Derivatives of 1,2,5-thiadiazole, intermediate compounds, methods of preparation and pharmaceutical composition

 

(57) Abstract:

Describes new derivatives of 1,2,5-thiadiazole or its kvaternikova form selected from compounds having the General formula I, in which W is oxygen or sulfur; R is selected from the group consisting of hydrogen, halogen, R4, -OR4, -SR4, -SO2R4and-Z-C4-12-(cycloalkenyl); R4selected from the group consisting of C1-15-alkyl, C2-15-alkenyl and C2-15-quinil, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CF3, phenyl, phenoxy, in which phenyl, phenoxy optionally substituted by one or more substituents independently selected from the group consisting of halogen, - CN, C1-4-alkyl, C1-4-alkoxy, -OF3, -CF3; or R is selected from the group consisting of-OR5Y, -SR5Y, OR5-Z,-Y,- SR5ZY, -O-R5Z-R4and Z represents oxygen or sulfur; R5is1-15-alkyl; Y represents 5 - or 6-membered heterocyclic group selected from tanila, pyridyl and thiazolidone; G is selected from usacycling or azabicyclic ring systems or G is not necessarily themeseastern substituted C1-6)-alkyl, in which the Deputy is NR6R7; R6and R7both represent hydrogen or C1-6-alkyl; one of R1and R2represents hydrogen and the other represents hydrogen or C1-6-alkyl; R3represents hydrogen or C1-5-alkyl; m represents 0, 1 or 2; p represents 0, 1 or 2; q is 1 or 2; r is 0, 1 or 2; represents a single or double bond, provided that when W is oxygen and G is alkyl, R is selected from the group consisting of hydrogen, R4, -OR4, -SR4, -SO2R4, -Z-C4-12-(cycloalkenyl), each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen and-CF3; or R is selected from the group consisting of OR5Y, -SR5Y, OR5-Z,-Y,- SR5ZY, -O-R5-Z-R4; Z represents oxygen or sulfur, R5is1-5-alkyl; or its pharmaceutically acceptable salt or MES. The invention relates to therapeutic active usacycling or azabicyclic compounds, method of their preparation and to pharmaceutical compositions comprising these compounds. The new compounds are useful in the treatment of 20 C.p. f-crystals, 5 table.

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The present invention relates to therapeutically active usacycling or azabicyclic compounds, method of their production and to compositions for pharmaceutical or veterinary use, comprising the said compound with a carrier. The new compounds are useful as stimulants of the cognitive functions of the anterior part of the brain and hippocampus mammals, and especially for the treatment of Alzheimer's disease.

Due to improve the overall health in the Western world diseases associated with old age are much more common now than in the past, and it is highly likely that there will be even more common in the future.

One of the symptoms associated with age, is the reduction of cognitive functions or abilities. This symptom is especially pronounced when the pathophysiological disease known as Alzheimer's disease. This disease combined, and most likely called it, with up to 90% degeneration muscarinic cholinergic neurons in the basal nucleus, which is part of nameless substances. These neurons are projected on prefrontal the brain and and hippocampus, namely the ability to learn, Association, consolidation, and recognition.

For Alzheimer's disease is characterized by the fact that, although cholinergic neurons degenerate, postsynaptic muscarinic receptors in the anterior part of the brain and mediated still exist. Therefore, muscarinic cholinergic agonists useful in the treatment of Alzheimer's disease, to suspend its progression and improve cognitive functions in the elderly.

The compounds of this invention are also useful analgesic agents and are therefore useful in the treatment of painful conditions.

Moreover, the compounds of this invention are useful in the treatment of glaucoma, psychosis, mania, bipolar disorders, schizophrenia or schizophrenia, depression, sleep disorders, epilepsy, cerebral ischemia and disorders of motor function of the gastrointestinal tract.

The aim of the invention is the provision of a new muscarinic cholinergic compounds.

The new compounds of this invention are heterocyclic compounds having the formula I'

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in which: W represents Soboh is UP>, -SR4, -SOR4, -SO2R4, (3-10)C cycloalkyl, (4-12)C-(cycloalkenyl), -Z(3-10)C cycloalkyl and-Z-(4-12)C-(cycloalkenyl), where R4is (1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil, each of which is optionally substituted by one or more halogen, -CN, CF3, Y, phenyl or phenoxy, where phenyl or phenoxy is optionally substituted with halogen, cyano, (1-4)C-alkyl, (1-4)alkoxy, -OCF3, -CF3, -CONH2or CSNH2; or R represents phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, cyano, (1-4)C-alkyl, (1-4)alkoxy, -OCF3, - CF3, -CONH2or CSNH2; or R represents a group-OR5Y, -SR5Y, OR5-Z,-Y,- SR5ZY, -O-R5-Z-R4or-S-R5-Z-R4where Z is oxygen or sulfur, R5is (1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil, and Y represents a 5 - or 6-membered heterocyclic group; and

G is selected from one of the following usacycling or azabicyclic ring systems;

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or G may be optionally substituted (3-8)C-cycloalkyl or optionally substituted (1-6)C-alkyl, in which the Deputy is-NR6R7;

R6and R7predstavitelnee ring;

R1and R2are independently hydrogen, (1-15)C-alkyl, (2-15)C-alkenyl, (2-5)C-quinil (1-10)C-alkoxy, (1-5)C-alkyl, substituted hydroxy group, -COR6CH2-OH, halogen, -NH2, carboxy or phenyl;

R3represents hydrogen, (1-5)C-alkyl, (2-5)C-alkenyl or (2-5)C-quinil;

n represents 0, 1 or 2;

m represents 0, 1 or 2;

p represents 0, 1 or 2;

q represents 1 or 2;

r represents 0, 1 or 2;

represents a single or double bond;

provided that when W is oxygen and G is alkyl, R is selected from the group consisting of hydrogen, amino, other6, NR6R7, R4, -OR4, -SR4, -SOR4, -SOR4, -SO2R4(3-10)C-cycloalkyl, (4-12)C-cycloalkenyl, -Z-(3-10)C-cycloalkyl and-Z-(4-12)C-(cycloalkyl), phenyl and benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, (1-4)C-alkyl, (1-4)alkoxy, -OCF3, -CF3, -CONH2or CSNH2; or R is-OR5Y, -SR5Y, OR5-Z,-Y,- SR5ZY, -O-R5-Z-R4or-S-R5-Z-R4where Z is oxygen or sulfur, R5is (1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil; or their pharmaceutically acceptable salts Illicium

the interaction of the compounds of formula III

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where P is R9SO2or halogen; R9is (1-8)C-alkyl or aryl; and R has the meanings given above, G-(CH2)r-W-h+where h+represents a metal alkoxide, G, W and r have the values defined above.

Another aspect of the present invention provides new compounds of formula IV and a method of producing compounds of the formula IV

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including the interaction of the compounds of formula III in which P represents chlorine

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connection R8N/(R10R11R12Si)(R13R14R15Si)/, where R has the meanings given above, R8represents lithium, sodium or potassium; Si means silyl; R10, R11, R12, R13, R14and R15independently selected from the group consisting of (1-6)C-alkyl, aryl and aryl(1-3)C-alkyl; R15and R16independently selected from the group consisting of hydrogen, R10R11R12Si, and R13R14R15Si. R is selected from the group consisting of hydrogen, amino, halogen, other6, NR6R7, R4, -OR4, -SR4, -SO2R4, (3-10)C-cycloalkyl, (4-12)2C-(cycloalkenyl), -Z(3-10)C-cyclol the ryh optionally substituted by one or more halogen, -CF3, -CN, Y, phenyl or phenoxy, where phenyl or phenoxy is optionally substituted with halogen, -CN, (1-4)C-alkyl, (1-4)alkoxy, -OCF3, -CF3, -CONH2or CSNH2; or

R represents phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, (1-4)C-alkyl, (1-4)alkoxy, -OCF3, -CF3, -CONH2or CSNH2; or

R is-OR5Y, -SR5Y, -OR5-Z,-Y,- SR5ZY, -O-R5-Z-R4or-S-R5-Z-R4where Z is oxygen or sulfur, R5is (1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil, and Y represents a 5 - or 6-membered heterocyclic group;

provided that when R is hydrogen, amine or halogen, R16must be selected from the group consisting of (R10R11R12Si) and (R13R14R15Si).

Finally, the present invention provides compounds of formula V:

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where W1selected from the group consisting of O, S and SO2;

R17selected from the group consisting of (1-6)C-alkyl, aryl, R19-substituted alkyl, and R19-substituted aryl;

R19selected from the group consisting of straight or branched (1-6)C-alkyl, straight or UP>20di(1-6)C-alkylamino, NO2, SR20, OR20, (3-8)C-cycloalkyl, (3-8)C-cycloalkyl-(1-3)C-alkyl, (5-8)C-cycloalkenyl, substituted (5-8)C-cycloalkenyl, (5-8)C-cycloalkenyl-(1-3)C-alkyl and (7-16)C-arylalkyl;

R20independently selected from the group consisting of hydrogen and (1-4)C-alkyl; in which the substituent R19can be attached to any available carbon atom;

R18is R4SO2Cl; Br or I;

provided that when W is O and R is (1-5)C-alkyl or aryl, then R18selected from R4SO2, bromine or iodine; or their pharmaceutically acceptable salt or solvate.

It should be understood that the invention extends to each of the stereoisomeric forms of the compounds of the present invention, as well as on the net diastereomers, pure enantiomeric and racemic forms of the compounds of this invention.

Further, the invention relates to a process for obtaining the intermediate compounds of formula II

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or III above, including the interaction of the compound (CN)2with R4-S-H or G(CH2)r-W-H, where P, R4, G, r, and W have the meanings given above, and

the connection that is formed subsequently sportsway herein, the term "treatment" includes the prevention of physical and/or mental condition, or improvement or elimination of physical and/or mental condition, if it occurs, or the characteristic withdrawal symptoms for this condition.

Used here in relation to the Deputy G-(CH2)r-W-thiadiazolyl fragment can be attached to any carbon atom usacycling or azabicyclic rings. Further, R1and R2Deputy G may be present in any position, including the point of connection between -(CH2)r-W-thiadiazoline fragment.

Used in respect of the Deputy G "R6and R7together with the nitrogen atom optionally form a 4 - to 6-membered ring" means that R6and R7each independently represents hydrogen, (1-6)C-alkyl, where R6and R7groups may not necessarily be connected, form a 4 - to 6-membered ring including the nitrogen. For example, United optional groups include, but are not limited to:

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Used here, the phrase "interacting with muscarinic cholinergic receptor" includes compounds that block cholinergic receptors or modulate these receptors. This phrase covers the effect observed when compounds act as agonists, partial agonists and/or antagonists of muscarinic holinergicheskoj the Finance alkoxide or alcoholate. Such alkoxide metals include, but are not limited to, Li+, K+, Na+Cs+and Ca++. Especially preferred alkoxide metals include Li+, K+and Na+.

Used herein, the term "halogen" denotes chlorine, bromine, fluorine and iodine. Particularly preferred Halogens include chlorine, bromine and iodine.

Used here, the phrase "one or more selected from" preferably refers to the number of substituents is from 1 to 3. This term is further preferably applies to 1 or 2 substituents.

The term(I-n)C aklil", where n' can represent from 2 to 15, used herein, represents a branched or linear alkyl group having from 1 to the specified number of carbon atoms. Typical (1-6)C alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, ISO-propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl and similar.

The term "2(2-n')C-alkenyl", where n' can contain from 3 to 10, as it is used in this description, is alafinova unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, non=CHCH2CH3), hexenyl, pentenyl and similar.

The term(2-5)C quinil" refers to an unsaturated branched or linear group having from 2 to 5 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 1-pentenyl and similar.

The terms "halogen(1-6)C-alkyl and halogen(2-6)C alkenyl" refer to alkyl or alkenylphenol Deputy, having one or more substituents selected independently from halogen atoms attached to one or more available carbon atoms. These terms include, but are not limited to, chloromethyl, 1-bromacil, 2-bromacil, 1,1,1-triptorelin, 1,1,2-triptorelin, 1,2,2-triptorelin, 2,2,2-triptorelin, triptorelin, triptorelin, 3-bromopropyl, 3-bromo-1-propenyl, 2-bromopropyl, 2-bromo-1-propenyl, 3-chlorobutyl, 3-chloro-2-butenyl, 2,3-dichloroethyl, 1-chloraniline, 2-chlorethylene, 5-fluoro-3-pentenyl, 3-chloro-2-bromo-5-hexenyl, 3-chloro-2-bromobutyl, trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 2,2-dichloroethyl, 1,4-dichloroethyl, 3-bromopentyl, 1,3-dichloroethyl, 1,1-dichloropropyl, and similar.

The term(2-10)C alkanoyl" represents a group of formula C(O)(1-9)C aklil. Typical (2-10)C alcoholnye group amino group. Examples of such groups are methylamino, ethylamino, isopropylamino, n-propylamino, (n-propyl)amino, (ISO-propyl)amino, n-Propylamine, tert-butylamine and similar.

The term "(3-n)C cycloalkyl", where n=4-8, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "substituted (5-n')C-cycloalkyl" refers to cycloalkyl group described above in which cycloalkyl group may be substituted by one to four substituents, independently selected from the group consisting of hydrogen, (1-6)C-alkyl, NO2, halogen, halogen(1-6)C alkyl, halogen(2-6)C alkenyl, (2-6)C alkenyl, CO2R2-, (1-6)C alkylamino, -SR20and OR20; where R20selected from the group consisting of (1-15)C alkyl, (2-15)C alkenyl, (2-15)C quinil.

The term "(3-8)C cycloalkyl-(1-3)alkyl" represents an alkyl group, substituted on the terminal carbon atom (3-8)C cycloalkyl group. Typical cycloalkenyl group include cyclohexenyl, cyclohexylmethyl, 3-cyclopentylpropionyl and similar.

The term "(5-8)C cycloalkenyl" is alafinova unsaturated ring having 5-8 carbon atoms. Such groups include, but are not limited to, Ziklag the l-1,4-dienyl, cyclooctyl-1,3,5-trienyl and similar.

The term "substituted (5-8)C cycloalkenyl" refers to cycloalkenyl group described above in which cycloalkenyl group may be substituted by substituents in an amount of from 1 to 4 independently selected from the group consisting of hydrogen, halogen (2-6)C alkenyl, (2-6)C alkenyl, COR20, (2-10)C alkanoyl, (7-16)C arylalkyl, CO2R20, (1-6)C alkylamino, -SR20and-OR2-; where R20selected from the group consisting of (1-15)C alkyl, (2-15)C alkenyl and (2-15)C quinil.

The term "(5-8)C cycloalkenyl-(1-3)alkyl" represents (1-3)C alkyl group, substituted on the terminal carbon (5-8)C cycloalkenyl group.

Used here, the phrase "5 - or 6-membered heterocyclic group" means a group containing from 1 to 4 nitrogen atoms, oxygen, or sulfur, or combinations thereof, and the said heterocyclic group is optionally substituted on carbon atom or atom/atoms/ nitrogen (1-6)alkyl, -CF3, phenyl, benzyl or Tienam, or a carbon atom in the heterocyclic group together with an oxygen atom form a carbonyl group, or the specified heterocyclic group is optionally condensed with a phenyl group. FR 1 heteroatom (for example, tifany, pyrrole, furan); 5-membered heterocycles having 2 heteroatoms in 1,2 or 1,3-positions (e.g., oksazolov, pyrazoles, imidazoles, thiazole, purines); 5-membered heterocycles having 3 heteroatoms (e.g., triazoles, thiadiazoles); 5-membered heterocycles having 3 heteroatoms; 6-membered heterocycles with one heteroatom (for example, pyridine, quinoline, isoquinoline, phenanthren, 5,6-cycloheptatrien); 6-membered heterocycles with 2 heteroatoms (e.g., pyridazine, cinnoline, phthalazine, pyrazine, pyrimidines, hintline); 6-membered heterocycles with 3 heteroatoms (e.g., 1,3,5-triazine); and 6-membered heterocycles with 4 heteroatoms. Especially preferred are tifany, pyridine and furans.

Used herein, the term "carboxy" refers to the Deputy with the ordinary meaning understood by the experts, in which the point of connection may be through a carbon atom or oxygen group.

Used in this description, the term "aryl" means an organic radical derived from an aromatic hydrocarbon, which removed one atom, for example, phenyl or naphthyl. Most preferably the aryl refers to (6-10)C aryl, in which aryl ring system, including any alkyl Samael may be substituted by one or two (1-6)C straight or branched alkilani. The term "aryl (1-3)C alkyl" refers to any aryl group that is attached to the main portion through the alkyl group.

Used herein, the term "phosphate/III/ connection" or "connection phosphorus /III/" is accepted in the art the meaning of the term. This term includes, for example, but not limited to, triphenylphosphine, three(p-tolyl)phosphine, tributylphosphine, three(p-dimethylaminophenyl)phosphine, triethylphosphine and trimethylphosphine. The average person is able to choose other suitable phosphorus compounds /III/ using methods and literary references, which are generally experts-chemists.

Used herein, the term "fluids of azodicarboxylate has adopted the technique of value. For example, the term encompasses, but is not limited to, diethylazodicarboxylate, diethylazodicarboxylate, diisopropylsalicylic and di-tert-utilisationbased. Specialist-chemist can determine other suitable diesters of azodicarboxylate using methods and literary sources available to a qualified chemist.

Examples of pharmaceutically acceptable salts include inorganic and organic acid additive salts such as hlog rmaceuticals acceptable additive salts of organic and inorganic acids, and include pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977), which are well known to the average expert. The compounds of this invention may form a solvate with standard solvents with low molecular weight using methods known to experts.

The compounds of this invention can be obtained using chemical processes illustrated in scheme I (see the end of the description). Starting materials for the process are shown industrially available or can be obtained using methods known to experts.

Used in scheme I, R, h+and G have the meanings given above. Used in scheme I, the term "Hal" refers to chlorine, bromine and R9SO2. Preferred oxidizing agents for the process of scheme I include Oxon and periodate sodium. Axon is particularly preferred oxidizing agent in the process scheme I. Compounds of formula 3, is shown in scheme I, in which the OR group is replaced with R4the group can be obtained using methods well known in the art. See, for example, U.S. patent N 5043345.

Further, the compounds of formula I can be obtained irestaurant nitrogen, oxygen or sulfur; R24selected from the group consisting of hydrogen, R4, R5, R6and R7; R25selected from the group consisting of SOR4and SO2R4; all other symbols have the meanings defined above.

Additional compounds of formula I can be obtained using the process illustrated by scheme III.

Used in scheme III, Hal, W, r and G have the meanings given above. Used in scheme III R22and R23independently selected from the group consisting of hydrogen, R6and R7.

Some intermediate compounds of the present invention can be obtained using the process shown in scheme IV.

Used in scheme IV, the symbols R8Si, R10, R11, R12, R13, R14, R15R15and R16have the meanings given above. For example, the connection R8N/(R10R11R12Si) (R13R14, R15Si)/ can be, but is not limited to, bis(tri-2-propulsion)Amin lithium bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide and potassium bis(tri-2-propulsion)amide and lithium bis(acidimetric)amide and sodium bis(1-propylaminosulfonyl)potassium amide, (three 2-propulsion)(2-butyldimethylsilyl)amide lithium (trimethylsilyl)(triphenylene)sodium amide, (dimethylphenylsilane)(acidimetric)amide potassium and similar. Most preferably, R15and R16are each hydrogen, when used in the process of scheme III to obtain compound 11 from compound 10. Intermediate compound 10 can nitroaromatic using standard procedures nitrosation. Preferred nitrogenous agent is soliditet; however, are suitable and others well-known nitrotyrosine agents. Used herein, the term "Cu(Br,I)" refers to the bromide copper (I) bromide copper (II) or copper iodide (I). Specialist evidently clear that the reagent bromide copper (I) bromide copper (II) or copper iodide (I) will determine substitution in the product of the process illustrated in scheme III.

Some compounds of the present invention can be preferably obtained by a process using hydroxyethylamine (G-OH), in which G has the values defined above, in the presence of phosphorus compounds (II) and diapir of azodicarboxylate, giving 1,2,5-thiadiazolidine, as shown in scheme V.

Group G have the meanings given to the P>, -SOR4, -SO2R4, (3-10)C-cycloalkyl, (4-12)C-(cycloalkenyl), -Z(3-10)C cycloalkyl and-Z-(4-12)C-(cycloalkenyl); R4selected from the group consisting of (1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen (s), -CF3, -CN, Y, phenyl and phenoxy, where phenyl or phenoxy optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, (1-4)C-alkyl, (1-4)alkoxy, -OCF3or-CF3; or R' is phenyl or benzyloxycarbonyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, (1-4)C-alkyl, (1-4)alkoxy, -OCF3and-CF3; or R' is selected from the group consisting of-OR5Y, -SR5Y, OR5-Z,-Y,- SR5ZY, -O-R5-Z-R4and-S-R5-Z-R4; Z represents oxygen or sulfur; R5selected from the group consisting of (1-15)C-alkyl, (2-15)C-alkenyl, and (2-15)C-quinil; Y represents a 5 - or 6-membered heterocyclic group; R1selected from the group consisting of phenyl, (1-15)C-alkyl, (2-5)C-alkenyl, (2-5)C-quinil and (NR2)3silt, (2-5)C-quinil, and (1-5)C-alkyl, substituted by one or more substituents selected from the group consisting of halogen and phenyl; W is oxygen or sulfur; R6and R7are independently (1-6)C-alkyl, or R6and R7together with the nitrogen atom form an optionally 4 - to 6-membered ring; R1and R2independently selected from hydrogen, (1-15)C-alkyl, (2-5)C-alkenyl, (2-5)C-quinil, (1-10)C-alkoxy, and (1-5)C-alkyl, substituted by one or more substituents independently selected from the group consisting of-COR6, halogen, and phenyl; R6represents hydrogen or (1-3)C-alkili R3selected from the group consisting of (1-5)C-alkyl, (2-5)C-alkenyl and (2-5)C-quinil; n represents 0, 1 or 2; m represents 0, 1 or 2; p represents 0, 1 or 2; q is 1 or 2; r is 0, 1 or 2; represents a single or double bond.

Preferred R1groups include phenyl, (1-15)C-alkyl, and (NR2)3. The process according to scheme IV is particularly advantageous, because this process gives way to the inversion of the stereochemistry at the carbon atom bearing the hydroxyl group in G.

Another basic process illustrated by scheme VI, includes the and phosphorous compounds /III/ and diapir of azodicarboxylate, giving unselected hydroxy-1,2,5-thiadiazolyl ether I", followed by reaction of compound I with R4OH, where R4has the values defined above, with a compound of phosphorus /III/ and W of azodicarboxylate, giving the diesters of 3,4-dihydroxy-1,2,5-thiadiazole, which are useful as muscarinic agonists and antagonists. (See, Org. Prep. and Procedure, 1969, 1, 255 - 258). The substituents shown in scheme VI, have the meanings given above.

Alternatively, the order of addition of alcohols may be reversed as shown above, giving an undelimited hydroxy-1,2,5-thiadiazolyl ether II, which later turns into the same end muscarinic active connection.

The process shown in scheme VII, includes the interaction of phenol or hydroxymatairesinol connection with compound III in the presence of phosphorus compounds (II) and diapir of azodicarboxylate, giving compound IV.

In compound III group G(CH2)rW has the meanings given above, and R6selected from the group consisting of R7, -OR7, -SR7, -SOR7, -SO2R7, (3-10)C-cycloalkyl, (4-12)C-(cycloalkenyl), -Z(3-10)C-cycloalkyl, and-Z-(4-12)C-(cycloalkenyl); R7is (1-15)C-alkyl, (2-15)C-and nami from the group consisting of halogen(s), -CF3, -CN, Y, phenyl and phenoxy; where phenyl and phenoxy optionally substituted by one or more substituents selected from the group consisting of halogen, -CN, (1-4)C-alkyl, (1-4)alkoxy, -COF3and CF3; provided that at least one atom alkyl group, R6substituted hydroxyl group, or R6is Deputy selected from the group consisting of-OR8Y, -SR8Y, OR8-Z,-Y,- SR8ZY, -O-R8-Z-R7and-S-R8-Z-R7where each-OR8Y, -SR8Y, OR8-Z,-Y,- SR8ZY, -O-R8-Z-R7and-S-R8-Z-R7replaced by alkylperoxyl; Y represents a 5-or 6-membered heterocyclic group; Z represents oxygen or sulfur; R8is (1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil; aryl and heteroaryl optionally are substituted by one or more substituents independently selected from the group consisting of halogen, -CN, (1-4)C-alkyl, (1-4)alkoxy, (1-4)C-alkylthio, (1-4)C-alkylation, (1-4)C-alkylsulfonate, -OCF3, NO2N(R7)2and-CF3; heteroaryl group is a 5 - or 6-membered heterocycle containing 1 to 4 nitrogen atoms, oxygen or sulfur or a combination thereof.

It is azoles with the processing of 3-halogen-4-alkylthio-1,2,5-thiadiazolo water hydroxides of alkali metals in the presence or absence of a dipolar aprotic solvent. This diagram Hal have the meanings given above, and M represents alkali metal, W is O or s

RRis hydrogen, R4, (3-10)C-cycloalkyl, (4-12)C-(cycloalkenyl), R4-Z-(3-10)C-cycloalkyl, and R4-Z-(4-12)C-(cycloalkenyl); R4selected from the group consisting of (1-15)C-alkyl, (2-15)C-alkenyl and (2-15)C-quinil, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen(s), -CF3, Y, phenyl, phenoxy; phenyl or phenoxy are optionally substituted by one or more substituents selected from the group consisting of halogen, (1-4)C-alkyl, (1-4)alkoxy and-CF3; or RRrepresents phenyl or benzyloxycarbonyl, each of which is optionally substituted by one or more substituents selected from the group consisting of hydrogen, (1-4)C-alkyl, (1-4)alkoxy and-CF3; or RRis R4-OR5Y, R4SR5Y, R4-OR5-Z-Y, R4-SR5ZY, R4O-R5-Z-R4or R4-S-R5-Z-; Z represents oxygen or sulfur;

R5selected from the group consisting of (1-5)C-alkyl, (2-15)C-alkenyl and (2-15)C-quinil; Y represents a 5 - or 6-membered, heterocycle the place with the nitrogen atom optionally form a 4 to 6 membered ring; R1and R2are independently hydrogen, (1-15)C-alkyl, (2-5)C-alkenyl, (2-5)C-quinil, (1-10)C-alkoxy, (1-5)C-alkyl substituted by a group-OH, -COR6CH2-OH, halogen, -NH2-, carboxy or phenyl; R6represents hydrogen or (1-3)C-alkyl; W is O or S; Hal is selected from chlorine, bromine, fluorine, iodine, and, if W is O, then Hal can represent SO2R4W R4is (1-3)C-alkyl or phenyl.

Compounds (II) are useful as intermediate compounds for obtaining 1,2,5-thiadiazole compounds. Specialist in this field, obviously, understands that the intermediate compound (II) are useful for obtaining 1,2,5-thiadiazole compounds, as shown by the processes of schemes I, II and III.

When G Deputy contains a secondary nitrogen atom, protected by a protective group, the protective group can be removed using standard methods well known to the average expert. Particularly preferred protecting group is a carbamate. One particularly useful sources relating to protective groups, is the publication of a Green Protecting Groups in Organic Synthesis, (John Willy & sons, new York, 1981).

The concentration of the reagents is not the AI and product yield.

The length of time to implement the processes described above is not essential. As is always the case in chemistry, the reaction rate depends on various factors, such as temperature and the exact connection that you want to receive. Over the course of the reaction can be monitored using techniques such as thin layer chromatography (TLC), liquid chromatography high resolution or high-performance liquid chromatography (HPLC), gas chromatography (GC) and spectroscopy nuclear magnetic resonance (NMR) to determine the degree of completion of reaction. The operator can obtain maximum outputs with the use of the process by increasing the reaction time. Alternatively, the operator may wish to get the maximum performance by terminating the reaction at the moment when it reaches economic degree completion.

When the product stage of the process is oil, it can be separated using standard methods. Such methods include distillation, instant or flash chromatography, HPLC and similar.

Used herein, the term "dysfunction or dysfunctionraven muscarinic cholinergic system but are not limited to, as glaucoma, psychosis, schizophrenia or schizophrenia-like psychosis status, depression, sleep disorder, epilepsy and disorder of motor function of the gastrointestinal tract. Other such conditions include Alzheimer's disease and incontinence.

Pharmacological properties of the compounds of the invention may be illustrated by determining their ability to inhibit specific binding3H-Oxotremorine-M (3H-Oxo). Birdsdall N. J. M., Hulme, E. C. and Burgen, A. S. V. (1980). "The Character of Muscarinic Receptors in Different Regions of the Rat Brain". Proc. Roy. Soc. London (Series B), 207, 1.

Using3H-Oxo noted muscarinic receptor in the Central nervous system (with a preference to domains of the receptor agonist). Using3H--Oxo noted three different site or site. These websites have the tool 1.8, 20 and 3000 nm, respectively. Using these experimental conditions only determine the sites of high and medium affinity.

Inhibitory effect of compounds on3H-Oxo binding reflects the affinity of muscarinic acetylcholine receptors.

All preparations are carried out at 0 - 4oC, unless otherwise noted. Fresh cortex (0,1-1 g) male Wistar rats (150-250 g) are homogenized for 5-10 seconds in 10 ml of 20 nm Hepes pH: 7.4, with Zia centrifuged for 15 minutes at 40,000 g. The precipitate is washed three times with buffer. At each stage of tablets sediment homogenized as before in 2 to 10 ml of buffer and centrifuged for 10 minutes at 40,000 g.

Final sediment homogenized in 20 nm Hepes pH:7.4 (100 ml per g of original tissue) and used for analysis of binding. To an aliquot of 0.5 ml is added 25 μl of test solution and 25 μl of3H-Oxotremorine (1.0 nm, final concentration), and is made by mixing and incubation for 30 minutes at 25oC. Nonspecific binding is determined by the triple repetition of using arecoline (1 μg/ml, final concentration) as the test substance. After incubation the sample is added to 5 ml ice buffer and the samples are poured directly on the filters of glass fiber Whatman GF/C in terms of suction and immediately washed with 2 times 5 ml mi ice buffer. The amount of radioactivity on the filters is determined by conventional liquid scintillation counting. Specific binding is the total binding minus nonspecific binding.

Test compounds are dissolved in 10 ml of water (if necessary, is heated on the steam bath in I before the calculation of the IC50(IR50). Experimental value is given as IC50(concentration (nm) of the test substance which inhibits the specific binding3H-oxo 50%).

IC50= (the concentration of the applied test substance) x (Cx/C0-Cx) nm, where C0is specific binding in control assays and Cxis the specific binding in the experimental analysis. (Calculations assume normal kinetics of mass action).

In addition, the pharmacological properties of the compounds of the invention can also be illustrated by determining their ability to inhibit3HPRZ (pirenzepine, /N-methyl-N3H/) binding to membranes from cerebral cortex of rats.

Pirenzepine selectively binds to a subtype of muscarinic receptors. Historically the type referred to as M1site, while sensitive to pirenzepine site is more appropriate. Although selective with respect to M1sites of pirenzepine also interacts with M2sites.

All preparations are carried out at 0 to 4oC, unless otherwise noted. Fresh cortex (0,1-19) male Wistar rats (150 - 250 g) homogenized for 5-10 seconds in 10 ml of CME 10 ml buffer, and the combined suspension centrifuged for 15 minutes at 4000 g. The precipitate is washed 3 times with buffer. At each stage sediment homogenized as before 3 10 ml of buffer and centrifuged for 10 minutes at 40,000 g.

The final precipitate homogenized in 20 nm Hepes pH:7.4 (100 ml per g of original tissue) and used for analysis of binding. To an aliquot of 0.5 ml is added 20 μl of test solution and 25 μl of3HPRZ (1.0 nm, final concentration); the samples are mixed and then incubated for 60 minutes at 20oC. Nonspecific binding is determined by three-fold with the use of atropine (1 mg/ml, final concentration) as the test substance. After incubation the sample is added to 5 ml ice buffer, and the samples are poured onto glass-fiber filters (Whatman GF/C under suction and immediately washed twice with 5 ml ice buffer. The magnitude of the radioactivity on the filters is determined using conventional liquid scintillation counting. Specific binding represents an amount equal to the difference between total binding and nonspecific binding.

Test compounds are dissolved in 10 ml water at concentrations of 0,2ptx2">

the test value is given as IC50(concentration in nm spitemare substance which inhibits the specific binding 3HPRZ 50%).

IC50= (applied concentration of the test substance) x (Cx/Co-Cx) nm, where Corepresents specific binding in control assays, and Cxspecific binding in the experimental analysis. (Calculations assume normal kinetics of mass action).

The experimental results obtained from testing some compounds of the present invention can be seen from the table. 1 (see the end of the description).

Table. 2 illustrates some additional compounds of formula I, as claimed in this application.

The compounds of this invention are effective in a wide range of doses. For example, in the treatment of adults can be used in dosages from about 0.05 to 100 mg, preferably from about 0.1 to 100 mg per day. The most preferred dose corresponds to a value from about 0.1 to 70 mg per day. When selecting the dose for patients suffering from disease of the Central nervous system, caused by dysfunction of muscarinic cholinergic system may often be necessary but such magnitude, how about 0.1 to 10 mg per day. The exact dose depends on the method of appointment, form of medication, which is assigned to the connection of the subject being treated, the body weight of the subject and the preference and experience of the physician or the person requiring the care of the patient.

The method can be any method that efficiently transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, and preferred oral way.

Typical compositions include a compound of formula I or its acid-additive pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable excipient, which can be a carrier or a diluent, or diluted with a carrier substance, or the specified connection can be made in the media, this form may be in the form of a capsule, sachet, paper or other container. In the manufacture of the compositions can be used conventional techniques to obtain pharmaceutical compositions. For example, the active compound is usually stitched with a carrier, or diluted novtel the EPA. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a carrier, excipient or environment active compounds. The active compound can be adsorbed on a granular solid container, for example in a sachet (wafers). Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyalkane castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, monoglycerides of fatty acids and diglycerides of fatty acids, PENTAERYTHRITE esters of fatty acids, hydroxymethylcellulose and polyvinylpyrrolidone. The finished form of the drug may also include wetting agents, emilyrose and suspendresume agents, protecting or preserving agents, sweetening or flavoring or flavoring agents. The finished formulation according to the invention can be formed in such a manner as to provide quick, deferred or delayed release of the active ingredient after his appointment to the patient using procedures well known in the art.

The pharmaceutical preparations can be sterilized and mixed, if W is Fermi and/or coloring substances and similar, that does not degrade harmful way with the active compounds.

For parenteral application, particularly suitable are injectisome solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxyalkane castor oil.

Tablets, coated tablets or capsules with media talc or carbohydrate carrier or binder or similar are particularly suitable for oral administration. Preferred carriers for tablets, coated tablets or capsules include lactose, corn starch and/or potato starch. A syrup or elixir can be used in those cases when it can be used sweetened media.

Usually the compounds are dispersed in a unit form comprising from about 0.1 to 100 mg and a pharmaceutically acceptable carrier in dosage unit.

The compounds of this invention can be suitable for appointment to the animals. Such animals include domesticated animals, such as livestock, laboratory animals and contained in home pet, and nadomestnih animals, such as living in the wild. More preferably, the animals are vertebrates. N is th mammal is man. For such purposes the compounds of this invention can be administered in the form of food supplements.

In order to more fully illustrate the operation of this invention, are the following preparative examples of finished forms. The examples are only illustrative and are not intended to limit the scope of the invention in any way.

Preparative form 1

Typical tablets suitable for use in this way, can be prepared using conventional techniques and may contain ingredients listed in table.3.

Preparative form 2

Hard gelatin capsules are prepared using the ingredients given in table. 4.

These ingredients are mixed and they fill hard gelatin capsules in the amount of 210,1 mg.

Preparative form 3

The following are suspensions, each containing 1 mg of drug per 5 ml dose (see table. 5).

The medication is passed through the sieve size 45 mesh U.S. and is mixed with the sodium carboxymethyl cellulose and syrup with the formation of a homogeneous paste. A solution of benzoic acid, flavoring and coloring agent is diluted to some share of the amount required.

Intermediates and methods of the present invention are useful for producing compounds having favorable activity of muscarinic receptors. Compounds of the present invention have such a useful activity muscarinic receptors. Some compounds and conditions covered by the scope of the present invention, are preferred. To obtain preferred compounds and creation of process conditions can be combined independently the following conditions, the embodiment of the invention, and compounds with characteristics listed in tabular form. The following list embodiments of the present invention is not intended to limit in any way the scope of this invention.

Some preferred characteristics of the compounds of formula I are the following:

A/ W is 0,

B/ r is 1 or 2,

C/ G selected from het-1 and het-5,

D/ G is unsaturated,

E/ G is het-4,

F/ G is azabicyclo having 7 ring carbon atoms and a nitrogen atom,

G/ G represents het-6,

H/ r is 0,

1/ R is selected from halogen, -OR5Y, -SR5Y, -OR5ZY, -SR5ZY,

-OR5ZR4, -SR5ZRM/ p is 2,

N/ v is 0 or S,

O/ G is het-2,

P/ G is a choice of the following heterocycles:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where is the point of joining -/CH2/r-W-group is as mentioned,

Q/ G group selected from the group consisting of

< / BR>
< / BR>
< / BR>
< / BR>
R/ G is not azabicyclo,

S/ G is het-3,

T/ R is not a group OR4in which R4is (1-3)C-alkyl,

U/ R4is (4-15)C-alkyl,

V/ G is azabicycles or azabicyclic group

W/ R is selected from the group consisting of-OR5Y, -SR5Y, -OR5ZY, -SR5ZY, -O-R4-Z-R5or-S-R4-Z-R5where Z is oxygen or sulfur, R5-(1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil, Y represents a 5 - or 6-membered heterocyclic group containing 1 to 4 nitrogen atoms, oxygen or sulfur or a combination thereof, R4-(1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil.

Especially preferred compounds of formula I have the characteristics of A-E characteristics of A, G, H, M; characteristics of G-O; A, H, R; B, I, J; J, K, S; A, K, Q; J, P, L; or characteristics of the F, G-J, m

Some preferred characteristics of the process and intermediate ORS/ R10, R11and R12each represents methyl,

D/ R is selected from the group consisting of phenyl, benzyloxycarbonyl, -OR5Y, -SR5Y, -OR5-Z,-Y,- SR5ZY, -O-R4Z-R5or-S-R4-Z-R5, -SOR4, (3-10)C-cycloalkyl, (4-12)C-(cycloalkenyl), -Z(3-10)C-cycloalkyl and-Z-(4-12)C-(cycloalkenyl), where Z represents oxygen or sulfur, R5is (1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil, Y represents a 5 - or 6-membered heterocyclic group containing 1 to 4 nitrogen atoms, oxygen or sulfur or a combination thereof, R4is (1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil,

E/ R is selected from the group consisting of halogen, -OR4and-SP4,

F/ G is azabicyclo having 6 ring carbon atoms and a nitrogen atom,

G R15and R16selected from the group consisting of a /R10R11R12Si/ and /R13R14R15Si/,

H/ R18is R4SO2,

I/ W is sulfur,

J/ R is selected from the group-OR, -SR, and I,

K/ R17represents alkyl or R19substituted alkyl,

L/ W' is sulfur or SO2,

M/ When the compound has formula V, R18is R4SO2Br or I,

N/ R is not OR is Yu or azabicyclic group

Q/ R is selected from the group consisting of-OR5Y-SP5Y, -OR5-Z,-Y,- SR5ZY, -O-R4-Z-R5or-S-R4Z-R5where Z is oxygen or sulfur, R5is (1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil, Y represents a 5 - or 6-membered heterocyclic group containing 1 to 4 nitrogen atoms, oxygen or sulfur or a combination thereof, R4is (1-15)C-alkyl, (2-15)C-alkenyl, (2-15)C-quinil.

Especially preferred characteristics of the process and intermediates of this invention are A-F; characteristics B, C, E; characteristics H, J, K; K, L, M; or the characteristics of B-F, I.

The invention will now be described in more detail with reference to the following examples. Examples are given for illustrative purposes and should not be construed as limiting in any way the scope of the invention.

Example 1

3-Chloro-4(1-butylthio)-1,2,5-thiadiazole

CYANOGEN (36 g, to 0.69 mol) was barotiwala in ether (250 ml) maintained at -10oC. To the solution was added dropwise diethylamine (3 ml) followed by adding dropwise 1-butyltin (47 ml, of 0.64 mol) at such a speed that the temperature did not exceed -5oC. the Reaction mixture was maintained at the temperature of the Il-distilled from the reaction mixture until as the temperature of the vessel did not reach the 50oC. the Reaction mixture was cooled to ambient temperature and then was added dropwise to a solution of monochloride sulfur (55 ml, 0,688 mol) in DMF (50 ml) which was cooled to 5oC.

The cooling was removed and the reaction mixture stirred over night. The reaction mixture was cooled in a bath of a mixture of ice and water, the excess monochloride sulfur was removed by careful addition of water while maintaining the temperature below 40oC. the Liquid was decentralise with semi-solid sulfur sludge, sulfur residue was pulverized with hexane. The aqueous fraction was extracted with hexane (3X), the combined extracts and RUB substances were washed with water, aqueous sodium bicarbonate, saline, dried, the solvent was evaporated. The residue was converted with 2 mm RT.art., giving a yellow liquid (24.6 g), so Kip. 105-110oC. (Compound 1).

Example 2

3-Chloro-4-butylsulfonyl-1,2,5-thiadiazole

The solution OksanaTM(12 g, 0,0195 mol) in water (60 ml) was vigorously mixed as dropwise added 3-chloro-4-butylthio-1,2,5-thiadiazole (2.1 g, of 0.01 mol) in THF (30 ml). After 24 hours, THF was evaporated, the residue was extracted with ether (3X). Extracts probyvala is receiving 30% ethyl acetate/hexane gave a colorless liquid (2.3 g). (Compound 2).

Example 3

3-Chloro-4-ethylthio-1,2,5-thiadiazole

CYANOGEN (36 g, 0.69 mol) was barotiwala in ether (250 ml) maintained at -10oC. To the solution was added dropwise diethylamine (3 ml) followed by adding dropwise ethanthiol (47 ml, of 0.64 mol) at such a speed that the temperature did not exceed -5oC. the Reaction mixture was kept at a temperature below 0oC for 5 hours, then stirred at ambient temperature over night. The ether was distilled from the reaction mixture as long as the temperature of the vessel did not reach the 50oC. the Reaction mixture was cooled to ambient temperature and then was added dropwise to a solution of monochloride sulfur (125 ml of 1.56 mol) in DMF (150 ml) which was cooled to 5oC. Cooling was removed and the reaction mixture stirred over night. The reaction mixture was cooled in a bath of a mixture of ethyl alcohol and ice, the excess monochloride sulfur was destroyed by adding dropwise water, the temperature was maintained below 35oC. the Liquid was decentralise with semi-solid precipitate of sulfur, the sulfur residue was pulverized with hexane. The aqueous fraction was extracted with hexane (3X), the combined extracts and raster is dealt with. The remainder of the brown liquid was converted at 3 mm Hg, giving a yellow liquid (an 80.2 g), so Kip. 91-96oC. (Compound 3).

Example 4.

3-Chloro-4-ethylsulfonyl-1,2,5-thiadiazole

The solution oxone (84 g, 0,137 mol) in water (400 ml) was rapidly mixed, with to it was added 3-chloro-4-ethylthio-1,2,5-thiadiazole (12.2 g, 0,067 mol) in THF (200 ml). After stirring over night THF was evaporated, the residue was extracted with ether (3X). The extracts were washed with water, aqueous sodium bicarbonate and brine, the solvent was then dried and evaporated, giving a clear liquid (13,6 g). (Compound 4).

Example 5

()-3-Methoxy-4-(1-azabicyclo/2.2.2/octyl-3-oxy)-1,2,5-thiadiazole

A solution of 1-azabicyclo/2.2.2/Octan-3-ol (1,36 g, 0,0104 mol in THF (20 ml) was treated dropwise 1.6 M n-butyllithium in hexane (7.4 ml, 0,0118 mol). To this solution was added 3-methoxy-4-methanesulfonyl-1,2,5-thiadiazole (2,08 g, 0,0107 mol) in THF (40 ml), the reaction mixture was heated to 40oC for 2 hours and then stirred over night at ambient temperature. The solvent was evaporated, the residue was pagkilala 1 standards. HCl, and the mixture was extracted with ether. The aqueous solution was podslushivaet and was extracted with ethyl acetate. Extractio (a 2.5% EtOH-0.25% of NH4OH-CHCl3), giving a clear oil. HCl salt oil (0.85 grams) was crystallized from methanol-ethyl acetate, so pl. 197-198oC. (Compound 5).

Example 6

()-3-Ethoxy-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

A solution of 1-azabicyclo/2,2,2/Octan-3-ol (0.75 g, 0,0059 mol) in THF (50 ml) was treated dropwise 1.6 M n-butyllithium in hexane (3,7 ml, 0,0059 mol). To this solution was added 3-ethoxy-4-methanesulfonyl-1,2,5-thiadiazole (1.0 g, 0,0048 mol) in THF (12 ml), the reaction mixture was heated to 60oC for 5 hours. The solvent was evaporated, the residue was pagkilala 1 standards. HCl, and the mixture was extracted with ether. The aqueous solution was podslushivaet and was extracted with ether. The extracts were washed with water, dried and the solvent was evaporated, yielding a clear oil. HCl salt oil (0,47 g), and recrystallized from 2-propanol, T. pl. 212-213oC. (Compound 6).

Example 7

()-3-Propyloxy-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

A solution of 1-azabicyclo/2.2.2/Octan-3-ol (1.1 g, 0,0087 mol) in THF (75 ml) was treated dropwise 1.6 M n-butyllithium in hexane (5.0 ml, 0,008 mol). To this solution was added 3-propyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.3 g, 0,0059 mol) in THF (15 ml), the reaction mixture was heated to 60oC in the th solution was podslushivaet and ekstragirovanija with ethyl acetate. The extracts were washed with water, dried and the solvent was evaporated, yielding a clear oil. HCl salt oil (0,59 g) crystallized from 2-propanol, T. pl. 218-219oC. (Compound 7).

Example 8

()-3-Butylochka-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole.

A solution of 1-azabicyclo/2,2,2/Octan-3-ol (2.2 g, 0,0168 mol) in THF (25 ml) was treated dropwise 1.6 M n-butyllithium in hexane (10,8 ml, 0,0173 mol). To this solution was added 3-Butylochka-4-methanesulfonyl-1,2,5-thiadiazole (1.98 g, 0,084 mol) in THF (25 ml), the reaction mixture was heated to 52oC for 3.5 hours. The solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous solution was podslushivaet and was extracted with ethyl acetate. The extracts were washed with water, dried and the solvent was evaporated, yielding a clear oil. HCl salt oil (2.0 g) was crystallized from methanol-ethyl acetate-ether, so pl. 204-205oC. (Compound 8).

Example 9

()-3-Pentyloxy-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

A solution of 1-azabicyclo/2,2,2/Octan-3-ol (0.75 g, 0,0059 mol) in THF (50 ml) was treated dropwise 1.6 M n-butyllithium in hexane (3,7 ml, 0,0059 mol). To this solution was added 3-pentyloxy-4-methanesulfonyl-1,2,5-thiadiazole is camping, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous solution was podslushivaet and was extracted with ether. The extracts were washed with water, dried and the solvent was evaporated, yielding a clear oil. HCl salt oil (0.75 g) was crystallized from ethyl acetate, so pl. 171-172oC. (Compound 9).

Example 10

()-3-Hexyloxy-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

A solution of 1-azabicyclo/2,2,2/Octan-3-ol (2.2 g, 0,0168 mol) in THF (25 ml) was treated dropwise 1.6 M n-butyllithium in hexane (10,8 ml, 0,0173 mol). To this solution was added 3-hexyloxy-4-methanesulfonyl-1,2,5-thiadiazole (2.2 g, 0,004 mol) in THF (25 ml), the reaction mixture was heated to 52oC for 3.5 hours. The solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous solution was podslushivaet and was extracted with ether. The extracts were washed with water, dried and the solvent was evaporated, yielding a clear oil. HCl salt oil (1,76 g) crystallized from ethyl acetate, so pl. 165-166oC. (Compound 10).

Example 11

()-3-(4-Methylpentylamino)4-(1-azabicyclo/2,2,2/octyl-3-oxy) -1,2,5-thiadiazole

A solution of 1-azabicyclo/2,2,2/Octan-3-ol (0.75 g, 0,0059 mol) in THF (50 ml) was treated dropwise 1.6 M n-utility is (1.2 g, 0,0045 mol) in THF (10 ml), the reaction mixture was heated to the temperature of reflux distilled for 6 hours. The solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous solution was podslushivaet and was extracted with ether. The extracts were washed with water, dried and the solvent was evaporated, yielding a clear oil. HCl salt oil (1.1 g) was crystallized from ethyl acetate, so pl. 179-180oC. (Compound 11).

Example 12

()-3-Chloro-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

A solution of 1-azabicyclo/2,2,2/Octan-3-ol (1.1 g, 0,0084 mol) in THF (25 ml) was treated dropwise a 1.6 M n-butyllithium in hexane (5,4 ml, 0,0086 mol). This solution was added dropwise to a solution of 3-chloro-4-butylsulfonyl-1,2,5-thiadiazole (2.1 g, 0,0086 mol) in THF (15 ml) at such a rate that the temperature did not exceed 32oC. After stirring for 3 days the reaction mixture was treated with water (10 ml), was diluted with ether (100 ml), was extracted IN HCl (25 ml). The aqueous solution was washed with ether, podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated, the residue was purified using radial chromatography (2.5% ethanol-0.25% ammonium hydroxide-chloroform), giving colored straw Giacosa 12.).

Alternative synthesis of ()-3-chloro-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole:

A solution of 1-azabicyclo/2,2,2/Octan-3-ol (1.2 g, 0,0092 mol) in THF (25 ml) was treated dropwise 1.6 M n-butyllithium in hexane (5,9 ml, 0,0095 mol). The solution was cooled to -8oC, was added dropwise a solution of 3-chloro-4-ethylsulfonyl-1,2,5-thiadiazole (1,83 g, 0,0086 mol) in THF (15 ml). After 15 minutes, the cooling was removed and the reaction mixture stirred over night. The reaction mixture was treated with water (10 ml), was diluted with ether (100 ml), was extracted IN HCl (25 ml). The aqueous solution was washed with ether, and podslushivaet and was extracted with ether. The extracts were dried and the solvent was evaporated, yielding the crude compound 12 (of 1.05 g) as a brownish liquid.

Alternative synthesis of ()-3-chloro-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

A mixture of 1-azabicyclo/2,2,2/Octan-3-ol (12.7 g, 0,1 mole), triethylamine (0.3 ml) and trichloromethane (150 ml) was cooled to 5oC, the mixture was barotiwala CYANOGEN (7,25 g, 0,139 mol). The reaction mixture is stirred for one hour, and then it was allowed to reach room temperature over night. The solvent was evaporated, the residue was dissolved in DMF (20 ml), the solution was added dropwise to a solution of S is ladenia filmed, the reaction mixture was Ekaterinovka to the 32oC. After 5 hours the reaction mixture was cooled and the excess of S2Cl2was destroyed by careful addition of water. The reaction mixture was diluted still water (300 ml), the aqueous solution was decenterable sulfur residue. The sulfur residue was pulverized with water, the combined aqueous solutions were evaporated to small volume (150 ml). The solution was washed with ether, and then podslushivaet 50% sodium hydroxide while maintaining the temperature below 30oC. the Mixture was extracted CHCl3the extracts were dried, the solvent was carefully evaporated. The residue was suspenderbelt in ether, dried, filtered and the solvent was evaporated, yielding (compound 12) (18,1 g) as a yellow oil, which slowly hardened.

Example 13

()-3-Propylthio-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

A solution of the crude compound 12 (1,67 g, 0,0068 mol) in DMF (25 ml) was treated with portions spiersbridge flocculent Na2S-9H2O (1.8 g, 0,0075 mol). After 40 minutes was added 1-bromopropane (1,25 g 0,010 mol), the reaction mixture is stirred over night. The solvent was evaporated, the residue was pagkilala 1N HCl, and the mixture was extracted with ether. The aqueous layer was podslushivaet and al. HCl salt (1.28 g) was crystallized from a mixture of CHCl3_EtOAc-ether, so pl. 174-176oC. (Compound 13).

Example 14

()-3-Butylthio-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

A solution of crude compound 12 (1.8 g, 0,0073 mol) in DMF (25 ml) was treated portion segerstrom flocculent Na2S-9H2O (1,94 g, 0,0081 mol). After 1 hour was added 1-iodobutane (2 g, to 0.011 mol), the reaction mixture is stirred over night. The solvent was evaporated, the residue was pagkilala 1N HCl, and the mixture was extracted with ether. The aqueous layer was podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated, yielding colored straw color liquid. HCl salt (1,82 g) was crystallized from a mixture of CHCl3-EtOAc-ether, so pl. 151-153oC. (Compound 14).

Example 15

()-3-Pentylthio-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

A solution of crude compound 12 (1,67 g, 0,0068 mol) in DMF (25 ml) was treated portion svejeispechennyi flocculent Na2S-9H2O (1.8 g, 0,0075 mol). After 1 hour, add 1-bromopentane (1,53 g 0,010 mol), the reaction mixture is stirred over night. The solvent was evaporated, the residue was pagkilala 1H HCl, and the mixture was extracted with ether. The aqueous layer was podslushivaet and AC. HCl salt (1.07 g) was crystallized from a mixture of trichloromethane/ethyl acetate-ether, so pl. 186-187oC /Connection 15).

Example 16

(S)-3-Pentylthio-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

A solution of (S)-1-azabicyclo/2,2,2/Octan-3-ol (2.0 g, 0,0157 mol) in THF (40 ml) was cooled to 10oC, when this was added dropwise 1.6 M n-utility in hexane (1 ml, to 0.016 mole). The resulting mixture was treated with water (10 ml), ether (170 ml) and was extracted 1N HCl (43 ml). The aqueous fraction was washed with ether, podslushivaet, the solvent was evaporated, giving an oil (1.7 g). The oil was dissolved in DMF (25 ml) was treated portion svejeispechennyi flocculent Na2S-9H2O (1,83 g, 0,0076 mole) and heated (40oC). After 2 hours 1.25 hours was added 1-bromopentane (1,58 g, 0,0105 mol) and the reaction mixture stirred over night. The solvent was evaporated, the residue was pagkilala 1N HCl, and the mixture was extracted with ether. The aqueous layer was podslushivaet, the solvent was evaporated, yielding colored straw liquid, which was purified using radial chromatography (5% EtOH-0.5% of NH4OH-CHCl3). HCl salt (0.87 g) was crystallized from a mixture of trichloromethane-ethyl acetate-ether, so pl. 194-195oC ()D= 25,41oC (ethanol). (Soedinenie connection 12 (1.8 g, 0,0073 mol) in DMF (25 ml) was treated portion svejeispechennyi flocculent Na2S-9H2O (1,94 g, 0,0081 mol). After 1 hour was added 1-hodgekin (2.3 g, to 0.011 mol) and the reaction mixture stirred over night. The solvent was evaporated, the residue was pagkilala 1N HCl and the mixture was extracted with ether. The aqueous layer was podslushivaet and was extracted with ether. The extracts were dried and the solvent was evaporated, yielding colored straw color liquid. HCl salt (1.0 g) was crystallized from a mixture of trichloromethane-ethyl acetate-ether, so pl. 165-167oC. (Compound 17).

Example 18

() -3-(3,3-Dimethylbutyl)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole

A solution of the crude compound 12 (1,05 g, 0,0043 mol) in DMF (25 ml) was treated portion svejeispechennyi flocculent Na2S-9H2O (1.24 g, 0,0051 mol). After 1 hour was added 1-bromo-3,3-dimethylbutan (1.18 g, to 0.007 mol), the reaction mixture is stirred over night. The solvent was evaporated, the residue was pagkilala 1N HCl and the mixture was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated, yielding colored straw liquid. HCl salt (0,41 g) was crystallized from a mixture of trichloro is 1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole

A solution of the crude compound 12 (1.0 g, 0,0041 mol) in DMF (25 ml) was treated with portions svejesmolotogo flocculent Na2S-9H2O (1.1 g, 0,0045 mol). After 1 hour was added 1-chloro-2-(2-tianity)ethane (1.1 g, 0,0062 mol), the reaction mixture is stirred over night. The solvent was evaporated, the residue was pagkilala 1N HCl, and the mixture was extracted with ether. The aqueous layer was podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated, the residue was purified using instant chromatography (10% ethanol-1% ammonium hydroxide - trichlorethane), giving liquid. HCl salt (0.88 g) was crystallized from ether, so pl. 179,5-181oC. (Compound 19).

Example 20

()-3-(2,2,3,3,3-Pentafluoropropyl)-4-(1-azabicyclo/2,2,2/octyl-3-oxy) -1,2,5-thiadiazole

A solution of the crude compound 12 (0.5 g, of 0.002 mol) in DMF (15 ml) was treated portion svejeispechennyi flocculent Na2S-9H2O (0,53 g, 0,0022 mol). After 1 hour was added 1-methane-sulfonate-2,2,3,3,3-pentafluoropropane (of 0.003 mol), the reaction mixture is stirred over night. The solvent was evaporated, the residue was pagkilala 1N HCl and the mixture was extracted with ether. The aqueous layer was podslushivaet and was extracted with ether. The extracts were dried, the solvent is'étang), giving liquid. HCl salt (0,016 g) crystallized from the ether, so pl. 138-140oC. (Compound 20).

Example 21

()-3-(3-(2-Thienyl)propylthio)-4-(1-azabicyclo/2,2,2/octyl-3-oxy) -1,2,5-thiadiazole

A solution of the crude compound 12 (0.6 g, 0,0024 mol) in DMF (15 ml) was treated portion svejeispechennyi flocculent Na2S-9H2O (0.6 g, 0,0027 mol). After 1 hour was added 1-chloro-3- (2-thienyl)propane (0.6 g, 0,0036 mol) and the reaction mixture stirred over night. The solvent was evaporated, the residue was pagkilala 1N HCl and the mixture was extracted with ether. The aqueous layer was podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated, the residue was purified using flash chromatography (10% tanol-1% ammonium hydroxide-trichlorethane), giving liquid. HCl salt (0.16 g) was crystallized from a mixture of ethanol-ethyl acetate, so pl. 194-196oC. (Compound 21).

Example 22

()-3-Butylthio-4-((1-azabicyclo/2,2,2/Octan-3-yl)-methoxy)-1,2,5-thiadiazole

A solution of 3-hydroxymethyl-1-azabicyclo/2,2,2/octane (1.4 g of 0.01 mol) in THF (30 ml) was treated with 1.6 M n-utility in hexane (6.5 ml, 0,0104 mol). The mixture was cooled to 10oC and added dropwise 3-chloro-4-ethylsulfonyl-1,2,5-thiadiazole (2,21 g, 0,0104 mol) in THF (10 ml). Cooling udalos the Il and was extracted 1N HCl (25 ml). The acidic extracts were washed with ether, podslushivaet and was extracted with ether. The extracts were dried and the solvent was evaporated, giving an orange liquid (1,82 g). The liquid was dissolved in DMF (32 ml) and was treated svejeispechennyi flocculent Na2S-9H2O (2.5 g, 0,0104 mole) portions. After 55 minutes the reaction mixture was processed in 1-iodobutane (2.6 g, of 0.014 mol) and heated to 44oC during the night. The solvent was evaporated, the residue was podslushivaet 1N HCl and the mixture was extracted with a mixture of ethyl acetate and ether (1: 1). The aqueous fraction was podslushivaet and was extracted with ether. The ether extract was dried, the solvent was evaporated, the residue was purified using radial chromatography (5% ethanol-0.5% ammonium hydroxide-trichlorethane) giving liquid. HCl salt (0.84 g) was crystallizability from a mixture of ethyl acetate and ether, so pl. 170-171oC. (Compound 22).

Example 23

()-Exo-3-pentylthio-4-(1-azabicyclo/3,2,1/octyl-6-oxy) -1,2,5-thiadiazole and ()-endo-3-pentylthio-4-(1-azabicyclo/3,2,1/octyl-6-oxy)-1,2,5-thiadiazole

A solution of endo/Exo mixture of 1-azabicyclo/3,2,1/Octan-6-ol (1,95 g, 0,0153 mol, see Sternbach, L. H; Kaiser, S. J. Amer. Chem, Soc. 1952, 74, 2215-2218) in THF (25 ml) was treated with 1.6 M n-butyllithium in hexane (9.6 ml, 0,0153 mol). When the mixture had cooled the l), the reaction mixture was stirred over night. The reaction mixture was treated with water, diluted with ether, and extracted 1 standards. HCl (32 ml). The acidic extracts were podslushivaet, was extracted with ether, the extracts were dried and the solvent was evaporated, giving an orange liquid (1,25 d). The liquid was dissolved in DMF (25 ml) and was treated with portions svejeispechennyi flocculent Na2S-9H2O (1,82 g, 0,0076 mol). After 40 minutes was added 1-bromopentane (1.55 g, 0,0103 mol), the reaction mixture is stirred over night. The solvent was evaporated, the residue was pagkilala and the mixture was extracted with ether. The aqueous fraction was podslushivaet, was extracted with ether, the extract was dried and the solvent was evaporated. The residue was purified using radial chromatography (2.5% ethanol-0.25% ammonium hydroxide-trichlorethane) with elution in the first place antisolar in liquid form. HCl salt (0.26 g) was crystallized from ethylene, so pl. 159-160oC. (Compound 23). Further elution gave the endo isomer in the form of liquid. HCl salt (0,23 g) crystallized from ethyl acetate, so pl. 190-193oC. (Compound 24).

Example 24

()-Endo-3-Butylochka-4-(1-azabicyclo/2,2,1/heptyl-3-hydroxy)-1,2,5-thiadiazole

The solution mixture ()-aizanoi bath and treated dropwise 1.6 M n-butyllithium in hexane (2.8 ml, 0,0044 mol). The cooling was removed, was added 3-Butylochka-4-methanesulfonyl-1,2,5-thiadiazole and the reaction mixture was heated to boiling under reflux for 6 hours. The solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous solution was podslushivaet and was extracted with ethyl acetate. The extracts were washed with water, dried and the solvent was evaporated, yielding a clear oil. Radial chromatography (5% ethanol-0.5% hidrosis ammonium-trichlorethane) with elution gave the target compound as the more polar of the two UV active spots. HCl salt of the target compound (0.5 g) was crystallized from ethyl acetate and a quarter mole of water, so pl. 161.5-163oC. (Compound 25).

Example 25

()-Exo-3-Butylochka-4-(1-azabicyclo/2,2,1/heptyl-3-hydroxy)-1,2,5-thiadiazole

Re-chromatography of the mixed fractions after separation of compound 25 (5% ethanol-0.5% ammonium hydroxide-trichlorethane) gave the less polar UV-active material. HCl salt (0.036 g) was crystallized from ethyl acetate and a quarter mole of water, so pl. 156-157oC. (Compound 26).

Example 26

()-3-Butylochka-4-(3-pyrrolidinyloxy)-1,2,5-thiadiazole

A suspension of NaH (of 0.066 g, 0,0028 mol) in THF (25 ml) was treated 1-SUP>o
C for 30 minutes. After cooling to ambient temperature was added 3-Butylochka-4-methanesulfonyl-1,2,5-thiadiazole (0.55 g, 0,0027 mol) in THF (5 ml) and the reaction to the death was heated to reflux distilled for 2.5 hours. The solvent was evaporated, the residue was treated with water-ice mixture and the mixture was extracted with ether. The extracts were washed with saline, dried, the solvent was evaporated. The residue was dissolved in ether (50 ml) and was treated by a slow current of HCl for 5 minutes. After stirring over night the reaction mixture was extracted with cold water. The aqueous fraction was washed with ether, podslushivaet and was extracted with ethyl acetate. The extracts were washed with saline, dried and the solvent was evaporated, yielding a clear oil. HCl salt (0,42 g) crystallized from ethyl acetate, so pl. 127-128oC (Compound 27).

Example 27

()-3-Butylochka-4-(1-methyl-3-pyrrolidinyloxy)-1,2,5-thiadiazole

A solution of 1-methyl-3-pyrrolidinyl (0.6 g, 0,0059 mol) in THF (20 ml) was treated with 1.6 M n-butyllithium in hexane (3.1 ml of 0.005 mol). To the solution was added 3-Butylochka-4-methanesulfonyl-1,2,5-thiadiazole (1.0 g, 0,0042 mol) and the reaction mixture was heated to reflux distilled during the night. Races were podslushivaet, were extracted and the extracts were washed with water, then dried, the solvent was evaporated, giving liquid. HCl salt (0.7 g) was crystallized from ethyl acetate, so pl. 157-158oC (Compound 28).

Example 28

()-3-Butylthio-4-(1-methyl-3-piperidinyloxy)-1,2,5-thiadiazole

A solution of 3-hydroxy-1-methylpiperidine (1.12 g, 0,0095 mol) in THF (25 ml) was treated with 1.6 M n-butyllithium in hexane (5.9 g, 0,0095 mol). The mixture was cooled to 8oC and treated dropwise 3-chloro-4-ethylsulfonyl-1,2,5-thiadiazole (1,83 g, 0,0086 mol) in THF (20 ml). The cooling was removed and the reaction mixture stirred over night. The mixture was treated with water, padillas 1 standards. HCl and diluted with ether. The aqueous fraction was washed with ether, podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated, giving a brownish liquid (1,95 g). The liquid was dissolved in DMF (38 ml) and was treated svejeispechennyi flocculent Na2S-9H2O (2,98 g, 0,0124 mole) portions. After 1 hour the mixture was treated 1-iodobutane (3.1 g, 0,0169 mol) and stirred for 64 hours. The solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous solution was podslushivaet and was extracted with ether. Extracti% ethanol-0.25% ammonium hydroxide-trichlorethane) gave the liquid, HCl salt which was crystallized from a mixture of trichloromethane-ethyl acetate-ether, so pl. 141-142oC. (Compound 29.).

Example 29

3 Butylthio-4-(1-methyl-4-piperidinyloxy)-1,2,5-thiadiazole

A solution of 4-hydroxy-1-methylpiperidine (1.12 g, 0,0095 mol) in THF (25 ml) was treated with 1.6 M n-butyllithium in hexane (5,9 ml, 0,0095 mol). The mixture was cooled to 8oC and treated dropwise 3-chloro-4-ethylsulfonyl-1,2,5-thiadiazole (1,83 g, 0,0086 mol) in THF (20 ml). The cooling was removed, the reaction mixture is stirred over night. The mixture was treated with water, padillas 1 standards. HCl and diluted with ether. The aqueous fraction was washed with ether, modelcialis and was extracted with ether. The extracts were dried, the solvent was evaporated giving a brown liquid (1.52 g). The liquid was dissolved in DMF (30 ml) and was treated with portions svejeispechennyi flocculent Na2S-9H2O (2,32 g, 0,0097 mol). After 50 minutes, the mixture was processed in 1-iodobutane (2.4 g, of 0.013 mol) and stirred for 63 hours. The solvent was evaporated, the residue was pagkilala dilute HCl, and the mixture was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated, yielding 1.3 g of liquid. HCl salt kristalose-4-(1-methyl-2-pyrrolidinyloxy)-1,2,5-thiadiazole

A solution of (S)-1-methyl-2-pyrrolidineethanol (0,86 g, 0,0075 mol). To the solution was added 3-Butylochka-4-methanesulfonyl-1,2,5-dideaza (1.2 g, of 0.005 mol), the reaction mixture was heated to reflux distilled for 6 hours. The solvent was evaporated, the residue was pagkilala cold 1 standards. HCl, and the mixture was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ethyl acetate. The extracts were washed with water, dried, the solvent was evaporated, giving liquid. HCl salt (to 0.72 g) was precrystallization from ethyl acetate, giving a white solid, so pl. 115-116oC (compound 31).

Example 33

3 Butylthio-4-(2-(diethylamino)ethoxy)-1,2,5-thiadiazole

A solution of 2-diethylaminoethylamine (1,11 g, 0,0095 mol) in THF (25 ml) was treated with 1.6 M n-butyllithium in hexane (5,9 ml, 0,0095 mol). The mixture was cooled to 8oC and treated dropwise 3-chloro-4-ethylsulfonyl-1,2,5-thiadiazole (1,83 g, 0,0086 mol) in THF (20 ml). The cooling was removed, the reaction mixture is stirred over night. The mixture was treated with water, padillas 1 standards. HCl and diluted with ether. The aqueous fraction was washed with ether, podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated giving a brown liquid (1.6 g). The liquid portions. After 50 minutes, the mixture was processed in 1-iodobutane (2,52 g, 0,0137 mol) and stirred for 46 hours. The solvent was evaporated, the residue was pagkilala dilute HCl, and the mixture was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography (5% ethanol-0.5% ammonium hydroxide-trichlorethane), giving liquid. HCl salt (1,15 g) was crystallized from a mixture of ethyl acetate and ether, so pl. 95 - 97oC. (Compound 34).

Example 34

Iodide 3-Butylochka-4-(2-(trimethylamino)ethoxy)-1,2,5-thiadiazole

A solution of compound 33 (0.5 g, 0,0018 mol HCl salt) in ethyl acetate (30 ml) was treated with iodomethane (0.3 ml) and stirred over night. The precipitate was collected, rinsed with ethyl acetate and dried, giving a white solid (0.64 g), so pl. 137 - 138oC. (Compound 35).

Example 35

3 Butylochka-4-(2-dimethylamino)ethylthio)-1,2,5-thiadiazole

Suspension of the hydrochloride of 2-dimethylaminoethanol (0,57 g of 0.004 mol) in THF (25 ml) was treated with 1.6 M n-butyllithium in hexane (5 ml, 0,008 mol). To the solution was added 3-Butylochka-4-methanesulfonyl-1,2,5-thiadiazole (0.71 g, 0,008 mol), the reaction mixture was heated to reflux distilled in Privalka, the residue was pagkilala cold 1 standards. HCl, and the mixture was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ether. The extracts were washed with water, dried, the solvent was evaporated. The residue was purified using radial chromatography (5% ethanol-0.5% ammonium hydroxide-trichlorethane), giving a reddish-brown liquid. HCl salt (0,22 g) was precrystallization from ethyl acetate, giving a white solid, so pl. 108 - 109oC. (Compound 36).

Example 36

3-Chloro-4-(1-propylthio)-1,2,5-thiadiazole

In ether (250 ml) maintained at -10oC barotiwala CYANOGEN. To the solution was added dropwise diethylamine (3 ml) followed by adding dropwise 1-propanethiol (57 ml, to 0.63 mole) in ether (25 ml) at such a rate that the temperature did not exceed -5oC. After 5 hours, cooling was removed and the reaction mixture stirred over night. From the reaction mixture was distilled ether as long as the temperature of the vessel did not reach the 50oC. the Reaction mixture was cooled to ambient temperature and was added dropwise to a solution of monochloride sulfur (125 ml of 1.56 mol) in DMF (125 ml) which was cooled in an ice-water bath. The cooling was removed, the reaction mixture was left of the former The reaction mixture was cooled in a mixture of ethanol and ice and excess monochloride sulfur was carefully destroyed by adding dropwise water (200 ml), so that the temperature did not exceed 30oC. the Mixture was extracted with hexane, the extracts were washed with saline, dried and the solvent was evaporated, the residue was flown at 1.5 mm Hg, giving a yellow liquid (98,6 g), so Kip. 84 - 94oC. Connection 37).

Example 37

(R)-3-Pentylthio-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

A solution of (R)-1-azabicyclo/2,2,2/Octan-3-ol (3.0 g, 0,0236 mol) in THF (40 ml) was cooled to 10oC, while to it was added dropwise 1.6 M n-utility in hexane (15 ml, 0,024 mol). The resulting mixture was treated with 3-chloro-4-ethylsulfonyl-1,2,5-thiadiazole (5,01 g, 0,0236 mol) in THF (5 ml) and stirred for 22 hours. The reaction mixture was treated with water (10 ml), ether (170 ml) and was extracted 1 standards. HCl (35 ml). The aqueous fraction was washed with ether, podslushivaet and was extracted with ether. The extracts were dried and the solvent was evaporated, giving an oil (2.35 g). The oil was dissolved in DMF (35 ml), was treated with portions svejeispechennyi Na2S-9H2O (2,53 g, 0,0105 mole) and heated (40oC). After 1.25 hours was added 1-bromopentane (2,18 g, 0,0145 mol), the reaction mixture is stirred over night at the 38oC. the Solvent was evaporated, the residue was pagkilala you were dried, the solvent was evaporated, yielding colored straw liquid, which was purified using radial chromatography (5% ethanol-0.5% ammonium hydroxide-trichlorethane). HCl salt (1.68 g) was crystallized from a mixture of trichloromethane and ethyl acetate, so pl. 195 - 196oC ()D= -24,6o(EtOH). (Compound 38).

Example 38

()-3-(4-Methylphenylthio)-4-(1-azabicyclo/2,2,2/acetyl-3-oxy)- 1,2,5-thiadiazole.

A solution of the crude compound 12 (1.65 g, 0,0067 mol) in DMF (25 ml) was treated with portions svejeispechennyi flocculent Na2S-9H2O (1,83 g, 0,0076 mol). After 1 hour was added 1-bromo-4-methylpentan (1.73 g, 0,0105 mol), the reaction mixture is stirred for three days at 40oC. the Solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ether. The extracts were dried and the solvent was evaporated, yielding solomonoarna liquid, which was purified using radial chromatography (5% ethanol-0.5% ammonium hydroxide-trichlorethane). HCl salt (0.74 g) was crystallized from a mixture of trichloromethane-ethyl acetate-ether, so pl. 183 - 185oC. (Compound 39).

Example 39

()-3-(3-Phenylpropyl)-4-(1-azabicyclo/2,2,2/octyl-3-oxy) -kennym flocculent Na2S-9H2O (0.97 g, 0,004 mol). After 1 hour was added 1-bromo-3-phenylpropane (1,11 g 0,056 mol), the reaction mixture is stirred for 17 hours at 50oC. the Solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous fraction was parsedecimal and was extracted with ether. The extracts were dried and the solvent was evaporated, yielding solomonoarna liquid, which was purified using radial chromatography (2.5% ethanol-0.25% ammonium hydroxide-trichlorethane). HCl salt (0,42 g) was crystallized from a mixture of trichloromethane-ethyl acetate-ether, so pl. 210 - 212oC. (Compound 40).

Example 40

()-3-(4-Cyanobenzyl)-4-(1-azabicyclo/2,2,2/octyl-3-oxy) -1,2,5-thiadiazole

A solution of crude compound 12 (1,15 g, 0,0047 mol) in DMF (25 ml) was treated with portions svejesmolotogo flocculent Na2S-9H2O (1.68 g, to 0.007 mol). After 1 hour was added 4-cyanobenzeneboronic (1.85 g, 0,094 mol) and the reaction mixture is stirred for 22 hours. The solvent was evaporated, the residue was pagkilala standards. HCl and the mixture was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated, yielding colored straw liquid, which cleaned what was Savalas from a mixture of trichloromethane, ethyl acetate and ether, so pl. 211 - 213oC. (Compound 41).

Example 41

()-3-(4-Forbesii)-4-(1-azabicyclo/2,2,2/octyl-3-oxy) -1,2,5-thiadiazole

A solution of the crude compound 12 (1,15 g, 0,0047 mol) in DMF (25 ml) was treated with portions svejesmolotogo flocculent Na2S-9H2O (1.68 g, to 0.007 mol). After 1 hour was added 4-tormentilla (1,37 g, 0,094 mol) and the reaction mixture is stirred for 22 hours. The solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated, yielding colored straw color liquid, which was purified using radial chromatography (5% ethanol-0.5% ammonium hydroxide-trichlorethane). HCl salt (0,89 g) crystallized from methanol-ethyl acetate-ether, so pl. 236 - 237oC. (Compound 42).

Example 42

()-3-(2-Feniletilic)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5 - thiadiazole.

A solution of the crude compound 12 (1,15 g, 0,0047 mol) in DMF (25 ml) was treated dropwise svejeispechennyi flocculent Na2S-9H2O (1.68 g, to 0.007 mol). After 1 hour the reaction mixture was cooled to -30oC and treated dropwise 1-Brock for 22 hours. The solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ether. The extracts were dried and the solvent was evaporated, yielding colored straw liquid, which was purified using radial chromatography (5% ethanol-0.5% ammonium hydroxide-trichlorethane). HCl salt (0,53 g) crystallized from methanol-ethyl acetate-ether, so pl. 181 - 183o. (Compound 43).

Example 43

()-3-(2-Phenylacetamido)-4-(1-azabicyclo/2,2,2/octyl-3-oxy/- 1,2,5-thiadiazole

A solution of the crude compound 12 (1,15 g, 0,0047 mol) in DMF (25 ml) was treated with portions svejesmolotogo flocculent Na2S-9H2O (1.68 g, to 0.007 mol). After 1 hour the reaction mixture was cooled to -50oC and treated dropwise 1-bromo-2-phenyloxirane (1.90 g, 0,0095 mol) in DMF (22 ml). The cooling was removed after 1 hour, the reaction mixture is stirred for 22 hours. When cooled to -30oC in the form of two portions was added to another solution of 1-bromo-2-phenyloxirane (1.90 g, 0,0095 mol) in DMF (5 ml). After 2 hours the solvent was evaporated, the residue was pagkilala 1 standards. HCl, and the mixture was extracted with ether. The aqueous fraction was podslushivaet and was extracted with trichloromethane. Extra radial chromatography (5% ethanol-0.5% ammonium hydroxide-trichlorethane). HCl salt (1.29 g) was crystallized from methanol-ethyl acetate-ether, so pl. 193 - 194oC. (Compound 44).

Example 44

Endo-3-Butylochka-4-(N-methyl-8-azabicyclo/3,2,1/octyl-3-oxy)- 1,2,5-thiadiazole

A solution of tropine (1,36 g of 0.0004 mol) in THF (25 ml) was treated dropwise 1.6 M n-butyllithium in hexane (5.9 g, 0,0095 mol). To this solution was added 3-Butylochka-4-methanesulfonyl-1,2,5-thiadiazole (2,04 g, 0,0086 mol) in THF (25 ml) and the reaction mixture was heated to 40oC for 19 hours. The solution was treated with water (40 ml), 5 standards. HCl (5.5 ml), the aqueous layer was separated and was podslushivaet. The aqueous solution was extracted with ether, the extracts were dried and the solvent was evaporated, yielding a clear oil. The oil was purified using radial chromatography (5% ethanol-0.5% ammonium hydroxide-trichloromethane) and HCl salt (1,49 g) was crystallized from a mixture of trichloromethane-ethyl acetate-ether, so pl. 168 - 169oC. (Compound 45).

Example 45

()-Exo-3-Butylochka-4-(6-N-methyl-8-azabicyclo/3,2,1/octane - 3-anoxi)-1,2,5-thiadiazole

A suspension of NaH (0.11 g, 0700275 mol) in THF (25 ml) was treated ()-Exo-6-hydroxychromone (1,36 g, 0,0094 mol) and the reaction mixture was heated to 50oC for 1 hour. To this solution was added 3-Butylochka-4-methanesulfonyl-arrivalsa, the residue was suspenderbelt in a mixture of ice and water, pagkilala and the mixture was extracted with ether, the extracts were washed with saline, dried and the solvent was evaporated, yielding a clear oil. The oil was purified using radial chromatography (2.5% ethanol-0.25% ammonium hydroxide-trichloromethane) and HCl salt (0,325 g) crystallized from achievethat, so pl. 178 - 179oC. (Compound 46).

Example 46

()-Exo-3-chloro-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole and ()-endo-3-chloro-4-(1-azabicyclo/3,2,1/octyl-6-oxy)-1,2,5-thiadiazole

A solution of endo-Exo mixture of 1-azabicyclo/3,2,1/Octan-6-ol (13 g, is 0.102 mol, see Sternbach, L. H; Kaiser, S. J. Amer. Chem. Soc. 1952, 74, 2215-2218), triethylamine (0.3 ml) and trichloromethane (100 ml) was cooled to 3oC and the solution was barotiwala CYANOGEN (7.7 g, 0,148 mol). After 1 hour, the cooling was removed, the reaction mixture is stirred for a further 3 hours and the solvent was evaporated. The residue was dissolved in DMF (30 ml) and added dropwise to a solution of S2Cl2(of 47.3 g of 0.35 mol) in DMF (30 ml) which was cooled in a bath of a mixture of ice and water. The cooling was removed, the reaction mixture was stirred over night, after further cooling, the excess of S2Cl2carefully destroyed by water. The mixture razbavlyali was evaporated to small volume (150 ml), was extracted with hexane. The aqueous solution was cooled, podslushivaet 50% sodium hydroxide and was extracted with trichloromethane. The extracts were dried, the solvent was carefully evaporated, the residue was suspenderbelt in ether and filtered. Evaporation of solvent gave a brown liquid (of 12.76 g), 0.8 g of a sample which was purified using radial chromatography (10% ethanol-1% ammonium hydroxide-trichlorethane).

The Exo isomer was elyuirovaniya first and turned into HCl salt (0.1 g) which crystallized from acetone, so pl. 226oC, decomp. (Compound 47). Further elution gave the endo isomer is crystallized as the HCl salt (0.2 g) from 2-propanol, T. pl. 199,5 - 201oC. (Compound 48).

Example 47

()-Endo-3-(4-cyanobenzyl)4-(1-azabicyclo/3,2,1/octyl-6 - oxy)-1,2,5-thiadiazole

A solution of the crude mixture of compound 47 and the connection 48 (2.3 g, 0,0094 mol) in DMF (34 ml) was treated with portions svejesmolotogo flocculent Na2S-9H2O (3,36 g of 0.014 mol). After 2 hours the reaction mixture was cooled to -30oC and treated dropwise 4-cyanobenzaldehyde (3.7 g, 0,0189 mol) in DMF (34 ml). The cooling was removed and after 1.5 hours the reaction mixture was treated with 5 standards. NaOH (4 ml). The thinner you is. the content of inorganic fillers extracts were dried, the solvent was evaporated, the residue was purified using radial chromatography (5% ethanol-0.5% ammonium hydroxide-ethyl acetate), giving the endo isomer. HCl salt (0.31 g) was crystallized from methanol-ethyl acetate-ether, so pl. 250 - 251oC. (Compound 49).

Example 48

3 Butylochka-4-(3-azetidinone)-1,2,5-thiadiazole

A suspension of sodium hydride (0.24 g, 0,006 mol) in THF (30 ml) was treated 1-tert-butylcarbamoyl-3-hydroxyazetidine (1.1 g, 0,006 mol), the reaction mixture is stirred for 1 hour, followed by addition of 3-Butylochka-4-methanesulfonyl-1,2,5-thiadiazole (1.0 g, 0,0042 mol) in THF (5 ml). The reaction mixture was heated to reflux distilled for 4 hours, the solvent was evaporated, the residue was treated with a mixture of ice and water, and the mixture was extracted with ethyl acetate. The extracts were dried and processed slow shock HCl for 3 minutes. After 0.5 hours the solvent was evaporated, the residue was treated with a mixture of ice and water, the solution was extracted with ether. The aqueous phase was podslushivaet, was extracted with ethyl acetate, the extracts were washed with saline, dried and the solvent was evaporated, yielding a clear oil. HCl salt (0,77 g) crystallized from 2-propanol, T. pl. 167-the Oia of sodium hydride (0.24 g, 0,006 mol) in THF (30 ml) was treated 1-tert-butylcarbamoyl-3-hydroxyazetidine (1.6 g, 0,0092 mol) and the reaction mixture is stirred for 1 hour. After cooling to 8oC was added 3-chloro-4-ethylsulfonyl-1,2,5 - thiadiazole (1,96 g, 0,0092 mol) in THF (5 ml), the reaction mixture is stirred for 30 minutes, cooling was removed within 30 minutes, the reaction mixture was heated to 35oC for 45 minutes. Heat was removed, the reaction mixture is stirred overnight and the solvent was evaporated. The residue was suspenderbelt in cold water, and the mixture was extracted with ethyl acetate, the extracts were washed with saline, dried, the solvent was evaporated, giving a reddish-brown liquid (2,98 g). The liquid solution in DMF (30 ml) was treated svejeispechennyi flocculent Na2S-9H2O (3.3 grams, 0,0138 mol). After 1 hour was added 1-iodobutane (2.1 ml), the reaction mixture is stirred for 2 hours, it was diluted with cold water and was extracted with ether. The ether was dried, the solvent was evaporated, the residue was dissolved in ethyl acetate, the solution was treated with a stream of dry HCl for 5 minutes. After 1 hour the reaction mixture was treated with a mixture of ice and water, the organic solvent was evaporated. An aqueous solution of actuarial was evaporated, giving a reddish-brown liquid, which was purified using radial chromatography (10% ethanol-1% ammonium hydroxide-chloroform). HCl salt (0,41 g) crystallized from ethyl acetate, so square 138 - 139oC. (Compound 51).

Example 50

()-TRANS-3-Butylochka-4-(2-dimethylaminoethoxy)- 1,2,5-thiadiazole

A suspension of sodium hydride (0.25 g, 0,006 mol) in THF (30 ml) was treated ()-TRANS-dietilaminoetoksietanola (0.8 g, 0,006 mol), the reaction mixture was heated to reflux distilled for 1 hour followed by the addition of 3-Butylochka-4-methanesulfonyl-1,2,5-thiadiazole (1.0 g, 0,0042 mol), heating was continued throughout the night. The solvent was evaporated, the residue was suspenderbelt in cold water and the mixture was padillas. The solution was extracted with ether, podslushivaet and was extracted with ethyl acetate. An ethyl acetate extracts were washed with saline, dried, the solvent was evaporated and the residue was purified using radial chromatography (10% ethanol-1% ammonium hydroxide-chloroform). HCl salt (0,98 g) crystallized from ethyl acetate, so pl. 148 - 149oC. (Compound 52).

Example 51

()-3-Butylthio-4-(3-pyrrolidinyloxy)-1,2,5-thiadiazole

A suspension of sodium hydride (0,22 g, 0,009 mol) in THF (30 ml) clicks the temperature of reflux distilled within 35 minutes. After cooling to 10oC was added 3-chloro-4-ethylsulfonyl-1,2,5-thiadiazole (1,96 g, 0,0092 mol) in THF (5 ml), the cooling was removed and the reaction mixture was heated to 35oC for 16 hours. The reaction mixture was diluted with water, was added ether and the ether extract was separated. The ether extract was washed with water, drying and the solvent was evaporated, giving a reddish-brown liquid (3,05 g). The liquid solution in DMF (42 ml) was treated svejeispechennyi flocculent Na2S-9H2O (3.3 grams, 0,0138 mol). After 1 hour was added 1-iodobutane (3.42 g, 0,0186 mol) and the reaction mixture stirred at 40oC for 16 hours. The solvent was evaporated, the residue was diluted with cold water and the mixture was extracted with ether. The ether extract was dried, the solvent was evaporated, the residue was dissolved in ether and the solution was treated with a stream of dry HCl for 5 minutes. After 66 hours, the reaction mixture was treated with a mixture of ice and water and the organic solvent was evaporated. The aqueous solution was extracted with ether, podslushivaet and was extracted with ether. The ether extracts were dried and the solvent was evaporated, giving a reddish-brown liquid, purified using radial chromatography (5% ethanol-0.5% ptx2">

Example 52

1-Chloro-2-(2-thio-5-trifloromethyl)ethane

a solution of 2-triptorelin (1.2 g, 0,0105 mol) (J. Fluorine Chem 1990, 46, 445 - 459) in THF (10 mg) was cooled to -40oC, of 1.6 M n-utility in hexane (6.5 ml, 0,0103 mol) was added dropwise while. After 2 hours the reaction mixture was cooled to -78oC and was added sulfur (0.32 g, of 0.01 mol), the reaction mixture is stirred for 2 hours. The cooling was removed and when the temperature reached 0oC, the reaction mixture was slaked with water and dilute sodium hydroxide. The mixture was extracted with ether, the aqueous phase was padillas and the mixture was extracted with ether. The final ether extracts were dried and the solvent was evaporated, yielding 2 g of material. This substance was added to a mixture of KOH (0.6 g, to 0.011 mol), N(butyl)4HSO4(0.3 g, about 0.001 mol) and 1-bromo-2-chlorethane) (1.4 g of 0.01 mol) in THF (20 ml), the reaction mixture was stirred at ambient temperature over night. The mixture was poured into water, extracted with methylene chloride, the extracts were dried, the solvent was evaporated. The residue was purified using instant chromatography (5% ethyl acetate-hexane), giving the liquid (0,42 g). (Compound 54).

Example 53

()-3-(2-(2-Thio-5-trifloromethyl)ethylthio)-4-(1 - azabicyclo/2.2 mi svejeispechennyi flocculent Na2S-9H2O (0,41 g, 0,0017 mol). After 1 hour was added 1-chloro-2-(2-thio-5-trifloromethyl)ethane (0,42 g, 0,0017 mol) and the reaction mixture stirred over night. The solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography (10% ethanol-1% ammonium hydroxide-chloroform), giving liquid. Oxalate salt (0,107 g) crystallized from 2-propanol, T. pl. 65 - 69oC. (Compound 55).

Example 54

2-(5-(2-Thienyl)thiophene)thiol

A solution of 2-(2-thienyl)thiophene (10 g, 0,0602 mol) in THF (50 ml) was cooled to -40oC and when this was added dropwise 1.6 M n-utility in hexane (37,2 ml, 0,0595 mol). After 2 hours the reaction mixture was cooled to -78oC and was added sulfur (1.8 g, 0,575 mol), the reaction mixture is stirred for 2 hours. The cooling was removed and when the temperature reached 0oC, the reaction mixture was slaked with water and dilute NaOH. The mixture was extracted with ether, the aqueous phase was padillas and the mixture was extracted with ether. The final ether extracts were dried and the solvent was evaporated, yielding to 9.9 g of the material is ol

A mixture of 2-(5-(2-thienyl)thiophene)thiol (1.2 g, 0,0061 mol), trebuchet potassium (0.5 g, 0,0045 mol) and traces of 18-crown-6 in THF (90 ml) was mixed for an hour and a half. To the solution was added compound 12 (1.0 g, 0,0041 mol) and the reaction mixture was heated to the temperature of reflux distilled during the night. The reaction mixture was poured into water, extracted with ether, the extracts were dried and the solvent was evaporated. The residue was purified using flash chromatography (5% ethanol-0.5% ammonium hydroxide-chloroform) and oxalate salt (0,41 g) crystallized from acetone, so pl. 215oC, decomp. (Compound 57).

Example 56

1-Chloro-2-(2-(5-(2-thienyl)thienyl)thio)ethane

The crude 2-(5-(2-thienyl)thiophene)thiol (3 g, 0,0152 mol) was added to a mixture of KOH (0,93 g, 0,0166 mol), N(butyl)4HSO4(0.51 g, 0,0015 mol) and 1-bromo-2-chlorethane ( 2.2 g, 0,0152 mol) in THF (100 ml), the mixture stirred over night at ambient temperature. The mixture was poured into water, extracted with methylene chloride, the extracts were dried and the solvent was evaporated giving the desired product (3.5 g). (Compound 58).

Example 57

()-3-(2-(2-(5-(2-Thienyl)thienyl)thio)ethylthio)-4-(1 - azabicyclo/2,2,2/-octyl-3-oxy)-1,2,5-thiadiazole

A solution of the crude compound 12 (0.5 g, 0,002 mol) 1 hour 1-chloro-2-(2-(5-(2-thienyl)thienyl)thio)ethane (0.6 g, 0,0023 mol) and the reaction mixture stirred over night. The solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous phase was podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated and the residue was purified using flash chromatography (5% ethanol-0.5% ammonium hydroxide-chloroform), giving liquid. Oxalate salt (0,43 g) crystallized from acetone, so pl. 102 - 105oC. (Compound 59).

Example 58

()-3-(2-Thienyl)thio)-4-(1-azabicyclo/2,2,2/octyl-3 - oxy)-1,2,5-thiadiazole

A mixture of 2-thiopental (0,42 g, 0,0036 mol) and potassium carbonate (0,59 g, 0,0043 mol) in DMF (20 ml) was heated to 60oC for 3 hours. To the solution was added compound 12 (0,89 g, 0,0036 mol) and the reaction mixture stirred over night. The reaction mixture was poured into 1 standards. HCl (50 ml), extracted with ether, the aqueous phase was podslushivaet and the mixture was extracted with ethyl acetate. An ethyl acetate extracts were dried, the solvent was evaporated and the residue was purified using flash chromatography (5% ethanol-0.5% ammonium hydroxide-chloroform). Oxalate salt (0,095 g) crystallized from acetone, so pl. 133 - 136oC. (Compound 60).

Example 59

()-3-(3-N-(2-Thiazolidone)proper (10 ml) was treated with portions svejesmolotogo flocculent Na2S-9H2O (0.55 g, 0,0023 mol). After 1 hour was added 1-chloro-3-N-(2-thiazolidone)propane (0,41 g, 0,0023 mol) and the reaction mixture stirred over night. The solvent was evaporated, the residue was pagkilala 1 standards. HCl and the mixture was extracted with ether. The aqueous layer was podslushivaet and was extracted with ether. The extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography (10% ethanol-1% ammonium hydroxide-chloroform), giving liquid. Oxalate salt (0,148 g) was crystallized from a mixture of acetone and ether, so pl. 70 - 75oC. (Compound 61).

Example 60

()-Exo-methyl-7-hydroxy-2-azabicyclo/2,2,2/Oct-5-ene-2 - carboxylate

A solution of 2.1 g (8,4 mole) methyl-7-acetoxy-7-cyano-2-azabicyclo/2,2,2/Oct-5-ene-2-carboxylate (J/ Org. Chem. 1989, 54, 2893) in 25 ml of ethanol and 5 ml was cooled in an ice bath. To this mixture was added 2.4 g (42 mole) KOH followed by the addition of 0.65 g (17 moles) of sodium borohydride. After 15 minutes the ice bath was removed and the reaction mixture is stirred for 16 hours. The reaction mixture was slaked by adding 25 ml of water, and then concentrated in vacuum. To the residue was added 25 ml of water and the mixture was extracted three times with 50 ml portions of ethyl acetate. Combining the extracts were dried over with the/hexane) on silica gel, giving 1.47 g of Exo-methyl-1-hydroxy-2-azabicyclo/2,2,2/Oct-5-ene-2-carboxylate and 135 mg of endo-methyl-7-hydroxy-2-azabicyclo/2,2,2/Oct-5-ene-2-carboxylate. (Compound 62).

()-Exo-methyl-6-hydroxy-2-azabicyclo/2,2,2/octane - 2-carboxylate

A solution of 1.47 g (8 mmol) of Exo-methyl-7-hydroxy-2-azabicyclo/2,2,2/Oct-5-ene-2-carboxylate and 0.15 g of 5% Pd/C at 50 methanol was gidrirovaniya at 50 psi (3,515 kg/sq. cm) in a Parr shaker for 5 hours at room temperature. Removal of the catalyst by filtration followed by evaporation under vacuum gave 1,43, (Compound 63).

Example 62

()-3-Butylthio-4-(Exo-2-methoxycarbonyl-2-azabicyclo/2,2,2/ Oct-6-yl-oxy)-1,2,5-thiadiazole

To a solution of 1.3 g (7.1 mmole) of Exo-methyl-6-hydroxy-2-azabicyclo /2,2,2/octane-2-carboxylate and 0.80 g (7.1 mmole) of potassium tert-butylate in 20 ml of THF was added 1.5 g (7.1 mmole) of 3-chloro-4-butylthio-1,2,5-thiadiazole. After stirring the mixture at room temperature for 20 hours was added 50 ml of saline solution and the solution was extracted 5 times with 50 ml portions of ethyl acetate. The combined extracts were dried over a mixture of NaCl/Na2SO4and was evaporated on a vacuum. Chromatography on silica gel (25% ethyl acetate-hexane) gave 1,42, (Compound 64).

Priaulx) was added to a solution of 3-butylthio-4-(Exo-2-methoxycarbonyl-2-azabicyclo/2,2,2/Oct - 6-yl-oxy)-1,2,5-thiadiazole in 10 ml of methylene chloride. After stirring for 5 hours at room temperature the solution was evaporated under vacuum. Was added 10 ml of saturated sodium bicarbonate and the solution was extracted three times with 20 ml portions of ethyl acetate. The combined extracts were dried over a mixture of sodium chloride and sodium sulfate and evaporated under vacuum. The residue was chromatographically on silica gel (10% ethanol-1% ammonium hydroxide-chloroform) and the resulting oil was turned into its oxalate salt. Recrystallization from a mixture of ethanol and ethyl acetate gave 789 g, so pl. 148 - 150oC. (Compound 65).

Example 64

3-Amino-4-butylthio-1,2,5-thiadiazole

1.04 g sample of 3-chloro-4-butylthio-1,2,5-thiadiazole was dissolved in 20 ml of THF and added to a 50 ml reaction vessel. The mixture was cooled to 0oC. In the specified reaction vessel was added dropwise a 10 ml sample of the bis(trimethylsilyl) amide sodium in THF (1.0 M). The mixture is stirred at 0oC. the Reaction mixture was extinguished using 50 ml of water after completion of the reaction. The pH of the mixture was brought to 2.0 using HCl. The mixture was mixed for 15 minutes and then brought to pH 11 with sodium hydroxide. The mixture was extracted using ether. 'or the SPS was purified using column chromatography. Yield 1.07 g (65%). N,N-bis-(trimethylsilyl)-3-amino-4-butylthio-1,2,5-thiadiazol was suspenderbelt 3 standards. HCl and heated to 50oC. the Mixture is stirred for 5 hours. The pH value was brought to 11 using NaOH. The mixture was extracted tert-butylmethylamine ether. The organic phases were combined, dried, filtered and concentrated to dryness. The yield of 0.43 g (45%). (Compound 66). The process was repeated essentially as described, giving 82% of the desired 3-amino-4-butylthio-1,2,5-thiadiazole.

Example 65

3-Bromo-4-butylthio-1,2,5-thiadiazole

0,42 g sample of copper bromide, 0.28 g of isoamylamine and 6 ml of acetonitrile was added to a 25 ml reaction vessel. The mixture was heated to 65oC. the combined acetonitrile and the mixture was added to 4 ml of the combined acetonitrile solution containing of 0.30 g of 4-amino-3-butylthio-1,2,5-thiadiazole. The mixture was mixed for 30 minutes at 65oC. the Mixture was cooled to room temperature and was extinguished 50 ml of 1 norms. HCl. The organic layers were combined, dried, filtered and concentrated to dryness. The yield of 0.38 g (94%). The resulting material was purified using column chromatography, giving 0,30 g (73%) of the substance. (Compound 67).

The process was carried out essentially as described above using the>()-3-(2,2,3,3,4,4,4-Heptafluorobutyrate)-4-(3-(1- azabicyclo/2,2,2/-octyloxy)/-1,2,5-thiadiazole

A solution of potassium tert-butylate (1.6 g, 0,0143 mol) in THF (12 ml) was treated 2,2,3,3,4,4,4-getattributenode (2 ml, to 0.016 mole). After 5 minutes was added compound 12 (0.75 g, of 0.003 mol), the reaction mixture is stirred for 2 hours followed by heating to a temperature of reflux distilled for 1.5 hours. After stirring at ambient temperature over night and heat up to the temperature of reflux distilled for 1.5 hours the solvent was evaporated, the residue was suspenderbelt in the water, and the mixture was extracted with ethyl acetate. The extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography (20% EtOH-2% NH4OH-CHCl3), giving an oil. Cleaners containing hydrochloride salt was crystallized from ethyl acetate-half mole of water in the form of a flocculent white solid (0,43 g), so pl. 168,5 - 169, 5mmoC. (Compound 69).

Example 67

()-3-(1-Butylthio)-4-/endo-6-(1-azabicyclo/3,2,1/ octyloxy)/-1,2,5-thiadiazole

A solution of potassium tert-butylate (0,62 g, 0,0055 mol) in THF (12 ml) was treated 1-azabicyclo endo-1-azabicyclo/3,2,1/octane-6-I (0.64 g, of 0.005 mole). After 5 minutes was added 3-chloro-4-(1-butylthio)-1,2,5-thiadiazole (1.2 g, 0 the strength and extracted with ether. The aqueous phase was podslushivaet and was extracted with ethyl acetate, the extracts were dried, washed with saline, dried and the solvent was evaporated. The residue was purified using radial chromatography (20% ethanol-2% ammonium hydroxide-chloroform). The HCl salt crystallized from ethyl acetate, giving a white solid (0.68 g). So pl. 201 - 202oC decomp. (Compound 70).

Example 68.

()-3-(3-Phenylpropyl)-4-/endo-6-(1-azabicyclo/3,2,1/ octyloxy)/-1,2,5-thiadiazole

A solution of compound 48 (0.9 g, 0,0037 mol) in DMF (25 ml) was treated with portions svejesmolotogo flocculent Na2S-9H2O (0.97 g, 0,004 mol). After 2 hours the reaction mixture was treated dropwise 1-bromo-3-phenylpropane (1,11 g, 0,0059 mol), the reaction mixture was stirred for 3.25 hours followed by adding dropwise an additional 1-bromo-3-phenylpropane (1,11 g, 0,0059 mol) in DMF (5 ml). After stirring overnight the solvent was evaporated, the residue was suspendible in water, pagkilala, and the mixture was extracted with ether. The aqueous phase was podslushivaet, was extracted with chloroform, the extracts were dried and the solvent was evaporated. The residue was purified using radial chromatography (methanol:ethyl acetate: hydroxide am the C. (Compound 72).

Example 69

()-3-/3-(4-Forfinal)propylthio/-4-/3-(1-azabicyclo/2,2,2/ octyloxy)-1,2,5-thiadiazole

A solution of the crude compound 12 (1,15 g, 0,0047 mol) in DMF (20 ml) was treated with portions svejesmolotogo flocculent Na2S-9H2O (1.68 g, to 0.007 mol). After 1 hour was added dropwise 1-chloro-3-(4-forfinal)propane (1.63 g, 0,0095 mol) in DMF (2 ml) and the reaction mixture is stirred for 2.5 days. The reaction mixture was then treated with additional 1-chloro-3-(4-forfinal)propane (0,815 g, 0,0047 mole) and heated at 35oC for 6 hours. The solvent was evaporated, the residue was pagkilala 1 standards. HCl, and the mixture was extracted with ether. The extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography (methanol: ethyl acetate: ammonium hydroxide/15: 30:1). HCl (0,19 g) was crystallized from a mixture of chloroform-ethyl acetate-ether, so pl. 189 - 191oC. (Compound 73).

Example 70

()-3-{ 3-/4-(Trifluoromethyl)phenyl)propylthio} -4-/3-(1- azabicyclo-/2,2,2/octyloxy)/-1,2,5-thiadiazole

A solution of compound 12 (1,15 g, 0,0047 mol) in DMF (20 ml) was treated dropwise svejeispechennyi flocculent Na2S-9H2O (1.68 g, to 0.007 mol). After 2 hours the reaction mixture was cooled Acciona the mixture was mixed for 2 hours. The cooling was removed, the reaction mixture was stirred 3.5 hours and again cooled to -35oC. the Reaction mixture is then further processed 3-/4-(trifluoromethyl)phenyl/propane (1.75 g, 0,0043 mol) in DMF (5 ml), the cooling was removed and the reaction mixture stirred over night. Added an additional 1-bromo-3-/4-(trifluoromethyl)phenyl/propane (0.75 g, 0,0008 mol) in DMF (5 ml), stirring was continued for 1.5 hours. The solvent was evaporated, the residue was suspenderbelt in the water, and the mixture was extracted with ether. The extracts were dried, the solvent was evaporated, the residue was purified using radial chromatography (methanol: ethyl acetate:ammonium hydroxide/15:30:1). HCl salt (0.32 g) was crystallized from a mixture of chloroform-ethyl acetate-ether, so pl. 182 - 184oC. (Compound 74).

Example 72

A solution of 1-butanol (92 ml, 1 mol) and triethylamine (3 ml) was cooled to -8oC and CYANOGEN (58 g of 1.12 mol) was slowly barotiwala through the solution while maintaining the temperature below 2oC. the Reaction mixture were then flown at 7 mm Hg, giving a clear liquid (118,4 g), so Kip. 43 - 49oC. (Compound 76).

Example 73

3-Chloro-4-Butylochka-1,2,5-thiadiazole

A solution of DMF (400 ml) and monochloride sulfur (230 ml) klaidas C. The cooling was removed, the reaction mixture is stirred over night. The reaction mixture was cooled on an ice-water bath and the excess monochloride sulfur was destroyed by adding dropwise water so that the temperature did not exceed 30oC. the Liquid was decentralise with semi-solid sludge and sulfuric sulfuric residue was pulverized with hexane. The aqueous fraction was extracted with hexane (3x), the combined extracts and soluble substances were washed with water, aqueous sodium bicarbonate, brine, dried and the solvent was evaporated. The yellow liquid residue was distilled at 14 mm Hg, giving a clear liquid (153 g). so Kip. 120 - 125oC. (Compound 77).

Example 74

3-Methylthio-4-Butylochka-1,2,5-thiadiazole

A solution of compound 77 (6 g, about 0.001 mol) in DMF (75 ml) was rapidly mixed as added crushed flaky Na2S-9H2O (8 g, 0,034 mol). After 1 hour was added itmean (3 ml, 0,048 mol) and the reaction mixture stirred 30 minutes. To the reaction mixture was added a mixture of ice-water (150 ml) and the mixture was extracted with hexane (3x). The extracts were washed with water twice, dried and the solvent was evaporated, giving a clear liquid (6,04 g). (Compound 78).

Example 75

3rd the pits connection 78 (0,0147 mol) in THF (45 ml). After stirring over night the organic matter was evaporated and the residue was extracted with ether (3x). The extracts were washed with water (2x), dried and the solvent was evaporated. The residue was purified using radial chromatography with elution with a mixture of 50% ethyl acetate-hexane, giving a clear colorless liquid (2,93 g), which hardened on standing, so pl. 39-40oC. (Compound 79).

Example 76

3-Methylthio-4-hexyloxy-1,2,5-thiadiazole

A solution of 3-chloro-4-hexyloxy-1,2,5-thiadiazole (CA 60, 2796e, 1964) (1.1 g, of 0.005 mol) in DMF (30 ml) was rapidly mixed and added chopped flaky Na2S-(H2O (1.5 g, 0,00625 mol). After stirring overnight was added itmean (2 ml) and the reaction mixture stirred 30 minutes. To the reaction mixture was added a mixture of ice and water (150 ml) and the mixture was extracted with ether (2x). The extracts were washed with water (2x), dried, the solvent was evaporated, giving a clear liquid (1,025 g) (Compound 80).

Example 77

3-Methylsulphonyl-4-hexyloxy-1,2,5-thiadiazole

To a solution of oxone (18,4 g of 0.03 mole) in water (100 ml) was added dropwise compound 80 (3.4 g, 0,0147 mol) in THF (50 ml). After stirring for 3 days organic substances which were Privalka. The residue was purified using radial chromatography with elution with a mixture of 50% ethyl acetate-hexane, giving a clear colorless liquid (3.58 g). (Compound 81).

Example 78

CYANOGEN-propylacetamide

A solution of 1-propanol (40 ml, 0,536 mol) and triethylamine (1.5 ml) was cooled to -8oC, after the solution was slowly barotiwala CYANOGEN (36 g, 0,69 mol) while maintaining the temperature below 2oC. the Reaction mixture were then flown at 20 mm Hg, giving a clear liquid (59 g), so pl. 63 - 64oC. (Compound 82).

Example 79

3-Chloro-4-propyloxy-1,2,5-thiadiazole

A solution of DMF (180 ml) and monochloride sulfur (120 ml of 1.5 mol) was cooled to 5oC and was added dropwise compound 82 (59 g, 0,527 mol) so that the temperature did not exceed 10oC. Cooling was removed and the reaction mixture stirred over night. The reaction mixture was cooled in a bath of a mixture of ice and water and excess monochloride sulfur was destroyed by adding dropwise water so that the temperature did not exceed 30oC. Liquid semi-solid precipitate of sulfur was decentralise and sulfur residue was pulverized with hexane. The aqueous fraction was extracted with hexane 3 times and the combined extracts and RUB substance was filtered still water has flown under 15 mm Hg, giving a clear liquid (79,9 g), so Kip. 103 - 106oC. (Compound 83).

Example 80

3-Methylthio-4-propyloxy-1,2,5-thiadiazole

A solution of compound 83 (11.1 g, 0,062 mol) in DMF (150 ml) was rapidly mixed and added chopped flaky Na2S-9H2O (16.4 g, 0,068 mol). After 1 hour was added itmean (6 ml 0,096 mol) and the reaction mixture stirred 30 minutes. To the reaction mixture was added a mixture of ice and water (300 ml) and the mixture was extracted with hexane (3 x). The extracts were washed with water (2 x), dried and the solvent was evaporated, giving a clear liquid (11,02 g). (Compound 84).

Example 81

3-Methylsulphonyl-4-propyloxy-1,2,5-thiadiazole

To a solution of oxone (20 g, 0,0325 mol) in water (100 ml) was added dropwise compound 84 (3 g, 0,0158 mol) in THF (50 ml). After stirring overnight the organic phases were washed with water (2x), dried and the solvent was evaporated, giving a colorless oil. The residue was purified using radial chromatography with elution with a mixture of 40% ethyl acetate-hexane, giving a clear colorless liquid (3,09 g), which hardened on standing. Recrystallization from hexane gave a white solid, so pl. 30 - 31oC. (Compound 85).

PrimoC and after the solution was barotiwala CYANOGEN (38 g, to 0.73 mol) maintaining the temperature below 2oC. the Reaction mixture was converted at 45 mm Hggiving a clear liquid (51 g), so Kip. 48 - 53oC. (Compound 86).

Example 83

3-Chloro-4-methoxy-1,2,5-thiadiazole

A solution of DMF (180 ml) and monochloride sulfur (120 ml of 1.5 mol) was cooled to 5oC and was added dropwise compound 86 (51 g, 0,607 mol) so that the temperature did not exceed 15oC. Cooling was removed and the reaction mixture stirred over night. The reaction mixture was cooled in a bath of a mixture of ice and water and excess monochloride sulfur was destroyed by adding dropwise water so that the temperature did not exceed 30oC. the Solution was then diluted with water (350 ml) and was converted with steam up until almost all of the distillate did not become homogeneous. The distillate was extracted with hexane (3x), the combined extracts were washed with water, aqueous sodium bicarbonate, brine, dried and the solvent was distilled as long as the volume was not 200 ml. of Hot mixture was filtered and cooled, giving white crystals (53 g). (Compound 87).

Example 84

3 Matiatia-4-methoxy-1,2,5-thiadiazole

A solution of compound 87 (9.4 g, SUB>2O (16.4 g, 0,068 mol). After 1 hour was added itmean (6 ml, 0,096 mol) and the reaction mixture stirred 30 minutes. Was added to a mixture of ice and water (350 ml) and the mixture was extracted with hexane. The extracts were washed with water (2x), dried and dissolved was carefully evaporated, giving a clear liquid (4.4 g). (Compound 88).

Example 85

3-Methylsulphonyl-4-methoxy-1,2,5-thiadiazole

To a solution of oxone (84 g, 0,0552 mol) in water (170 ml) was added dropwise compound 88 (4.4 g, or 0.027 mol) in THF (80 ml). After stirring for 5 hours the organic phase was evaporated and the residue was extracted with ether (3x). The extracts were washed with water (2x), dried and the solvent was evaporated, giving a flocculent white solid (2.76 g), so pl. 110,5 - 111,5oC. (Compound 89).

Example 86

3-Chloro-4-pentyloxy-1,2,5-thiadiazole

A solution of 1-pentanol (60 ml of 0.55 mol) and triethylamine (1.5 ml) was cooled to -8oC and through the solution slowly barotiwala CYANOGEN (36 g, 0,69 mol) maintaining the temperature below 2oC. the Reaction mixture is stirred for another hour at -5oC, then dropwise added to a solution of DMF (180 ml) and monochloride sulfur (120 ml of 1.5 mol), which was cooled to 5oC, while maintaining t is AI night. The reaction mixture was cooled in a bath of a mixture of ice and water and excess monochloride sulfur was decomposed by adding dropwise water so that the temperature did not exceed 30oC. the Liquid was decentralise with semi-solid precipitate of sulfur and the sulfur residue was pulverized with hexane. The aqueous fraction was extracted three times with hexane and the combined extracts and RUB substances were washed with water, aqueous sodium bicarbonate, brine, dried and the solvent was evaporated. The yellow liquid residue was flown at 9 mm Hggiving a clear liquid (of 92.7 g), so Kip. 129 - 135oC. (Compound 90).

Example 87

3-Methylthio-4-pentyloxy-1,2,5-thiadiazole

A solution of compound 90 (12.8 g, is 0.06 mol) in DMF (150 ml) was rapidly stirred and to it was added crushed flaky Na2S-9H2O (16.4 g, 0,068 mol). After 1 hour was added itmean (6 ml, 0,096 mol), the reaction mixture is stirred for 30 minutes. Was added to a mixture of ice and water (300 ml) and the mixture was extracted with hexane (3 x). The extracts were washed with water (2 x), dried and the solvent was evaporated, giving a clear liquid (12,6 g). (Compound 91).

Example 88

3-Methylsulphonyl-4-pentyloxy-1,2,5-thiadiazole

To a solution of oxone (72 g, 0,117 menia nights of organic matter was evaporated and the residue was extracted with ether (3x). The extracts were washed with water (2 x), dried and the solvent was evaporated, giving a colorless oil. The residue was purified using flash chromatography with elution with a mixture of 40% ethyl acetate-hexane, giving a clear colorless liquid (13 g). (Compound 92).

Example 89

3-Chloro-4-ethoxy-1,2,5-thiadiazole

The ethanol (60 ml of 1.02 mol) and triethylamine (1.5 ml) was cooled to -8oC and through the solution while maintaining the temperature below 2oC barotiwala CYANOGEN (59 g of 1.13 mol). The reaction mixture then was added dropwise to a solution of DMF (275 ml) and monochloride sulfur (225 ml, of 2.81 mol), which was cooled to 5oC, the temperature of the DMF solution was maintained below 10oC. Cooling was removed and the reaction mixture stirred over night. The reaction mixture was cooled in a bath of a mixture of ice and water, the excess monochloride sulfur was destroyed by adding dropwise water so that the temperature did not exceed 30oC. was Added additional water (400 ml), the reaction mixture was subjected to internal distillation with steam up until the distillate became almost homogeneous. The distillate was extracted with hexane (3x), the combined extracts were washed with water, aqueous sodium bicarbonate, salt prozrachnuy liquid (154,3 g), so Kip. 88 - 93oC. (Compound 93).

Example 90

3-Methylthio-4-ethoxy-1,2,5-thiadiazole

A solution of compound 93 (16.5 g, 0,1 mol) in DMF (250 ml) was rapidly mixed adding this crushed flaky Na2S-9H2O (27 g, 0,113 mol). After 1 hour was added itmean (9,5 ml, 0,153 mol), the reaction mixture is stirred for 1 hour. To the reaction mixture was added a mixture of ice and water (400 ml) and the mixture was extracted with hexane (3x). The extracts were washed with water (2 x), dried and the solvent was evaporated, giving a clear liquid (12.5 g). (Compound 94).

Example 91

3-Methylsulphonyl-4-ethoxy-1,2,5-thiadiazole

To a solution of oxone (90 g, 0,146 mol) in water (435 ml) was added dropwise compound 19 (12.5 g, 0,071 mol) in THF (220 ml). After stirring over night the organic matter was evaporated and the residue was extracted with ether (3 x). The extracts were washed with water (2 x) and the solvent was evaporated, giving a white solid. Recrystallization from ether gave a white solid (9,9 g) so pl. 95 - 95oC. (Compound 95).

Example 92

3-Chloro-4-(4-methylpentylamino)-1,2,5-thiadiazole

A solution of 4-methylpentan-1-ol (25 ml of 0.25 mol) and triethylamine (1 ml) was cooled to -8oC, through Rasmus then stirred for another hour at -5oC, and then was added dropwise to a solution of DMF (75 ml) and monochloride sulfur (49 ml) which was cooled to 5oC while maintaining the solution temperature below DMF 10oC. Cooling was removed and the reaction mixture stirred over night. The reaction mixture was cooled in an ice-water bath and the excess monochloride sulfur was destroyed by adding dropwise water so that the temperature did not exceed 35oC. the Liquid was decentralise with semi-solid precipitate of sulphur, sulphur residue was pulverized with hexane (3×), the combined extracts and RUB substances were washed with water, aqueous sodium bicarbonate, brine, dried and the solvent was evaporated. The yellow liquid residue was flown at 4.5 mm Hg, giving a clear liquid (40,45 g), so Kip. 120 - 124oC. (Compound 96).

Example 93

3-Methylthio-4-(4-methylpentylamino)-1,2,5-thiadiazole

A solution of compound 96 (22 g of 0.1 mol) in DMF (250 ml) was rapidly mixed and thereto were added crushed flaky Na2S-9H2O (27 g, 0,113 mol). After 1 hour was added itmean (9,5 ml, 0,153 mol), the reaction mixture is stirred for 30 minutes. To the reaction mixture was added a mixture of ice and water (300 ml), the mixture was extracted with hexane (3 x). Extrene 97).

Example 94

3-Methylsulphonyl-4-(4-methylpentylamino)-1,2,5-thiadiazole

To a solution of oxone (119 g, rate of 0.193 mol) in water (600 ml) was added dropwise compound 97 (21,6 g, 0,093 mol) in THF (300 ml). After stirring over night the organic layers were evaporated and the residue was extracted with ether (3 x). The extracts were washed twice with water, dried and the solvent was evaporated, giving a colorless oil. The residue was purified by HPLC (8 l gradient hexane to 40% ethyl acetate-hexane), yielding a clear, colorless liquid (19.7 g). (Compound 98).

Example 95

3-(1-Butylochka)-4-/endo-(+, -)-6-(1-azabicyclo/3,2,1/octyloxy)/ -1,2,5-thiadiazole

A solution of potassium tert-butylate (0,62 g, 0,0055 mol) in THF (12 ml) was treated endo-(+, -)-1-azabicyclo/3,2,1/octane-6-I (0.64 g, 0,005 mol. After 5 minutes was added 3-chloro-4-(1-Butylochka)-1,2,5-thiadiazole (1.5 g, 0,0072 mol). After stirring overnight the solvent was evaporated, the residue was diluted with water, pagkilala and was extracted with ether. The aqueous phase was podslushivaet and was extracted with ethyl acetate, the extracts were dried, washed with saline, dried and the solvent was evaporated. The residue was purified using radial chromatography (20% ethanol-2% ammonium hydroxide-chloroform). HCl is e 71).

Example 96

()-3-(2-Methylthioethyl)-4-(1-azabicyclo/2,2,2/octyl-3-oxy) -1,2,5-thiadiazole

A solution of 3-(2-methylthioethyl)-4-hydroxy-1,2,5-thiadiazole (0.45 g) and triphenylphosphine (0.7 g) was cooled in a mixture of ice and water during this time was dropwise added diethyldithiocarbamic (0.4 ml). After the additions were added ()-1-azabicyclo/2,2,2/Octan-2-ol (0.33 g), the cooling was removed and the reaction mixture is stirred for 1 hour. The solvent was evaporated, the residue was suspenderbelt in the water, and the mixture was padillas and rinsed with ether. The aqueous solution was podslushivaet and was extracted with ethyl acetate. The extracts were dried, the solvent was evaporated, the residue was purified using radial chromatography with elution with a mixture of 10% ethanol with 1% ammonium hydroxide-chloroform and the product was transformed into HCl salt. Recrystallization from acetone gave 0.6 g of white crystals, so pl. 177 - 178oC. (Compound 99).

The following compounds were synthesized essentially in the same way as the connection 99.

Example 97

()-3-(1-Azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

Sample 3-hydroxy-1,2,5-thiadiazole (0.28 g), triphenylphosphine (0.7 g), diethyldithiocarbamate (0.4 ml) and ()-1-azabicyclo-/2,2,2/Octan-3-ol (0.33 g) gave cleaners containing hydrochloride salt 98

()-3-Hexyl-4-(1-azabicyclo)2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

Sample 3-hexyl-4-hydroxy-1,2,5-thiadiazole (0,93 g), triphenylphosphine (1.31 g), diethyldithiocarbamate (0.8 ml) and ()-1-azabicyclo/2,2,2/Octan-3-ol (0.64 g) gave cleaners containing hydrochloride salt of ()-3-hexyl-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole, so pl. 163-164oC decomp. (1,11 g). (Compound 101).

Example 99

()-3-Butylsulfonyl-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 the thiadiazole

A solution of tert-betulina potassium (1.2 g) in THF (50 ml) was treated ()-1-azabicyclo/2,2,2/octane-3-I (1.3 g). After 10 minutes the reaction mixture was cooled in a mixture of ice and water, one portion was added compound 1 (2.3 g). The cooling was removed and after 2 hours, the solution was heated to reflux distilled for 4 hours. The solvent was evaporated, the residue was suspenderbelt in the water, and the mixture was padillas and was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ethyl acetate. The extracts were washed with water, brine, dried and the solvent was evaporated, yielding compound 14 (1,95 g). The oil was dissolved in dilute 0.5 to guest. HCl (17 ml) was cooled in a mixture of ice and water for 5 minutes was added a solution of oxone (6 g) in water (25 ml). The cooling was removed and after 4 hours the excess omissus the 5 standards. sodium hydroxide and was extracted with ethyl acetate. The extracts were washed with saline, dried and the solvent was evaporated, yielding ()-3-butylsulfonyl-4-(1-azabicyclo/2.2.2/octyl-3-oxy)-1,2,5-thiadiazole in the form of a yellow oil (1.6 g) HCl salt crystallized from 2-propanol in the form of a white solid substance, so pl. 180-181oC. (Compound 102).

Example 100

()-3-Propylsulfonyl-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 the thiadiazole

Using essentially the same procedure as for compound 102, ()-1-azabicyclo/2,2,2/Octan-3-ol (4 g) and compound 37 (4.9 g) gave ()-3-propylsulfonyl-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole (4,2 g) as a reddish-brown liquid that hardened when standing, so pl. 77-78oC. (Compound 103).

Example 101

()-3-(4,4,4-Triptoreline)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

A solution of 4,4,4-triptoreline (0.75 g) in THF (20 ml) was cooled to 0oC was added tert-butyl potassium (0.65 g). After 5 minutes was added a solution of compound 102 (0.6 g) in THF (5 ml) and the reaction mixture is stirred for 1 hour. The reaction mixture was extinguished 5 standards. HCl (1.5 ml) and the solvent was evaporated. The residue was suspenderbelt in the water and was extracted with ether. The aqueous phase ALSA using radial chromatography with elution with a mixture of 20% ethanol-1% ammonium hydroxide-chloroform, giving a clear oil. HCl salt was precrystallization from a mixture of ethyl acetate and ether, giving a white solid, so pl. 122-124oC (0,43 g). (Compound 104).

The following compounds were obtained essentially the same way.

Example 102

()-3-(2-Butenyloxy)-4-(1-azabicyclo/2,2,2/octyl-3-hydroxy-1,2,5-thiadiazole

Using essentially the same procedures that were used to obtain compound 104, 2-butanol (0.45 g) and compound 102 gave after chromatography, ()- 3-(2-butanolate)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole (0.45 g) as an HCl salt that crystallized from 2-propanol, T. pl. 200-201oC. (Compound 105).

Example 103

()-3-(Cyclopropylmethoxy)-4-)1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using basically the same procedure that was used when the connection 104, cyclopropylmethanol (0.5 ml) and compound 102 (0.6 g) gave after chromatography, ()- 3-(cyclopropylmethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy) -1,2,5-thiadiazole (0.45 g) as an HCl salt that crystallized from acetone, so pl. 217-218oC. (Compound 106).

Example 104

()-3-(3-Phenylpropionate)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using VI is 2 (0.66 g) gave after chromatography, ()- 3-(3-phenylpropionate)-4-(1-azabicyclo/2,2,2/octyl-3-oxy) -1,2,5-thiadiazole as an HCl salt (0.66 g), which is crystallized from a mixture of ether and chloroform, so pl. 184-186oC. (Compound 107).

Example 105

()-3-(3-Butenyloxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using essentially the same procedure that was used when the connection 104, 3-butenyl (0.5 ml) and compound 102 (0.6 g) gave after chromatography, ()- 3-(3-butenyloxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole (-0,47 g) as an HCl salt that crystallized from acetone, so pl. 198-199oC. (Compound 108).

Example 106

()-3-(TRANS-2-butenyloxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using essentially the same procedure that was used when the connection 104, TRANS-2-butenal (0.45 g) and compound 102 (0.6 g) gave after chromatography, ()- 3-(TRANS-2-butenyloxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole (0.51 g) as an HCl salt that crystallized from 2-propanol, T. pl. of 182.2-184oC. (Compound 109).

Example 107

()-3-(CIS-2-butenyloxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using essentially the same procedure that was used when the connection 104, CIS-2-butanol (0.45 g) and compound 102 (0.5 g) gave after chromatographies from acetone, so pl. 178-179oC. (Compound 110).

Example 108

()-3-(2-Methoxyethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using essentially the same procedure that was used to obtain compound 104, 2-methoxyethanol (0.45 g) and compound 102 (0.5 g) gave after chromatography, ()- 3-(2-methoxyethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole (0.32 g) as an HCl salt that crystallized from acetone, so pl. 131-134oC. (Compound 111).

Example 109

()-3-(2-Phenoxyethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2.5 - thiadiazole

Using essentially the same procedure that was used to obtain compound 104, 2-Phenoxyethanol (0.55 g) and compound 102 (0.4 g) gave )-3-(2-phenoxyethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole as an HCl salt, which (of 0.43 g) was crystallized from a mixture of ether and chloroform, so pl. 213-215oC. (Compound 112).

Example 110

()-3-(3-butinox)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using essentially the same procedure that was used when the connection 104, 3-butynol (0.27 g) and compound 102 (0.4 g) gave after chromatography, ()- 3-(3-butinox)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole in the form ">

Example 111

()-3-(2-Cyclopropylmethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

Using essentially the same procedure that was used to obtain compound 104, 2-cyclopropylethanol and compound 102 (0.5 g) gave after chromatography, ()- 3-(2-cyclo-propietari)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole (0,48 g) as an HCl salt that crystallized from acetone, so pl. 192-193oC. (Compound 114).

Example 112

()-3-(2-(Methylthio)ethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using essentially the same procedure that was used to obtain compound 104, 2-(methylthio)ethanol and compound 102 (0.5 g) gave after chromatography, ()- 3-(2-methylthio)ethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole (0.4 g) as an HCl salt that crystallized from acetone, so pl. 187-188oC. (Compound 115).

Example 113

()-3-(3-Chloropropoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

Using essentially the same procedure that was used when the connection 104, 3-chloropropanol (0.5 ml) and compound 102 (0.4 g) gave after chromatography, ()- 3-(3-chloropropoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole (0.25 g) as an HCl salt, which crystallize is hydroxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using the same procedure that was used when the connection 104, 4-torbutrol (0.6 g) and compound 102 (0.4 g) gave after chromatography, ()- 3-(4-terbutaline)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

(0.34 g) as an HCl salt that crystallized from a mixture of acetone-ethyl acetate, so pl. of 180.5-181,5oC. (Compound 117).

Example 115

()-3-(2-(4-Chlorophenoxyacetic)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole

Using essentially the same procedure that was used when the connection 104. 2-(4-chlorophenoxy)ethanol (0,77 g) and compound 102 (0.4 g) gave after chromatography()-3-(2-(4-chlorphenoxy)ethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole as an HCl salt that crystallized from a mixture of simple ether-chloroform, so pl. 224-226oC. (Compound 118).

Example 116

()-3-(3-(2-Methoxy-5-pyridyl)propyloxy)-4-(1-azabicyclo/2,2,2/octyl - 3-oxy)-1,2,5-thiadiazole

Using essentially the same procedure that was used when the connection 104, 3-(2-methoxy-5-pyridyl)propanol (0.75 g) and compound 102 (0.4 g) gave after chromatography()-3-(3-(2-methoxy-5-pyridyl)propyloxy)-4-(1-azabicyclo/2,2,2/ octyl-3-oxy)-1,2,5-thiadiazole as an HCl salt (0,48 g), which crystallins-3-chloro-2-propenyloxy)-4-(1-azabicyclo/2,2,2/octyl - 3-oxy)-1,2,5-thiadiazole

Using essentially the same procedure that was used when the connection 104, except that the reaction was carried out at -15oC, TRANS-3-chloro-2-propanol (0.5 g) and compound 102 (0.4 g) gave after chromatography, ()- 3-(TRANS-3-chloro-2-propenyloxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole (0.33 g) as an HCl salt that crystallized from acetone, so pl. 176,5-177,5oC. (Compound 120).

Example 118

()-3-(2-(4-Pertenece)ethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy) -1,2,5-thiadiazole

Using essentially the same procedure that was used to obtain compound 104, 2-(4-pertenece)ethanol (0,53 g) and compound 102 (0.4 g) gave after chromatography()-3-(2-(4-pertenece)ethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole as an HCl salt (0,43 g), which crystallized from a mixture of ether and chloroform, so pl. 187-189oC. (compound 121).

Example 119

()-3-(4-Pentyloxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using essentially the same procedure that was used when the connection 104, 4-pentenol (0.6 ml) and compound 102 (0.4 g) gave after chromatography, ()- 3-(4-pentyloxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole (0,37 g) as an HCl salt, motoropolis)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using the same procedure that was used when the connection 104, 3-forproposal (0.4 ml) and compound 102 (0.4 g) gave after chromatography, ()- 3-(3-forproposals)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole (0.3 g) as an HCl salt that crystallized from acetone, so pl. 206-207oC. (Compound 123).

Example 121

()-3-(Cyclobutylmethyl)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using essentially the same procedure that was used when the connection 104, cyclobutylmethyl (0.6 ml) and compound 102 (0.4 g) gave after chromatography, ()- 3-(cyclobutylmethyl)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole (0.33 g) as an HCl salt that crystallized from acetone, so pl. 212-213oC. (Compound 124).

Example 122

()-3-(3,3,3,2,2-Pentafluoropropyl)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole

Using essentially the same procedure that was used when the connection 104, 3,3,3,2,2-pantotropha (0,69 ml) and compound 102 (0.4 g) was obtained after chromatography ()-3-(3,3,3,2,2-pentafluoropropyl)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole as an HCl salt (0,44 g), which crystallized from a mixture of ether and chloroform, so pl. 185-186oC. (Conn Is using essentially the same procedure what was used when the connection 104, 2-phenylthio)ethanol (0.71 g) and compound 102 (0.4 g) gave after chromatography, ()- 3-(2-(phenylthio)ethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole as an HCl salt (0,37 g), which crystallized from a mixture of ether and chloroform, so pl. 187-189oC. (Compound 126).

Example 124

()-3-(2-(1-Naphthyloxy)ethoxy)-4-(1-azabicyclo/2,2,2/octal/-3-hydroxy-1,2,5 - thiadiazole

Using essentially the same procedure that was used to obtain compound 104, 2-(1-naphthyloxy)ethanol (0,839 g) and compound 102 (0.4 g) was obtained after chromatography()-3-(2-(1-naphthyloxy)ethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole as an HCl salt (0.51 g), which crystallized from a mixture of ether and chloroform, so pl. 223-225oC. (Compound 127).

Example 125

()-3-(2-(4-Bromophenoxy)ethoxy)-4-(1-azabicyclo/2,2,2/octal/-3-hydroxy-1,2,5 - thiadiazole

Using essentially the same procedure that was used to obtain compound 104, 2-(4-bromophenoxy)ethanol (0.97 g) and compound 102 (0.4 g) gave after chromatography()-3-(2-(4-bromophenoxy)ethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole as an HCl salt (0,53 g), which crystallized from a mixture of ether and chloroform, so pl. p.223-224oC. (Compound 128).

Olya (9 ml) and of potassium tert-butylate (1.5 g) was treated with compound 102 (0.8 g). After stirring over night the reaction mixture was heated to 55oC for 1 hour. The reaction mixture then was cooled, it was diluted with water and extracted with ethyl acetate. The extracts were washed with saline, dried and the solvent was evaporated, giving a clear liquid. The liquid was purified using radial chromatography with elution with a mixture of 20% ethanol-2% ammonium hydroxide-chloroform, and then crystallized from ether, giving a white solid (0.45 g), so pl. 119,5 is 120.5oC. (Compound 129).

Example 127

3 Butylthio-4-hydroxy-1,2,5-thiadiazole

A solution of compound 1 (20,9 g), DMSO (20 ml) and 2 norms. NaOH (205 ml) was heated to the temperature of reflux distilled during the night. The solution was cooled to 15oC and was added concentrated HCl up until the pH became 1. The solid was collected, rinsed with water and dried, giving a solid (17,68 g). Recrystallization from heptane gave white crystals, so pl. 72-72,5oC. (Compound 130).

Example 128

()-Exo-3-butylthio-4-(1-azabicyclo/2,2,1/heptyl-3-hydroxy)-1,2,5-thiadiazole

A solution of triphenylphosphine (0.7 g) and compound 130 (0.5 g) in THF (20 ml) was cooled in a mixture of ice and water. Diethyldithiocarbamic (0,4 removed and after 1 hour the solvent was evaporated. The residue was suspenderbelt in cold water, pagkilala and was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ethyl acetate. The extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography with elution with a mixture of 5% ethanol-0.5% ammonium hydroxide - chloroform, giving a clear oil. The HCl salt crystallized from ethyl acetate as white crystals (0,44 g). So pl. 147-148oC. (Compound 131).

Example 129

()-3-(2-(3-1,2,5-Thiadiazole)ethoxy)-4-(1-azabicyclo/2,2,2/-octyl - 3-oxy)-1,2,5-thiadiazole

A solution of triphenylphosphine (0.35 g) and 3-hydroxy-1,2,5-thiadiazole (0.14 g) in THF (15 ml) was cooled in a mixture of ice and water. Diethyldithiocarbamic (0.21 g) was added dropwise, followed by addition of ()-3-(2-hydroxyethoxy)-4-(1-azabicyclo/2,2,2/-octyl-3-oxy)-1,2,5 - thiadiazole (0.35 g). The cooling was removed, the reaction mixture is stirred for 1 hour, the solvent was evaporated. The residue was suspenderbelt in cold water, pagkilala and was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ethyl acetate. The extracts were washed with saline and dried, the solvent was evaporated, the residue was purified using radial chromatography with LWIR Cetona in the form of a white powder (0.34 g), so pl. 178-179oC. (Compound 132).

Example 130

()-Exo-3-Butylochka-4-(7-azabicyclo/2,2,1/heptyl-3-hydroxy)-1,2,5 - thiadiazole

A solution of Exo-7-azabicyclo/2,2,1/heptane-3-ol (0.4 g) (see J. Org. Chem. 1994, 59, 1771) in THF (25 ml) was cooled in a mixture of ice and water, and is treated dropwise 1.6 M n-utility in hexane (3.5 ml). The cooling was removed and after 15 minutes was added compound 79 (0.65 g). After another 45 minutes the reaction mixture was heated to the temperature of reflux distilled during the night. The solvent was evaporated, the residue was suspenderbelt in the water, and the mixture was padillas and was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ethyl acetate. The extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography with elution with a mixture of 5% ethanol-0.5% ammonium hydroxide-chloroform, then with 10% ethanol-1% ammonium hydroxide-chloroform, giving a clear oil. The HCl salt crystallized from a mixture of ethyl acetate and ether, in the form of a flocculent white crystals (0.4 g), so PL 116-117oC. (Compound 133).

Example 131

()-3-Butylochka-4-(3-piperidinyloxy)-1,2,5-thiadiazole

Suspension of the hydrochloride of ()-3-hydroxypiperidine (0.5 g) in THF (20 ml) was treated dropwise 1.6 M n-butyllithium in hexane hours. The solvent was evaporated, the residue was suspenderbelt in cold water, pagkilala and was extracted with ether. The aqueous fraction was podslushivaet and was extracted with chloroform. The extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography with elution with a mixture of 10% ethanol - 1% ammonium hydroxide - chloroform, giving a clear oil. The HCl salt crystallized from ethyl acetate as a white solid (0,38 g). so pl. 124-125oC. (Compound 134).

Example 132

3 Butylochka-4-(cyl-IR-2-aminocyclopentane)-1,2,5-thiadiazole

Suspension of the hydrochloride CIS-1R-2-aminocyclopentane (0.35 g) in THF (25 ml) was cooled in a mixture of ice and water and this was added 1.6 M n-utility in hexane (3.2 ml). The cooling was removed and after 30 minutes was added compound 79 (0.3 g) and the reaction mixture was heated to reflux distilled for 1 hour. Added additional connection 79 (0.3 ng) and the reaction mixture was heated to reflux distilled during the night. The solvent was evaporated, the residue was suspenderbelt in a mixture of ice and water, pagkilala and was extracted with ether. The aqueous fraction was podslushivaet, was extracted with chloroform, the extracts were dried, the solvent was evaporated and the residue was purified colored straw oil. The HCl salt crystallized from ether in the form of a reddish-brown solid (0,19 g) So pl. 105-106oC. (Compound 135).

Example 133

()-Endo-3-hexyloxy-4-(1-azabicyclo/3,2,1/octyl-6-oxy)-1,2,5-thiadiazole

A solution of tert-betulina potassium (0.65 g) in THF (15 ml) was treated ()-endo-1-azabicyclo/3,2,1/octane-6-I (0.64 g). After 10 minutes, was added 3-chloro-4-hexyloxy-1,2,5-thiadiazole (1.4 g) and the reaction mixture stirred for 3 days. The solvent was evaporated, the residue was suspenderbelt in a mixture of ice and water, and the mixture was padillas and was extracted with ethyl acetate. The extracts were dried and the solvent was evaporated. The residue was purified using radial chromatography with elution with a mixture of 20% ethanol-2% ammonium hydroxide - chloroform, giving a clear oil (0.5 g). The HCl salt crystallized from ethyl acetate, giving a white solid, so pl. 160-161oC. (Compound 136).

Separated enantiomers of endo-1-azabicyclo/3,2,1/Octan-6-ol was obtained by restoring the divided ketones (see new patent), as described in the reference source.

Example 134

(5S, 6S)-Endo-3-butylthio-4-(1-azabicyclo/3,2,1/octyl-6-oxy)-1,2,5-thiadiazole

A solution of potassium tert-butylate (0.65 g) in THF (25 ml) was treated (5S, 6S)-aalas compound 1 (1.2 g). The cooling was removed and the reaction mixture stirred over night. The solvent was evaporated and the residue was suspenderbelt in a mixture of ice and water, and the mixture was padillas and was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ethyl acetate, the extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography with elution with a mixture of 20% ethanol - 2% ammonium hydroxide - chloroform, giving the oil, HCl salt crystallized from ethyl acetate in the form of a flocculent white crystals (0,59 g), so pl. 201oC ()D= 11,44o(EtOH). (Compound 137).

Example 135

(5R, 6R)-Endo-3-butylthio-4-(1-azabicyclo/3,2,1/octyl-6-oxy)-1,2,5 - thiadiazole

Using the procedure described for connection 137, (5R, 6R)-endo-1-azabicyclo/3,2,1/Octan-6-ol (0.65 g), tert-butyl potassium (0.65 g) and compound 1 (1.2 g) gave a flocculent white crystals of the HCl salt specified in the connection header (0,62 g), so pl. 201-202oC ()D= -12,35o(ethanol). (Compound 138).

Example 136

1-Azabicyclo/4.3.0/Nona-6,8-Dien-5-he

A solution of ethyl-4-(N-pyrrole)butanoate (see Tetrahedron Letters, 1994, 35, 3905) (of 3.64 g) in methylene chloride (400 ml) was treated dropwise 1 M tribromide boron in methylenchlorid Organic matter was separated, was filtered aqueous sodium bicarbonate, brine, dried and the solvent was evaporated. The residue was purified by HPLC using a gradient of 10% ethyl acetate-hexane to 30% ethylacetate, giving an oil (5.2 g). (Compound 139).

Example 137

()-CIS+TRANS-1-azabicyclo/4.3.0/Nona-5-Ola

A mixture of compound 139 (5,2 g), 5% Rh/Al2O3(1.3 g) in ethanol (95 ml) was treated with hydrogen at 60 lb./square inch (4,219 kg/sq. cm) for 2 hours. Was added to another aliquot of Rh/Al2O3(1.3 g) and hydrogenation continued throughout the night. The catalyst was removed and the solvent was evaporated, giving an oil (4,2 g), which was suitable for alcohols mass spectrum, m/e = 141. (Compound 140).

Example 138

()-TRANS-3-butylthio-4-(1-azabicyclo/4.3.0/nonyl-5-oxy)-1,2,5 - thiadiazole

A solution of compound 140 (0.7 g) in THF (20 ml) was treated tert-butyl potassium (0.6 g). After 5 minutes, was added compound 1 (1.1 g). The reaction mixture is stirred for 1 hour and then heated to reflux distilled for 1 hour. The solvent was evaporated, the residue was suspenderbelt in a mixture of ice and water and the mixture was padillas. After extraction with ether, the aqueous fraction was podslushivaet and was extracted etiolate when elution with a mixture of 5% ethanol-0.5% ammonium hydroxide-chloroform, giving the oil. The HCl salt crystallized from ethyl acetate as a white solid (0.21 g). So pl. 162-163oC. (Compound 141).

Example 139

()-CIS-3-butylthio-4-(1-azabicyclo/4.3.0/nonyl-5-oxy)-1,2,5-thiadiazole

Further elution during chromatographic purification of compound 141 was given another transparent oil. The HCl salt crystallized from ethyl acetate as a white solid (0.18 g), so pl. 125-126oC. (Compound 142).

Example 140

()-TRANS-3-butylthio-4-(2-dimethylaminoethoxy)-1,2,5-thiadiazole

A solution of potassium tert-butylate (0.7 g) in THF (20 ml) was treated ()-TRANS-2-dietilaminoetoksietanola (0.8 g). After 10 minutes the reaction mixture was cooled in a mixture of ice and water was added compound 1 (1.25 g). The cooling was removed and the reaction mixture stirred over night. After heating to reflux distilled for 2 hours the solvent was evaporated, the residue was suspenderbelt in a mixture of ice and water and the mixture was padillas. The mixture was extracted with ether and the aqueous phase was podslushivaet. Extraction with ethyl acetate, drying of the extracts, evaporation of solvent and purification using radial chromatography with elution with a mixture of 10% ethanol - 1% ammonium hydroxide - chloropurine substance (0.55 g). so pl. 124-125oC. (Compound 143).

Example 141

3 Butylthio-4-(2-dimethylaminoethoxy)-1,2,5-thiadiazole

A solution of potassium tert-butylate (0.6 g) in THF (20 ml) was treated with 2-dimethylaminoethanol (0.5 ml). After 5 minutes was added compound 1 (of 1.05 g) and the reaction mixture is stirred for 2 hours. The solvent was evaporated, the residue was suspenderbelt in a mixture of ice and water, and the mixture was padillas. The mixture was extracted with ether, then the aqueous fraction was podslushivaet. Extraction with ethyl acetate, drying of the extracts, evaporation of solvent and purification of residue by using a radical chromatography with elution with a mixture of 5% ethanol - 0.5% ammonium hydroxide-chloroform gave an oil. The HCl salt crystallized from ethyl acetate as a white solid (0.47 in), so pl. 104-105oC. (Compound 144),

Example 142

()-TRANS-3-Butylthio-4(N-tert-butylcarbamoyl-4-hydroxypyrrolidine-3-oxy)- 1,2,5-thiadiazole

A mixture of NaOH (0.12 g) and DMF (15 ml) was treated with compound 130 (0.95 g) and the reaction mixture is stirred for 1 hour. The solution was processed 3,4-epoxy-N-tert-butilgidroksianizola (0.8 g) and the solution was heated at 60oC during the night. The temperature of the reaction mixture was then increased to 110oC technicalization. The extracts were washed with water, salt solution, the extracts were dried and the solvent was evaporated. The residue was purified using radial chromatography with elution with a mixture of 50% ethyl acetate-hexane, giving oil (0,44 g). (Compound 145).

Example 143

()-TRANS-3-butylthio-4(4-hydroxy-pyrrolidin-3-oxy)-1,2,5 - thiadiazole

A solution of compound 145 (0,44 g) in ethyl acetate (15 ml) was cooled in a mixture of ice and water, and during this time for 2 minutes was introduced a stream of dry HCl. The cooling was removed and after 5 minutes the solvent was evaporated. The residue was dissolved in cold water, was extracted with ether and the aqueous phase was podslushivaet. The aqueous phase was extracted with ethyl acetate, the extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography with elution with a mixture of 20% ethanol - 2% ammonium hydroxide-chloroform, giving a white solid. The HCl salt crystallized from a mixture of acetone-ether in the form of a white solid (0,23 g), so pl. 106-108oC. (Compound 146).

Example 144

()-Endo-3-Butylochka-4-(1-azabicyclo/3,2,1/octyl-6-oxy)-1,2,5 - thiadiazol

A solution of potassium tert-butylate (of 0.62 g) in THF (10 ml) were processed ()-endo-1-azabicyclo/3,2,1/octane-6-I (0.64 g). After 5 minutes the reactions the blend was mixed for the night. The solvent was evaporated, the residue was suspenderbelt in a mixture of ice and water, and the mixture was padillas and the mixture was extracted with water. The aqueous fraction was podslushivaet, was extracted with ethyl acetate, the extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography with elution with a mixture of 20% ethanol - 1% ammonium hydroxide-chloroform. The HCl salt crystallized from ethyl acetate, giving a white solid (0.21 g), so pl. 172-173oC. (Compound 147).

()-3-(4-Phenylbutyl)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using essentially the same procedure that was used to obtain compound 40, compound 12 (1,15 g) and 1-iodine-4-phenylbutane (4,92 g) gave ()-3-(4-phenylbutyl)-4-(1-azabicyclo-/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole in the form of HCl (0,59 g), crystallized from a mixture of ether-ethyl acetate-chloroform, so pl. 136-139oC. (Compound 148).

Example 146

()-3-(3-Phenyl-2-propylthio)-4-(1-azabicyclo/2,2,2/-octyl-3-oxy)- 1,2,5-thiadiazole

Using essentially the same procedure that was used to obtain compound 44, compound 12 (1,15 g) and senamirmir (0.73 g) gave ()-3-(3-phenyl-2-propylthio)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole as an HCl salt (0,095 g), crystalliza-Forfinal] propane-3-anti)-4-(1-azabicyclo/2,2,2/octyl-3-hydroxy)- 1,2,5-thiadiazole

Using essentially the same procedure that was used to obtain compound 40, compound 12 (1,15 g) and 1-chloro-3-(4-forfinal)propane-3-one (3,52 g) gave()-3-(3-/4-forfinal/propane-3-anti)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole as an HCl salt (0.375 g), crystallized from a mixture of ether-ethyl acetate-chloroform, so pl. 203-204oC. (Compound 150).

Example 148

()-3-(3-[N-Phenothiazinyl]propylthio)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole

Using essentially the same procedure that was used to obtain compound 13, compound 12 (1,15 g) and 1-bromo-3-(N-phenothiazinyl)propane (1,25 d) give ()-3-[N-phenothiazinyl/propylthio)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole as an HCl salt (0.35 g), crystallized from a mixture of ethyl acetate, so pl. 194-196oC. (Compound 151).

Example 149

()-3-(3-/4-Forfinal/-3-/4-pertenece/propylthio)-4- (1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

Using essentially the same procedure that was used to obtain compound 13, compound 12 (1,15 g) and 1-chloro-3-(4-forfinal)-3-(4-pertenece)propane (2.6 g) gave()-3-(3-/4-forfinal/-3-/4-pertenece/propylthio)-4-(1-azabicyclo/2,2,2/- octyl-3-oxy)-1,2,5-thiadiazole in the form of the oxalate salt (0,42 g), crystallizes is methylphenoxy/propylthio)-4-(1-azabicyclo/ 2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

Using essentially the same procedure that was used to obtain compound 13, compound 12 (1,15 g) and 1-chloro-3-phenyl-3-(4-triptoreline)propane (2.0 g) gave()-3-(3-/4-triptoreline/propylthio)-4-(1-azabicyclo/ 2,2,2/octyl-3-oxy)-1,2,5-thiadiazole in the form of the oxalate salt (0,198 g), crystallized from a mixture of chloroform and ether, so pl. 74-83oC. (Compound 153).

Example 151

()-3-(4,4,4-Cryptosporidia)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole

Using essentially the same procedure that was used to obtain compound 13, compound 12 (1,16 g) and bromo-4,4,4-triptorelin (1,81 g) gave ()-3-(4,4,4-cryptosporidia)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole as an HCl salt (1,43 g), crystallized from a mixture of chloroform and ether, so pl. 128-130oC. (Compound 154).

Example 152

()-3-(3-/3-Pyridyl/propylthio)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole

Using essentially the same procedure that was used to obtain compound 13, compound 12 (1,15 g) and bromo-3-(3-pyridyl)propane (1.42 g) gave()-3-(3-/3-pyridyl/propylthio)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5 - thiadiazole as an HCl salt (0,92 g), crystallized from a mixture of chloroform-ether-ethyl acetate, so pl. 202-204o
Using essentially the same procedure that was used to obtain compound 72, compound 48 (1,15 g) and bromo-2-phenoxy-ethane (3.8 g) gave ()-endo-3-(2-PHENOXYACETIC)-4-(1-azabicyclo/2,2,2/octyl-6-oxy)-1,2,5 - thiadiazole as an HCl salt (0.11 g), crystallized from a mixture of chloroform-ether-ethyl acetate, so pl. 144-146oC. (Compound 156).

An alternative procedure get ()-Exo-methyl-6-hydroxy-2-azabicyclo/2,2,2/octane-2-carboxylate

()-Exo-methyl-2-azabicyclo/2,2,2/Oct-5-ene-7-one-2-carboxylate

Hydrooxide potassium (39.9 g, 712 mmol) was added to a solution of methyl 7-acetoxy-7-cyano-2-azabicyclo/2,2,2/Oct-5-ene-2-carboxylate (J. Org. Chem. 1989, 54, 2893) (35.5 g, 142 mmole), ethanol (450 ml) and water (90 ml). The mixture is stirred at room temperature for 2 hours. The ethanol was removed by evaporation, and then the aqueous residue was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, then evaporated. Was carried out purification using preparative HPLC on silica gel with elution 10-100% ethyl acetate in hexano, giving ()-Exo-methyl-2-azabicyclo/2,2,2/Oct-5-ene-7-one-2-carboxylate (9,2 g, 50.8 mmol).

()-Exo-Methyl-2-azabicyclo/2,2,2/Oct-6-one-2-carboxylate

Sample ()-Exo-methyl-2-azabicyclo/2,2,2/Oct-ri 35 lb./square inch (2,461 kg/sq cm) at room temperature for 1 hour. The catalyst was filtered off and the filtrate was evaporated, yielding ()-Exo-methyl-2-azabicyclo/2,2,2/Oct-6-one-2-carboxylate (9 g).

()Exo-Methyl-6-hydroxy-2-azabicyclo/2,2,2/octane-2-carboxylate

Sodium borohydride (1.4 g, 36,1 mmole) was added to a mixture of ()-Exo-methyl-2-azabicyclo/2,2,2/Oct-6-one-2-carboxylate (6 g, 32,8 mmole) and heptahydrate of trichloride cerium (13,4 g, 36,1 mmole) in methanol (55 ml) at 0oC. the Mixture is stirred at room temperature over night. The reaction mixture was evaporated, the residue was taken in water, then was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, and then evaporated. The residue was purified using flash chromatography on silica gel with elution 25% ethyl acetate in hexano, giving ()-Exo-methyl-6-hydroxy-2-azabicyclo/2,2,2/octane-2-carboxylate (3.6 g, 19.5 mmol).

()-endo-Methyl-6-hydroxy-2-azabicyclo/2,2,2/octane-2-carboxylate

Was split ()-Exo-methyl-6-hydroxy-2-azabicyclo/2,2,2/octane-2-carboxylate and ()-endo-methyl-6-hydroxy-2-azabicyclo/2,2,2/octane-2-carboxylate by HPLC on silica gel with elution with a gradient of 10% to 80% ethyl acetate-hexane.

Example 154

()-Ecobalance to a solution of ()-Exo-methyl-6-hydroxy-2-azabicyclo/2,2,2/octane-2-carboxylate (3.6 g, 19.5 mmol) in tetrahydrofuran (200 ml) at room temperature. The reaction mixture is stirred for 1 hour, after which was added 3-chloro-4-propylthio-1,2,5-thiadiazole (3.8 g, 19.5 mmol) in tetrahydrofuran (50 ml) and the mixture stirred for 16 hours at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, and then evaporated. The residue was purified using preparative HPLC on silica gel with elution 5-50% ethyl acetate in hexano, giving [Exo] -()-Exo-3-propylthio-4-(2-methoxycarbonyl-2-azabicyclo/2,2,2/octyl - 6-oxy)-1,2,5-thiadiazole (2.1 g, 6.1 mmole). (Compound 157).

Example 155

()-Exo-3-propylsulfonyl-4-(2-methoxycarbonyl-2-azabicyclo/2,2,2/octyl- -hydroxy)-1,2,5-thiadiazole

The solution oxone (7.6 g, 12.4 mmole) in water (30 ml) was added to a solution of ()-Exo-3-propylthio-4-(2-methoxycarbonyl-2-azabicyclo-/2,2,2/octyl-6-oxy)- 1,2,5-thiadiazole (2.1 g, 6.1 mmole), water (10 ml) and tetrahydrofuran (20 ml). The mixture is stirred at room temperature for 16 hours. The reaction mixture was extracted with diethyl ether (CH ml). The organic extracts were washed with water, saturated aqueous sodium bicarbonate, water, dried over with the 6-oxy)-1,2,5-thiadiazole (2.4 g). (Compound 158).

Example 156

()-Exo-3-(4,4,4-triptoreline)-4-(2-methoxycarbonyl-2-azabicyclo/2,2,2/ octyl-6-oxy)-1,2,5-thiadiazole

Sodium hydride (4.1 mmole) was added to a solution of 4,4,4-triptoreline in tetrahydrofuran (35 ml) at room temperature. The mixture was mixed for 2 hours, after which the reaction mixture was added ()-Exo-3-propylsulfonyl-4-(2-methoxycarbonyl-2-azabicyclo/2,2,2/ octyl-6-oxy)-1,2,6-thiadiazole (1.0 g, 2.7 mmole) in tetrahydrofuran (5 ml). The reaction mixture was heated under conditions of reflux distilled for 16 hours. The reaction mixture was poured into brine, and then was extracted with ethyl acetate (CH ml). The organic extracts were dried over magnesium sulfate, giving ()-Exo-3-(4,4,4-triptoreline)-4-(2-methoxycarbonyl-2-azabicyclo/ octyl-6-oxy)-1,2,5-thiadiazole (1.0 g, 2.5 mmole). (Compound 159).

Example 157

()-Exo-3-(4,4,4-triptoreline)-4-(2-azabicyclo/2,2,2/octyl - 6-oxy)-1,2,5-thiadiazole

Trimethylsilylmethyl (0.4 ml, 3.0 mmole) was added to a solution of ()-Exo-3-(4,4,4-triptoreline)-4-(2-methoxycarbonyl-2-azabicyclo/ 2,2,2/octyl-6-oxy)-1,2,5-thiadiazole (1.0 g, 2.5 mmole) and dichloromethane (30 ml). Reactiona the mixture was heated under conditions of reflux distilled for 16 hours, then poured into a metal is by using radial chromatography on silica gel with elution with 2% ethanol/ 10% triethylamine in ethyl acetate, letting ()-Exo-3-(4,4,4-triptoreline)-4-(2-azabicyclo/2,2,2/octyl-6-oxy)- 1,2,5-thiadiazole, which was allocated in the form of an oxalate salt, giving 251 mg (so pl. 115-120oC). (Compound 160).

Example 158

()-Exo-3-(hexyloxy)-4-(2-azabicyclo/2,2,2/octyl-6-oxy)- 1,2,5-thiadiazole

Essentially the same procedure,sportswea for connection 160, with the replacement of 4,4,4-triptoreline hexane, giving ()-Exo-3-(hexyloxy)-4-(2-azabicyclo/2,2,2/octyl-6-oxy)-1,2,5 - thiadiazole-oxalate (so pl. 128-130oC). (Compound 161).

Example 159

()-Endo-3-(4,4,4-triptoreline)-4-(2-azabicyclo/2,2,2/octyl - 6-oxy)-1,2,5-thiadiazole

From ()-endo-methyl-6-hydroxy-2-azabicyclo/2,2,2/octane-2-carboxylate was obtained ()-endo-3-(4,4,4-triptoreline)-4-(2-azabicyclo/2,2,2/octyl - 6-oxy)-1,2,5-thiadiazole using essentially the same procedure that was used for the synthesis of compound 160. The compound was separated in the form of the oxalate salt (so pl. 151-153oC). (Compound 162).

Example 160

()-Exo-3-(2-[fervency] ethylthio)-4-(2-methoxycarbonyl- (2-azabicyclo/2,2,2/octyl-6-oxy)-thiadiazole

Nonahydrate sodium sulfate (1 g, 4.1 mmole) was added to ()-Exo-3-propylsulfonyl-4-(2-methoxycarbonyl- (2-azabicyclo/2,2,2/octyl-6-oxy)-thiadiazole (1,3, 3.5 mmole) in di is allelse 2-bromacil-4-forfinally ester (0.9 g, 4.2 mmole) in dimethylformamide (5 ml). The mixture was mixed for 1 hour at 100oC, then for 16 hours at room temperature. The reaction mixture was poured into brine, and then was extracted with ethyl acetate (3 x 150 ml). The organic extracts were combined and dried over magnesium sulfate, then evaporated. The residue was purified using radial chromatography on silica gel with elution 30% ethyl acetate in hexano, giving ()-Exo-3-(2-pertenece)ethylthio)-4-(2-methoxycarbonyl-2 - azabicyclo/2,2,2/octyl-6-oxy)-1,2,5-thiadiazole (0.9 g, 2.1 mmole). (Compound 163).

Example 161

()-Exo-3-(2-pertenece)ethylthio)-4-(2-azabicyclo/2,2,2/octyl - 6-oxy)-1,2,5-thiadiazole

Trimethylsilylmethyl (0.4 ml, 2 mmole) was added to a solution of ()-Exo-3-(2-pertenece)ethylthio)-4-(2-azabicyclo/2,2,2/octyl - 6-oxy)-1,2,5-thiadiazole (0.9 g, 2.1 mmole) and dichloromethane (50 ml). The reaction mixture was heated under conditions of reflux distilled for 16 hours, then poured in methanol (25 ml), stirred at room temperature for 15 minutes, then evaporated, the residue was purified using radial chromatography on silica gel with elution with a mixture of 2% ethanol 10% triethylamine in ethyl acetate, giving ()-Exo-3-(2-pertenece)ethylthio)-4-(2-Isabel the Association 164).

Example 162

()-Endo-3-propylthio-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole,

Sample ()-endo-1-azabicyclo/3,2,1/Octan-6-ol (5.1 g, 40 mmol) was added to a solution of potassium tert-butylate (5,4 g, 48 mmol) in 120 ml of THF and cooled in an ice bath. Added connection 37 (8,0, 41 mmol) and the reaction mixture is stirred for 3 hours at room temperature. Was added ethyl acetate, the organic layer was washed with water, dried over sodium sulfate and condensed, giving 10.0 g of the crude product. HPLC purification with elution with a mixture of 5% ethanol-chloroform with 0.5% ammonium hydroxide gave 8 g ()-endo-3-propylthio-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole in the form of oil, 71%. (Compound 165).

Example 163

()-Endo-3-propylthio-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole .

A solution of ()-endo-3-propylthio-4-(1-azabicyclo/3,2,1/octyl - 6-hydroxy-1,2,5-thiadiazole (5.7 g) in 1 norms. HCl (24 ml) was cooled in a mixture of ice and water and dropwise during 5 minutes was added Oxon cases (36.8 g) in water (75 ml). The cooling was removed and after 5 hours, the excess oxidizing agent is destroyed with NaHSO3. The reaction mixture was poured into ice and the pH was brought to 12. The mixture was extracted with ethyl acetate, the extracts were washed with water, R is-6-oxy)- 1,2,5-thiadiazole in the form of an oil (4.6 g). (Compound 166)

Example 164

()-Endo-3-(4,4,4-triptoreline)-4-(1-azabicyclo/3,2,1/octyl-6 - oxy)-1,2,5-thiadiazole

A solution of 4,4,4-triptoreline (0.32 g) in THF (15 ml) was cooled with a mixture of ice and water and processed tert-butyl potassium (0.4 g). To the reaction mixture was added dropwise a solution of compound 166 (0.4 g) in THF (10 ml) and the mixture stirred for one hour. The reaction mixture was diluted with cold water, the pH was brought to 12, and the mixture was extracted with ethyl acetate. The extracts were dried and the solvent was evaporated. The residue was treated with dry HCl in ether, the resulting crystals are collected, washed with ether and dried, giving a white solid (0.16 g), so pl. 155-156oC. (Compound 167).

The following compounds were obtained essentially by the same procedure when replacing 4,4,4-triptoreline the corresponding alcohol.

Example 165

()-Endo-3-(2-butenyloxy)-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and 2-butanol in the form of a salt with a yield of 89%, so pl. 200-201oC. (Compound 168).

Example 166

()-Endo-3-(TRANS-2-butenyloxy)-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and TRANS-2-butanol in the form of the HCl salt with a/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and 2-methylthioethyl in the form of the HCl salt with a yield of 85%, so pl. 169-170oC. (Compound 170).

Example 168

()-Endo-3-(2-[4-methyl-1,3-thiazol-5-yl]ethoxy)- 4-(1-azabicyclo/3,2,1/octyl-6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 2-(4-methyl-1,3-thiazol-5-yl)-ethanol in the form of the HCl salt with a yield of 73%, so pl. 171-172oC. (Compound 171).

Example 169

()-Endo-3-(4-methylthiophenethylamine)- 4-(1-azabicyclo/3,2,1/octyl-6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 4-methylthioribose alcohol in the form of the HCl salt with a yield of 28%, so pl. 155-156oC. (Compound 172).

Example 170

()-Endo-3-(2-teenrotica)-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and 2-thiophenemethyl in the form of the HCl salt with a yield of 29%, so pl. 134-135oC. (Compound 173).

Example 171

()-Endo-3-(2-cyclohexyloxy)-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and 2-cyclohexenone in the form of the HCl salt with a yield of 55%, so pl. 179-180oC. (Compound 174).

Example 172

()-Endo-3-(3-pentyloxy)-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and 3-pentanol in the form of the HCl salt with a yield of 40%, so pl. 118-119oC. (Compound 175).

P is s 166 and 3-hexenol in the form of the HCl salt with a yield of 27%, so PL 134-135oC. (Compound 176).

Example 174

()-Endo-3-(3-chloropropoxy)-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and 3-chloropropanol in the form of the HCl salt with a yield of 48%, so pl. 131-132oC. (Compound 177).

Example 175

()-Endo-3-(2-[2-Naftali] ethoxy)-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and 2-(2-Naftali)ethanol in the form of the HCl salt with a yield of 34%, so pl. 134-139oC. (Compound 178).

Example 176

()-Endo-3-(4-methyl-3-pentyloxy)-4-(1-azabicyclo/3,2,1/- octyl-6-hydroxy-1,2,5-thiadiazole

Was obtained from compound 166 and 4-methyl-3-pentanol in the form of the HCl salt with a yield of 98%, so pl. 113-114oC. (Compound 180).

Example 177

()-Endo-3-(CIS-2-butenyloxy)-4-(1-azabicyclo/3,2,1/- octyl-6-hydroxy-1,2,5-thiadiazole

Was obtained from compound 166 and CIS-2-butanol in the form of the HCl salt with a yield of 37%, so pl. 151-152oC. (Compound 181).

Example 178

()-Endo-3-(cyclopropylmethoxy)-4-(1-azabicyclo/3,2,1/- octyl-6-hydroxy-1,2,5-thiadiazole

Was obtained from compound 166 and cyclopropylmethanol in the form of the HCl salt with a yield of 50%, so pl. 165-166oC. (Compound 182).

Example 179

()-Endo-3-(2-methoxyethoxy)-4-(1-azabicyclo/3,2,1/- octyl-6-hydroxy-1,2,5-thiadiazole

Was obtained and the er 180

()-Endo-3-(3-butenyloxy)-4-(1-azabicyclo/3,2,1/- octyl-6-hydroxy-1,2,5-thiadiazole

Was obtained from compound 166 and 3-butanol in the form of the HCl salt with a yield of 20%, so pl. 168-169oC. (Compound 184).

Example 181

()-Endo-3-(2-cyclopropylmethoxy)-4-(1-azabicyclo/3,2,1/- octyl-6-hydroxy-1,2,5-thiadiazole

Was obtained from compound 166 and 2-cyclopropylethanol in the form of the HCl salt with a yield of 76%, so pl. 152-153oC. (Compound 185).

Example 182

()-Endo-3-(3-butenyloxy)-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and 3-butanol in the form of the HCl salt with a yield of 65%, so pl. 198-199oC. (Compound 186).

Example 183

()-Endo-3-(4,4,4,3,3,2,2-getAttributes)-4-(1-azabicyclo/3,2,1/ octyl-6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 4,4,4,3,3,2,2-getattributenode in the form of the HCl salt with a yield of 23%, so pl. 192-193oC. (Compound 187).

Example 184

()-Endo-3-(2/cryptomailer/ethoxy)-4-(1-azabicyclo/3,2,1/ octyl-6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 2-(3-triptoreline)ethanol in the form of the HCl salt with 38%, so pl. 118-120oC. (Compound 188).

Example 185

()-Endo-3-(2-[2-thienyl] ethoxy)-4-(1-azabicyclo/3,2,1/ octyl-6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 2-(-thienyl)ethanol in the form of the XI)-4-(1-azabicyclo/3,2,1/ octyl-6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 3,3,3,2,2-pentafluoropropanol in the form of the HCl salt with a yield of 77%, so pl. 208-209oC. (Compound 190).

Example 187

()-Endo-3-(2-phenoxyethoxy)-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and 2-Phenoxyethanol in the form of the HCl salt with a yield of 80%, so pl. 165-166oC. (Compound 191).

Example 188

()-Endo-3-(4-n-butylbenzyl)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 4-n-butylbenzyl alcohol in the form of the HCl salt with a yield of 18%, so pl. 168-169oC. (Compound 192).

Example 189

()-Endo-3-(3-[4-methoxyphenyl] propoxy)-4-(1 - azabicyclo/3,2,1/octyl-6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 3-(4-methoxyphenyl)propanol in the form of the HCl salt with a yield of 54%, so pl. 161-162oC. (Compound 193).

Example 190

()-Endo-3-(4-forbindelse)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 4-fermentelos alcohol in the form of the HCl salt with 71% yield, so pl. 163-164oC. (Compound 194).

Example 191

()-Endo-3-(2,4-deferasirox)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 2,4-differenziava alcohol in the form of the HCl salt with a yield of 17%, so pl. 168-169oC. (Soy is-thiadiazole

Was obtained from compound 166 and 4-cryptomaterial alcohol in the form of the HCl salt with a yield of 8%, T. pl. 185-186oC. (Compound 196).

Example 193

()-Endo-3-(4-torbooks)-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and 4-torbutrol in the form of the HCl salt with a yield of 56%, so pl. 142-143oC. (Compound 197).

Example 194

()-Endo-3-(4-tert-butylbenzyl)-4-(1 - azabicyclo/3,2,1/octyl-6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 4-tert-butylbenzyl alcohol in the form of the HCl salt with a yield of 40%, so pl. 192-194oC. (Compound 198).

Example 195

()-Endo-3-(1-cyclopropylmethoxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and ()-1-cyclopropylethanol in the form of the HCl salt with a yield of 39%, so pl. 171-172oC. (Compound 199).

Example 196

()-Endo-3-(2-cyclohexylmethoxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 2-cyclohexylethane in the form of the HCl salt with a yield of 15%, so pl. 139-141oC. (Compound 200).

Example 197

()-Endo-3-(3-methyl-2-butenyloxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 3-methyl-2-butanol in the form of the HCl salt with a yield of 60%, so pl. 149-150oC. (Compound 20 was Obtained from compound 166 and 4-cyclohexylmethanol in the form of the HCl salt with a yield of 9%, so pl. 130-132oC. (Compound 202).

Example 199

()-Endo-3-(3-buten-2-oxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and ()-3-butyn-2-ol with a yield of 58% in the form of HCl salt, so pl. 179-180oC. (Compound 203).

Example 200

()-Endo-3-(3-methyl-3-phenylmethoxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 3-methyl-3-phenylbutane in the form of the HCl salt with a yield of 34%, so pl. 145-147oC. (Compound 204).

Example 201

()-Endo-3-(3-forproperty)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 3-forproposal in the form of the HCl salt with a yield of 72%, so pl. 147-148oC. (Compound 205).

Example 202

()-Endo-3-(3-[2-Thienyl] propoxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 3-(2-thienyl)propanol with a yield of 75%, so pl. 140-142oC. (Compound 206).

Example 203

()-3-(2-[4-Fervency] ethylthio)-4-(1-azabicyclo/2,2,2/octyl - 3-oxy)-1,2,5-thiadiazole

Using essentially the same procedure that was used to obtain compound 44, compound 12 (1,15 g) and 1-bromo-(4-pertenece)ethane (3,65 g) gave()-3-(2-[4-fervency]ethylthio)-4-(1-azabicyclo/2,2,2/octyl-3 - oxy)-1,2,5-thiadiazole as an HCl Sol the example 204

()-3-(2-Methylthioethyl)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole

A solution of 3-(2-methylthioethyl)-4-hydroxy-1,2,5-thiadiazole (0.45 g) and triphenylphosphine (0.7 g) was cooled in a mixture of ice and water as was added dropwise diethyldithiocarbamic (0.4 ml). After addition was added ()-1-azabicyclo/2,2,2/Octan-3-ol (0.33 g), the cooling was removed and the reaction mixture is stirred for 1 hour. The solvent was evaporated, the residue was suspenderbelt in the water, and the mixture was padillas and rinsed with ether. The aqueous solution was podslushivaet and was extracted with ethyl acetate. The extracts were dried, the solvent was evaporated, the residue was purified using radial chromatography with elution with a mixture of 10% ethanol-1% ammonium hydroxide-chloroform, the product was turned into salt. Recrystallization from acetone gave 0.6 g of white crystals so pl. 177-178oC. (Compound 208).

The following compounds were synthesized essentially in the same manner as the connection 208.

Example 205

()-3-(1-Azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

3-hydroxy-1,2,5-thiadiazole (0.28 g), triphenylphosphine (0.7 g), diethyldithiocarbamic (064 ml) and ()-1-azabicyclo/2,2,2/Octan-3-ol (0.33 g) gave cleaners containing hydrochloride salt of ()-3-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-Tyl-3-oxy)-1,2,5-thiadiazole

3-hexyl-4-hydroxy-1,2,5-thiadiazole (0,93 g), triphenylphosphine (1.31 g), diethyldithiocarbamic (0.8 ml) and ()-1-azabicyclo/2,2,2/Octan-3-ol (0.64 g) gave cleaners containing hydrochloride salt of ()-3-hexyl-4-(1-azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole, so pl. 163-164oC decomp. (1,11 g). (Compound 210).

Example 207

3 Butylthio-4-hydroxy-1,2,5-thiadiazole

A solution of compound 1 (20,9 g), DMSO (20 ml) and 2 norms. sodium hydroxide (205 ml) was heated over night to reflux distilled. The solution was cooled to 15oC and was added concentrated HCl up until the pH is not 1. The solid was collected, rinsed with water and dried, giving a solid (17,68 g). Recrystallization from heptane gave white crystals, so pl. 72-72,5oC. (Compound 211).

Example 208

()-3-(2-[3-{ 1,2,5-Thiadiazole} ]ethoxy)-4 - azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole

A solution of triphenylphosphine (0.35 g) and 3-hydroxy-1,2,5-thiadiazole (0.14 g) in THF (15 ml) was cooled in a mixture of ice and water. Was added dropwise diethyldithiocarbamic (0.21 g) followed by addition of ()-3-(2-hydroxyethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole (0.35 g). The cooling was removed, the reaction mixture is stirred for 1 hour and the solvent was evaporated. The remainder of suspenders with ethyl acetate. The extracts were washed with saline, dried, the solvent was evaporated and the residue was purified using radial chromatography with elution with a mixture of 10% ethanol-1% ammonium hydroxide-chloroform, giving a clear oil. The HCl salt crystallized from acetone as a white powder (0.34 g), so pl. 178-179oC. (Compound 212).

Example 209

()-Exo-3-Butylthio-4-(1-azabicyclo/2,2,1/heptyl-3-hydroxy)- 1,2,5-thiadiazole

A solution of triphenylphosphine (0.7 g) and compound 317620 (0.5 g) in THF (20 ml) was cooled with a mixture of ice and water. Dropwise added diethyldithiocarbamic (0.4 ml) followed by add ()-endo-3-hydroxy-1-azabicyclo/2,2,1/heptane (0.29 grams). The cooling was removed and after 1 hour the solvent was evaporated. The residue was suspenderbelt in cold water, pagkilala and was extracted with ether. The aqueous fraction was podslushivaet and was extracted with ethyl acetate. The extracts were dried, the solvent was evaporated and the residue was purified using radial chromatography with elution with a mixture of 5% ethanol-0.5% ammonium hydroxide-chloroform, giving a clear oil. The HCl salt crystallized from ethyl acetate as white crystals (0,44 g), so pl. 147-148oC. (Compound 213).

Example 210

()-Endo-3-(2-[4-chlorophenyl] atoda 50%, HCl salt, so pl. 136-138oC. (Compound 214).

Example 211

()-Endo-3-(2-[4-forfend] ethoxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 2-(4-forfinal)ethanol with a yield of 61%, HCl salt, so pl. 135-136oC. (Compound 215).

Example 212

()-Endo-3-(3-[3-were] ethoxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 2-(3-were)ethanol with a yield of 57%, HCl salt, so pl. 114-115oC. (Compound 216).

Example 213

()-Endo-3-(phenylethane)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 2-phenylethanol with yield 70%, HCl salt, so pl. 135-136oC. (Compound 217).

Example 214

()-Endo-3-(2-[3-thienyl] ethoxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 2-(3-thienyl)ethanol with a yield of 62%, HCl salt, so pl. 142-144oC. (Compound 218).

Example 215

()-Endo-3-benzyloxy-4-(1-azabicyclo/3,2,1/octyl-6-oxy)- 1,2,5-thiadiazole

Was obtained from compound 166 and benzyl alcohol with 71% yield, HCl salt, so pl. 180-181oC. (Compound 219).

Example 216

()-Endo-3-(4-triftormetilfosfinov)-4-(1 - azabicyclo/3,2,1/octyl-6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 tx2">

Example 217

(5S, 6S)-endo-3-(4-forbindelse)-4-(1-azabicyclo/3,2,1/octyl-6 - oxy)-1,2,5-thiadiazole

Was obtained from (5S,6S)-compound 166 and 4-fermentelos alcohol with a yield of 35%, HCl salt, so pl. 181-182oC. (Compound 221).

Example 218

(5R, 6R)-endo-3-(4-forbindelse)-4-(1-azabicyclo/3,2,1/octyl-6 - oxy)-1,2,5-thiadiazole

Was obtained from (5R,6R)-compound 166 and 4-fermentelos alcohol with a yield of 68%, Malatya salt, so pl. 106-107oC. (Compound 222).

Example 219

(5S,6S)-endo-3-(4-cryptomaterial)-4-(1 - azabicyclo/3,2,1/octyl-6-oxy)-1,2,5-thiadiazole

Was obtained from (5S,6S)-compound 166 and 4-cryptomaterial alcohol with a yield of 52%, HCl salt, so pl. 138-140oC. (Compound 223).

Example 220

(5R,6R)-endo-3-(4-cryptomaterial)-4-(1 - azabicyclo/3,2,1/octyl-6-oxy)-1,2,5-thiadiazole

Was obtained from (5R,6R)-compound 166 and 4-cryptomaterial alcohol with a yield of 71%, Malatya salt, so pl. 114-115oC. (Compound 224).

Example 221

(5R,6R)-endo-3-(2-cyclopropylmethoxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from (5R, 6R)-compound 166 and 2-cyclopropylethanol with the release of 84%, Malatya salt, so pl. 111-112oC. (Compound 225).

Example 222

(5S,6S)-endo-3-(2-cyclopropylethyl the exit 78%, malata salt, so pl. 109-110oC. (Compound 226).

Example 223

(5R, 6R)-endo-3-(3-methyl-2-butenyloxy)-4-(1-azabicyclo/3,2,1/octyl-6 - oxy)-1,2,5-thiadiazole

Was obtained from (5R,6R)-compound 166 and 3-methyl-2-butanol with the release of 31%, Malatya salt, so pl. 141-142oC. (Compound 227).

Example 224

()-Endo-3-(2-cyclopropylmethoxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 2-cyclopropylethanol exit 67%, Malatya salt, so pl. 100-101oC. (Compound 228).

Example 225

()-Endo-3-(3-cyclopropylmethoxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 3-cyclopropylethanol exit 62%, Malatya salt, so pl. 114-115oC. (Compound 229).

Example 226

()-Endo-3-(1-cyclopropylmethoxy)-4-(1-azabicyclo/3,2,1/octyl - 6-oxy)-1,2,5-thiadiazole

Was obtained from compound 166 and 1-cyclopropylethanol with the release of 78%, Malatya salt, so pl. 161-162oC. (Compound 230).

Example 227

()-Exo-3-(1-azabicyclo/2,2,1/heptyl/-3-oxy)-1,2,5-thiadiazole

Was obtained in the same manner as the connection 131. ()-Exo-3-(1-azabicyclo/2,2,1/heptyl-3-hydroxy)-1,2,5-thiadiazole was obtained from 3-hydroxy-1,2,5-thiadiazole (0.14 g), triphenylphosphine (0.35 g) dietinduced the PLN. (Compound 231).

Example 228

()-3-(3-[3-Trifluoromethyl-4-chlorophenyl]propoxy)-4-(1 - azabicyclo/2,2,2/-octyl-3-oxy)-1,2,5-thiadiazole

Using the same procedure that was used when the connection 103, (3-trifluoromethyl-4-chlorophenyl)propanol and connection 102 gave after chromatography()-3-(3-[3-trifluoromethyl-4-chlorophenyl]propoxy)-4-(1 - azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole as an HCl salt, so pl. 144-145oC. (Compound 232).

Example 229

()-3-(3-Phenylpropoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole

Using the same procedure that was used when the connection 103, 3-phenylpropanol and connection 102 gave after chromatography, ()- 3-(3-phenylpropoxy)-4-(1 - azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole as an HCl salt, so pl. 194-195oC. (Compound 233).

Example 230

(R)-3-(2-Cyclopropylmethoxy)-4-(1-azabicyclo/2,2,2/octyl-3-oxy)- 1,2,5-thiadiazole

Using the same procedure that was used when the connection 114, 2-cyclopropylethanol and connection 102, which was obtained previously from (R)-1-azabicyclo/2,2,2/Octan-3-ol, gave after chromatography (R)-3-(2-cyclopropylmethoxy)-4-(1 - azabicyclo/2,2,2/octyl-3-oxy)-1,2,5-thiadiazole as an HCl salt that Chris is iadiza

A mixture of compound 93 (8,2 g), 2 norm. of sodium hydroxide (100 ml) and DMSO (10 ml) was heated to reflux distilled during the night. The reaction mixture was cooled and extracted with ether. The aqueous fraction was padillas concentrated HCl and cooled for 30 minutes using a mixture of ice and water. The solid substance was collected from the mixture by filtration and were washed with a small amount of cold water, giving white crystals (4.4 g). Recrystallization from heptane gave white flakes, so pl. 104,5-105,5oC. (Compound 235).

Example 232

3 Propylthio-4-hydroxy-1,2,5-thiadiazole

A mixture of 3-chloro-4-propylthio-1,2,5-thiadiazole (compound 37) (10 g), 2 norm. NaOH (100 ml) and DMSO (10 ml) was heated to reflux distilled within 24 hours. The solution was cooled and extracted with ether. The aqueous fraction was padillas concentrated HCl and cooled in a mixture of ice and water for 3 hours, the resulting solid was collected, washed with a small amount of cold water, giving a white solid (8,15 g). Recrystallization from heptane gave white crystals, so pl. 84-85oC. (Compound 236).

1. Derived 1,2,5-thiadiazole or its kvaternikova form selected from compounds having obroda, halogen, R4, -OR4, -SR4, -SO2R4and-Z-C4-12(cycloalkenyl);

R4selected from the group consisting of C1-15-alkyl, C2-15-alkenyl and C2-15-quinil, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CF3, phenyl, phenoxy, in which phenyl, phenoxy optionally substituted by one or more substituents independently selected from the group consisting of halogen, -CN, C1-4-alkyl, C1-4-alkoxy, -OCF3, -CF3; or R is selected from the group consisting of-OR5Y, -SR5Y, OR5-Z,-Y,- SR5ZY, -O-R5-Z-R4;

Z represents oxygen or sulfur;

R5represents C1-15-alkyl;

Y represents a 5 - or 6-membered heterocyclic group selected from tanila, pyridyl and thiazolidine;

G is selected from one of the following usacycling or azabicyclic ring systems:

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or G represents optionally substituted C3-C8-cycloalkyl or optionally substituted C1-6-alkyl, in which the Deputy is-NR6R7;

R6and R7both are entering or C1-6-alkyl;

R3represents hydrogen or C1-5-alkyl;

m represents 0, 1 or 2;

n represents 0, 1 or 2;

p represents 0, 1 or 2;

q represents 1 or 2;

r represents 0, 1 or 2;

provided that when W is oxygen and G is alkyl, R is selected from the group consisting of hydrogen, R4, -OR4, -SR4, -SO2R4, -Z-C4-12-(cycloalkenyl), each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen and-CF3; or R is selected from the group consisting of-OR5Y, -SR5Y, OR5-Z,-Y,- SR5ZY, -O-R5-Z-R4;

Z represents oxygen or sulfur;

R5represents C1-15-alkyl;

or its pharmaceutically acceptable salt or MES.

2. Connection on p. 1, in which W represents s

3. The compound according to any one of p. 1 or 2, in which r is 0.

4. The compound according to any one of p. 1 or 3, wherein W is 0.

5. The compound according to any one of paragraphs.1 to 4, in which G is selected from the group consisting of het-1, het-2, het-3, het-5, het-6 and het-7.

6. Connection on p. 1, in which G is selected from the group

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()-3-methoxy-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-ethoxy-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-propyloxy-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-Butylochka-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-pentyloxy-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-hexyloxy-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(4-methylpentylamino)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-chloro-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-propylthio-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-butylthio-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-pentylthio-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

(S)-3-pentylthio-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-hexylthio-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3,3-dimethylbutyl)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-(2-tianity)ethylthio)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2,2,3,3,3-pentafluoropropyl)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-(2-thienyl)propylthio-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-butylthio-4-(1-azabicyclo[2.2.2] Octan-3-yl)methoxy)-1,2,5-thiadiazole,

l-6-oxy)-1,2,5-thiadiazole,

()-endo-3-Butylochka-4-(1-azabicyclo[2.2.1] heptyl-3-hydroxy)-1,2,5-thiadiazole,

()-Exo-3-Butylochka-4-(1-azabicyclo[2.2.1] heptyl-3-hydroxy)-1,2,5-thiadiazole,

()-3-Butylochka-4-(3-pyrrolidinyloxy)-1,2,5-thiadiazole,

()-3-Butylochka-4-(1-methyl-3-pyrrolidinyloxy)-1,2,5-thiadiazole,

()-3-butylthio-4-(1-methyl-3-piperidinyloxy)-1,2,5-thiadiazole,

3 butylthio-4-(1-methyl-3-piperidinyloxy)-1,2,5-thiadiazole,

(S)-3-Butylochka-4-(1-methyl-3-pyrrolidinyloxy)-1,2,5-thiadiazole,

(S)-3-Butylochka-4-(2-pyrrolidinyloxy)-1,2,5-thiadiazole,

3 Butylochka-4-(2-(dimethylamino)ethoxy)-1,2,5-thiadiazole,

3 butylthio-4-(2-(diethylamino)ethoxy)-1,2,5-thiadiazole,

3 Butylochka-4-(2-(trimethylamino)ethoxy)-1,2,5-thiadiazole iodide,

3 Butylochka-4-(2-(dimethylamino)ethylthio)-1,2,5-thiadiazole,

(R)-3-pentylthio-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(4-methylphenylthio)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-phenylpropyl)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(4-cyanobenzyl)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(4-forbesii)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-feniletilic)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-phenylacetamido-4-(1-azabicyclo[2.2.2] octyl-3-hydroxy)-1,2,�-4-(6-(N-methyl-8-azabicyclo[3.2.1] Octan-3-anoxi))-1,2,5-thiadiazole,

()-Exo-3-chloro-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-chloro-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(4-cyanobenzyl)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

3 Butylochka-4-(3-azetidinone)-1,2,5-thiadiazole,

3 butylthio-4-(3-azetidinone)-1,2,5-thiadiazole,

()-TRANS-3-Butylochka-4-(2-dimethylaminoethoxy)-1,2,5-thiadiazole,

()-butylthio-4-(3-pyrrolidinyloxy)-1,2,5-thiadiazole,

()-3-(2-(2-thio-5-trifloromethyl)ethylthio)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-(5-(2-thienyl)thienyl)thio)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-(2-(5-(2-thienyl)thienyl)thio)ethylthio)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-N-(2-thiazolidone)propylthio)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-butylthio-4-(Exo-2-azabicyclo[2.2.2] Oct-6-yloxy)-1,2,5-thiadiazole,

()-3-(2,2,3,3,4,4,4-heptafluorobutyrate)-4-[3-(1-azabicyclo[2.2.2] octyl-hydroxy)]-1,2,5-thiadiazole,

()-3-(1-butylthio)-4-[endo-6-(1-azabicyclo[3.2.1] octyloxy)] 1,2,5-thiadiazole,

()-3-(3-phenylpropyl)-4-[endo-6-(1-azabicyclo[3.2.1] octyloxy)] 1,2,5-thiadiazole,

()-3-[3-(4-forfinal)propylthio] -4-[3-(1-azabicyclo[2.2.2]octyloxy)]-1,2,5-thiadiazole,

()-3-{ 3-[4-(trifluoromethyl)phenyl] propylthio} -4-[3-(1-azabicyclo and its pharmaceutically acceptable salt.

9. The compound according to any one of paragraphs.1 to 8, in which, if G is a saturated azabicyclic group having from 7 to 11 carbon atoms and the ring nitrogen, and in which the ring nitrogen atom is separated from W 2 or 3 ring carbon atoms, then R is selected from the group consisting of R4and-Z-C4-12-(cycloalkenyl), in which R4selected from the group consisting of optionally substituted C5-15-alkyl, optionally substituted C2-15-alkenyl and optionally substituted C2-15-quinil, in which the Deputy is one or more substituents independently selected from the group consisting of halogen, -CF3, phenyl, phenoxy; in which phenyl or phenoxy optionally substituted by one or more substituents selected from the group consisting of halogen, -CN, C1-4-alkyl, C1-4-alkoxy, -OCF3, -CF3; or R4represents substituted C1-4-alkyl, in which the Deputy chosen from-CF3; or R represents a group-OR5Y, -SR5Y, -OR5-Z,-Y,- SR5ZY, -O-R5-Z-R4.

10. The compound according to any one of paragraphs.1 to 9, in which p represents 0 or G is selected from the group consisting of het-1, het-2, het-3, where n, m, p are each 0 or 1; het-4, het-5, het-6, in which the PMU PP.1 - 10, in which G represents azacyclonol system.

12. Connection on p. 1, which is selected from the group consisting of the following compounds:

()-3-(2-methylthioethyl)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-hexyl-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-butylsulfonyl-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-propylsulfonyl-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(4,4,4-triptoreline)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-butenyloxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(cyclopropylmethoxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-phenylpropionate)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-butenyloxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(TRANS-2-butenyloxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(CIS-2-butenyloxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-methoxyethoxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-phenoxyethoxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-butinox)-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-cyclopropyl)-1,2,5-thiadiazole,

()-3-(3-chloropropoxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(4-terbutaline)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-[4-chlorophenoxy] ethoxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-[2-methoxy-5-pyridyl] propyloxy)-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(TRANS-3-chloro-2-propenyloxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-[4-fervency] ethoxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(4-pentyloxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-forproposals)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(cyclobutylmethyl)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3,3,3,2,2-pentafluoropropyl)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-[phenylthio] ethoxy-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-[4-bromophenoxy] ethoxy)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-Exo-3-butylthio-4-(1-azabicyclo[2.2.1] heptyl-3-hydroxy)-1,2,5-thiadiazole,

()-3-(2-[3-{ 1,2,5-thiadiazolidine} ] ethoxy)-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-Exo-3-Butylochka-4-(7-azabicyclo[2.2.1] heptyl-3-hydroxy)-1,2,5-thiadiazole,

()-3-Butylochka-4-(3-piperidinyloxy)-1,2,5-thiadiazole,

3-butylacetate,

(5S, 6S)-endo-3-butylthio-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

(5R, 6R)-endo-3-butylthio-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-TRANS-3-butylthio-4-(1-azabicyclo[4.3.0] nonyl-5-oxy)-1,2,5-thiadiazole,

()-CIS-3-butylthio-4-(1-azabicyclo[4.3.0]nonyl-5-oxy)-1,2,5-thiadiazole,

()-TRANS-3-butylthio-4-(2-dimethylaminoethoxy)-1,2,5-thiadiazole,

3 butylthio-4-(2-dimethylaminoethoxy)-1,2,5-thiadiazole,

()-TRANS-3-butylthio-4-(N-tert-butylcarbamoyl-4-hydroxypyrrolidine-3-oxy)-1,2,5-thiadiazole,

()-TRANS-3-butylthio-4-(4-hydroxy-pyrrolidin-3-oxy)-1,2,5-thiadiazole,

()-endo-3-Butylochka-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-3-(4-phenylbutyl)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-phenyl-2-propylthio)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-[4-forfinal]-3-[4-fervency]propylthio-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-phenyl] -3-[4-triptoreline] propylthio-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(4,4,4-cryptosporidia)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(3-[3-pyridyl] propylthio)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-endo-3-(2-PHENOXYACETIC)-4-(1-azabicyclo[2.2.2] octyl-6-oxy)-1,2,5-thiadiazole,

()-Akzo.2.2] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(4,4,4-triptoreline)-4-(2-azabicyclo[2.2.2] octyl-6-oxy)-1,2,5-thiadiazole,

()-Exo-3-(2-[fervency] ethylthio)-4-(2-methoxycarbonyl-(2-azabicyclo[2.2.2]octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(2-[fervency] ethylthio)-4-(2-azabicyclo[2.2.2] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-propylthio-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-propylsulfonyl-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(4,4,4-triptoreline)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(2-butenyloxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(TRANS-2-butenyloxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(2-methylthiouracil)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(2-(4-methyl-1,3-thiazol-5-yl)ethoxy)-4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(2-teenrotica)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(2-cyclohexyloxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(3-pentyloxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(3-hexyloxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(3-chloropropoxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(4-methyl-3-octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(cyclopropylmethoxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(2-methoxyethoxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(3-butenyloxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(2-cyclopropylmethoxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(3-butenyloxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(4,4,4,3,3,2,2-getAttributes)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-[2-(3-triptoreline)ethoxy] -4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-[2-(2-thienyl)ethoxy] -4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(3,3,3,2,2-pentafluoropropane)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(phenoxyethoxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(4-n-butylbenzyl)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-[3-(4-methoxyphenyl)propoxy] -4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(4-forbindelse)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(2,4-deferasirox)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-[4-triptoreline)benzyloxy] -4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(1-cyclopropylmethoxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(2-cyclohexylmethoxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(3-methyl-2-butenyloxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(4-cyclohexylmethoxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(3-buten-2-oxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(3-methyl-3-phenylmethoxy)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-(3-forproperty)-4-(1-azabicyclo[3.2.1] octyl-6-oxy)-1,2,5-thiadiazole,

()-endo-3-[3-(2-thienyl)propoxy] -4-(1-azabicyclo[3.2.1]octyl-6-oxy)-1,2,5-thiadiazole,

()-3-(2-[4-fervency] ethylthio)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-methylthioethyl)-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-hexyl-4-(1-azabicyclo[2.2.2]octyl-3-oxy)-1,2,5-thiadiazole,

()-3-(2-[3-{ 1,2,5-thiadiazolidine} ] ethoxy-4-(1-azabicyclo[2.2.2] octyl-3-oxy)-1,2,5-thiadiazole,

()-Exo-3-butylthio-4-(1-azabicyclo[2.2.1] heptyl-3-hydroxy)-1,2,5-thiadiazole.

13. The compound according to any one of paragraphs.1 - 12, which represents azosoedinenii.

14. The compound according to any one of paragraphs.1 - 12, which represents endoskeletal.

16. The compound according to any one of paragraphs.1 through 14, in which G represents 2.2.1-Isabelline Deputy.

17. The compound according to any one of paragraphs.1 - 16, which is useful for treating conditions associated with the modulation of muscarinic cholinergic receptors.

18. The compound according to any one of paragraphs.1 - 16, which is useful when interacting with muscarinic cholinergic receptors.

19. The compound of formula V

< / BR>
in which W' is selected from the group consisting of O, S and SO2;

R17represents C1-C6-alkyl;

R18represents chlorine or bromine.

20. Connection on p. 19, in which W' represents S or SO2.

21. Connection on p. 19, which is selected from the group consisting of the following compounds:

3-chloro-4-butylthio-1,2,5-thiadiazole,

3-chloro-4-ethylthio-1,2,5-thiadiazole,

3-chloro-4-(1-propylthio)-1,2,5-thiadiazole,

3-bromo-4-butylthio-1,2,5-thiadiazole,

3-chloro-4-ethylsulfonyl-1,2,5-thiadiazole,

3-chloro-4-butylsulfonyl-1,2,5-thiadiazole,

3-chloro-4-propylsulfonyl-1,2,5-thiadiazole,

3-chloro-4-methylsulphonyl-1,2,5-thiadiazole,

3-chloro-4-intercultural-1,2,5-thiadiazole and

3-chloro-4-(4-methylphenylsulfonyl)-1,2,5-thiadiazole.

22. Connection on p. 21, which is selected from the azole,

3-chloro-4-(1-propylthio)-1,2,5-thiadiazole,

3-bromo-4-butylthio-1,2,5-thiadiazole,

3-chloro-4-ethylsulfonyl-1,2,5-thiadiazole,

3-chloro-4-butylsulfonyl-1,2,5-thiadiazole.

23. The method of obtaining compounds of formula II or III

< / BR>
< / BR>
in which P represents halogen;

W represents oxygen or sulfur;

R represents OR4or SR4;

G is selected from one of the following usacycling or azabicyclic ring systems:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or G may be optionally substituted C3-C8-cycloalkyl or optionally substituted C1-6-alkyl, in which the Deputy is-NR6R7;

R6and R7both represent hydrogen or C1-6-alkyl;

one of R1and R2represents hydrogen and the other represents hydrogen or C1-6-alkyl;

R3represents hydrogen or C1-5-alkyl;

n represents 0, 1 or 2;

m represents 0, 1 or 2;

p represents 0, 1 or 2;

q represents 1 or 2;

r represents 0, 1 or 2;

comprising a) reaction (CN)2with a compound selected from the group consisting of R4-V-H in which V represents O or S, and G(CH2)r-W-H, and (b) to waistcoat with muscarinic cholinergic receptors comprising as active ingredient a compound according to any one of paragraphs.1 - 18 in combination with one or more pharmaceutically acceptable carriers or diluents for him.

Priority points:

24.10.1994 on PP.1 - 7, 9 - 11, 13 - 15, 17 - 24;

01.06.1995 on PP.8, 12, 16.

 

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