washed with water (8 ml) and dried over sodium sulfate. The solvent is evaporated in vacuum, obtaining a remainder of the crude product, which was subjected to vacuum distillation, obtaining of 26.4 g of purified colorless oil.

(ii) To a cooled (0° (C) the solution (± )-TRANS-2-[bis(2-methoxyethyl)amino] cyclohexanol (4,63 g, 20.00 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (50 ml) via cannula solution was added methanesulfonamide (of 1.55 ml, 20.00 mmol) in dichloromethane (50 ml). The addition was completed within 5 min, the reaction mixture was stirred in ECENA the next hour at 0° C and then at room temperature for 4 hours. The reaction mixture was washed with water (2× 30 ml) and the combined aqueous wash was extracted again with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, getting to 4.87 g of the crude nelfinavir.

(iii) To sodium hydride, 80% oil suspension, pre-washed hexane (3× 10 ml), (0.6 g, 25,00 mmol) in anhydrous dimethylformamide (50 ml) via cannula was added a solution of 2-naphtenate (3.4 g, 20.00 mmol) in anhydrous dimethylformamide (50 ml). The addition was accompanied by bubbling hydrogen, the reaction mixture was stirred at room temperature for 90 minutes Mesilate obtained above in stage (ii)was dissolved in dry dimethylformamide (50 ml) and the resulting solution was rapidly added (3 min) through the cannula to the reaction mixture. The reaction mixture was heated to 90° C for 2 hours, then the temperature was lowered to 40° and the reaction mixture was stirred over night. The reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts were washed with saturated aqueous solution of sodium chloride (300 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 8.1 g of oil which was dissolved in 1 M aqueous rest the re Hcl (50 ml) and the volume was brought to 200 ml with water. The acidic aqueous solution was extracted with diethyl ether (2× 100 ml) and then was podslushivaet to pH 10 with 50% aqueous sodium hydroxide solution. Basic aqueous solution was extracted with ethyl ether (2× 100 ml), the combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining a remainder of 3.58 g of the crude free aminoether. The crude product was purified by chromatographic column on silica gel 60, 70-230 mesh, obtained from BDH Inc., using as eluent a mixture of methanol and dichloromethane (2:8.vol.), and received the pure free base. The product was dissolved in diethyl ether (50 ml) and was turned into monohydrochloride salt by adding a solution of Hcl in ether (50 ml). The solvent is evaporated in vacuum, and received 0.75 g specified in the connection header (not recrystallized).

Example 14

Monohydrochloride (1R,2R)/(1S,2S)-2-(4-morpholinyl)-1-(3,4-dichlorophenoxy)cyclohexane

(Compound No. 14)

In General, the approach used for the synthesis of this compound, similar to those shown in figure 1.

(i) (1R,2R)/(1S,2S)-2-(4-morpholinyl)cyclohexanol: a mixture of cyclohexene oxide (206,5 ml, 2 mol, 98%) and research (175 ml, 2 mol) in water (60 ml) was heated under reflux for 3.5 hours. To the reaction mixture was added morpholine (5.3 ml), then the mixture was heated under reflux for another 1.5 h for C is the conclusion of the reaction. Then the cooled reaction mixture was distributed between 40% aqueous NaOH solution (100 ml) and diethyl ether (200 ml). The aqueous layer was separated from the organic layer and was twice extracted with additional diethyl ether (2× 100 ml). The combined organic extracts were dried over sodium sulfate and the solvent evaporated in vacuum. Vacuum distillation gave 342,3 g (92.4 per cent) specified in the connection header.

(ii) To a cooled (0° (C) to a solution of (1R,2R)/(1S,2S)-2-(4-morpholinyl)cyclohexanol (40,76 g, 0.22 mol) and triethylamine (36,60 ml, 0.26 mol) in dichloromethane (400 ml) was added dropwise a solution of methanesulfonamide (20,53 ml, 0.26 mol) in dichloromethane (50 ml). The reaction mixture was stirred at 0° C for 45 min and then at room temperature for 3 hours. Then the reaction mixture was washed with water (2× 100 ml); the combined re-washing was extracted with dichloromethane (100 ml). The combined organic extracts were dried over sodium sulfate and the solvent evaporated in vacuum, obtaining the crude mesilate, suitable for the next stage without any further purification.

(iii) 3,4-Dichloroethylenes alcohol: To a solution of lithium aluminum hydride (7,79 g, 195 mmol) in anhydrous diethyl ether (435 ml) slowly via addition funnel for solids was added in powder form 3,4-dichlorophenoxy acid is the (27,20 g, 130 mmol). After complete addition, the reaction mixture was heated under reflux for 12 hours. The reaction was suppressed by careful addition of a saturated aqueous solution of sodium sulfate (20 ml), then the resulting insoluble material was filtered and the filtrate was concentrated in vacuum, obtaining 25,09 g of the desired alcohol.

(iv) To NaH (6,00 g, 0.2 mol, 80% dispersion in oil) in anhydrous ethylene glycol dimethyl ether (200 ml) was added a solution of 3,4-dechlorination alcohol (38,87 g, 0.2 mol) in anhydrous ethylene glycol dimethyl ether (100 ml). The resulting mixture was stirred for 3 hours at ambient temperature in an argon atmosphere.

(v) Mesilate (ii) in anhydrous ethylene glycol dimethyl ether (100 ml) was quickly added to the alkoxide (iv) and the resulting reaction mixture was immediately heated under reflux for 16 hours. To the cooled reaction mixture was added water (200 ml) and the organic solvent evaporated in vacuum. The resulting aqueous solution was then diluted with water (200 ml) and the pH was brought to pH 1.5 to 10% aqueous solution of Hcl. The acidic aqueous layer was extracted with diethyl ether (500 ml) to remove unreacted 3,4-dechlorination alcohol. Further alkalinization of the aqueous layer with 5 M aqueous solution of NaOH to a pH of 5.7 with subsequent extrac the Oia diethyl ether gave the crude specified in the title compound, contaminated with some remaining nelfinavir (ii). The solvent from the organic extract with a pH of 5.7 evaporated in vacuo, then the residue was heated under reflux in a mixture of ethanol - water (1:1 vol./about., 200 ml) in the presence of sodium hydride (4.12 g, 0.1 mol) for 2 hours to hydrolyze the remaining nelfinavir. The cooled reaction mixture was diluted with water (300 ml) and the organic solvent evaporated in vacuum. the pH of the remaining aqueous solution was brought to a pH of 5.7 6 M aqueous solution of Hcl, followed by extraction with diethyl ether (700 ml). The organic extract was concentrated in vacuum, obtaining the net aminoether. Then the remaining product was distributed between 1 M aqueous solution of Hcl (300 ml) and dichloromethane (300 ml). The acidic aqueous solution was twice extracted with additional dichloromethane (2× 300 ml). The combined organic layers were dried over sodium sulfate, the solvent was evaporated in vacuum and the residue was recrystallized from a mixture of ethanol - hexane (3:7 vol./about., 700 ml), receiving an average of 49.3 g specified in the title compound, having the elemental composition indicated in table 1.

Example 15

Monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(1-naphthenate)cyclohexane

(Compound No. 15)

In the synthesis of compound No. 15 are guided by the sequence of reactions shown in figure 4A and figures is 4V, the synthesis is described in detail below.

(i) N-Butyloxycarbonyl-3-pyrrolidino: To a cooled (-60° (C) to a solution of (R)-(+)-3-pyrrolidinone (20,0 g, 98%, 224,9 mmol) and triethylamine (79,2 ml, 99%, 562 mmol) in dichloromethane (200 ml) was added dropwise a solution of benzylbromide cases (33.8 ml, 95%, 224,9 mmol) in dichloromethane (80 ml). After completion of the addition, which lasted for 45 min, the reaction mixture (yellow suspension) was allowed to warmed to room temperature and was stirred in an argon atmosphere at room temperature overnight. Then the reaction mixture was extinguished 1M aqueous solution of Hcl (350 ml) and the collected organic layer. The acidic aqueous layer was extracted with dichloromethane (2× 150 ml) and the combined organic layers were dried over sodium sulfate. Evaporation of the solvent in vacuo gave 59,62 g of pale yellow oil, which is then kept under high vacuum for 15 min, receiving 58,23 g (17% of the excess of theoretically calculated yield) of the crude indicated in the title compound, suitable for the next stage without any further purification.

(ii) N-Butyloxycarbonyl-3-pyrrolidine: To a cooled (-60° (C) the solution oxalicacid (23 ml, 98%, 258,6 mmol) in dichloromethane (400 ml) was added dropwise a solution of anhydrous dimethyl sulfoxide (36,7 ml, 517,3 mmol) in dichloromethane (20 ml) with such speed, the button to keep the temperature below -40° C. Then the reaction mixture was stirred at -60° C for 15 minutes and Then was added dropwise a solution of N-benzyloxycarbonyl-3-pyrrolidinone (58,22 g, stage (i), not more 224,9 mmol) in dichloromethane (80 ml), keeping the temperature of the reaction mixture below -50° C. Then the reaction mixture was stirred at -60° C for 30 min before adding triethylamine (158,3 ml, 99%, 1,125 mol). The resulting mixture was allowed to warmed to room temperature and then washed with water (600 ml), 1 M aqueous solution of Hcl (580 ml) and water (400 ml). The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining in the rest of 54.5 g of amber oil, which is then kept under high vacuum with stirring at room temperature for 25 min, and received 52,08 g (5.6% of the excess of theoretically calculated yield) of the crude indicated in the title compound, suitable for the next stage without any further purification.

(iii) 7-Benzyloxycarbonyl-1,4-dioxa-7-azaspiro[4.4]nonan: a Mixture of N-benzyloxycarbonyl-3-pyrrolidinone (51,98 g, stage ii, not more 224,9 mmol) and ethylene glycol (18.8 ml, 99+%, 337,4 mmol) in toluene (180 ml) in the presence of catalytic amounts of monohydrate para-toluenesulfonic acid (1.04 g, 5.4 mmol) was heated under reflux in an apparatus of the Dean and stark within 16 hours of the century Then the reaction mixture was diluted with additional toluene (250 ml) and washed with saturated aqueous sodium bicarbonate (150 ml) and saturated aqueous sodium chloride (2× 150 ml). The combined aqueous layers was extracted again with toluene (100 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum, obtaining in the rest of 79.6 g of a dark oil. The crude product was dissolved in ethanol (500 ml) and passed through a layer of activated charcoal (80 g), discoloring solution. The coal is washed with additional ethanol (1000 ml) and toluene (500 ml). The filtrate was concentrated in vacuo and then kept under high vacuum for 1 hour, receiving 63,25 g (6.8% of the excess of theoretically calculated yield) of the crude indicated in the title compound, suitable for the next stage without any further purification.

(iv) 1,4-dioxa-7-azaspiro[4.4]nonan: a Mixture of 7-benzyloxycarbonyl-1,4-dioxa-7-azaspiro[4.4]nonane (34,79 g, stage iii, not more 123,7 mmol) and 10% Pd-C (13,9 g) in ethanol (90 ml) was subjected to hydrogenolysis (60 pounds per square inch, of 0.41 MPa) in shaking the Parr apparatus at room temperature for 1.5 hours. The catalyst was filtered, the solvent evaporated in vacuo, and the residue was passed by pumping under high vacuum for 20 min, receiving 15,86 g u is asanoha the title compound (yield of 99.3%).

(v) (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol: a mixture of 1,4-dioxa-7-azaspiro[4.4]nonane (23,54 g, stage iv, not more than 182 mmol), cyclohexene oxide (22,6 ml, 98%, 219 mmol) and water (7.8 ml) was heated at 80° C for 2 hours. Then the reaction mixture was distributed between 40% aqueous solution of sodium hydroxide (60 ml) and diethyl ether (120 ml). Basically the aqueous layer was twice extracted with additional diethyl ether (2× 120 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuum. Then the residue was passed by pumping under high vacuum at 50° C for 1 hour under stirring to remove excess cyclohexene oxide) and received 32,79 g of the crude indicated in the title compound (yield 79.3 percent).

(vi) To a cooled (0° (C) to a solution of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol (27,47 g, 120 mmol, stage v) and triethylamine (15,86 g, 156 mmol) in dichloromethane (240 ml) was added dropwise methanesulfonanilide (18,23 g, 156 mmol). The reaction mixture was stirred at 0° C for 45 min and then at room temperature for 3 hours. Then the reaction mixture was washed with a mixture of water - saturated aqueous solution of sodium bicarbonate (1:1 vol./about., 120 ml). Wash layers were collected and re-extracted with dichloromethane (120 ml). Obyedinennaya extracts were dried over sodium sulfate, the solvent is evaporated in vacuo, and the residue was passed by pumping under high vacuum for 4 hours, at the output received raw mesilate, suitable for the next stage without any further purification.

(vii) To sodium hydride (4,32 g, 144 mmol)suspended in anhydrous ethylene glycol dimethyl ether (80 ml), was added a solution of 1-naphtenate (25,31 g, 144 mmol) in anhydrous ethylene glycol dimethyl ether (80 ml). Then the reaction mixture was stirred at room temperature for 4 hours.

(viii) (1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(1-naphthenate)cyclohexane: Solution nelfinavir (vi) in anhydrous ethylene glycol dimethyl ether (80 ml) was quickly added to the alkoxide (vii) and the resulting reaction mixture was immediately heated to boiling under reflux in an argon atmosphere for 66 hours. The cooled reaction mixture is extinguished with water (200 ml) and the organic solvent evaporated in vacuum. The remaining aqueous solution was diluted with water (500 ml) and acidified with 10% aqueous Hcl solution to a pH of 0.5. The acidic aqueous layer was extracted with diethyl ether (2× 500 ml)to extract unreacted 1-naphthenates. the pH of an aqueous solution brought to a pH of 4.8 5 M aqueous solution of NaOH and then was extracted with diethyl ether (600 ml). Then the aqueous solution was podslushivaet D. the pH to 5.7 and was extracted with diethyl ether (600 ml). The same procedure was repeated at pH 6.5 and 12.1. Analysis of different essential extracts using gas chromatography showed that organic extracts at pH 4,8; of 5.7 and 6.5 contain specified in the title compound, whereas the ether extract at pH of 12.1 contains only unidentified inclusions. The organic extracts obtained at pH 4,8; of 5.7 and 6.5, were combined and dried over sodium sulfate. The solvent is evaporated in vacuo, and the residue was passed by pumping under high vacuum for 3.5 hours, and received 35,82 g (75% yield) specified in the title compound, suitable for the next stage without any further purification.

(ix) monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(1-naphthenate)cyclohexane: a Solution of (1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(1-naphthenate)cyclohexane (13,73 g, 36,0 mmol, stage vi) with 6 M aqueous solution of Hcl (50 ml) in 2-butanone (200 ml) was distilled under reflux for 12 hours. Butanone evaporated in vacuum and the remaining aqueous solution was brought to 250 ml with water. The aqueous solution was extracted with diethyl ether (2× 200 ml) and then dichloromethane (2× 200 ml). The combined dichloromethane extracts were dried over sodium sulfate, and the solvent evaporated in vacuum. The remaining oil was subjected to azeotropic drying with toluene. The obtained adhesive product energy is a rule stirred overnight in diethyl ether (500 ml) rubbing from time to time to initiate crystallization of the reaction product. The resulting solid material was collected and dissolved in a small amount of dichloromethane (~10 ml), the addition of a large amount of diethyl ether (~400 ml) induced recrystallization. The solid material was collected, dried in vacuum for 3 hours and got 9.3 g (76% yield) specified in the title compound, having the elemental composition indicated in table 1.

Example 16

Monohydrochloride (1R,2R)/(1S,2S)-2-(1-acetylpiperidine)-1-(2-naphthenate)cyclohexane

(Compound No. 16)

Compound No. 16 was obtained according to the procedure similar to the procedure shown on figure 1, and described in more detail in Example 14.

(i) (1R,2R)/(1S,2S)-2-(1-acetylpiperidine)-1-cyclohexanol: a mixture of 1-acetylpiperidine (5 g, 39 mmol) and cyclohexene oxide (3,95 ml, 39 mmol) in water (1.2 ml) was heated under reflux for 16 hours. The cooled reaction mixture was distributed between 40% aqueous NaOH solution (20 ml) and diethyl ether (2× 20 ml). The combined organic layers were dried over sodium sulfate, and the solvent evaporated in vacuum, obtaining 7,63 g specified in the title compound as white crystals (yield 87%).

(ii) To a cooled (0° (C) to a solution of (1R,2R)/(1S,2S)-2-(1-acetylpiperidine)-1-cyclohexanol (3,65 g, 16.2 mmol) and triethylamine (3.4 ml, 24 mmol) in dichloromethane (50 ml) was added dropwise a solution of methanesulfonamide (1.5 ml, 20 mmol) in dichloromethane (50 ml). The reaction mixture was stirred at 0° C for one hour and then allowed her to be heated to the ambient temperature. Then the reaction mixture was washed with water (2× 50 ml) and the combined re-washing was extracted with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and the solvent evaporated in vacuum, obtaining the crude mesilate, suitable for the next stage without any further purification.

(iii) To a suspension of sodium hydride (0.8 g, 24 mmol), previously washed with genusname (2× 15 ml) in anhydrous dimethylformamide (50 ml), was added a solution of 2-naphtenate in anhydrous dimethylformamide (50 ml). The resulting mixture was stirred at room temperature for 30 minutes

(iv) Monohydrochloride (1R,2R)/(1S,2S)-2-(1-acetylpiperidine)-1-(2-naphthenate)cyclohexane: solution nelfinavir (ii) in anhydrous dimethylformamide (50 ml) was quickly added to alkoxide mixture (iii) and the resulting mixture was heated up to 80° C for 16 hours. The cooled reaction mixture was poured into ice water (800 ml) and was extracted with ethyl acetate (3× 200 ml). The combined organic extracts re-washed with brine (200 ml) and the solvent evaporated in vacuum. In the remaining oil was poured in water (80 ml) and obtained in accordance with the ATA aqueous solution was acidified to pH 2 with 6 M aqueous Hcl. The acidic aqueous solution was extracted with diethyl ether (3× 40 ml)to extract unreacted 2-naphthenates. the pH of the aqueous layer was brought to pH 10 with 50% aqueous NaOH solution and was extracted with diethyl ether (3× 40 ml). The combined organic extracts were dried over sodium sulfate and the solvent evaporated in vacuum, obtaining the crude free aminoether. Purification using chromatography on a column of silica gel using as eluent a mixture of ethyl acetate - dichloromethane (1:1 vol./about.) gave the pure free base. The transformation in cleaners containing hydrochloride salt was performed using a solution of Hcl in ether followed by recrystallization in a mixture of ethanol - diethyl ether, to receive specified in the title compound, having the elemental composition indicated in table 1.

Example 17

Monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(2,6-dichlorophenoxy)cyclohexane

(Compound No. 17)

Connection # 17 received in 10 stages in accordance with the procedure described in Example 15. Stage (i)to(v) are identical stages in Example 16.

(vi) To a cooled (0° (C) to a solution of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol (27,77 g, 120 mmol) and triethylamine (22 ml, 156 mmol) in dichloromethane (240 ml) was added methanesulfonamide (12,32 ml, 156 mmol). The reaction mixture was stirred at 0° during the 45 min and then at room temperature for 3 hours. The reaction mixture was washed with water (2× 100 ml) and the combined re-washing was extracted with dichloromethane (120 ml). The combined organic extracts were dried over sodium sulfate and the solvent evaporated in vacuum, obtaining the crude mesilate, which is then maintained by pumping under high vacuum for 4 hours before using on stage ix.

(vii) 2,6-Dichloroethylenes alcohol: To a suspension of lithium aluminum hydride (of 13.75 g, 365,75 mmol) in anhydrous diethyl ether (500 ml) through a funnel to add solids was added 2,6-dichlorophenoxy acid (50 g, 243,75 mmol). The resulting reaction mixture was heated under reflux for 16 hours and then extinguished by slow addition of a saturated aqueous solution of sodium sulfate (25 ml). The resulting suspension was stirred for 3 hours and then filtered, the insoluble material was carefully washed with diethyl ether (2× 100 ml). The combined ethereal filtrates were dried over sodium sulfate and the solvent evaporated in vacuum, obtaining at the output of 38.6 g (yield 85%) specified in the connection header.

(viii) To sodium hydride (144 mmol, 4,32 g, 80% oil dispersion) in anhydrous ethylene glycol dimethyl ether (80 ml) was added a solution of 2,6-dechlorination alcohol (27,65 g, 144 mmol) in anhydrous etilenglikolevye ether (80 ml). The resulting mixture was stirred at room temperature in an argon atmosphere for 4 hours.

(ix) (1R,2R)/(1S,23)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(2,6-dichlorophenoxy)cyclohexane: mesilate (vi) in anhydrous ethylene glycol dimethyl ether (80 ml) was quickly added to alkoxide mixture (viii) and the resulting mixture was immediately heated under reflux for 66 hours. The cooled reaction mixture was poured into water (200 ml) and the organic solvent evaporated in vacuum. The remaining aqueous solution was diluted with additional water to a volume of 700 ml, acidified to pH 0.5 with 6 M aqueous Hcl and was extracted with diethyl ether (2× 600 ml). the pH of the aqueous layer was brought to pH 5.9 and then the aqueous solution was extracted with diethyl ether (700 ml). The organic extract was dried over sodium sulfate, and the solvent evaporated in vacuum, obtaining 34,0 g specified in the title compound (yield 70%).

(x) Monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(2,6-dichlorophenoxy)cyclohexane Mixture of (1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(2,6-dichlorophenoxy)cyclohexane (15,85 g of 38.9 mmol, step ix) and 6 M aqueous Hcl (100 ml) in 2-butanone (400 ml) was heated under reflux for 16 hours. The cooled reaction mixture was diluted with water (100 ml) and the organic solvent viparis is whether in vacuum. The organic layer was further diluted with water (400 ml), was extracted with diethyl ether (500 ml) and dichloromethane (2× 600 ml). The combined dichloromethane extracts were dried over sodium sulfate, and the solvent evaporated in vacuum. In the azeotropic distillation with toluene has been specified in the title compound, which was then dried under high vacuum for 15 min cleaners containing hydrochloride salt was led by trituration in diethyl ether, the crystals were collected and subjected to recrystallization from a mixture of ethanol - diethyl ether, receiving 11,85 g of pure product (yield 77%), having the elemental composition indicated in table 1.

Example 18

Monohydrochloride (1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro-[4.4]non-7-yl]-1-(1-naphthenate)cyclohexane (Compound No. 18)

(1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(1-naphthenate)cyclohexane (1.2 g, 3.14 mmol, from Example 15, step (viii)) in diethyl ether (80 ml) was treated with a solution of Hcl in ether. The solvent is evaporated in vacuum and the residue was poured in diethyl ether, as a result of rubbing received solid, which was collected and precipitated from a mixture of dichloromethane - diethyl ether, receiving 0,85 g specified in the title compound, having the elemental composition indicated in table 1.

Example 19

Monohydrochloride (1R,2S)/(1S,2R)-2-(4-morpholinyl)-1-[(2-trifluoromethyl)the dryer is toxi]cyclohexane

(Compound No. 19)

(i) 2-(4-Morpholinyl)cyclohexanone: To a cooled (-70° (C) the solution oxalicacid (20 ml, 0.23 mol) in dichloromethane (500 ml) was added dropwise a solution of anhydrous dimethyl sulfoxide (34 ml, 0.48 mol) in dichloromethane (50 ml) and the resulting mixture was stirred for 5 min at a temperature below -60° C. Then was added dropwise a solution of (1R,2R)/(1S,2S)-2-(4-morpholinyl)cyclohexanol (37,05 g, 0.2 mol) in dichloromethane (50 ml) to maintain the reaction temperature below -60° and the reaction mixture was stirred for 15 min Triethylamine (140 ml) was added dropwise to the reaction mixture, maintaining the reaction temperature below - 50° and then the reaction mixture was allowed to warm to room temperature. The reaction mixture was poured into water (600 ml) and the aqueous layer was separated and was extracted with dichloromethane (2× 500 ml). The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuum. Vacuum distillation gave of 35.1 g (yield 96%) specified in the connection header.

(ii) 2-(4-morpholinyl)cyclohexanol: To a cooled (0° (C) suspension of sodium borohydride (2.14 g, 56 mmol) in isopropanol (120 ml) was added a solution of 2-(4-morpholinyl)cyclohexanol (24,7 g, 135 mmol, stage i) in isopropanol (80 ml). The resulting reaction mixture was stirred at 0° C for 10 min and then in ECENA 30 min at ambient temperature. To the reaction mixture were added water (200 ml) and the organic solvent evaporated in vacuum. Then the remaining aqueous solution was extracted with ethyl acetate (4× 50 ml), the combined organic extracts were dried over sodium sulfate and the solvent evaporated in vacuum, obtaining 22,48 g specified in the title compound, suitable for the next stage without any further purification.

(iii) (1S,2R)/(1R,2S)-2-(4-morpholinyl)cyclohexyl-2-(trifluoromethyl)phenyl acetate: a Mixture of 2-(4-morpholinyl)cyclohexanol (7,41 g, 40 mmol, stage ii), 2-(trifluoromethyl)phenylacetic acid (of 10.21 g, 49 mmol) and monohydrate para-toluenesulfonic acid (40 mg) in toluene (60 ml) was heated under reflux in an apparatus of the Dean and stark within 48 hours. To the cooled reaction mixture was added saturated aqueous sodium bicarbonate solution (40 ml), the aqueous layer was separated and was extracted with ethyl acetate (3× 50 ml). The combined organic layers were dried over sodium sulfate and the solvent evaporated in vacuum, obtaining a mixture of (1S,2R)/(1R,2S)-2-(4-morpholinyl)cyclohexyl 2-(trifluoromethyl)phenylacetate and (1R,2R)/(1S,2S)-2-(4-morpholinyl)cyclohexyl 2-(trifluoromethyl)phenylacetate. Chromatography CIS/TRANS mixture on a dry column using as eluent a mixture of ethyl acetate - hexanol (+0.5% Isopropylamine, vol./about.) gave 3,19 g of the crude specified in the header is soedineniya mixed with starting material 2-(4-morpholinyl)cyclohexanol. The crude product was distributed between dichloromethane (30 ml) and 0.5 M aqueous solution of Hcl (7 ml). The aqueous layer was separated and additionally was extracted with dichloromethane (2× 18 ml). The combined organic layers were dried over sodium sulfate and the solvent evaporated in vacuum. As a result of recrystallization from a mixture of ethanol - hexanol received 2,78 g specified in the connection header.

(iv) Monohydrochloride (1S,2R)/(1R,2S)-2-(4-morpholinyl)-1-[(2-trifluoromethyl)venetucci]cyclohexane: To a mixture of (1S,2R)/(1R, 2S)-2-(4-morpholinyl)cyclohexyl 2-(trifluoromethyl) phenylacetate (1.64 g, 4,28 mmol, stage iii) and sodium borohydride (332 mg, to 8.70 mmol) in anhydrous tetrahydrofuran (35 ml) at reflux was added a solution of definate TRIFLUORIDE boron (8.2 ml, 65 mmol) for 1.5 hours. The reaction mixture was suppressed by addition of water (~70 ml), the organic solvent is evaporated in vacuo and the pH of the remaining aqueous solution was brought to a pH of 9.6. The aqueous layer was extracted with diethyl ether (2× 70 ml), the combined organic extracts were dried over sodium sulfate and the solvent evaporated in vacuum. Then the residue was distributed between 0.5 M aqueous solution of Hcl (50 ml) and diethyl ether (2× 50 ml). The aqueous solution was podslushivaet to a pH of 5.9 and was extracted with diethyl ether (50 ml). The organic layer was collected, dried over sodium sulfate and RA is the solvent evaporated in vacuum, receiving the crude free aminoether. The free base was transferred to monohydrochloride salt by distribution between 0.5 M aqueous solution of Hcl (10 ml) and dichloromethane (10 ml). The acidic aqueous solution was extracted again with dichloromethane (10 ml), the combined organic extracts were dried over sodium sulfate and the solvent evaporated in vacuum. Recrystallization from a mixture of ethanol - hexanol gave 636 mg (yield 38%) indicated in the title compound, having the elemental composition indicated in table 1.

Example 20

Monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-[3-(cyclohexyl)propoxy]cyclohexane

(Compound No. 20)

(i) 3-Cyclohexyl-1-propyl bromide: To a cooled (0° C) 3-cyclohexyl-1-propanol (5 g, to 35.15 mmol) was slowly added to the solution trichromate phosphorus (1.1 ml, 17.6 mmol) in dichloromethane (2 ml). After complete addition, the reaction mixture was allowed to warmed to room temperature and was stirred for 4 hours. The reaction was suppressed by the addition of saturated aqueous sodium bicarbonate solution (5 ml) and 10% NaOH (10 ml). The resulting mixture was extracted with diethyl ether (3× 50 ml), the combined organic extracts were dried over sodium sulfate and the solvent evaporated in vacuum, obtaining oil. Vacuum distillation gave 3.4 g (yield 47%) specified in the connection header.

(ii) (1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-[3-(cyclohexyl)propoxy]cyclohexane: To a suspension of sodium hydride (200 mg, with 8.33 mmol) in anhydrous dimethylformamide (20 ml) was added a solution of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl]cyclohexanol (1.5 g, 6.6 mmol) in anhydrous dimethylformamide (10 ml). The resulting mixture was stirred at room temperature for 30 min and then quickly added a solution of 3-(cyclohexyl)propyl bromide (1,67 g, 8,15 mmol) in anhydrous dimethylformamide. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (200 ml) and then extracted with ethyl acetate (3× 50 ml). The combined organic extracts repeatedly washed with saline (50 ml)and the solvent evaporated in vacuum. The residue was washed with water (50 ml) and the pH was brought to a pH of 1.0 with 6 M aqueous Hcl. The acidic aqueous solution was extracted with diethyl ether (2× 50 ml), then was podslushivaet to pH 5.0-5.5 with 5 M aqueous NaOH solution and was extracted with diethyl ether (3× 50 ml). The combined organic extracts at pH 5.0-5.5 was concentrated in vacuum, obtaining the crude specified in the title compound, suitable for the next stage without any further purification.

(iii) Monohydrochloride (1R,2S)/(1S,2R)-2-(3-ketopropionic)-1-[3-(cyclohexyl)propoxy]cyclohexane: (1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-[3-(cyclohexyl)propoxy]cyclohexane (ii) in a mixture of 6 M aqueous RA the creators Hcl - butanone (1:4 vol./about., 100 ml) was heated under reflux for 16 hours. The cooled reaction mixture was concentrated in vacuo and the remaining aqueous solution was diluted with water (~50 ml). The acidic aqueous solution was extracted with ethyl ether (50 ml) and then dichloromethane (3× 50 ml). Dichloromethane extracts were dried over sodium sulfate, and the solvent evaporated in vacuum, obtaining the crude specified in the header connection. Cleaners containing hydrochloride salt was led by trituration in a mixture of diethyl ether - hexanol (1:1 vol./about., ~200 ml) and then laid siege from a mixture of dichloromethane - diethyl ether - hexanol, gaining 0.8 g specified in the title compound, having the elemental composition indicated in table 1.

Example 21

Monohydrochloride (1R,2R)/(1S,2S)-2-(3-acetoxypropionyl)-1-(1-naphthenate)cyclohexane

(Compound No. 21)

(i) Monohydrochloride (1R,2R)/(1S,2S)-2-(3-hydroxypyrrolidine)-1-(1-naphthenate)cyclohexane: To a cooled (-0° (C) to a solution of sodium borohydride in isopropanol (20 ml) solution was added monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(1-naphthenate)cyclohexane (1,4 g, 3.75 mmol) in isopropanol (30 ml). The resulting mixture was stirred at 0° C for 15 min and then for 30 min at room temperature. The reaction was suppressed by the addition of water, the reaction mixture is evaporated, the DOS is and the residue was washed with dichloromethane (2× 20 ml). Dichloromethane washing was dried over sodium sulfate and the solvent evaporated in vacuum, obtaining specified in the header of the connection.

(ii) Monohydrochloride (1R,2R)/(1S,2S)-2-(3-acetoxypropionyl)-1-(1-naphthenate)cyclohexane: then the intermediate product alcohol (i) was heated under reflux in acetic anhydride (15 ml) for 2 hours. The excess acetic anhydride was removed in vacuo; the residue was taken in water (100 ml) and was extracted with diethyl ether (2× 30 ml). The aqueous solution was podslushivaet to pH 8.0 and extracted with diethyl ether (3× 50 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuum. The remaining oil was dissolved in a small amount of dichloromethane and added to a large volume of diethyl ether to initiate crystallization of 1.0 g (yield 65%) indicated in the title compound, having the elemental composition indicated in table 1.

Example 22

Monohydrochloride (1R,2R)/(1S,2S)-2-(4-morpholinyl)-1-[(2,6-dichlorophenyl)methoxy]cyclohexane

(Compound No. 22)

Compound No. 22 was obtained according to the procedure for the synthesis of esters of Williamson. To a suspension of sodium hydride, 80% oil dispersion (337 mg, 11 mmol) in ethylene glycol dimethyl ether (20 ml) was added a solution of (1R,2R)/(1S,2S)-2-(4-morpholinyl)-1-cyclohexanol (2.0 g, a 10.8 mmol) in ethylene glycol dimethyl ether (10 ml). Recip is nnow resulting reaction mixture was stirred at room temperature in an argon atmosphere for 3 hours, then solution was added 2,6-dichlorobenzamide in ethylene glycol dimethyl ether (10 ml)and the reaction mixture was heated under reflux for 16 hours. The cooled reaction mixture was poured into water (40 ml) and the organic solvent evaporated in vacuum. The remaining aqueous solution was diluted with additional water (60 ml) and acidified to pH 0.5 with 6 M aqueous Hcl. The acidic aqueous solution was extracted with diethyl ether (2× 40 ml), and then the pH was brought to pH 5.5. Extraction with diethyl ether (3× 50 ml) followed by drying over sodium sulfate and concentration in vacuo gave pure aminoether. Cleaners containing hydrochloride salt was besieged by treatment of the free base with a solution of Hcl in ether. Recrystallization from a mixture of acetone - methanol - diethyl ether to give 2.6 g (yield 68%) mentioned in the title compound, having the elemental composition indicated in table 1.

Example 23

Monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-[(2,6-dichlorophenyl)methoxy]cyclohexane

(Compound No. 23)

Connection # 23 received in 7 stages according to the procedure described in Example 15. Stage (i)to(v) were identical to the stages described in Example 15. Synthesis of ester (stage vi) was performed according to the procedure for the synthesis of esters Williamson, as in the Example No. 22.

(vi) (1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]n the n-7-yl]-1-[(2,6-dichlorophenyl)methoxy]cyclohexane: To a suspension of sodium hydride, 80% oil dispersion (222 mg, of 7.25 mmol) in ethylene glycol dimethyl ether (20 ml) was added a solution of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol (1.5 g, 6,60 mmol, step (v) of Example 15) in ethylene glycol dimethyl ether (10 ml). The resulting mixture was stirred at room temperature for 2 hours and then the solution was added 2,6-dichlorobenzyl bromide (1.9 g, 7.9 mmol) in ethylene glycol dimethyl ether (10 ml). The reaction mixture was heated under reflux for 16 hours in an atmosphere of argon, the solvent is evaporated in vacuum and the residue was taken in water (70 ml). The aqueous solution was acidified to pH 0.5 with 6 M aqueous Hcl and then was extracted with diethyl ether (2× 40 ml). Alkalinization of the aqueous solution to pH 4.5-5.5, subsequent extraction with diethyl ether (4× 40 ml), drying the combined organic extracts over sodium sulfate and evaporation of the solvent in vacuo gave specified in the header of the intermediate connection.

(vii) Monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-[(2,6-dichlorophenyl)methoxy]cyclohexane: intermediate product ketal (stage vi) in a mixture of 6 M HCl - butanone (1:4 vol./about., 100 ml) was heated under reflux for 16 hours. Butanone evaporated in vacuum and the remaining aqueous layer was diluted with additional water (100 ml). The acidic aqueous layer was AKST who was agarawala diethyl ether (2× 40 ml) and then dichloromethane (3× 40 ml). The combined dichloromethane extracts were dried over sodium sulfate and the solvent evaporated in vacuum, obtaining specified in the crude title compound. The product was led by trituration in diethyl ether and again besieged from a mixture of dichloromethane - diethyl ether, obtaining 1.8 g (yield 72%) indicated in the title compound, having the elemental composition indicated in table 1.

Example 24

Monohydrochloride (1R,2R)/(1S,2S)-2-(3-hydroxypyrrolidine)-1-(2,6-dichlorophenoxy)cyclohexane

(Compound No. 24)

To a solution of compound No. 17 (5.0 g, 12.7 mmol) in isopropanol (120 ml) was added a powder of sodium borohydride (2.0 g, of 52.8 mmol) and the resulting mixture was stirred at room temperature until completion of the reaction. The reaction extinguished with water (40 ml) and then concentrated to dryness. The residue was washed with dichloromethane (50 ml); the filtrate was dried over sodium sulfate, concentrated in vacuum, obtaining mentioned in the title compound, which crystallized after 3 hours in high vacuum. The results of elemental analysis of the product are shown in table 1.

Example 25

Monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(2,2-diphenylmethoxy)cyclohexane

(Compound No. 25)

Compound No. 25 received in 10 stages in accordance with a procedure identical to the procedure is, described in Examples 15 and 17. Stage (i)to(v) are identical stages in Example 15.

(vi) To a cooled (0° (C) to a solution of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol (2.0 g, 8,8 mmol) and triethylamine (2.1 ml, 15 mmol) in dichloromethane (30 ml) was added methanesulfonamide (0.9 ml, 11,44 mmol). The reaction mixture was stirred at 0° C for 45 min and then at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (25 ml), washed with water (2× 25 ml) and the combined re-washing was extracted with dichloromethane (25 ml). The combined organic extracts were dried over sodium sulfate and the solvent evaporated in vacuum, obtaining the crude mesilate, which is then maintained by pumping under high vacuum for 30 min before use on stage ix.

(vii) (2,2-Diphenyl)ethyl alcohol: lithium aluminum hydride (2.85 g, 23,56 mmol) in anhydrous diethyl ether (150 ml) was added in powder form diphenyloxazole acid (5.0 g, 56 mmol). The resulting reaction mixture was gently heated under reflux for one hour. The reaction extinguished saturated aqueous solution of sodium sulfate and the resulting precipitate was filtered. The filtrate was concentrated in vacuum, obtaining 4.0 g (yield 86%) specified in the connection header.

(viii) To sodium hydride, prior is sustained fashion washed hexane (253 mg, 10,56 mmol) in suspension in ethylene glycol dimethyl ether (15 ml) was added a solution of 2,2-diphenylethanol alcohol (2,09 g, 10,56 mmol, stage vii) in ethylene glycol dimethyl ether (15 ml). The resulting mixture was stirred at room temperature in an argon atmosphere for 30 minutes

(ix) (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1-(2,2-diphenylmethoxy)cyclohexane: mesilate (vi) in ethylene glycol dimethyl ether (20 ml) was rapidly added to the alkoxide (viii) and the reaction mixture was heated under reflux for 5 days. The cooled reaction mixture was concentrated in vacuo, the residue was taken in water (50 ml) and the pH was brought to a pH of 1.0 with 6 M aqueous Hcl. The acidic aqueous solution was extracted with diethyl ether (2× 50 ml), the aqueous layer was collected and podslushivaet to a pH of 6.0. Extraction with diethyl ether (2× 50 ml) followed by drying over sodium sulfate and evaporation of the solvent in vacuo gave 1.55 g (yield 43%) specified in the connection header.

(x) Monohydrochloride (1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(2,2-diphenylmethoxy)cyclohexane Mixture of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1-(2,2-diphenylmethoxy)cyclohexane (1.55 g, 3.8 mmol) in 6 M HCl-butanone (1:4 vol./about., 50 ml) was heated under reflux for 2 hours. Butanone evaporated in vacuo, and the residue was taken in water (50 ml). The aqueous solution was extracted with di is tilov ether (2× 50 ml); the aqueous layer was collected and was extracted with dichloromethane (2× 50 ml). The combined dichloromethane extracts were dried over sodium sulfate and concentrated in vacuum, obtaining specified in the crude title compound. The product was led by trituration in diethyl ether and re-deposition from a mixture of dichloromethane - diethyl ether, getting to 1.21 g (yield 80%) indicated in the title compound, having the elemental composition indicated in table 1.

Example 26

Monohydrochloride (1R,2R)/(1S,2S)-2-(3-thiazolidine)-1-(2,6-dichlorophenoxy)cyclohexane

(Compound No. 26)

(i) (1R,2R)/(1S,2S)-2-(3-thiazolidine)cyclohexanol: To the anhydrous magnesium perchlorate (12,93 g, 53.3 per mmol) was added to a solution of cyclohexene oxide (6,1 ml, 58.6 mmol) in anhydrous acetonitrile (25 ml)and the resulting mixture was stirred at room temperature for 20 minutes Then added to the solution of thiazolidine (5,16 g, 55,0 mmol) in anhydrous acetonitrile, and the reaction mixture was heated at 35° C for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was distributed between water (350 ml) and diethyl ether (350 ml). The aqueous layer was separated and was extracted again with diethyl ether (350 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuum, obtaining the crude product. The crude amino is Peart was purified by chromatography on a dry column using as eluent a mixture of ethyl acetate - hexanol (1:1 vol./vol.), and received 4.83 g (yield 47%) specified in the connection header.

(ii) To a cooled (0° (C) to a solution of (1R,2R)/(1S,2S)-2-(3-thiazolidine)cyclohexanol (3,17 g of 16.9 mmol) and triethylamine (is 3.08 ml, 22 mmol) in dichloromethane (30 ml) was added dropwise methanesulfonanilide (1,74 ml, 22 mmol). The reaction mixture was stirred at 0° C for one hour and then at ambient temperature for 3 hours. The reaction mixture was diluted with dichloromethane (20 ml) and washed with water (2× 30 ml). United re-washing was extracted with dichloromethane (25 ml) and the combined organic extracts were dried over sodium sulfate. Evaporation of the solvent in vacuo gave mesilate, suitable for the next stage without any further purification.

(iii) To sodium hydride, 80% dispersion in oil (608 mg, to 20.28 mmol) in ethylene glycol dimethyl ether (30 ml) was added a solution of 2,6-dechlorination alcohol (a 3.87 g, to 20.28 mmol, Example 4, stage vii) in ethylene glycol dimethyl ether (15 ml). The resulting mixture was stirred at room temperature in an argon atmosphere for 2 hours.

(iv) Monohydrochloride (1R,2R)/(1S,2S)-2-(3-thiazolidine)-1-(2,6-dichlorophenoxy)cyclohexane: Mesilate (ii) in ethylene glycol dimethyl ether (15 ml) was quickly added to the alkoxide (iii) and reaction the second mixture was heated under reflux for 40 hours. The cooled reaction mixture was poured into water (100 ml)and the organic solvent evaporated in vacuum. The remaining aqueous solution was diluted with additional water (100 ml) and the pH was brought to pH of 1.5. The acidic aqueous layer was extracted with diethyl ether (3× 100 ml), the combined organic extracts were dried over sodium sulfate and the solvent was removed in vacuum, obtaining the crude free base. The product was purified by chromatography on a dry column, using as eluent a mixture of ethyl acetate - hexanol (1:10 vol/vol.), receiving 2.4 g of pure free aminoether. Pure product (1.0 g) were transferred to the cleaners containing hydrochloride salt by treatment with a solution of Hcl in ether, and the resulting salt was recrystallized from a mixture of acetone - diethyl ether, got 0,69 g specified in the title compound, having the elemental composition indicated in table 1.

Example 27

Monohydrochloride (1R,2S)/(1S,2R)-2-(3-ketopropionic)-1-(1-naphthenate)cyclohexane

(Compound No. 27)

Connection # 27 received in 8 stages in accordance with synthesis scheme shown on figure 3. Stage (i) no (iv) were identical to the stages described in Example 15.

(v) (1R,2R)/(1S,2S)-1-(1-naphthenate)-2-cyclohexanol: To the anhydrous magnesium perchlorate (270 mg, 1.2 mmol) in anhydrous acetonitrile (1.7 ml) was added cyclohexene oxide (0.12 g, 1.2 mm is eh). The resulting mixture was stirred for 15 min at room temperature and then was added 1-naphtenate (2.7 g, 10,15 mmol). The reaction mixture was heated with reflux condenser and heated to the reaction mixture was added additional cyclohexene oxide (2.0 ml, 2.0 g, 20 mmol) at a rate of 0.4 ml/hour. Heating was stopped after 16 hours and the cooled reaction mixture was distributed between diethyl ether (50 ml) and saturated aqueous sodium bicarbonate (30 ml). The aqueous layer was separated and was extracted twice with additional diethyl ether (2× 40 ml). The combined organic extracts repeatedly washed with water (15 ml), brine (15 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave specified in the crude title compound, suitable for the next stage without any further purification.

(vi) 1-(1-Naphthenate)-2-cyclohexanone: To a solution of (1R,2R)/(1S,2S)-2-(1-naphthenate)-1-cyclohexanol (1.0 g, stage v) in dimethylformamide (20 ml) in small portions was added pyridinium dichromate (5.0 g, 13,2 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 ml) and the resulting suspension was extracted with diethyl ether (3× 50 ml). The combined organization is organic extracts again washed with 1 M aqueous NaOH solution (30 ml), saline solution (30 ml) and dried over sodium sulfate. Evaporation of the solvent gave 1.0 g of the crude indicated in the title compound, suitable for the next reaction stage.

(vii) (1R,2S)/(1S,2R)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1-(1-naphthenate)cyclohexane: To a solution of (1,4-dioxa-7-azaspiro[4.4]nonane (of 5.17 g, 40 mmol) and 1-(1-naphthenate)-2-cyclohexanone (1,79 g, to 6.58 mmol, stage vi, 77% purity) in anhydrous methanol (10 ml) was added 5 N solution of Hcl in methanol (2.7 ml) and then cyanoborohydride sodium (397 mg, 6 mmol). Then the reaction mixture was diluted with anhydrous methanol (7 ml) and stirred at room temperature for 16 hours. The reaction mixture was suppressed by addition of 6 M aqueous Hcl (40 ml), the organic solvent is evaporated in vacuum, the remaining aqueous solution was diluted to 100 ml with water and the pH was brought to pH 0.5 with 6 M aqueous Hcl. The acidic aqueous layer was extracted with diethyl ether (100 ml); the aqueous layer was separated and was podslushivaet to a pH of 6.7 with 5 M aqueous solution of NaOH. Extraction with diethyl ether (100 ml) followed by drying over sodium sulfate and evaporation of the solvent in vacuo, after purification by chromatography on a dry column using as eluent mixtures of ethyl acetate - hexanol (from 1:9 to 1:6.about., + 0,5% vol./about. isopropylamino) gave 1.28 g of the crude (1R,2S)/(1S,2R)-2-(1,4-di the KSA-7-azaspiro[4.4]non-7-yl)-1-(1-naphthenate)cyclohexane and (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1-(1-naphthenate)cyclohexane. Separation of (1R,2S)/(1S, 2R)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1-(1-naphthenate)cyclohexane from (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro-[4.4]non-7-yl)-1-(1-naphthenate)cyclohexane was performed using preparative HPLC (Waters Delta Prep 4000, PrePak cartridge 40× 100 mm, isopropanolamine (2:98.about., +0,05% vol./about. diethylamine)to give 590 mg specified in the connection header.

(viii) Monohydrochloride (1R,2S)/(1S,2R)-2-(3-ketopropionic)-1-(1-naphthenate)cyclohexane Mixture of (1R,2S)/(1S,2R)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1-(1-naphthenate)cyclohexane (480 mg, of 1.23 mmol, stage vii) in 6 M Hcl aqueous solution - butanone (1:4 vol./about., 40 ml) was heated under reflux for 2 hours. The organic solvent is evaporated in vacuo, the residual aqueous solution was diluted to 50 ml with water and was extracted twice with diethyl ether (2× 50 ml) and then three times with dichloromethane (3× 50 ml). The combined dichloromethane extracts were dried over sodium sulfate, and the solvent evaporated in vacuum, the remaining oil was then dried via azeotropic distillation of toluene. Specified in the title compound was led by rubbing in hexano (430 mg, yield 93%), the connection had elemental composition indicated in table 1.

Table 1
ConnectionFormulaCalculated Found
1C22H30NO2ClWith 70,29, N 8,04, N of 3.73%With 69,36, N 8,17, N of 3.73%
2C22H30NO2ClWith 70,29, N 8,04, N of 3.73%With 69,78, N Of 8.06, N of 3.56%
3C18H27NO2BrClWith 53,41, N 6,72, N of 3.46%With 53,16, N 6,77, N 3,35%
4With22H30NO3CLWith 67,42, N 7,72, N 3,57%With 67,31, N Of 7.75, N 3,59%
5C18H27NO3BrClWith 51,38, N 6,47, N of 3.33%With 51,38, N 6,21, N 3,28%
6C20H32NO4ClWith 62,24, N At 8.36, N 3,63%With 61,69, N 8,64, N 3,63%
7C22H30NOClWith 73,41, N 8,40, N 3,89%With 73,26, N 8,64, N 3,94%
8C20H28NO2SClWith 62,89, N 7,39, N 3,67%With 61,94, N 7,42, N 3,70%
9C20H28NO2SClWith 62,89, N 7,39, N 3,67%WITH 62,53, N 7,56. N 3,64%
10C18H27NO2BrClWith 53,41, N 6,72, N of 3.46%With 53,29, N 6,94, N 3,57%
11C18H27NO2BrClWith 53,41, N 6,72, N of 3.46%WITH 52,61, N. ,46, N 4,01%
12C21H34NO4ClWith 63,06, N To 8.57, N 3,50%With 62,45, N To 8.41, N 3,45%
14With18H26NO2CL3With 54,77, N 6,64, N 3,55%With 58,80, N 6,85, N 3,51%
15C22H28NO2ClWith 70,67, N Of 7.55, N of 3.75%With 70,12, N Of 7.55, N of 3.73%
16With24H33NO2CL· N2OWith 63,63, N 8,23, N 6,18%With 62,93, N 8,56, N 6,05%
17C18H24NO2Cl3With 55,05, N 6,16, N 3,57%With 54,39, N 6,30, N 3,49%
18C24H32NO3ClWith 68,97, N 7,72, N 3,35%With 68,49, N Of 7.64, N 3,31%
19C19H27NO2ClF3With 57,94, N 6,91, N 3,35%With 57,75, N 6,91, N 3,59%
20C19H34NO2ClWith 66,35, N 9,96, N 4,07%With 66,22, N 9,72, N 4,12%
21C24H32NO3ClWith 68,97, N 7,72, N 3,35%With 67,52, N 7,99, N 3,17%
22C17H24NO2Cl2·H2OWith 51,21, N 6,57, N 3,51%With 51,03, N 6,57, N 3,36%
23C17 H22NO2Cl2With 53,91, N 5,86, N 3,70%With 53,88, N 5,79, N 3,59%
24C18H26NO2Cl3·H2OWith 52,38, N 6,84, N 3,39%With 53,98, N 7,24, N of 3.33%
25C24H30NO2ClWith 72,07, N 7,56, N 3,50%With 71,87, N. EUR 7.57, N 3,51%
26C17H24NOCl3SWith 51,46, N 6,10, N 3,53%With 51,48, N 5,86, N 3,44%
27C22H28NO2ClWith 70,67, N Of 7.55, N of 3.75%With br70.63, N 7,53, N 3,65%

Example 27-

Monohydrochloride (±)-TRANS-[2-morpholino-1-93-(2,4-dimethoxy)cinnamyl)]cyclohexane

i) the Original TRANS-aminocyclohexanol was obtained in accordance with example 1 of PCT/SA/00280.

ii) To a cooled to 0° With the solution (±)-TRANS-(2-morpholino)cyclohexanol (3.0 g, 16,20 mmol) and triethylamine (3.4 ml, 24,00 mmol) in dichloromethane (50 ml) via cannula was added a solution of methanesulfonamide (of 1.55 ml, 20.00 mmol) in dichloromethane (50 ml). The addition was completed within 5 minutes, after which the reaction mixture was additionally stirred for 45 minutes at 0° and then at room temperature for another 1 hour. The reaction mixture was washed with water (2× 30 ml) and the combined aqueous leaching fraction was subjected to the reverse extraction with dichloromethane (30 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuum with the formation of 4.71 g of the crude nelfinavir.

iii) To a stirred solution of ethyl TRANS-2,4-dimethoxycinnamic (7.5 g, 34 mmol) in toluene (100 ml) at room temperature was added a solution of DIBAL (100 ml, 1 M in exno). The addition was continued for about 2 hours, then the reaction mixture was left overnight under stirring at room temperature. The reaction mixture was treated slowly at 0° adding water (10 ml), then the solution was stirred for another 2 hours and filtered. The filtrate was dried over sodium sulfate and the solvent was removed in vacuum.

iv) sodium Hydride, 80% dispersion, previously washed with hexane (3× 10 ml) (0,60 g, 25,00 mmol) in anhydrous dimethylformamide (50 ml) via cannula was added to a solution of 2,4-dimethoxyphenol alcohol (4,2 g, 21,62 mmol) in anhydrous dimethylformamide (50 ml). After the addition was barbotirovany hydrogen, the reaction mixture was stirred at room temperature for 1 hour.

v) Via cannula quickly (3 minutes) was added a solution of nelfinavir in dimethylformamide (50 ml). The reaction mixture was heated to 80° C for 0.5 hour, then the temperature was lowered to 50° and the reaction mixture was left under stirring overnight. The reaction mixture was poured into a mixture of ice and water (800 ml) and the ex who was regionali with ethyl acetate (3× 200 ml) and dried over sodium sulfate. After evaporation of rectorates in vacuum was obtained a dark red oil. The crude product was purified on a chromatographic column with silica gel 60, 70-230 mesh production BDH Inc., using as eluent a mixture of ethyl acetate-dichloromethane (1:1 vol./about.) obtaining pure free base (1.4 g). The product was dissolved in dichloromethane (50 ml), filtered and mixed with acetic acid (3 ml). The solvent is evaporated in vacuum to obtain 1.4 g specified in the connection header.

Elemental analysis. Calculated for C21H31NO4Cl (Mm 481,59): 62,35%, N 8,16%, N 2,91%. Found: 62,87%, N 8,35%, N 2,92%.

Biological indicators of monohydrochloride (±)-TRANS-[2-morpholino-1-93-(2,4-dimethoxy)cinnamyl)]cyclohexane were obtained using the methods disclosed in example 28 PCT/SA/00280. Determined the value of the volume of infusion compounds (micromoles/kg / min)required to reduce by 50% the rate of arrhythmias in animals exposed to drugs (ED50AA) compared to control animals that received blank media. The value of the ED50AA for this connection is 0,82, and it is within the limits established for typical compounds of the invention in Table 3. The ECG parameters when using this compound were determined as described in example 29 PCT/SA/00280. Intervals, P-R, QS and Q-T had the following values: P-R=18, QRS=16 and Q-T=3,5. Each value is within the limits established for typical compounds of the invention in Table 4.

Also identified modulating properties against ion channels for the connection of the estimated values of the ED25for the three indices (It, ERP and VFT) block of cardiac sodium and potassium channels. The value of the ED25corresponds to the volume of infusion (micromoles/kg / min)required to achieve a 25% increase in the measured parameter is compared with the control animals. The details of the experience described in examples 29 and 30 PCT/SA/00280. For this connection were defined with the following values: It=4, VFT=3 and ERP=3, each of which is within the limits established for typical compounds of the invention in Table 5 description of the present invention.

Example 28

Evaluation of antiarrhythmic efficacy

Antiarrhythmic efficacy was assessed by examining the influence of compounds on the frequency of occurrence of arrhythmias in the consciousness of rats exposed to occlusion of a coronary artery. Rats weighing 200-300 g were subjected to preparatory surgery and were divided into groups randomly. In each case, during preparation for surgery, the animals were anestesiologi the halothane gas. In the left femoral artery was injected cannula for measurement of mean arterial blood on the means and sampling of blood. In the left femoral vein was also introduced cannula for injection of drugs. Opened the cavity of the chest, and a plastic obturator freely placed around the left anterior descending coronary artery. Then the cavity of the chest was closed. ECG was recorded by inserting electrodes placed along the anatomical axis of the heart. All connections to the cannula and electrodes taken out in the interscapular area. Random and double-blind fashion in about 0.5 to 2 hours after surgery was infusional filler or test the connection. 15 minutes after the start of infusions obturator delayed thus to obtain a coronary artery occlusion. Within 30 minutes after occlusion followed ECG, arrhythmia, blood pressure, heart rate and mortality. Arrhythmias were recorded in the form of paroxysmal ventricular tachycardia (VT) and ventricular fibrillation (FG) and evaluated in accordance with Curtis, M.J. and Walker, M.J.A., Cardiovasc. Res. 22:656(1988) (see table 2).

td align="left"> >1 episode of VT or PI or both types of arrhythmia (total duration >60 sec)
Table 2
ScoreDescription
00-49 REE
150-499 REE
2>499 RGA and/or 1 episode spontaneously reversible adipose tissue or FG
3
4Adipose tissue or PI or both types of arrhythmia (total duration 60-119 sec)
5Adipose tissue or PI or both types of arrhythmia (total duration >119 sec)
6FG fatal, starting > than through 15
 minutes after occlusion
7FG fatal, starting between 4 min and 14 min 59 sec after occlusion
8FG fatal, starting in the interval between 1 min and 3 min 59 sec after occlusion
9FG fatal, starting <than 1 min after occlusion.
where: RJA = early ventricular beats

VT = ventricular tachycardia

FG = ventricular fibrillation

Rats were excluded from the study if the concentration of potassium in the serum before occlusion was not in the range of 2.9-3.9 mm. Occlusion corresponds to an increase in the height of the R-wave and the elevation of the segment "S-T"; and the area of occlusion (measured after death using the perfusion of the dye cardiogreen) within 25%-50% of the total weight of the left ventricle.

Table 3 describes the test results the Finance connections, described here, as the values of the rate of infusion in micromoles/kg/min (ED50AA), which will reduce the evaluation of arrhythmias in treated animals up to 50%from the assessment of arrhythmias in animals treated only filler, in which dissolve the tested drug.

Table 3
ConnectionED50AA
  
10, 8
21,0
32,1
42,0
53,0
64,0
74,0
81,0
91,0
102,0
111,0
141,5
150,43
171,1
191,4
211,4
221,8
232,1
240, 6
252,5
266,5

Example 29

Measurement of ECG parameters

In this example, the COI is litovali rats weighing 200-250 g Animals were anestesiologi the introduction of 60 mg/kg pentobarbitone in b/W. In the carotid artery and jugular vein were introduced cannula for measuring blood pressure and injection drugs, respectively. ECG was recorded using electrodes placed along the anatomical axis of the heart. All compounds were given in the form of a bolus injection.

We measured various parameters of the ECG. Table 4 describes the results of the tests in the ED25(micromoles/kg), which represent the dose needed to obtain the increase of the measured parameter by 25% (ND = no data). The increase in the interval P-R and increased QRS interval indicates the blocking of sodium channels in the heart, while the increase in the interval Q-T suggests additional blocking potassium channels in the heart, which is typical for antiarrhythmic agent of type 1A.

Table 4
ConnectionPRQRSQT
1NDND2,5
25,682,0
332163,0
6NDNDND
71,11,5 0,9
14-a 21.51,4
1515,87,83,4
1730264,2
211,72,31,6
23-17, 22,7
241,41,61,0
262,3-10

Example 30

Evaluation of blocking sodium channels

Rats were prepared according to the previous procedure. Two silver stimulating electrodes were inserted through the chest and implanted in the left ventricle. To determine the threshold current for the capture threshold current of ventricular fibrillation and effective refractory period, used the stimulation of rectangular pulses (Howard, P.G. and Walker, M.J.A., West. Pharmacol. Soc. 33:123-127 (1990)). Table 5 contains the values of the ED25for these indicators blocking sodium channels in the heart, where the ED25is the infusion rate of the compound in micromoles/kg/minute required to cause a 25% increase compared with the control. Cases increase the refractoriness indicate additional blocking potassium channels. The threshold current is La capture consists of the values of "It". The threshold current of atrial presents values “PIP”. Effective refractory period is represented by values “ETA”.

Table 5
ConnectionItPGPETA
12,81,41,5
20,90,71,3
35,8ND4,0
70,70,20,4
146,4-1,7
1551,21,6
1767,37,1
237,66,25
241,71,21,1
2610,59of 5.4

Example 31

Model AF-induced stimulation of the vagus nerve in dogs

General methods

Mongrel dogs of either sex weighing 15-49 kg was anestesiologi morphine (2 mg/kg initially followed in the/with the introduction of 0.5 mg/kg every 2 hours) and α -chloralose (120 mg/kg in subsequent infusion by 29.25 mg/kg/h; St.-Georges et al., 1997). Lung ventilation dogs p is bodily mechanical room air with added oxygen through an endotracheal tube at a speed of from 20 to 25 breaths/minute volume of respiration, based nomograms. Measured the amount of gases in the arterial blood and maintained in the physiological range (S2>90%, pH 7,30-7,45). In the femoral artery is injected with a catheter to check blood pressure and measurement of gases in the blood, in both the femoral vein is injected with a catheter for the introduction of drugs and sampling of venous blood. The lumen of the catheter kept open with heparinized 0.9% saline solution. Body temperature was maintained at a level 37-40° using warming blankets.

Heart was opened through a median thoracotomy and created pericardial suspension. For recording and stimulation in the right ventricle was injected three bipolar electrode made of stainless steel, coated with Teflon™ ), and one electrode for registration was introduced in the left atrial appendage. Programmable stimulator (Digital Cardiovascular Instruments, Berkeley, CA) was used for stimulation of the right atrium 2 MS pulses at twice diastolic threshold. Two electrodes made of stainless steel, coated with Teflon™ ), was injected into the left ventricle, one for reception and the other for stimulation. Ventricular pacemaker, to include on-demand (GBM 5880, Medtronics, Minneapolis, MN)was used to stimulate the ventricles mode 90 beats/minute in the case when W is during AF, caused by stimulation of the vagus nerve) speed of contraction of the ventricles was extremely low. For registration leads II and III ECG, electrogram the Atria and ventricles, blood pressure and signals artificially induced as a result of stimulation, used the sensor ID R23 is applied, electrophysiological amplifier (Bloom Associates, Flying Hills, PA) and a paper chart recorder (Astromed MT-95000, Toronto, ON, Kanada). Wandering nerves in the neck was separated, twice luigirules and dissected, and the electrodes were introduced into each nerve (see below). To block changes β -adrenergicheskih effects on heart nadolol was administered with an initial dose of 0.5 mg/kg in subsequent 0.25 mg/kg every two hours.

The model of atrial fibrillation

Evaluated the effect of drugs on termination of long-term FP supported during continuous stimulation of the vagus nerve. Monopolar electrodes in the form of a hook (stainless steel, insulated with Teflon™ covered except for the distal segment with a length of 1-2 cm) was injected through the needle 21 gauge in every nerve and parallel to the barrel of each nerve. In most experiments we used monopolar stimuli generated by a stimulator (model DS-9F, Grass Instruments, Quincy, MA.), configured to apply 0.1 MS rectangular pulses with a frequency of 10 Hz and at a voltage, which is set at 60%, cotirorevogue to get asystole. In some experiments we used bipolar stimulation. The voltage required to obtain asystole, is in the range between 3-20 volts. Under control conditions gave a short pulse of imposing the fast rhythm of the atrium (10 Hz, four times the diastolic threshold) to induce AF, which usually lasted more than 20 minutes. Voltage for stimulation of the vagus nerve was installed in the control conditions and then regulated in each treatment, in order to maintain the same a bradycardia effect. AF was defined as a rapid (>500 per minute in the control conditions) irregular rhythm of the contractions of the Atria with the changing structure of electrogram.

Measurement of electrophysiological parameters and response to stimulation of the vagus nerve

Diastolic threshold current was determined when the duration of the main loop 300 MS by increasing the current by the addition of 0.1 mA up to get a stable grip. For subsequent protocols, the current was set at a level exceeding the diastolic threshold twice. ETA the Atria and ventricles was measured using the method of extrastimulation within S1S2 intervals during the duration of the basic cycle of 300 MS. Early extrastimuli S2 was administered every 15 major incentives. The S1S2 interval was increased by 5 MS. until the ostopenia capture, the longest S1S2 interval was consistently reduced to obtain the propagating signal that defines the ETA. Diastolic threshold and the ETA was determined again and were averaged to obtain a single value. Typically, these values were within 5 MS. The interval between artificial stimulus and the peak of the local electrogram was measured as an indicator of the speed of conduction. Cycle duration of AF (PCFP) was measured during caused by stimulation of the vagus OP by counting the number of cycles (the number of beats-1) 2-second interval in each section of the Atria, where he held the check. Three dimensions PCPP were averaged to obtain the final values PCPP for each experimental condition.

In most part of the experiments was determined by the relationship between the voltage of the stimulus and heart rate during stimulation of the vagus nerve in the control conditions. Wandering nerves stimulated, as described above, at different values of voltage to determine the voltage which caused the asistoliei (defined as sinus pause lasting more than 3 seconds). Each experimental condition was seen in response to stimulation of the vagus nerve, and the voltage is regulated to maintain speed heart rate in response to stimulation wander what his nerve constant. In those cases when it was impossible to get asistoliei, stimulation of the vagus nerve brought up to tension, which allows you to maintain two 20-minute episode of AF induced by stimulation of the vagus nerve in the control conditions (see below).

The protocols of experiments

Study of the experimental group are summarized in table 6. Each dog received only one drug in the doses given in table 6. In the first series of experiments, we studied the range of doses followed a blind test, which gave 1-3 doses. All drugs were injected in/using infusion pump with solutions of drugs, freshly prepared in plastic containers on the day of the experiment. The parameters of stimulation of the vagus nerve was identified in the control conditions, as described above, and checked the maintenance of AF for 20 minutes during stimulation of the vagus nerve in the control conditions. After AF was determined diastolic threshold and ETA atrium and ventricle. Subsequently, these parameters are re-estimated in the atrium during stimulation of the vagus nerve. Electrophysiological testing usually took 15-20 minutes. Seen in response to stimulation of the vagus nerve, which is expressed in heart rate, and Protocol-induced stimulation of the vagus nerve, AF/electrophysiological test the simulation was repeated. Received a blood sample before the introduction of the drug and re-started caused by stimulation of the vagus nerve, OP. Five minutes later, one of the processing tools were administered in doses shown in table 6. The entire dose was infused for 5 minutes and immediately after that took a blood sample. Maintenance infusion did not. If the OP stopped within a 15 minute period of time, repeated electrophysiological measurements in controlled conditions and took a blood sample. If the OP did not stop when the first dose (within 15 minutes), took a blood sample and continued stimulation of the vagus nerve, to give the opportunity to return to sinus rhythm. Repeated electrophysiological measurements and selected third and final blood sample for this dose. AF initiated again and repeated the Protocol caused by stimulation of the vagus nerve, AF/drug infusions/electrophysiological testing up until the OP did not stop when the action of the medicinal product.

Statistical analysis

The data obtained for the group, expressed as mean ± the standard deviation. Statistical analysis was carried out for effective doses for PCFP and ETA using a t-test with correction of Bonferroni for multiple comparisons. The action of the drug on blood pressure, heart rate, diastolic threshold of the ECG intervals were evaluated with a median dose, required for termination of AF. Used the last couple of tests and took the value of p<0,05 to indicate statistical significance.

Table 6

Experimental groups and doses of medicines
Drug-Wed-inThe limits of the test dose (µmol/kg)Dose effective for termination of AF (µmol/kg)The average dose required for termination of AF (µmol/kg)The average dose required for termination of AF (µmol/kg)
flecainide1,25-104-2,5;

1-10
4±22,5

Individual drug was administered to each dog within the given doses up to and including termination of AF. Shows the number of dogs in which the OP stopped at each dose (the number of dogs dose, in µmol/kg). Shows the average ± standard deviation, and the median dose required for termination of AF. Each dog received only one drug.

This method was evaluated a number of compounds of the invention. The results show that all the tested compounds are effective as a means of termination of AF in the model, caused by stimulation of the vagus nerve AF in dogs. The degree of translation of the rhythm is similar to the indicators, reported for many other drugs of class I and class III in this model. The effectiveness of flecainide taken as control in this study was comparable with the efficiency of what was reported previously. All drugs were extended PCFP before termination of AF; actions that, in General, consistent with the wavelength in the model to re-log pulse (re-entry) for termination of AF. The tested compounds of this invention did not reduce blood pressure or heart rate with a median dose required for termination caused by stimulation of the vagus nerve, OP. Heart rate in response to stimulation of the vagus nerve was similar in all groups and did not change under the action of any of the tested compounds. Stimulation of the vagus nerve at a voltage, which is set at 60% of the voltage required to obtain asystole (10±1 volt), caused a pause of 1.3±0.1 seconds.

Example 32

The model of sterile pericarditis dogs

This model was used to characterize the mechanisms of AF and atrial flutter (TA). Waldo and his colleagues discovered that the OP depends on the circulation of excitation and that the end of AF is usually an area of slow conduction. This model dogs were prepared by pollination of OTKRYTOGO the atrium talc, followed by “pulse” by imposing the rhythm of the atrium in a few days after recovery. The OP is able to coil two days after surgery, but no later than the fourth day after the surgical preparation; pre-emptive induced rhythm is sustained atrial fibrillation. Indutsiruemoi OP on the second day several varies, so that only 50% of dogs can withstand AF (usually <60 minutes) for the required 30 minutes. However, sustained atrial flutter, which is manifested by the fourth day, capable of induction in most cases. Atrial flutter easier “mapped” to determine the mechanisms of action of drugs. Indutsiruemoi FP decreases after the fourth day after surgery similar to AF, which often develops after surgical operations on the heart, which simulates a model of sterile pericarditis. In the etiology of surgical AF may be involved component of inflammation, which will give the degree of selectivity in relation to ischemia or selective to acid drug. Similarly, although the operation of the arterial-coronary artery bypass grafting (CABG) is to facilitate state of the cerebral ventricles, and in these patients there may be a risk of mild ischemia atrial due to arterial coronary artery disease (CAD). Although myocardial fibrillation JW is Auda rare, there is a relationship between artery stenosis atrioventricular node and the risk of AF after CABG surgery. Violation of the Autonomous innervation of the Atria in the surgery may also play a role in AF after creating CABG.

Methods

Research on the model of sterile pericarditis dogs was conducted to determine the potential and effectiveness of compound 1 on termination of atrial fibrillation/atrial flutter. Atrial flutter or fibrillation was induced in 2-4 days after creating a sterile pericarditis in adult mongrel dogs weighing 19 kg to 25 kg In all cases fibrillation or atrial flutter lasted longer than 10 minutes. All studies were performed in accordance with guidelines established by our Institutional Committee for the protection and use of animals (Institutional Animal Care and Use Committee), the politics of the American heart Association on the use of animals in scientific research (the American Heart Association Policy on Research Animal Use) and policy health Services on the use of laboratory animals (the Public Health Service Policy on Use of Laboratory Animals).

Creating a model of atrial/atrial flutter with sterile pericarditis

The model of sterile pericarditis dogs were created as described previously. During surgical OPE the emission in the eye of the right atrium, the beam Bachman and saddening part of the left atrium near the proximal portion of the coronary sinus was vivalis pair of wire electrodes, stainless steel, covered except for the tip of the FEP polymer (elastomer is a copolymer of tetrafluoroethylene and hexaferrite) (Flexon, Davis and Desk). The distance between each electrode in each pair was approximately 5 mm These wire electrodes were derived through the chest wall out back in the interscapular area for later use. After surgery, the dogs were given antibiotics and analgesics and were then given an opportunity to recover. Postoperative care included the introduction of antibiotics and analgesics.

All dogs, starting from the 2nd day after the operation, attempted induction of stable atrial fibrillation/atrial flutter in a state of consciousness without the use of sedatives in order to ensure indutsiruemoi and stability fibrillation/atrial flutter, to test the efficacy of drugs. Stimulation of the Atria was performed using electrodes sewn during the initial surgery. On the 4th day after surgery, when were induced stable atrial fibrillation, carried out the study with an open chest.

For research to open the chest every dog who was anestesiologi pentobarbital (30 mg/kg/in) and have mechanical ventilation with 100% oxygen using anesthetic apparatus Boyle model 50 (Harris-Lake, Inc.). The body temperature of each dog during the research was supported in normal physiological limits with warm blankets. The shot of the dogs before the thorax was opened, conducted high-frequency cut-off beam GIS to create a complete atrioventricular (AV) block using a standard electrode catheter method. This was done to minimize overlapping complexes atrium and ventricle during subsequent registration monopolar electrogram the Atria after the induction of atrial flutter. After you have created a complete AV-block, the effective frequency of contraction of the ventricles was supported by the stimulation of the ventricles with a speed of 60 to 80 beats per minute by using a pulse generator Medtronic 5375 Pulse Generator (Medtronic Inc.), the input stimuli through electrodes introduced into the right ventricle during the initial surgery.

The definition of thresholds of incentives and refractory periods during electrostimulation

For the induction of AF/TA used one of the two previously described methods: (1) introduction of one or two early atrial extrasystoles after a series of 8-stimulated beats the Atria when the cycle length of 400 MS, 300 MS, 200 MS or 150 MS or (2) rapid stimulation of the Atria during periods of from 1 to 10 seconds, with increasing frequency, so that it exceeded the spontaneous sinus rhythm between 10 and 50 beats per minute as long until were induced fibrillation of the Atria or not was observed loss of 1:1 distribution of retrograde pulse to the Atria. Stimulation of the Atria either performed using electrodes in the appendage of the right atrium, or the electrodes in the posterior inferior part of the left atrium. All treatments stimulation was performed using incentives, twice the threshold for each of the main thrust of rhythm, using a modified programmable Medtronic stimulator 5325, powered from the battery using pulse width of 1.8 MS.

After the induction of stable atrial fibrillation/atrial flutter (lasting more than 10 minutes) was measured cycle length of atrial/atrial flutter and conducted an initial mapping and analysis to determine the localization of the re-circulation of excitation during atrial/atrial fibrillation. Atrial fibrillation was defined as the rapid rhythm of the Atria (frequency >240 beats per minute), which was characterized by a constant cycle time between strikes, polarity, morphology and amplitude of the recorded bipolar electrogram.

The Protocol for testing the efficacy of drugs

1. Effective refractory periods (ETA) was measured in three places: the appendage of the right atrium (SCP), the rear part of the left auricle (SLP), the beam is of Ahman Ghulam (PB), at two times the main loop 200 and 400 MS.

2. Induction of AF or TA stimulation. These attempts was carried out for one hour. If not was no induction of arrhythmia, further research in this day did not.

3. If the induction was successful, the OP was supposed to last for 10 minutes. Then provided the waiting period for spontaneous termination or 20 minutes, even if the termination occurred before.

4. Then AF was induced again and was given 5 minutes before the infusion of the drug.

5. Then there was the infusion of the drug in the form of a bolus over 5 minutes.

6. If the OP stopped with the first dose, then took a blood sample and repeat the measurement of the ETA.

7. Five minutes were provided for termination of AF substance. If there was no termination, within 5 minutes gave the second dose.

8. After stopping and measurement of the ETA made another attempt to induce AF within a ten-minute period.

9. If re-induction was successful and lasted for 10 minutes, took a blood sample and the study was repeated, starting with step No. 3 above.

10. If re-induction was not possible, the study was completed.

Example 33

Determination of blocking pain

Guinea pigs br is whether (back only) and 6 aliquot (50 µl) solution of the compound (10 mg/ml) were injected with directly under the skin, to form a 6 blisters that were outlined permanent marker. Pain responses were assessed, as described above, each blister in regular intervals up to 4 hours after injection and record the duration of the blocking pain sensations from three animals for each of the test solution.

Table 7
ConnectionThe duration of block (hours)
12,5
23
32,5
113
Saline0

This method has been evaluated a number of compounds of the present invention. The results showed that all the tested compounds are effective in episodes of cessation of atrial/atrial flutter on this model. During processing of the medicinal product was not observed proaramme or adverse cardiovascular disorders.

All publications and patent applications mentioned in this specification, is included for information as if each individual publication or patent application was specifically and individually included in the description.

From the foregoing it should be clear that although here for purposes of illustration, described specific options, the antes of the invention, can be carried out in various modifications without departure from the essence and, without leaving the scope of the invention. Accordingly, the invention is not limited by anything except the attached claims.

1. The compound of formula (I), or MES, or its pharmaceutically acceptable salt:

where independently in each case, X is selected from a direct link, -C(R6, R14)-Y - and-C(R13)=CH-;

Y is selected from a direct link, O, S and C1-C4alkylene;

R13selected from hydrogen, C1-C6of alkyl,C3-C8cycloalkyl, unsubstituted aryl and benzyl;

R1and R2independently selected from C3-C8alkoxyalkyl,1-C8hydroxyalkyl and C7-C12aralkyl; or

R1and R2taken together with the nitrogen atom to which they are directly connected in the formula (I), form a ring denoted by formula (II):

where the ring of formula (II) formed by the nitrogen as shown as well as an additional three to nine ring atoms independently selected from carbon, nitrogen, oxygen and sulfur; where any two adjacent atoms of the ring may be connected by single or double bonds, and any one or more of the carbon atoms in the ring can the be substituted by one or two substituents, selected from hydrogen, hydroxy, C1-C3hydroxyalkyl, oxo, C2-C4acyl, C1-C3of alkyl, C2-C4alkylcarboxylic, C1-C3alkoxy, C1-C20alkanoyloxy, or can be substituted with the formation of five - or six-membered spiroheterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur, and any two adjacent additional carbon atom of the ring may be condensed with C3-C8carbocyclic ring, any one or more additional nitrogen atoms of the ring may be substituted by substituents selected from hydrogen, C1-C6of alkyl, C2-C4acyl, C2-C4hydroxyalkyl and C3-C8alkoxyalkyl; or

R1and R2taken together with the nitrogen atom to which they are directly connected in the formula (I), may form a bicyclic ring system selected from the following: 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]Octan-2-yl, 3-azabicyclo[3.1.0]hexane-3-yl and 3-azabicyclo[3.2.0]heptane-3-yl;

R3and R4independently associated with the cyclohexane ring shown in formula (I) in positions 3-, 4-, 5 - or 6-, and independently selected from hydrogen, hydroxy, C1-C6the alkyl and C1-C6alkoxy and, when R3and R4associated with one and the f atom cyclohexane ring, they can together form a five - or six-membered spiroheterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur;

R5, R6and R14independently selected from hydrogen, C1-C6of alkyl, aryl and benzyl, or R6and R14taken together with the carbon to which they are bound, can form Spyros3-C5cycloalkyl;

A is selected from C5-C12of alkyl, C3-C13carbocyclic rings and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII):

where R7, R8and R9independently selected from hydrogen, bromine, chlorine, fluorine, carboxy, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifloromethyl,2-C7alkanoyloxy, C1-C6of alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, aryl and N(R15,R16), where R15and R16independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6of alkyl;

where R10and R11independently selected from hydrogen, bromine, chlorine, fluorine, carboxy, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifloromethyl,2-C7alkanoyloxy, C1 -C6of alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl and N(R15,R16), where R15and R16independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6of alkyl;

where R12selected from hydrogen, bromine, chlorine, fluorine, carboxy, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifloromethyl,2-C7alkanoyloxy, C1-C6of alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl,1-C6thioalkyl and N(R15,R16), where R15and R16independently selected from hydrogen, acetyl, methanesulfonyl and C1-C6of alkyl; Z is selected from CH, CH2, O, N and S, where Z may be directly associated with X, as shown in the formula (I), when Z is CH or N, or Z may be directly associated with R17when Z is N, and R17selected from hydrogen, C1-C6of alkyl, C3-C8cycloalkyl, unsubstituted aryl and benzyl;

including their single enantiomeric, diastereomeric and geometric isomers and mixtures thereof.

2. The compound according to claim 1, having the formula (IX), or MES or pharmaceutically acceptable salt:

where independently in each case,

X is selected from a direct link, -CH=CH - and-C(R6,R14)-Y-;

Y is selected from a direct link, O, and S;

R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R14And Z have the meanings given in claim 1;

including their single enantiomeric, diastereomeric and geometric isomers and mixtures thereof.

3. The compound according to claim 1, having the formula (X), or MES, or pharmaceutically acceptable salt:

where independently in each case,

X is selected from a direct link, -CH=CH - and-C(R6,R14)-Y-;

Y is selected from a direct link, O, and S;

R1, R2, R6and R14have the meanings as in claim 1;

R3and R4independently associated with cyclohexanebis ring in positions 4 or 5 independently selected from hydrogen and C1-C6alkoxy;

A is selected from C5-C12of alkyl, C3-C8cycloalkyl and any of formulas (III),(IV),(V) and (VI)as defined in claim 1, where Z, R7, R8, R9, R10, R11and R12have the meanings given in claim 1;

including their single enantiomeric, diastereomeric and geometric isomers and mixtures thereof,

4. The compound according to claim 1, having the formula (XI), or MES, or supplied with the ski acceptable salt:

where independently in each case,

R1and R2have the meanings given in claim 1;

R3and R4independently associated with cyclohexanebis ring in positions 4 or 5 independently selected from hydrogen and methoxy;

A is selected from C5-C12of alkyl, C3-C8cycloalkyl and any of formulas (III), (IV), (V) and (VI)as defined in claim 1, where Z, R7, R8, R9, R10, R11and R12have the meanings given in claim 1; including their single enantiomeric, diastereomeric and geometric isomers, and mixtures thereof.

5. The compound according to claim 1, having the formula (XII), or MES, or pharmaceutically acceptable salt:

where independently in each case,

R1and R2have the meanings given in claim 1;

R3and R4independently associated with cyclohexanebis ring in positions 4 or 5 independently selected from hydrogen and methoxy;

A is selected from C5-C12of alkyl, C3-C8cycloalkyl and any of formulas (III), (IV), (V) and (VI)described in claim 1, where Z, R7, R8, R9, R10, R11and R12have the meanings given in claim 1;

including their single enantiomeric, diastereomeric and geometric isomers, and their mixture is.

6. The compound according to claim 1, having the formula (XIII), or MES, or pharmaceutically acceptable salt:

where independently in each case,

X is selected from a direct link, and-CH=CH-;

R1and R2have the meanings given in claim 1;

R3and R4independently associated with cyclohexanebis ring in positions 4 or 5 independently selected from hydrogen and methoxy;

A is selected from C3-C8cycloalkyl and any of formulas (III), (IV), (V), (VI), (VII) and (VIII)described in claim 1, where R8and R9have the meanings defined in claim 1, R7, R10, R11and R12are hydrogen, Z is selected from O,S and N-R17where R17selected from hydrogen and methyl; provided that may be selected from the formulae (VII) and (VIII) only when X is a direct link;

including their single enantiomeric, diastereomeric and geometric isomers, and mixtures thereof.

7. The compound according to claim 1, having the formula (XIV), or MES, or pharmaceutically acceptable salt:

where independently each R1and R2have the meanings given in claim 1; And a is selected from any of formula (III), (IV), (V) and (VI)described in claim 1, where R7, R10, R11and R12represent hydrogen, R8and R9illegal is isimo selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulfonamido, methanolate, methoxycarbonyl, nitro, sulfamyl, thiomethyl, trifloromethyl, methyl, ethyl, methoxy, ethoxy and NH2provided that at least one of R8and R9is not hydrogen; Z is selected from O and S;

including their single enantiomeric, diastereomeric and geometric isomers, and mixtures thereof.

8. The compound according to claim 1, having the formula (XV), or MES, or pharmaceutically acceptable salt:

where independently in each case,

R1and R2have the meanings given in claim 1;

And selected from any of formula (III), (IV), (V) and (VI)described in claim 1, where R7, R10, R11and R12represent hydrogen, R8and R9independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulfonamido, methanolate, methoxycarbonyl, nitro, sulfamyl, thiomethyl, trifloromethyl, methyl, ethyl, methoxy, ethoxy and NH2provided that at least one of the radicals R8and R9is not hydrogen; Z is selected from O and S;

including their single enantiomeric, diastereomeric and geometric isomers, and mixtures thereof.

9. The compound according to claim 1, having the formula (XVI), or MES, or pharmaceutically acceptable salt:

where independently in each case, X is selected from a direct link, TRANS-CH=CH-, -CH2- and-CH2-O-;

R1and R2both are methoxyethyl or, taken together with the nitrogen atom to which they are linked, form a ring selected from pyrrolidinyl, cloperastine, acetoxypiperidine, hydroxypyrrolidine, thiazolidine, piperidine, Ketobemidone, acetylpiperidine, 1,4-dioxa-7-azaspiro[4.4]non-7-yl, hexahydroazepin, morpholinyl, N-methylpiperazine and 3-azabicyclo[3.2.2]nonanal; a is selected from cyclohexyl, monochlorophenol, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2-bromophenyl, 2,4-dibromophenyl, 3-bromophenyl, 4-bromophenyl, 1-naphthyl, 2-naphthyl, 3-benzo-(b)-thiophenyl, 4-benzo(b)thiophenyl,(2-trifluoromethyl)phenyl, 2,4-di(trifluoromethyl)phenyl and (4-trifluoromethyl)phenyl,

including their single enantiomeric, diastereomeric and geometric isomers, and mixtures thereof.

10. The compound or mixture comprising compounds selected from the group consisting of the following:

(+)-TRANS-[2-(4-morpholinyl)-1-(2-naphthenate)]cyclohexane;

(-)-TRANS-[2-(4-morpholinyl)-1-(2-naphthenate)]cyclohexane;

(+)-TRANS-[2-(4-morpholinyl)-1-(1-naphthenate)]cyclohexane;

(-)-TRANS-[2-(4-morpholinyl)-1-(1-naphthenate)]cyclohexane;

(+)-TRANS-[2-(4-morpholinyl)-1-(4-bromophenetole)]cyclohexane;

(-)-tra is s-[2-(4-morpholinyl)-1-(4-bromophenetole)]cyclohexane;

(+)-TRANS-[2-(4-morpholinyl)-1-[2-(2-naphthoxy)ethoxy)]cyclohexane;

(-)-TRANS-[2-(4-morpholinyl)-1-[2-(2-naphthoxy)ethoxy)]cyclohexane;

(+)-TRANS-[2-(4-morpholinyl)-1-[2-(4-bromophenoxy)ethoxy]]cyclohexane;

(-)-TRANS-[2-(4-morpholinyl)-1-[2-(4-bromophenoxy)ethoxy]]cyclohexane;

(+)-TRANS-[2-(4-morpholinyl)-1-(3,4-dimethoxyphenoxy)]cyclohexane;

(-)-TRANS-[2-(4-morpholinyl)-1-(3,4-dimethoxyphenoxy)]cyclohexane;

(+)-TRANS-[2-(1-pyrrolidinyl)-1-(1-naphthenate)]cyclohexane;

(-)-TRANS-[2-(1-pyrrolidinyl)-1-(1-naphthenate)]cyclohexane;

(+)-TRANS-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophene-3-yl)-ethoxy)]cyclohexane;

(-)-TRANS-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophene-3-yl)-ethoxy)]cyclohexane;

(+)-TRANS-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophene-4-yl)-ethoxy)]cyclohexane;

(-)-TRANS-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophene-4-yl)ethoxy)]cyclohexane;

(+)-TRANS-[2-(4-morpholinyl)-1-(3-bromophenetole)]cyclohexane;

(-)-TRANS-[2-(4-morpholinyl)-1-(3-bromophenetole)]cyclohexane;

(+)-TRANS-[2-(4-morpholinyl)-1-(2-bromophenetole)]cyclohexane;

(-)-TRANS-[2-(4-morpholinyl)-1-(2-bromophenetole)]cyclohexane;

(+)-TRANS-[2-(4-morpholinyl)-1-(3-(3,4-acid)-1-propoxy)]cyclohexane;

(-)-TRANS-[2-(4-morpholinyl)-1-(3-(3,4-acid)-1-propoxy)]cyclohexane;

(+)-TRANS-[2-[bis(2-methoxyethyl)am the Nile]-1-(2-naphthenate)]-cyclohexane;

(-)-TRANS-[2-[bis(2-methoxyethyl)aminol]-1-(2-naphthenate)]-cyclohexane;

(1R,2R)/(1S,2S)-2-(4-morpholinyl)-1-(3,4-dichlorophenoxy)cyclohexane;

(1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(1-naphthenate)cyclohexane;

(1R,2R)/(1S,2S)-2-(1-acetylpiperidine)-1-(2-naphthenate)-cyclohexane;

(1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(2,6-dichlorophenoxy)cyclohexane;

(1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(1-naphthenate)cyclohexane;

(1R,2S)/(1S,2R)-2-(4-morpholinyl)-1-[(2-trifluoromethyl)venetucci]cyclohexane;

(1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-[3-(cyclohexyl)propoxy]cyclohexane;

(1R,2R)/(1S,2S)-2-(3-acetoxypropionyl)-1-(1-naphthenate)cyclohexane;

(1R,2R)/(1S,2S)-2-(4-morpholinyl)-1-[(2,6-dichlorophenyl)methoxy]cyclohexane;

(1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-[(2,6-dichlorophenyl)-methoxy]cyclohexane;

(1R,2R)/(1S,2S)-2-(3-hydroxypyrrolidine)-1-(2,6-dichlorophenoxy)cyclohexane;

(1R,2R)/(1S,2S)-2-(3-ketopropionic)-1-(2,2-diphenylmethoxy)-cyclohexane;

(1R,2R)/(1S,2S)-2-(3-thiazolidine)-1-(2,6-dichlorophenoxy)cyclohexane;

(1R,2S)/(1S,2R)-2-(3-ketopropionic)-1-(1-naphthenate)cyclohexane;

and their pharmaceutically acceptable salts.

11. The composition having antiarrhythmic activity, suitable for treating or preventing arrhythmia in a warm-blooded animal, including active soy is inania in combination with a pharmaceutically acceptable carrier, excipient or diluent, wherein the active compounds it contains the compound according to any one of paragraphs. 1-10 in an effective amount.

12. The composition according to claim 11, characterized in that the specified fibrillation is a cardiac arrhythmia.

13. The composition according to claim 11, characterized in that the specified arrhythmia refers to a group, including atrial fibrillation, ventricular fibrillation, atrial fibrillation and ventricular fibrillation.

14. The composition having antiarrhythmic activity, suitable for modulating the activity of ion channels in warm-blooded animals or in vitro, comprising the active compound in combination with a pharmaceutically acceptable carrier, excipient or diluent, wherein the active compounds it contains the compound according to any one of paragraphs. 1-10 in an effective amount.

15. The composition having antiarrhythmic activity, suitable for the treatment or prevention of diseases, conditions or disorders in warm-blooded animals, which are responsible for modulating the activity of ion channels, including the active compound in combination with a pharmaceutically acceptable carrier, excipient or diluent, wherein the active compounds it contains the compound according to any one of paragraphs. 1-10 in an effective amount.

16. Comp the position indicated in paragraph 15 wherein the disease, condition or disorder refers to a group that includes arrhythmia, disease of the Central nervous system, convulsions, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, gastrointestinal disorders, urinary incontinence, mucous colitis, cardiovascular disease, cerebral ischemia or myocardial ischemia, hypertension, long QT syndrome, stroke, migraine, eye diseases, diabetes, myopathy, myotonia Becker, pregnant myasthenia, congenital paramythia, malignant hyperthermia, gipercalziemiceski periodic paralysis, myotonia Thomsen, autoimmune diseases, graft rejection in organ transplantation or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease, senility or dementia, and alopecia.

17. The composition having antiarrhythmic activity, is appropriate for analgesia or local anesthesia in a warm-blooded animal in need, including an active compound in combination with a pharmaceutically acceptable carrier, excipient or diluent, wherein the active compounds it includes the connection on l is the Bohm PP. 1-10 in an effective amount.

18. The composition having antiarrhythmic activity, suitable for enhancing libido in a warm-blooded animal in need, including an active compound in combination with a pharmaceutically acceptable carrier, excipient or diluent, wherein the active compounds it contains the compound according to any one of paragraphs. 1-10 in an effective amount.

19. A method of treating or preventing arrhythmia in a warm-blooded animal, including the introduction of a warm-blooded animal in need, a therapeutically effective amount of the active means, wherein as the active tool, used as a compound according to any one of paragraphs. 1-10.

20. The method according to claim 19, characterized in that the specified fibrillation is a cardiac arrhythmia.

21. The method according to claim 19, characterized in that the specified arrhythmia is Adrianna arrhythmia or atrial fibrillation.

22. The method according to claim 19, characterized in that the specified arrhythmia is ventricular fibrillation or ventricular fibrillation.

23. The method according to claim 19, characterized in that the specified arrhythmia is atrial fibrillation.

24. The method according to claim 19, characterized in that the specified arrhythmia is ventricular fibrillation.

25. Method of modulating activity of ion channels in warm-blooded animals, vklyuchayuthie warm-blooded animal, in need, a therapeutically effective amount of the active means, characterized in that the active tool is used as a compound according to any one of paragraphs. 1-10.

26. A method of treating or preventing diseases, conditions or disorders in warm-blooded animals, which are responsible for modulating the activity of ion channels, including the introduction of a warm-blooded animal in need, a therapeutically effective amount of the active means, characterized in that the active tool is used as a compound according to any one of paragraphs. 1-10.

27. The method according to p, wherein the disease, condition or disorder refers to a group that includes arrhythmia, disease of the Central nervous system, convulsions, epileptic spasms, depression, anxiety, schizophrenia, Parkinson's disease, respiratory disorders, cystic fibrosis, asthma, cough, inflammation, arthritis, allergies, gastrointestinal disorders, urinary incontinence, mucous colitis, cardiovascular disease, cerebral ischemia or myocardial ischemia, hypertension, long QT syndrome, stroke, migraine, eye diseases, diabetes, myopathy, myotonia Becker, myasthenia pregnant, congenital paramythia, malignant hyperthermia, gipercalziemiceski periodic paralysis, myotonia Thomsen, auto is Monnie disease, graft rejection in transplantation of an organ or bone marrow transplantation, heart failure, hypotension, Alzheimer's disease, senility or dementia, and alopecia.

28. Way for local analgesia or local anesthesia in a warm-blooded animal, including the introduction of a warm-blooded animal in need, a therapeutically effective amount of the active means, characterized in that the active tool is used as a compound according to any one of paragraphs. 1-10.

29. A way to enhance libido in a warm-blooded animal, including the introduction of a warm-blooded animal in need, enhancing the number of active means, characterized in that the active tool is used as a compound according to any one of paragraphs. 1-10.

30. The method of modulating the in vitro activity of ion channels, including the introduction of an effective amount of a compound according to any one of paragraphs. 1-10 in ion channel in vitro.

Priorities:

01.04.1998 - all claims, except signs: R1and R2selected from C1-8hydroxyalkyl or R1and R2taken together with the nitrogen atom to which they are directly connected, the mean ring of formula (II), with an additional three atoms in the ring, where any two adjacent atoms of the ring may be linked single Il the double bonds, additional carbon atom of the ring (II) can be replaced With1-20alkanoyloxy;

05.02.1999 - signs: R1and R2selected from C1-8hydroxyalkyl; or R1and R2taken together with the nitrogen atom to which they are directly connected, the mean ring of formula (II) , with an additional three atoms in the ring, where any two adjacent atoms of the ring may be connected by single or double bonds, and the additional carbon atom of the ring (II) can be replaced With1-20alkanoyloxy.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

The invention relates to new triaromatic the vitamin D analogues of General formula (I):

where R1- CH3or-CH2HE, R2-CH2HE, X-Y - linkage of formula (a) or (C)

where R6- H, lower alkyl, W is O, S or-CH2-, Ar1, Ar2the cycles of formula (e), (j), (k), (m)

R8, R9, R11, R12- H, lower alkyl, halogen, HE, CF3,

R3-

where R13, R14- lower alkyl, CF3, R15- H, acetyl, trimethylsilyl, tetrahydropyranyl, or their salts

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to derivatives of 2-phenyl-benzo(b) furan and thiophene, which may be suitable for the treatment of dependent estrogenos diseases, such as prostatic hyperplasia, breast cancer, endometrial cancer, populating infertility and melanoma

The invention relates to piperazinone derivatives, to processes for their production, to their use and to the containing pharmaceutical compositions

The invention relates to omega-Amida N-arylsulfonamides formula I

and/or stereoisomeric forms of the compounds I and/or physiologically acceptable salts of the compounds I where R1means phenyl, phenyl, substituted once with halogen, the rest of the heterocycle of the following groups: morpholine, pyrrolidine; R2means N; R3means -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen to which they are bound, form a residue of formula IIa, IIe

moreover, in formula IIa, IIe q indicates an integer of zero or 1, Z denotes the carbon atom or a covalent bond, and R8means a hydrogen atom or halogen, or R3means -(C1-C4)-alkyl-C(O)-Y, where Y means the remainder of the formula IIC or IId

moreover, in formulas IIc and IId, R8means H or halogen, R9means H, or R3means -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)about-N(R4)-R5and R9has the above values, means the integer 2 and R is substituted by-O-, And means covalent bond, B means -(CH2)m- where m is zero, X is-CH=CH-

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)

The invention relates to a method of obtaining thiazolidine and its salts by reacting hexamethylenetetramine formula (I) with applied or its salts of the formula (II), where X(-)represents an acid residue in a polar solvent

The invention relates to compounds of formula (I) and (II) the value of the radicals R1-R18presented in the description, with the ability to inhibit prenyltransferase

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to chemical compounds, specifically to 3-phenyl-5-[(2 oksifenil)AMINOPHENYL] -methyladenine as an inhibitor of oxidation processes of organic substances, and can be used as an antioxidant hydrocarbons, fats, oils, fatty acids, and drugs [6]

There are various antioxidants (phenols, aromatic amines, naftaly, sulfur-containing compounds) capable of small input quantities to inhibit oxidative transformations [1] are Applied in this as well as heterocyclic compounds, derivatives of N-phenylamine-1,2,3,4-tetrahydropyridine, and 1,2-(11,21-benzimidazole)hydropyridine), in particular for the stabilization of fats [2, 3] Structural analogue of the proposed antioxidant is anti-corrosion additive to synthetic lubricating oils, 2-(3,5-DI-tert-butyl-4-hydroxy)-phenyl-3-benzyl-4-thiazolidone formula [4]

< / BR>
The purpose of the invention the expansion of the range of antioxidants, improving the efficiency of stabilization of oxidative transformations of organic substances

The invention relates to new derivatives of 2-methyl-3-etoxycarbonyl-5-(2'-cyano-3'-aminopropyl-2'-enylidene)pyrrolin - 2-it-4 or 2-(2'-cyano-3'-aminopropyl-2'-enylidene)indolinone-3 of the General formula 1

< / BR>
where, if R = COOC2H5, R1= CH3, R2+ R3= (CH2)5(a) R2+ R3= CH2CH2OCH2CH2(b) R2= H, R3= CH2C6H5(C) R2= H, R3= CH2C6H4OCH3-4 (g) R2= H, R3= CH2C6H3(OCH3)-3,4 (d) R + R1= CH = CH-CH = CH R2= R3= H (e) R2= H, R3= (CH2)6(W) R2= H, R3= CH2CH2N(C2H5)2(C) R2= H, R3= CH2CH(OH)CH2OH and R2+ R3= CH2CH2OCH2CH2(K) R2+ R3= CH2CH2N(CH3)CH2CH2(l) R2+R3=CH2CH2= H, R3= CH2C6H4OCH3-4 (o) R2= H, R3= CH2C6H3(OCH3)-3,4 (p) R2= H, R3= CH(CH3)C6H5(p) R2= H, R3= CH2CH2C6H5(c) R2= H, R3= CH2CH2C6H3(OCH3)-3,4 (t) R2= H, R3= CH(CH3)CH2C6H5(u) R2= H, R3= C6H5(f) R2= H, R3= C6H4OCH3-4 (x) with antihypertensive activity
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