A derivative of 2-substituted saccharin and pharmaceutical composition exhibiting inhibitory activity against elastase

 

(57) Abstract:

The invention relates to the chemistry of heterocyclic compounds exhibiting inhibitory activity against elastase. The inventive derivative of 2-substituted saccharin of formula I

< / BR>
where L is-O-, -S-, -SO - or-SO2-; m and n are independently 0 or 1; R1is a substituted phenyl, heterocycle or substituted heterocycle, or when L is-O-, and n is 1, R1represents cycloheptatrien-2-yl, or when L is-S-, and n is 1, R1represents the cyano-or (lower alkoxy)-thiocarbonyl, or when L is-SO2- and n is 1, R1represents a lower alkyl or trifluoromethyl; R2represents hydrogen; R3is hydrogen, primary or secondary lower alkyl or lower alkoxyl, R4is hydrogen or 1-3 different substituent, and pharmaceutical composition thereof. 2 S. and 9 C.p. f-crystals, 8 PL.

The invention relates to new derivatives of 2-substituted saccharin, which inhibit the enzymatic activity of proteolytic enzymes, pharmaceutical compositions containing these derivatives, with the way their PR is diseases, associated with degeneration of the tissues, such as emphysema, remotedly arthritis and pancreatitis, in which the main part is proteolysis, using inhibition of proteolytic enzymes, non-toxic reagents. When biomedical research is widely used protease inhibitors. The most abundant class of proteolytic enzymes are semipretioase. Some semipretioase on the basis of specificity for their substrates are characterized as chymotrypsinogen or lastsavedby. Chymotrypsin or chymotrypsinogen enzymes usually tearing of the peptide bond in proteins in the place where the amino acid residue on the side of the carbonyl usually represents Trp, Tyr, Phe, Met, Leu or another amino acid residue, which contains an aromatic or large alkyl side chains. Elastase or lastsavedby enzymes usually tearing of the peptide bond at the place, where amino acid residue on the carbonyl side of the link, usually represents Ala, Val, Ser, Leu, or other similar, smaller but the size of the amino acids. As chymotrypsinogen and lastsavedby enzymes were detected in the leukocytes, the cells of breast and pancreatic juice highest organogenesis, which are inhibitors of semipretioase. For example, in U.S. patent 4 659 855 (applicant Powers) proposed to use as inhibitors of elastase derived arylsulfonate. Doherty and others in the U.S. patent 4 547 371 and 4 623 645 offer the use of cephalosporinases and cephalosporinases, which, allegedly, are potent elastase inhibitors suitable for the treatment of inflammatory conditions, especially arthritis and emphysema.

Teshima and others[J. Biol. Chem. 257 (9), 5085-5091 (1982)] report the results of studies on the impact on semipretioase (elastase of human leukocytes, elastase pancreatic pigs, cathepsin G and bovine chymotrypsin A) 4-Mitrofanovich esters and thioesters of N-crittercontrol.com, 2-substituted-4H-3,1-benzoxazin-4-ones, 2-substituted-4-khinazolinov and 2-substituted-4-chlorination.

Cha, Biochem. Pharmacol. 24, 2177-2185 (1975) discusses the kinetic approach to study the binding of inhibitors macromolecules, such as enzymes, and methods for determining parameters such as the inhibition constants, speed of reaction and the concentration of bound and unbound enzyme.

It is known that certain derivatives of 2-sumamente USA 4 195 023 Mulvey offers R1-2-R2CO-1,2-benzisothiazol-3-ones, benzoinum ring which R1represents halogen, alkoxyl, alkoxycarbonyl, hydrogen, alkylamino, dialkylamino-, amino - or nitro-group, and R2is hydrogen, alkyl, alkenyl, quinil, ciclacillin, the halogenated phenyl, heteroaryl or substituted by heteroaryl, and R1-2-A-CO-sacharine, where R1has the same meaning as the substituents bentinho rings 1,2-benzisothiazol-3-ons, and A represents an alkyl, alkenyl, quinil, cycloalkyl, forfinal, heteroaryl or substituted heteroaryl. It is said that these compounds possess inhibitory activity relative to elastase and may be suitable for the treatment of emphysema.

In U.S. patent 4 276 298 Jones with staff offers 2-R-1,2-benzisothiazolinone-1,1-dioxides, where R is a phenyl, substituted with fluorine, the two nitro groups, trifluoromethyl, cyano, alkoxycarbonyl, alkylcarboxylic, carboxyla, carbamoyl, alkylsilanes, alkylsulfonyl, N,N-dialkylamino, cryptomaterial, cryptomaterial, triftormetilfullerenov and triptoreline or R represents pyridyl, substituted by the groups mentioned above for phenyl, the basics, especially inhibitory activity relative to elastase, and they can be used in the treatment of emphysema, rheumatoid arthritis and other inflammatory diseases.

Powers [Biochem. 24, 2048-2058 (1985)] presented a study on the inhibition of four chymotrypsinogen enzymes, cathepsin G protease I and II cells of the rat mammary glands, chymase human skin and chymotrypsin AN-forolaherencia and N-(2,4-dicyanovinyl)saccharin.

Svotoda and others [Coll. Czech. Chem. Commun. 51, 1133-1139 (1986)] describe getting 4-hydroxy-2H-1,2-benzothiazin-3-carboxylates of the intramolecular condensation of Dickman esters 2H-1,2-benzisothiazol-3-one-2-acetate-1,1-dioxide.

U.S. patent 4 263 393 (applicant Chen), U.S. patent 4 350 752 and 4 363 865 (applicant Reczek and others) and U.S. patent 4 410 618 (s Vanmeter and others) are related to photographic reagents (Reczek 4 350 752 and patent Vanmeter and others) photographic dyes (Reczek 4 363 865) and photographic elements and film units (Chen). They offer a variety of 2-substituted sacharine suitable for such uses, for example, 2-kolmetoaline (described Chen), photographic reagents associated with iminomethylene blocking group via a heteroatom, as described in patent Reczek 4 350 752), diff is described Reczek in the patent 4363865), and N-arylmethylidene described as a secure photographic reagents, which include the remainder of the organic photographic reagent containing a heteroatom through which it is connected with a blocking group (patent Vanmeter), Reczek in the patent 4 350 752, in particular, indicated as compound 28 varieties of 2-(1-phenyl-1H-tetrazol-5-yl-thiomethyl)saccharin, and Vanmeter, in particular, has proposed a series of 2-(R1-1H-tetrazol-5-yl-thiomethyl)sharenow substituted on methylene function Arola or tert-BUTYLCARBAMATE group.

Freed in U.S. patent 3 314 960 proposed 2-(1,1,3-trioxo-1,2-benzisothiazol-2-yl)glutarimide, which allegedly can be used as sedatives.

In Japanese patent publication 72/00419 described a number of 2-RZ-sharenow, which, as stated, possess strong activity against pyricularia rice, bacteria, causing zavedenii shell rice, Helminthosporium leaf spots of rice and bacterial disease that causes zavedenii leaves of rice, and in which RZ is a lower alkoxyl, butoxyethoxy, ethylthioethyl, di-(lower alkyl)-aminoethoxy, ethylthiourea, 2-chloroethoxy, 1-(2-propenyloxy) group, 1-(2-propenyloxy)-group, 2-saharinen, chlorophenylthio, menzilcioglu (or chlorobenzylthio), acetochlor, dichloracetate, benzoyloxy (or benzoyloxy substituted by chlorine or nitro-group), acetylthiourea, dichloroacetylene, chlorobenzothiazole, methyl - or ethylcarboxylate, dimethylcarbamoyl, phenylcarbamoyloxy, acylcarnitine, phenylcarbonylamino, dimethylthiocarbamate, editiontype, ethoxycarbonylethyl, toxiciology and ethylthioxanthone.

In French patent 1 451 417 serves 2-chlorotriazine as an intermediate connection when receiving N-metalshark d,l-TRANS-chrysanthemate used as an insecticide, and in U.S. patent 3 002 884 (applicant Lo) described 2-chloro-, 2-bromo - and 2-iodotoluene used as fungicidal funds.

PCT application WO 90/13549 (s Dunlap and others) describes derivatives of saccharin used as inhibitors of proteolytic enzymes and having the structural formula:

< / BR>
where:

L is-O -,- S-, -SO - or-SO2-;

m and n each independently represents 0 or 1;

R1represents halogen, lower alkanoyl, 1-oxoproline, the alkyl]-amino, or di-(lower alkyl)-amino group (or a heterocycle, selected from 1H-(5-tetrazolyl), 5-oxo-1-tetrazolyl, 5-tikos-1-tetrazolyl (if R2defined below, is not phenylthiourea), pyrimidinyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-phthalimide, 2(1,3,4-thiadiazolyl) 5-(1,2,4-thiadiazolyl), 5-thioxo-3-(1,2,4-thiadiazolyl), 4-(5-oxo, 1,3,4-thiadiazolyl), 4-(5-tikos-1,3,4-thiadiazolyl), 3-(1,2,4-triazolyl), 4-(1,2,4-triazolyl), 1-(1,2,3-triazolyl), 2 imidazolyl or 3/1,2,4-triazolo-[4,3-a]-pyridinyl, or such heterocycles, substituted on any available nitrogen atom by lower alkyl, hydroxy-(lower alkyl), cycloalkyl, 2-, 3 - or 4-pyridine, carboxy-(lower alkyl), (lower alkoxy)-carbonyl-(lower alkyl), aminocarbonyl-(lower alkyl), (lower alkyl)-aminocarbonyl(lower alkyl), di-(lower alkyl)-aminocarbonyl(lower alkyl), amino-(lower alkyl), (lower alkyl)-amino-(lower alkyl), di-(lower alkyl)-amino-(lower alkyl), 4-morpholinyl-(lower alkyl), 1-piperidinyl-(lower alkyl), 1-pyrrolidinyl-(lower alkyl) or phenyl [or phenyl substituted by amino, (lower alkyl)-amino, di-(lower alkyl)-amino, (lower alkane)-aminopropoxy, N-(lower alkyl)-(lower alkane)-aminopropoxy, carboxy-(lower alkane)-aminopropoxy, carboxyla, Carbo-(lower alkoxycarbonyl, lower alkyl, amino, (lower alkyl)-amino, di-(lower alkyl)-amino group, cycloalkyl-amino group, mercaptopropyl, (lower alkyl)-tigraphy, amino-(lower alkyl)-tigraphy, (lower alkyl)-amino-(lower alkyl)-tigraphy, di(lower alkyl)-amino-(lower alkyl)-tigraphy, 4-morpholinyl-(lower alkyl)-tigraphy, 1-piperidinyl-(lower alkyl)-tigraphy, 1-pyrrolidinyl-(lower alkyl)-tigraphy, Carbo-(lower alkoxyl) or phenyl [or phenyl, substituted amino group, a (lower alkyl)-amino, di-(lower alkyl)-amino, (lower alkane)-aminopropoxy, N-(lower alkyl)-(lower alkane)-aminopropoxy, lower alkyl, lower alkoxyl, or halogen]

R2is hydrogen, Carbo-(lower alkoxyl), phenyl or phenylthiourea;

R3is hydrogen, halogen, primary or secondary lower alkyl, lower alkoxyl, Carbo-(lower alkoxyl), phenyl, fluoro-(lower alkyl), lower alkenyl or cyano;

R4represents hydrogen or 1-2 substituents selected from halogen, ceanography, nitro, amino, (lower alkane)-aminopropyl, phenyl-(lower alkane)-aminogroup, diphenyl-(lower alkane)-aminogroup, (lower alkyl)-sulfanilamide lower alkyl, cycloalkyl, polyhalomethanes lower alkoxyl, hydroxyl, lower alkoxyl, carboxyl, oximetry, formyl, aminomethyl, (lower alkyl)-sulfonyl, (polyhalomethanes lower alkyl)-sulfonyl, (lower alkyl)-sulfonylamino-sulfonyl and (lower alkoxy)-poly-(lower alkylene)-oxypropyl; and CHR2the group has always attached or to a heteroatom of a fragment of L, defined above, or it is attached to the heteroatom of a fragment of R1provided that

(i) if m and n are 0 and all R2, R3and R4represent hydrogen, R1may not be halogen;

(ii) if m=0, n=1, L is-S-, and each of R2, R3and R4represents hydrogen, R1there can be 1-phenyl-1H-(5-tetrazolyl);

(iii) if m=0, n=1, L is-O - or-S-, and all R2, R3and R4represent hydrogen, R1may not be the lowest alkanoyl;

(iv) if m= 0, n= 1, L is-O-, -S - or-SO-and all R2, R3and R4represent hydrogen, or m=0, n=1, L is-S-, R2and R4represent hydrogen, and R3is halogen, or if m=0, n=1, L is-SO - or-SO2-, R2represents a Carbo-(lower alkoxy), and R3and R4

< / BR>
In the compounds of the formula I L represents-O-, -S-, -SO - or-SO2-; m and n are independently 0 or 1;

R1represents phenyl, substituted 1-[4-(lower alkyl)-piperazine-1-yl]-carbonyl, 4-morpholinylcarbonyl, formyl, (lower alkoxy)-carbonyl, 4-teamorganization, or S-dioxide, hydroxy-(lower alkyl), halogenated lower alkyl, 4-morpholinyl-(lower alkyl)-aminocarbonyl, 4-morpholinyl-(lower alkoxy)-carbonyl, 1-[4-(lower alkyl)-piperazine-1-yl-(sulfonium, 4-morpholine-(lower alkoxyl), di-(lower alkyl)-amino-(lower alkyl)-aminosulfonyl or N-(lower alkyl)-derived, lower alkyl)-sulphonium, 4,5-dihydrooxazolo-2-yl, (lower alkyl)-tetrazol-5-yl, 4-morpholinylcarbonyl, nitrophenylthio, carboxyla, or di-(lower alkyl)-fosforom,

or is any of the above group in conjunction with the substitution of the phenyl by halogen, lower alkyl, lower alkoxyl, nitrogroup, amino, (lower alkyl)-amino group or pyridazin-3-yl, 4-pyrone-3-yl, quinoline-8-yl, 1,3,4-oxadiazol-2-yl, coumarin-7-yl, saccharin-6-yl, imidazol-1*ILA, 1,3,4-triazole-2-yl, thiazol-2-yl, 2-tikos-2,3-dihydro-1,3,4-oxadiazol-3-yl, 1,2,5-thiadiazol-3-yl, 2-thioxo-2,3-dihydro-1,3,4-thiadiazole-3-yl, 2-thioxo-2,3-dihydro-1,3,4-thiadiazol-5-yl, 1,2,3-triazole-2-yl, 1,2,4-triazine-5-yl, 5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine-3-yl, isoxazol-5-yl, isoxazol-3-yl, 4,5-dihydro-5-oxo-1,2,4-oxadiazol-4-yl, pyridyl, 1,1,3-triakistetrahedron-1,2,5-thiadiazol-2-yl, 6,7-dihydro-1H-1,2,4-triazolo-[3,4-b] [1,3] triazine-3-yl, 4,5-dihydro-5-oxo-1,2,4-oxadiazol-4-yl, 2,5-dioxopiperidin-1-yl, 3-indolyl, oxazol-2-yl, triazole-4-yl, 2,3-dihydro-oxo-5-phenyl-1,3,4-thiadiazol-3-yl, 2,3-dihydro-2-oxo-5-phenyl-1,3,4-oxadiazol-3-yl, 6-oxo-1,2-dihydro-1,2, -4-triazine-1-yl, 1,2,3-triazine-1-yl and 1-indolyl,

or said heterocycle substituted on any available nitrogen atom by lower alkyl, hydroxy-(lower alkyl), cycloalkyl, 2-, 3 - or 4-pyridinyl, (lower alkoxy)-carbonyl*/, (lower alkoxy)-carbonyl-(lower alkyl), aminocarbonyl-(lower alkyl), (lower alkyl)-aminocarbonyl-(lower alkyl), di-(lower alkyl)-amino-carbonyl-(lower alkyl), amino-(lower alkyl), (lower alkyl)-amino-(lower alkyl), di-(lower alkyl-(amino-(lower AOM [or phenyl, substituted by amino, (lower alkyl)-amino, di-(lower alkyl)-amino, (lower alkane)-aminopropoxy, N-(lower alkyl)-(lower alkane)-aminopropoxy, carboxy-(lower alkane)-aminopropoxy, carboxyla, (lower alkoxy)-carbonyl, lower alkoxyl or halogen]

or said heterocycle substituted on any available carbon atom by nitro-group, a lower alkyl, amino, (lower alkyl)-amino, di-(lower alkyl)-amino group, cycloalkylation, mercaptopropyl, (lower alkyl)-thio group, amino-(lower alkyl)-tigraphy, (lower alkyl)-amino-(lower alkyl)-tigraphy, di-(lower alkyl)-amino-(lower alkyl)-tigraphy, 4-morpholinyl-(lower alkyl)-tigraphy, 1-piperidinyl-(lower alkyl)-tigraphy, 1-pyrrolidinyl-(lower alkyl)-diography) (lower alkoxy)-carbonyl, di-(lower alkyl)-amino-(lower alkyl), 4-morpholinyl-(lower alkyl)-amino group, cyano, 1-piperidinyl-(lower alkyl), hydroxy-(lower alkyl), phenylsulfonyl, toluensulfonyl, halogen, tri-(lower alkyl)-Sillam, carboxyla or its salt with an alkali metal, fullam, trifluoromethyl, 2-benzothiazolyl, (lower alkyl)-sulphonium, aminocarbonyl, benzyl, 4-morpholinyl, pyridinyl, netshieldusername, benzyloxypropionic, hydroxyl, 4-morpholinyl-(lower alkyl, benzoyl or benzoyl substituted lower, alkoxyl or halogen, or phenyl [or phenyl substituted by amino, (lower alkyl)-amino, di-(lower alkyl)-amino, (lower alkane)-aminopropoxy, N-(lower alkyl)-(lower alkane)-aminopropoxy, lower alkyl, lower alkoxyl, halogen, trifluoromethyl, (lower alkoxy)-poly-(lower alkoxyl), methylendioxyphenyl or (lower alkoxy)-carbonyl]< / BR>
or a heterocycle selected from 1H-(5-tetrazolyl-),5-oxo-1-tetrazolyl, 5-thioxo-1-tetrazolyl (if R2defined below, is not phenylthiourea), pyrimidinyl, 2-benzo-casalilla, 2-benzothiazolyl, 2-phthalimide, 2-(1,3,4-thiadiazolyl), 5-(1,2,4-thiadiazolyl), 5-thioxo-3-(1,2)4-thiadiazolyl), 4-(5-oxo-1,3,4-thiadiazolyl), 4-(5-thioxo-1,3,4-thiadiazolyl), 3-(1,2,4-triazolyl), 4-(1,2,4-triazolyl), 1,2,3-triazole-1-yl, 2-imidazolyl and 3-(1,2,4-triazolo[4,3-a] pyridine being substituted on any available carbon atom of the di-(lower alkyl)-amino-(lower alkyl), 4-morpholinyl-(lower alkyl)-amino group, cyano, 1-piperidinyl-(lower alkyl), hydroxy-(lower alkyl), phenylsulfonyl, toluensulfonyl, halogen, tri-(lower alkyl)-serialphiles, aminocarbonyl, benzyl, 4-morpholinyl, pyridinyl, lower alkoxyl, pyrazinium, (lower alkoxy)-carbonyl-(lower alkyl), di-(lower alkyl)-aminosulfonyl, 1-piperidinylcarbonyl, benzyloxypropionic, hydroxyl, 4-morpholinyl-(lower alkyl), benzoyl or benzoyl substituted by lower alkoxyl or halogen, or phenyl substituted by trifluoromethyl, (lower alkoxy)-poly-(lower alkoxyl), methylendioxyphenyl or (lower alkoxy)-carbonyl,

or, if R4is carboxy-(lower alkoxyl), (lower alkoxy)-carbonyl-(lower alkoxyl) or di-(lower alkyl)-aminocarbonylmethyl, the heterocycle is a 1-phenyl-tetrazol-5-Il,

or, if L is-O-, and n is 1, R1represents cycloheptatrien-2-yl; when L is-S-, and n is 1, R1represents the cyano-or (lower alkoxy)-thiocarbonyl; or, if L is-SO2- and n is 1, R1represents a lower alkyl or trifluoromethyl;

R2is hydrogen, (lower alkoxy)-carbonyl, phenyl or phenylthiourea;

R3is hydrogen, halogen, primary or secondary lower alkyl, lower alkoxyl, (lower alkoxy)-carbonyl, Fe is BR>R4represents hydrogen or 1-3 substituent selected from halogen, ceanography, nitro, amino, (lower alkane)-aminopropyl, phenyl-(lower alkane)-aminogroup, diphenyl-(lower alkane)-aminogroup, (lower alkyl)-sulfonyl-amino group, polyflor-(lower alkyl)-sulfonylamino, aminosulfonyl, lower alkyl, polyhalomethanes lower alkyl, cycloalkyl, polyhalomethanes lower alkoxyl, hydroxyl, lower alkoxyl, carboxyl, oximetry, formyl, aminomethyl, (lower alkyl)-sulfonyl, (polyhalomethanes lower alkyl)-sulfonyl, (lower alkyl)-sulfonylmethane, (lower alkoxy)-(lower alkoxyl) (lower alkoxy)-poly-(lower alkylene)-oxypropyl, carboxy-(lower alkoxyl), (lower alkoxy)-carbonyl-(lower alkoxyl) or di-(lower alkyl)-aminocarbonylmethyl; provided, that

(1) when n is 0, R1can only be a heterocycle, and CHR2can only be linked to a ring nitrogen atom, R1and

(2) when m is 0, n is 1, L is-O-, -S - or-SO-, and R2, R3and R4all represent hydrogen, or when m is 0, n is 1, L is-S-, R2and R4represent hydrogen, and R3yavlyaetsya)-carbonyl, and R3and R4are both hydrogen, then R1may not be substituted by phenyl.

According to the invention offers new derivatives of 2-substituted saccharin of formula I which possess inhibitory activity relative to protease enzymes and which are suitable for the treatment of degenerative diseases.

On the other hand, the invention relates to compositions used to treat degenerative diseases and containing a pharmaceutical carrier and new derivatives of 2-substituted saccharin of formula I in an amount effective for the inhibition of proteolytic enzymes.

An additional aspect of the invention is the provision of a method of use of these 2-substituted sharenow formula I in obtaining medicinal product used for the treatment of degenerative disease in a patient in need of such treatment, and containing the specified 2-substituted saccharin in an amount effective for the inhibition of proteolytic enzymes.

Preferred compounds of formula I, described above, are compounds of formula I where m is 0, R2is hydrogen, R3represents hydrogen, Gal is l, lowest alkoxy, (lower alkoxy)-(lower alkoxy), (lower alkoxy)-poly-(lower alkylene)-hydroxy group, carboxy-(lower alkoxy) or (lower alkoxy)-carbonyl-(lower alkoxy), and

n is 1, L is-O-, and R1represents phenyl, substituted 1-[4-(lower alkyl)-piperazine-1-yl] -carbonyl, 4-morpholinylcarbonyl, 4-teamorganization or S-dioxide, 4-morpholinyl-(lower alkyl)-aminocarbonyl, 4-morpholinyl (lower alkoxy)-carbonyl, 1-[4-(lower alkyl)-piperazine-1-yl] -sulfonyl, di-(lower alkyl)-amino-(lower alkyl)-aminosulfonyl, and/or 4-morpholinylcarbonyl or 1,2,5-thiadiazole-Z-yl or 1,2,5-thiadiazol-Z-yl, substituted 4-morpholinyl, or isoxazolyl, substituted (lower alkoxy)-carbonyl; or

n is 1, L is-S-, and R1represents a 1,3,4-oxadiazol-2-yl, substituted on any available carbon atom by fullam, benzyl, pyridinyl, pyrazinium or phenyl; or

n is 0, and R1represents a 1,2,3-triazole-1-yl or 1,2,3-triazole-2-yl, substituted on any available carbon atom of the cyano-or (lower alkyl)-sulphonium.

In particular, preferred compounds are compounds in which L represents-O - or-S-, m is 0, is, methyl, ethyl, propyl, isopropyl, sec-butyl, methoxy, ethoxyl, isopropoxy or phenyl, and in which R4represents hydrogen, 7-chloro-5-nitro-group, 6-nitro-group, 5-amino, 5-acetoaminophen, 5-(3,3-diphenyl-propionamide)-group, 5-(1,1,3,3-TETRAMETHYLBUTYL), 6-hydroxyl, 7-hydroxyl, 5-methoxy, 6-methoxy, 7-methoxy, 5,6-dimethoxy, 5,7-dimethoxy, 6,7-dimethoxy, 6[-(2-methoxyethoxy)ethoxyl] 7-[2-(2-methoxyethoxy)ethoxyl] 7-carboxymethoxy, 7-(tert-butoxycarbonyl)methoxy, 7 dimethylaminocarbonylmethyl, 6-propyl-7-methoxyl, 5,7-dimethoxy-6-methyl or 5-hydroxy-6-metoxy.

It should be understood that compounds having the General structural formula I, in the chemical literature usually referred to as 1,2-benzisothiazol-(2H)-3-he-1,1-dioxides. However, for brevity, such compounds are referred to as derivatives of saccharin, and in this patent in the description of the compounds of the invention and their biological properties used this terminology.

Used herein, the terms "lower alkyl", "lower alkoxy" and "low alkali" refers to monovalent aliphatic radicals, including radicals branched chain, containing from 1 to 10 carbon atoms. Thus, alkyl (or alkanoyl) a fragment of such groups include sebl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethyl-butyl, 2-hexyl, 3-hexyl, 1,1,3,3-TETRAMETHYLBUTYL, 1,1-dimethyloctyl etc. Lowest alkanol contains from 2 to 10 carbon atoms and is branched or unbranched.

Used herein, the term "halogen" or "halo" means fluorine, chlorine, bromine or iodine.

Used herein, the term "cycloalkyl" denotes a carbocyclic ring containing 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl which may be substituted on any carbon atom of the ring by one or more lower alkyl groups.

Used herein, the term "lower alkenyl" means a monovalent unsaturated radicals, including radicals branched chain containing from 3 to 10 carbon atoms, and, thus, these radicals include 1-(2-propenyl), 1-(2-butenyl), 1-(1-methyl-2-propenyl), 1-(4-methyl-2-pentenyl), 4,4,6-trimethyl-2-heptenyl etc.

Compounds of the invention inhibit the activity of semiprotect, in particular elastase of human leukocytes and chymotrypsinogen enzymes, and they are therefore useful in the treatment of degenerative diseases, such as emphysema, revatio enzyme compounds of the invention are split on relations between functions methylene (CHP2and ZnR1and that the group ZnR1is separated in the form of the anion, which, thus, can be characterized as the leaving group. It is assumed that this splitting will be facilitated by the presence of electron-acceptor group, such as cyano, halogen, the nitro-group, carboxyl, (lower alkoxy)-carbonyl, acyl, or phenylthiourea R1functionality, thereby increasing its electronegativity, which can be expressed as the values of the pKa of the acid form of the leaving group, which ideally should be less than 7. A particularly preferred group of such compounds are the compounds of formula I in which R3is not hydrogen.

Another aspect of the invention relates to a method of obtaining these derivatives 2-saccharin, which includes the interaction of 2-geometricaly or alkaline salt of a fragment of LnR1or with a fragment of LnR1in the presence of an acid acceptor.

Another aspect of the invention relates to a method of obtaining these derivatives 2-saccharin, which includes the interaction of alkali metal salts or tallic salt of 2-unsubstituted saccharin or with a fragment of halo,-CHR2-LnR1with the floor is the group of product nagkalat with getting 2[1-(phenylsulfonyl)propyl-LnR1] saccharin, by heating the latter to obtain 2-[1-(2-propenyl)-LnR1]saccharin.

Another aspect of the invention is to provide a method of obtaining 4-primary or secondary-(lower alkyl)-R4-2-unsubstituted sharenow used as intermediates in the synthesis of the corresponding derivatives of 2-saccharin, which includes the interaction of 2-(primary lower alkyl)-N, N-di-(lower alkyl)-benzamide (lower alkyl) lithium in an inert organic solvent; the interaction of the resulting lithium salt with (lower alkyl and/or halogen; the interaction of the resulting 2-primary or secondary-(lower alkyl)-R4-N,N-di-(lower alkyl)-benzamide (lower alkyl)-lithium; the interaction of the resulting lithium salt with sulfur dioxide followed by interaction in the presence of a base with hydroxylaminosulphate; and heating the product in an acid environment.

For example, the compounds of formula I where m is 0, R2is hydrogen, and L represents-O - or-S-get-interaction-derived 2-geometricaly formula I, where R1is halogen, R2is hydrogen, m and n is 0, R3and R4have prisutstvie acceptor acid, such as a carbonate of an alkali metal, three or n(lower alkyl)-amine, lower alcoholate of an alkali metal or thallium, or hydride of an alkali metal, or you can use an alkaline salt of a fragment of LnR1. The reaction is carried out in an organic solvent, inert under the reaction conditions, for example, acetone, methyl ethyl ketone (MEK), tetrahydrofuran (THF), diethyl ether, dimethylformamide (DMF), methylene chloride (MDC) or in the lower alcohols, in the temperature range from room temperature up to the boiling point of the used solvent. The corresponding compounds in which L is-SO - or-SO2-, produced by oxidation of the corresponding compounds of the formula I, in which L is-S-, one or two molar equivalents of that ideal, nagkalat, such as 3-chlormadinone acid.

On the other hand, the compounds of formula I in which m is 0, can be obtained by the interaction of the salt saccharin and alkali metal or thallium (obtained by reaction of the corresponding 4-R3-R4-2-unsubstituted saccharin with an alcoholate of an alkali metal or lower alcoholate thallium) with halo,-CHR2-LnR1fragment, where R1, R2, R3, R4, L and n have the meanings given above, however, the salt of the alkali metal can be used only when R2is hydrogen. The reaction is carried out in an inert organic solvent, for example, in a lower alcohol or dimethylformamide, at temperatures in the range of 20oC to the boiling point of the used solvent.

The compounds of formula I where m is 1, and R2is hydrogen, produced by interaction of the compound 3-(phenylthio)propyl-Ln-R1obtained by the reaction of LnR1-propylchloride with thiophenoxide sodium ethyl ketone (MEK), N-chlorosuccinimide getting connection type 3-chloro-3-(phenylthio)propyl-LnR1. Reaction of the latter with tallic salt of the corresponding 4-R3-R4-saccharin and the same conditions as described above, when obtaining the compounds of formula I from the salt saccharin and halo-CHR2-LnR1fragment leads to the formation of 2-[1-(phenylthio/propyl)-LnR1]saccharin. Oxidation of this compound to the corresponding 2-[1-(phenylsulfonyl)propyl-LnR1] saccharin followed by heating the product in alkylenglycol ether, for example, etilenglikolevye ether leads to the formation of compounds of formula I, where m is the th alkanoyl, R2is hydrogen, L is-O-, m is 0, n is 1 and R3and R4have the meanings given above, is produced by interaction of the corresponding 2-Oxymetazoline with the appropriate acid anhydride in the presence of catalytic amounts of mineral acids or strong organic acids, for example, in the presence of sulfuric acid or para-toluenesulfonic acid.

The compound of formula I, where n is 0 and R1represents a 1,2,3-triazole-1-yl, obtained by condensation of the corresponding compounds of formula I, where R1represents a halogen, with an alkali metal azide and then cyclopentadienes the resulting azide with the corresponding substituted or unsubstituted acetylene. The preferred alkali metal azide is sodium azide. The condensation is carried out with or without heating or cooling, preferably at room temperature, in an inert solvent, for example benzene, toluene or dimethylformamide, you may be using a crown ether such as 18-crown-6-ether. The cycloaddition reaction is preferably carried out by heating in the same inert solvent 2-geometricaly formula I, where R1is halogen, R2is hydrogen, m and n p>R4-2-unsubstituted sacharine required to obtain compounds of the formula I, where R1, L, m and n have the values given above, get methods described D Alelio and others [J. Macromol. Sci-Chem. A3(5), 941 (1969)] and Saari, etc. [Het. Chem. 23, 1253 (1986)] By the method described Saari, methyl ester of the corresponding Anthranilic acid get in the normal way of substituted Anthranilic acid and diazotized of ester. Then salt the page interacts with the sulfur dioxide and chloride copper with the formation of chloride of sulfonyl, which then interacts with concentrated ammonium hydroxide with the formation of substituted derivatives of saccharin of formula II. The reaction of the latter with formaldehyde in a solvent (lower alcohol) formed 2-hydroxy-methylcholine formula III, which upon reaction with thionylchloride or trihalide phosphorus give the corresponding derivatives of 2-geometricaly. This method can be illustrated as follows:

< / BR>
where R3and R4have the meanings given above and X represents halogen.

Geometricaly formula I, where R1is halogen, R2is hydrogen, m and n are 0, and R3and R4have the meanings given the saccharin with sulfurylchloride in an inert organic solvent, for example, in methylene chloride, ethylene dichloride (EDC) or carbon tetrachloride, at temperatures from 0 to 30oC.

The compounds of formula II, where R3represents or primary or secondary lower alkyl, which are used as intermediates in the synthesis of compounds of formula I, described above, will receive one of two methods. The compounds of formula II, where R3is a primary lower alkyl, produced by interaction of 4-methyl-R4-2-unsubstituted saccharin with two molar equivalents (lower alkyl)-lithium in an inert organic solvent, e.g. THF, and the interaction of the resulting lithium salt with one molar equivalent of halogen lower alkyl, both of which reaction is carried out at a temperature of from -50 to -80oC.

The compounds of formula II, where R3is either primary or secondary lower alkyl, is obtained by reaction of 2-(primary lower alkyl)-R4-N,N-di-(lower alkyl)-benzamide with one molar equivalent (lower alkyl)-lithium in the presence of Tetra-(lower alkyl)-ethylene diamine in an inert organic solvent, for example THF, and the interaction of the resulting lithium salt with one molar equivalent of the halide of the lower alkyl when temperature is s alkyl)-benzamid then interacts with one molar equivalent (lower alkyl)-lithium in the presence of Tetra-(lower alkyl)-ethylene diamine in an inert organic solvent, for example, THE, and the resulting lithium salt interacts with sulfur dioxide at a temperature of from -50 to -80oC with subsequent reaction of the obtained product with hydroxylaminosulphate in the presence of a base. After that, the resulting 2-(lower alkyl)-R4-6-amino-sulfonyl-N, N-di-(lower alkyl)-benzamid heated in an acid environment for the implementation of the cyclization it to the desired 4-primary or secondary-(lower alkyl)-R4-2-unsubstituted-saccharin of formula II. Preferably the cyclization carried out in boiling glacial acetic acid. If the original substance is 2-(lower alkyl)-R4-N,N-di-(lower alkyl)-benzamide lower alkyl group in position 2 represents methyl, alkylation leads to the formation of compounds in which the lower alkyl group in position 2 is a linear or branched, depending on whether linear or branched (lower alkyl)-halide was used for alkylation. On the other hand, if the original substance of the lower alkyl group in position 2 contains more than one carbon atom, the alkylation takes place on the carbon atom adjacent to the benzene ring, and leads to the formation of products containing in position 2 Storico the filling of the compounds of formula II requires the construction of two rings, the nucleus of saccharin. Thus, to obtain compounds in which R3represents the lowest alkoxy, and R4is the 7-hydroxyl, 3,3-dithio-bipropion acid is converted into the acid chloride of bis-acid reaction of this acid chloride tiomila, and then the acid chloride interacts with two molar equivalents of benzylamine with the formation of bis-n-benzylamine. In the interaction of this amide with chloride sulfuricum in a solvent such as MDC, EDC or carbon tetrachloride, is formed 5-chloro-2-benzyl-2H-isothiazol-3-one, which oxidize one mole equivalent of nagkalat, such as natantia acid or 3-chloro-adventia acid, 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide. In the interaction of this compound under pressure and when heated with 2-(lower alkoxy)-furan in an organic solvent such as benzene, toluene or xylene, is formed of 4-(lower alkoxy)-7-hydroxy-2-benzyl-1,2-benzisothiazol-2H-3-one-1-oxide. If necessary, you can implement the interaction between the hydroxy-group, in position 7, and (lower alkyl)-halogen or (lower alkoxy)-poly-(lower alkoxy)-(lower alkyl) halide to obtain the corresponding 4,7-di-(lower alkoxy) -, or 4-(NCDs shall Islena this product one molar equivalent of nagkalat, as described above, with subsequent catalytic dibenzylammonium leads to the formation of the corresponding 4-(lower alkoxy)-7-R4-2-unsubstituted sharenow.

For a change of functional groups in the compounds of the invention can be used other simple chemical transformations which are conventional and well known to the specialists working in this field of chemistry. For example, when necessary, can be conducted by catalytic reduction of the nitro group to obtain the corresponding aminosilane compounds, acylation aminosilane connection with obtaining the corresponding amides or oxidation of sulfides or sulfoxidov with obtaining relevant sulfoxidov or sulfones.

Standard methods of biological tests showed that the compounds of formula I possess inhibitory activity relative to the elastase of human leukocytes (HLE) and chymotrypsin, and therefore they can be used in the treatment of degenerative diseases, such as emphysema, rheumatoid arthritis, and pancreatitis.

The compounds of formula I, containing the basic functions can be converted into the salt form (salt accession acids is special regenerated from the salt form (salt accession acid), i.e., by treating this salt-cooled) weak aqueous solutions of bases, for example, solutions of carbonates and bicarbonates of alkali metals. Foundation, regenerated thus, can be brought into interaction with the same or a different acid, while again get the same or another salt accession acid. Thus, bases and their salts accession acid readily interconvertible.

Thus, some compounds of the formula I containing acid functions, i.e. functions carboxylic acid, can be converted into their salt form by interaction of this acid with a base, such as hydroxide of alkali metal or ammonium hydroxide, or organic bases, such as alkyl, dialkyl, or trialkylamine, and these acids can be regenerated from the salts by treatment of the salts with aqueous solutions of acids.

Therefore, you should take into account that the formula I not only represents the structural configuration of the bases and acids of the formula I, but it also reflects the structural organization that are common to all compounds of formula I, regardless of whether these compounds in the form of a free base, free acid is soedineniya formula I and their salts have inherent pharmacological activity type which will be more fully described below. This inherent pharmacological activity can be used in a valuable form for pharmaceutical purposes by applying themselves of the free bases or free acids, or salts formed from pharmaceutically acceptable acids and bases, i.e., acids and bases, whose anions or cations in effective doses of the salts are harmless to the body of the animal, so that the healing properties inherent in the common structural organization, represented by the free bases and free acids, not distorted by the side effects attributed to these anions or cations.

When using this pharmacological activity of salts of course, it is preferable to use pharmaceutically acceptable salts. Although the insolubility in water, high toxicity and lack of crystalline character may make some particular types of salts are unsuitable or less desirable for use as such in a specific pharmacological use, but water-insoluble or toxic salts can be converted to the corresponding pharmaceutically acceptable basis by the decomposition of these salts in an aqueous solution of a base or we pharmaceutically acceptable salt reactions dual decomposition, including an anion or cation, for example, ion-exchange methods.

Besides usefulness in pharmaceutical applications, these salts are useful as characterizing or identifying derivatives of the free bases or free acids or in the cleaning process or selection. Like all salts such characterization or purification may be used, if necessary, for regenerating pharmaceutically acceptable free bases or free acids by the interaction of the salt with an aqueous solution of a base or aqueous acid solution, or, on the other hand, they can be converted into pharmaceutically acceptable salt, for example, ion-exchange methods.

In this case, a new feature of these compounds is within the concept of the bases and cationic and anionic forms 4-R3-R4-2-substituted sharenow formula I, and not in any particular acid or basic fragment, i.e., not in the anion of the acid or base cation associated with the salt forms of these compounds; more likely to be acidic or basic fragments, i.e., anions which can be associated with the salt forms are in themselves neither new nor determinative, and therefore can be Liu is whether acids.

The compounds of formula I of the invention can be prepared for pharmaceutical use by putting them in a uniform dosage form, such as tablets or capsules for oral use, or in pure form or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, Arabic gum, etc. in Addition, these compounds can be prepared for oral, parenteral use or consumption in the form of an aerosol inhalation, or in the form of aqueous solutions of water-soluble salts of these compounds, or in the form of an alcohol, glycol or oil solutions, or in the form of water-oil emulsions, the same way get the regular medicinal substance.

In such compositions, the percentage of the active component can be varied so as to obtain an acceptable dose. The dose entered a particular patient will vary depending on the clinical assessment, using as criteria: the method of administration, duration of treatment, weight and physical condition of the patient, the effectiveness of the active component and the susceptibility of his patient. Consequently, an effective amount of dosage of active companioni in the best interests of the patient.

The molecular structure of the compounds of this invention were decoded on the basis of IR and NMR spectra. These patterns were confirmed by the correspondence between calculated and found by the method of elementary analysis values that determine the content of the items.

The following examples are given to further illustrate this invention but not to limit the scope of its claims. All melting points are inaccurate.

Example 1. Powdered potassium hydroxide (7.4 g; 132 mmol; 2 equivalents) was mixed with 100 ml of dimethylsulfoxide (DMSO) and stirred the mixture for 5 minutes Then to the mixture was added dropwise 6-methylanthranilic acid (10.0 g; 66 mmol) and methyl iodide (4.52 ml; 73 mmol; 1.1 equivalent). The reaction mixture was stirred at room temperature for 30 min, then diluted with 250 ml diethyl ether, washed with water (3 x 10 ml), dried over MgSO4and concentrated. The crude product was filtered through a layer of annealed silica gel (32-63), was suirable a mixture of diethyl ether: hexane 1:9 and got to 4.23 g of methyl ester of 6-methylanthranilic acid in the form of oil, yield 39%1H NMR (300 MHz, CDCl3: 7,078 (1H, triplet, J=to 7.67 Hz); 6,529 (2H, doublet, J=7,79 Hz); 5,111 (2H, Shir the latter), 2950 (weak), 1690 (strong), 1605 (strong).

Obtained in stage (a) methyl ester of 6-methylanthranilic acid (to 4.23 g; 25.6 mmol) was dissolved in 25 ml of acetic acid and cooled the solution to 0oC. To the solution was added 45 ml of concentrated hydrochloric acid and was obtained slurry yellowish-brown color. To the slurry was added dropwise with stirring a solution of sodium nitrate (1.89 g; a 27.4 mmol; 1.07 equivalent) in 8 ml of water, the resulting orange solution was stirred at 0oC for 1 h, and then was added in six portions to a mixture of chloride dihydrate copper (2) (2,18 g; 12.8 mmol; 0.5 equivalent) and sulfur dioxide (6.3 g; excess) in 33 ml of acetic acid, 6 ml of water at 0oC. the Dark green solution was stirred at room temperature overnight, poured into 300 ml of water, cooled with ice, the separated solid was collected, dried by suction and received 1,11 g chloride sulfonyl, which was immediately added to ammonium hydroxide (100 ml), cooled with ice, and stirred at room temperature overnight. The solution was acidified to pH 1 with concentrated HCl, the resulting precipitate was collected, dried in the air and received 729 mg (yield 12% ) 4-methylcholine, melting point 225-226oC. 1-1): 3400 (weak), 3100 (strong), 3000 (strong); 1720 (strong); 1580 (average). Mass spectrometry (FDMS): m/e 197 (M+).

Obtained in stage (b) 4-metalshark (500 mg, 2.54 mmol) was dissolved 2.53 ml of warm ethanol (steam bath). After the formation of the homogeneous solution to it was added dropwise formalin (37% in methanol; 1,76 ml; excess). The solution was allowed to cool to room temperature, and then kept it at 0oC for 4 days. The resulting solid was collected, dried in the air and received 476 mg (yield 82%) of 2-oxymethyl-4-methylcholine, melting point 196-198oC.1H NMR (300 MHz, CDCl3): 7,767 (1H, triplet, J=6.75 Hz); 7,732 (1H, doublet, J=7,72 Hz); 7,600 (1H, doublet, J= 6,64 Hz); 5,361 (2H, doublet, J=8,00 Hz); 3,296 (1H, triplet, J= 8,16 Hz); 2,793 (3H singlet). IR (KBr, cm-1): 3505 (strong); 3070 (average); 1735 (strong); 1580 (average).

Obtained in stage (c) 2-oxymethyl-4-metalshark (76 mg; 0.33 ml) was mixed with acetic anhydride (1 ml, excess) was added 2 drops of concentrated sulfuric acid. The reaction mixture was stirred at room temperature for 2 h, at this time, thin layer chromatography (TLC) observed non-polar spot. The reaction mixture was diluted is 2
SO4solvent was removed and received 64 mg (yield 72%) of 2-acetoxymethyl-4-methylcholine, melting point 198-205oC (decomp. ).1H NMR (300 MHz, CDCl3): 7,8 (2H, multiplet); to 7.64 (1H, doublet, J 6,18 Hz); of 5.84 (2H, singlet); 2,82 (3H, singlet); of 2.15 (3H, singlet), IR (KBr, cm-1): 2920 (weak); 1745 (strong); 1735 (strong); 1630 (weak). Mass spectrometry (FDMS): m/e 269 (M+).

Example 2. Using the procedure described above in example 1, the reaction between 6-chlorantraniliprole acid (5 00 g; 29,2 mmole) and iodine stands (2,75 ml; 44 mmol; 1.5 equivalents) in the presence of powdered potassium hydroxide (4,08 g; 72,7 mmol, 2.5 equivalents) and received 4,22 g (yield 78%) of methyl ester of 6-chlorantraniliprole acid in the form of butter.1H NMR (300 MHz, CDCl3): 7,077 (1H, triplet, J=8,06 Hz); 6,744 (1H, doublet, J=6,7 Hz); 6,575 (1H, doublet, J=8,25 Hz); 4,871 (1H, broad singlet); 3,929 (3H, singlet). IR (neat, thin layer, cm-1): 3480 (average), 3380 (average); 2950 (weak); 1705 (strong); 1610 (strong).

4-hariharan was obtained by the same method that was used in the synthesis of 4-methylcholine using methyl ether 6-chlorantraniliprole acid (4,22 g, 22.7 mmol) in 22 ml of acetic acid, concentrated HCl (40 ml) and sodium nitrate (1.68 g; a 24.3 mmol) in 7 ml of water, prevalent) and sulfur dioxide (6.5 g; excess) in 30 ml of acetic acid and 5 ml of water. The resulting chloride sulfonyl were processed as described above, 150 ml of ammonium hydroxide and received of 3.07 g of pale yellow solid 4-hariharan, melting point 245-246oC, 62%1H NMR (300 MHz, CD3CN): 7,918 (1H, double doublet, J=7,39, 1,91 Hz); 7,865 (1H, triplet, J= 7,52 Hz); 7,829 (1H, broad doublet, J=7,30 Hz). IR (KBr, cm-1): 3570 (strong); 3520 (strong); 2950 (strong, broad); 1735 (strong); 1630 (average). Mass spectrometry (FDMS): m/e 217 (M+).

2-oxymethyl-4-hariharan was obtained in the same way that 2-oxymethyl-4-metalshark in example 1 from 4-hariharan (1,00 g; 4,60 mmol) and formalin (37% 3,22 ml; excess). All attempts to crystallize viscous oily product led to decomposition of the initial substances and so the next stage was used this product without crystallization.

2-acetoxymethyl-4-hariharan was obtained in the same way that 2-acetoxymethyl-4-metalshark in example 1, the crude 2-oxymethyl-4-hariharan (0.34 g; 1.4 mmol) and acetic anhydride (2.5 ml) with 2 drops of sulfuric acid. In this case, after selecting the product was purified by filtration through a layer of silica gel and elution with a mixture of diethyl ether: hexane 1:1, melting 138-142oC.1H NMR (300 MHz, CDCl3): 7,921 (1H, double doublet, J=6,54, 2,63 Hz); 7.874 inches (1H, triplet, J=7,98 Hz); 7,842 (1H, double doublet, J=6,70, 2.20 Hz); 5,869 (2H, singlet); 2,172 (3H, singlet), IR (KBr, cm-1): 1745 (strong); 1735 (average, shoulder); 1575 (weak). According to the analysis by combustion:

The]. C 41,46; H 2,78; N A 4.83;

Found, C 41,17; H 2,81; N 4,75.

Example 3. The crude 2-oxymethyl-4-hariharan from example 2 (609 mg; 2,46 mmol max) was mixed with 5 ml of diethyl ether and added chloride thionyl (3 ml, excess). The resulting mixture was heated until complete dissolution was stirred at room temperature overnight, diluted with 20 ml diethyl ether, filtered through a layer of celite, covered with sand, and suirable diethyl ether. After removal of the solvent was obtained 430 mg of the crude chloromethylphosphonic. Part of the substance (225 mg) was used in further reactions. The residue (205 mg) was chromatographically on evaporative column with silica gel, was suirable a mixture of 40% diethyl ether/pentane and received 137 mg of 2-chloromethyl-4-hariharan, melting point 135-136oC.1H NMR (300 MHz, CDCl3): 7,925 (1H, double doublet, J=6,62, and 2.26 Hz); 7,882 (1H, triplet, J=8,18 Hz); 7,846 (1H, double doublet, J=7,42, a 2.36 Hz); 5,561 (2H, singlet). IR (KBr, cm-1): 3090 (with diprosone, obtained in example 3 (225 mg; 0.85 mmol) and sodium salt of 1-phenyl-5-mercapto-1H-tetrazole (200 mg) 1.01 mmol; 1.2 equivalents) was dissolved in 5 ml acetone and a solution of yellowish-brown color. After 10 min was observed sediment, and after stirring over night at room temperature the mixture was not detected (data analysis thin-layer chromatography) of 2-chloromethyl-4-hariharan. The reaction mixture was poured into water and was extracted with methylene chloride (3 x 25 ml). The combined extracts were dried over Na2SO4concentrated, and the residue was chromatographically on evaporative column with silica gel and was suirable a mixture of diethyl ether:hexane 1:1. The main fraction was collected and received 122 mg of 4-chloro-2-/1-phenyl-1H-tetrazol-5-altimeter/saccharin in a solid white color, melting point 175-177oC,1H NMR (300 MHz, CDCl3: 7,813 (3H, multiplet); 7,515 (5H, singlet); 5,710 (2H, singlet), IR (KBr, cm-1): 3080 (weak); 1740 (strong); 1590 (weak). Mass spectrometry (FDMS): m/e 407 (M+; 230 (M+PMT); 178 (1% PMT).

Example 5. Chloromethylphosphonate (337 mg of the crude substance; a maximum of 1.27 mmol), obtained according to the method described in example 3, was dissolved (as possible) in 10 ml of acetone. It races the promotional mix at room temperature for 3 days. The mixture is then diluted with methylene chloride (50 ml), washed with water (3 x 25 ml), dried over Na2SO4concentrated and filtered through a layer of silica gel (eluent a mixture of diethyl ether and hexane 1:1). The substance thus obtained was chromatographically on evaporative column with silica gel, was suirable a mixture of diethyl ether:hexane 1:1 and received 44 mg (yield of 8.5%) 4-chloro-2-/4-phenyl-5-mixoterin-1-ylmethyl/saccharin, melting point 158-162oC.1H NMR (300 MHz, CDCl3): 7,981 (1H, doublet, J=7,12 Hz); 7,95 (2H, multiplet); 7,887 (1H, triplet, J=6,74 Hz); 7,864 (1H, doublet, J=to 7.32 Hz); 7,567 (3H, multiplet); 6,392 (2H, singlet), IR (KBr, cm-1): 1745 (strong); 1185 (strong). Mass spectrometry (FDMS): m/e 407 (M+); 230 (M+PMT).

Example 6. A mixture of 2-/chloromethyl/saccharin (0,98 g, 4.2 mmol), 1-(3-acetamidophenyl)-5-mercapto-1H-tetrazole (1 g, 4.2 mmol) and potassium bicarbonate (0.84 g, 8.4 mmol) in 50 ml of methyl ethyl ketone was heated at 50oC in nitrogen atmosphere overnight. The reaction mixture was cooled, poured into in HCl, diluted with chilled water (300 ml), decantation with water semi-solid substance that hardened when grinding with hot ethyl acetate. The obtained solid white recrystallization from acetonitrile the needles white, melting point 195-196oC (decomp. ).1H NMR (90 MHz, CDCl3): is 2.05 (3H, singlet); the 5.65 (2H, singlet). Mass spectrometry (FDMS): m/e 430 (M+).

The]. C 47,43; H 3,28; N 19,52;

Found, C 47,02; H 3,27; N 19,53.

Example 7. A mixture of 2-(methyl bromide)saccharin (2.7 g, 9.8 mmol), 1-(3-heptane-amido-phenyl)-5-mercapto-1H-tetraza (3 g, 9.8 mmol) and potassium carbonate (3.4 g, 24.5 mmol) was heated under reflux in methyl ethyl ketone (50 ml) in nitrogen atmosphere for 1 h Then the mixture was cooled and poured into aqueous sodium bicarbonate solution, cooled with ice. With the resulting semi-solid substance white decantation layer of water. Semi-solid substance was washed with water, then dissolved in hot acetonitrile, the solution was treated with activated charcoal and filtered. From the filtrate drove in a vacuum solvent, and the resulting solid was chromatographically (silica gel-95: 5 CH2Cl2: acetone) and the received light oil. This oil was led from hot ethanol and received 1.6 g solid white 2[1-(3-heptanedione)-1H-tetrazol-5-ylthio-methyl] saccharin, melting point 146-147,5oC.1H NMR (90 MHz, CDCl3(2H, singlet). Mass spectrometry (FDMS): m/e 500 (M+).

the mol) and sodium salt of 5-mercapto-1-methyl-1H-tetrazole (1,49 g, the 10.8 mmol) was heated under reflux in methyl ethyl ketone (75 ml) for 2 hours Then the mixture was cooled, poured into dilute aqueous sodium bicarbonate solution, precipitated with ice, and was twice extracted with methylene chloride. The combined organic extracts were dried over Na2SO4and in the vacuum drove away from them solvent. The crude product was chromatographically (silica gel - 95:5 CH2Cl2: diethyl ether), and the resulting oil was led from hot isopropanol and obtained 2.7 g (yield 80%) solid white color 2-[1-methyl-1H-tetrazol-5-ylthio-methyl]-saccharin, melting point 106-110oC.1H NMR (90 MHz, CDCl3): of 5.55 (2H, singlet). Mass spectrometry (FDMS): m/e 311 (M+).

The]. C 38,58; H-2.91 IN; N 22,49;

Found, C 38,53; H 2,79; N 22,60.

Example 9. A mixture of 2-(chloromethyl)saccharin (3 g, 12.9 mmol), 1-cyclohexyl-5-mercapto-1H-tetrazole (2.37 g, 12.9 mmol) and potassium carbonate (4,45 g is 32.2 mmol) was heated under reflux in methyl ethyl ketone (50 ml) for 1 h Then the reaction mixture was cooled, poured into dilute aqueous sodium bicarbonate solution, cooled with ice, and was twice extracted with ethyl acetate. The combined organic extracts washed voegel; methylene chloride) and received 2 g of 2-[1-cyclohexyl-1H-tetrazol-5-altimeter]saccharin as a white foam, which was led from hot cyclohexane) melting point 103-105oC.1H NMR (90 MHz, CDCl3): the 5.65 (2H, singlet). Mass spectrometry (FDMS): m/e 379 (M+).

The]. C 47,48; H TO 4.52; N 18,46;

Found, C 47,84; H Br4.61; N 18,36.

Example 10. A mixture of meta-chlormadinone acid (0,43 g, to 2.67 mmol) and 2-(1-phenyl-1H-tetrazol-5-altimeter)saccharin (1 g, to 2.67 mmol) in methylene chloride was stirred at room temperature for 24 hours of Analysis by thin layer chromatography (TLC) (95 5 CH2Cl2diethyl ether) showed the presence of a source of sulfide. Was added an additional amount (0.2 g) nagkalat, after which the mixture was stirred for two days. Then the reaction mixture was washed with sodium bicarbonate solution, dried over Na2SO4and in the vacuum drove away from the solvent. The residue was chromatographically (silica gel 95 5 CH2Cl2diethyl ether) and got a foam, which was led from diethyl ether and was identified 0.52 g of 2-[1-phenyl-1H-tetrazol-5-ylsulphonyl] saccharin in a solid white color, melting point 161-162oC.1H I is retic. C 46,27; H 2,85; N 17,98;

Found, C 46,00; H 2,83; N 17,76.

Example 11. A mixture of 2-bromomethyl-5-nitrosourea (2 g, 6.2 mmole) and sodium salt of 1-phenyl-5-mercapto-1H-tetrazole was heated under reflux for 2 h in a mixture containing 40 ml of methyl ethyl ketone and 10 ml of dimethylformamide (DMF). Then the reaction mixture was cooled and poured into dilute aqueous sodium bicarbonate solution, cooled with ice. The resulting solid white color was filtered, washed with water and dried in the air. To remove soluble impurities this substance is homogenized with a mixture of methylene chloride and acetone (50:50) and filtered. The remaining solid was recrystallization from a mixture of acetonitrile:ethanol 2:1 and received 1.5 g of 5-nitro-2-[1-phenyl-1H-tetrazol-5-altimeter]saccharin in the form of solid substances not quite white, melting point 189-190oC.1H NMR (90 MHz, DMSO-d6): of 5.75 (2H, singlet). Mass spectrometry (FDMS) m/e 418 (M+).

The]. C 43,06; H 2,41; N 20,09;

Found, C 42,29; H 2,43; N 20,13.

Example 12. A mixture of meta-chlormadinone acid (2.2 g, 12.8 mmol) and 2-(phenylsulfinyl)saccharin (3.75 g) 11)6 mmol) was stirred at room temperature in 50 ml of methylene chloride for 2 hours After which the acid was removed by filtration, and the solid washed with a small amount of methylene chloride. The filtrate was washed with an aqueous solution of sodium bicarbonate, dried over Na2SO4and in the vacuum kept him solvent. The resulting solid was recrystallization from a mixture of ethanol: acetonitrile 50: 50 and got 2-(phenylsulfonyl)saccharin in a solid white color, melting point 169-171oC.1H NMR (90 MHz, DMSO-d6), CDCl3: of 5.15 (2H, singlet). Mass spectrometry (FDMS): m/e 196 (M+-PMT).

The]. C 49,84; H 3,29; N 4,15;

Found, C 49,92; H 3,24; N 4,13.

Example 13. A mixture of meta-chlormadinone acid (0.9 g, 5.37 mmol) and 2-(2-pyrimidinyl)saccharin (1.5 g, 4.8 mmol), obtained according to procedures similar to those described in examples 9 and 11, in 75 ml of methylene chloride was stirred at room temperature overnight. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, dried over Na2SO4and in the vacuum drove away from the solvent. Part of this crude product (0.5 g) was retained for direct transformation into sulfon, and the remaining substance was chromatographically (silica gel 95 5 CH2Cl2acetone). After recrystallization from a mixture of ethanol: ACETC (decomp.).1H NMR (90 MHz, CDCl3, DMSO-d6): from 5.1 to 5.5 (2H, quadruplet).

The]. C 44,57; H 2,81; N 13,00;

Found, C Of 44.67; H 2,84; N 12,97.

Example 14. A mixture of meta-chlormadinone acid (0.4 g, 2.3 mmol) and sulfoxide (0.75 g, 2.3 mmol) obtained in example 13, was stirred at room temperature in 50 ml of methylene chloride, watching the reaction using the method of thin-layer chromatography (TLC) (95 5 MDS:acetone). After 2 h stirring was still some number of source sulfoxide; to the reaction mixture was added an additional portion of nagkalat and continued stirring overnight. Then was added 100 ml of methylene chloride and the mixture was washed with sodium bicarbonate solution. The organic layer was dried over Na2SO4and the solvent is kept in vacuum. After recrystallization of the residue from a mixture of acetonitrile: ethanol was obtained 0.95 g of 2-(2-pyrimidinemethanol-methyl)-saccharin in a solid white color, melting point 225-227oC (decomp.). 1H NMR (90 MHz, DMSO-d6): 5,78 (2H, singlet), Mass spectrometry (M+): m/e 196 (M+PMT), 339 (M+).

The]. C 42,47; H TO 2.67; N 12,38;

Found, C 42,20; H 2,62; N 12,46.

Example 15. A mixture of 2-(chloromethyl)Oriental is during the night, and then boiled under reflux for 45 minutes, the Reaction mixture was cooled, poured into dilute aqueous sodium bicarbonate solution, cooled with ice, and was twice extracted with ethyl acetate. The combined organic extracts were washed with sodium bicarbonate solution and water, dried over Na2SO4and then finally dried in vacuum. The residue was chromatographically (silica gel; methylene chloride) and got the oil, which was led from the hot mixture of cyclohexane and diethyl ether. The resulting solid was recrystallization from ethanol and obtained 0,92 g of 2-(4-nitrophenoxide-)saccharin as shiny white plates, melting point 162-164oC.1H NMR (90 MHz, CDCl3), DMSO-d6): 5,95 (2H, singlet). Mass spectroscopy (FDMS) m/e 334 (M+).

The]. C 50,30; H 3,02; N SCORED 8.38;

Found, C 50,06; H-2.91 In; N 8,28.

Example 16. 5-nitro-2-(1-phenyl-1H-tetrazol-5-altimeter)saccharin (4 g, 9,56 mmole) obtained in example 11, was dissolved in 250 ml of tetrahydrofuran and put the solution in swinging the bottle Parra. In the atmosphere of nitrogen to the solution was added two spatula 10% palladium on coal, after which the mixture was shaken in a hydrogen atmosphere (hydrogen pressure of about 4 ATA) was tragically methylene chloride. The organic layer was dried over Na2SO4that drove him into the vacuum of the solvent, and the resulting yellow foam homogenized with warm ethanol, cooled and filtered. Was allocated to the corresponding derivative of 5-aminocoumarin (0.5 g), which was a solid cream color. Mass spectroscopy (FDMS) m/e (M+).

A mixture of the above derived 5-aminocoumarin (0.5 g, 1,29 mmol) and 3,3-diphenylpropylamine (0,315 g of 1.29 mmole) in 50 ml of acetonitrile was heated under reflux for 2.5 hours Analysis by thin layer chromatography showed the presence of some amount of starting amine. After adding a small amount of acid chloride of the reflux was continued for 1.5 h and then the reaction mixture was cooled and poured into water, cooled with ice (400 ml). After 30 min the mixture was filtered, the obtained solid substance, yellowish-brown washed with water and dried in the air. After chromatography was carried out on a column of silica gel (95: 5 methylene chloride:diethyl ether) was obtained a foam, which was led from ethanol and obtained 0.68 g of 5-(3,3-diphenylpropylamine)-2-(1-phenyl-1H-tetrazol-5-altimeter)of saccharin in the form of TV.

1H NMR (90 MHz, CDCl3): of 3.25 (1H, doublet); and 4.8 (2H, triplet); 5,6 (2H, singlet); 6,9 8,2 (multiplet, Ar). Analysis by NMR showed the presence of two molecules crystallized ethanol 1,25 (triplet); 3,7 (quadruplet). According to the analysis of combustion: for C30H24N6O42+ 2C2H5OH

The]. C 59,28; H 5,27; N 12,2;

Found, C 58,09; H 5,15; N 12,09.

Example 17. Methyl ester 2-chloro-2-phenylthiourea acid was obtained according to the method described in the literature [Fleming and J. Iqbal, Tetra Lett. 24, 327 (1983); M. Campbell and other Tetra Lett, 21, 3305 (1980)]

Saccharin (10 g, the 54.6 mmol) was dissolved in weak heating in 500 ml of ethanol. To the solution was added dropwise a thallium ethylate (13,6 g of 54.6 mmol) obtained homogeneous mixture was stirred at room temperature for 2 h, then was cooled, filtered, and the solid is washed with cold ethanol. Crystalline solid grayish-white color was dried in a desiccator under vacuum and was received with 19.4 g (yield 92%) tallic salt of saccharin.

The mixture tallic salt of saccharin (1.78 g, 4.6 mmol) and methyl ester of 2-chloro-2-phenylthiourea acid (1 g, 4.6 mmol) in 25 ml of dimethylformamide was stirred at 60oC for 7 h and Then the mixture was cooled and poured into water, the OHL is Le chromatography was carried out on a column of silica gel (methylene chloride) received light oil, which was led from hot ethanol and obtained 0.87 g (yield 51%) of the methyl ester of 2-phenylthio-2-(2-saharinen)acetic acid as white needles, melting point 144-146oC.

1H NMR (90 MHz, CDCl3): of 3.8 (3H, singlet); 5,95 (1H, singlet); 7,2-8,15 (N, multiplet). Mass spectrometry (FDMS): m/e 363 (M+).

A solution of methyl ester 2-phenylthio-2-(2-saharinen)acetic acid (2 g, 5.5 mmol) and chloride Sulfuryl (0.74 g, 5.5 mmol) in 50 ml of methylene chloride was stirred at room temperature for 2 hours the Solvent was removed in vacuo, and the yellow oil was led from the warm ethanol and received 0,94 g of the product. Analysis by NMR showed the presence of more than 50% of the original substance. To the mixture containing the crude product, added another source substance (1 g, a 2.75 mmol) and dissolved everything in methylene chloride. To the solution was again added chloride Sulfuryl (0.5 ml) and the mixture was stirred at room temperature for 12 hours Treating the mixture as described above, received 0,66 crude methyl ester 2-chloro-2-(2-saharinen)acetic acid, which is immediately used in the next stage.

A mixture of the chloride (0.66 g of the crude mixture) and 1-phenyl-5-mercapto-1H-tetrazole in the e stirring at room temperature for 2 days the reaction mixture was poured into water, chilled with ice. Filtered the solid, yellowish-brown washed with water and dried in the air. After chromatography was carried out on a column of silica gel (methylene chloride) was obtained foam is not quite white, which was led from ethanol and obtained 0.36 g of methyl ester of 2-(1-phenyl-1H-tetrazol-5-ylthio)-2-(2-saharinen)acetic acid in the form of a crystalline solid white color, melting point 160-162oC.

1H NMR (90 MHz, CDCl3): 3.8 (singlet); 7,05 (1H, singlet); 7,4-8,1 (N, multiplet). Mass spectrometry (FDMS): m/e 431 (M+).

For C17H13N5O52< / BR>
The]. C 47,33; H 3.04 FROM; N 16,23;

Found, C 47,15; H 3,09; N 16,30.

Example 18. To a suspension of 6.0 g (0.03 mmol) of copper iodide (1) in 100 ml of tetrahydrofuran was added 25 ml of dimethyl sulfide, the resulting yellow solution was cooled to -78oC and added to it dropwise 23 ml of a 3.0 M solution of magnirostris (0.06 mol) in diethyl ether. The resulting solution is pale yellow-orange color was stirred in nitrogen atmosphere at -78oC for 1 h, and then processed to 3.02 g (0.03 mmol) of 2-cyclo-hexanone in 10 ml of tetrahydrofuran. The resulting mixture was allowed to warm to t amasyali for 30 min, was treated with 8.0 g (0.09 mol) of methyl ether of cyanopyridine acid, and then left overnight at room temperature. The reaction mixture was poured into 100 ml of 2N hydrochloric acid, the organic layer was separated, and the aqueous phase was again extracted with methylene chloride. The combined organic extracts were dried to dryness in vacuo, and the residue was washed with ammonium chloride, then with water, then with brine, and then dried to dryness and was obtained 3.2 g of methyl ester of 2-phenylcyclohexane-6-it-carboxylic acid in the form of butter.

The latter compound (3.0 g, of 0.013 mol), benzylmercaptan 4.8 g (0,039 mole) and 1 g of resin Amberlyst15 (Pohm and Haas) was heated in chloroform under reflux for 20 h, then to the mixture was added 1.5 g of resin and optionally heated for 4 hours then the mixture was cooled to room temperature, filtered, the filtrate was dried to dryness in vacuo, the residue triturated with hexane, the solid was filtered and was received of 0.85 g (yield 19% ) a mixture of methyl ester of 2-benzylthio-6-phenylcyclohexyl-2-ene-carboxylic acid and methyl ester-2-benzyl-thio-6-phenylcyclohexane-1-ene-carboxylic acid, 0.6 g (0,0018 mol) which was heated with 2.0 g of 2,3-dichloro-5,6-dicyano-benzoquinone in 25 ml of toluene at < var1 methylene chloride:hexane, the eluate was dried to dryness and received 0.3 g (yield 67%) of methyl ester of 2-benzylthio-6-vinylbenzoic acid.

This ester (6,52 g, 0,0016 mole), dissolved in 10 ml of methylene chloride, diluted with 20 ml of acetic acid and 5 ml of water, the mixture was cooled to -10oC and barbotirovany through her chlorine (gas) as long as you do not stop exothermic reaction. Then the mixture was stirred for 10 min, dried to dryness in a vacuum and received 0,41 g (yield 85%) of methyl ester of 2-chlorosulfonyl-6-phenyl-benzoic acid, which was dissolved in 10 ml of tetrahydrofuran was added under cooling in a bath of dry ice/acetone to 25 ml of concentrated solution of ammonium hydroxide. The reaction mixture was extracted with methylene chloride, the organic phase was removed and the aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and was extracted with methylene chloride. The organic extracts were washed with brine, dried, evaporated to dryness and was obtained 0.33 g (yield 97%) of 4-fenilalanina.

Following the procedure described in example 21, the reaction between 4-phenylalaninol (0.33 g, 0,0012 mol) and chlorocarbonylsulfenyl (0.3 g, 0,0019 mol) in 15 ml of toluene in the presence of 0.08 g (0,0025 mol) of tetrabutylammonium bromide and got to 0.48 g (yield 100%) 2-finition is 5%) of 2-chloromethyl-4-fenilalanina.

Example 19. A solution of 2-(feilharber)-saccharin (b g, 0,0071 mol) and sodium salt of 1-phenyl-5-mercapto-tetrazole (1.4 g, 0,0071 mol) in 30 ml of dimethylformamide was heated at 55oC for 3.5 h, then stirred at room temperature for 16 h and poured into ice-cold water containing a dilute solution of sodium bicarbonate. Separated solid was collected, washed with water, dried in air, was chromatographically on a column of silica gel, elwira a mixture of methylene chloride:diethyl ether 98:2, and received 2 g (yield 63% ) 2-1(-phenyl-1H-tetrazol-5-ellipticity)saccharin, melting point 192-193oC.

Example 20. The solution of sodium salt of saccharin (a 4.53 g of 0.022 mol) and 1-phenyl-4-chloromethyl-tetrazole-5-thione (5 g, of 0.022 mol) in 50 ml of dimethylformamide was heated at 130oC for 4 h, then cooled and poured into ice-cold water. Separated solid was collected, washed with water, dried and chromatographically on a column of silica gel, elwira methylene chloride; received 4.8 g (yield 58%) of 2-(1-phenyl-5-mixoterin-4-ylmethyl)saccharin, melting point 140-142oC.

Example 21. A mixture of 3.27 g (0,012 mol) 4-brachina [Japanese patent publication 58 (79,034, C. A. 7773W)1984] of potassium tert-butylate is Ola was heated under reflux in nitrogen atmosphere for 8 h, and then at room temperature for 16 hours Then the reaction mixture was cooled, diluted with ethyl acetate and washed the organic layer bicarbonate, water and brine, then dried over magnesium sulfate and evaporated to dryness in a vacuum. The remaining solid was recrystallization from a mixture of toluene-hexane and received 3,86 g (yield 64%) of 4-bromo-2-phenyl-dimethylalanine, the melting point of 174.5-178oC.

To a solution of this compound (3,27 g, 0,0085 mol) in 85 ml of methylene chloride was added dropwise under stirring of 1.02 ml (0,0127 mol) chloride Sulfuryl. The mixture was stirred at room temperature for 1.5 h, concentrated in vacuo, and the residue is triturated with hexane, filtered and received 2,61 g crude product, which was recrystallization from a mixture of toluene-hexane and received 2.24 g (yield 85%) of 2-chloromethyl-4-bromo-saccharin, melting point 157-159oC.

Example 22A. To a solution of 8.0 ml (0,053 mol) of tetramethylethylenediamine (TMEDA) in 350 ml of tetrahydrofuran at -70oC was added 42 ml of 1.3 M solution of sec-utility (by 0.055 mol) in hexane and the mixture was stirred for 15 minutes To this solution was added dropwise with stirring a solution of 2-methoxy-N, N-diethylbenzamide (10,36 g 0,050 mol) in 150 ml of tetrahydro maintaining the reaction temperature below -50oC to until the reaction mixture became acidic (analysis damp litmus paper). Then the mixture was stirred at room temperature for 2 h, diluted with 450 ml of hexane, the resulting solid is collected, dissolved in 200 ml of water, was treated with a mixture of 65 g of sodium acetate was added in portions with stirring, hydroxylamine-O-acid (21,5 g at 0.19 mol). Separated solid white were collected, dried and received? 7.04 baby mortality g (49%) of 2-amino-sulfonyl-6-methoxy-N, N-diethylbenzamide, melting point 190-194,5oC. a Mixture of this product (4.3 g, 0.015 mol) in 75 ml of dioxane and 25 ml of concentrated hydrochloric acid was heated on the steam bath for 70 hours, then cooled, concentrated in vacuo, diluted with water and ice and was very podslushivaet concentrated solution of sodium hydroxide. The mixture was extracted with methylene chloride, the organic extracts were isolated product and received 1.29 g (yield 40%) 4-methoxycoumarin. Other, more preferred method the cyclization of 2-aminosulfonyl-6-methoxy-N,N-diethylbenzamide 4-methoxycoumarin with the release of 65% was conducted by heating under reflux in glacial acetic acid for 6,5 hours

Using the method, n is ifidon (1.31 ml, 0,0097 mol) in toluene in the presence of potassium tert-butylate (0,72 g, 0,0064 mol) and tetrabutylammonium bromide (174 mg, 0,00054 mol) and got to 1.23 g (yield 69%) of 4-methoxy-phenyldimethylsilane, the melting temperature of 152.5-154,5oC (from a mixture of amylacetate-hexane). 1,02 g (of 0.003 mol) of the substance was treated with chloride sulfuricum (0,36 ml, 0,0045 mol) in methylene chloride and received 282 mg (yield 36%) of 2-chloromethyl-4-methoxycoumarin, melting point 169-174oC.

Example 22B. To a solution of tetramethylethylenediamine (4,74 ml 0,031 mol) in 300 ml of tetrahydrofuran (missed before use through alumina) was added 2-ethyl-N,N-diethylbenzamide (5.8 g, 0.03 mol). The solution was cooled to -78oC and treated 34,9 ml of a 0.9 M solution of sec-utility (0,031 mol) in cyclohexane. At the end of the addition the mixture was stirred for 20 min, and then processed with a solution of ethyl iodide (3.2 ml, 0.04 mol), maintaining the temperature of the mixture -78oC. were Then given the ability of the mixture to warm to room temperature, then stirred for 16 h, and then poured into water. The resulting oil was separated, was chromatographically on a column of silica gel, elwira 10% ethyl acetate/hexane, and received 2.86 g (yield 43%) of 2-fluoro-butyl-N,N-diethylbenzene-butyl-N,N-diethylbenzamide (10,45 g, 0.045 mol), dissolved in 70 ml of tetrahydrofuran was added to 39,2 ml of a 1.2 M solution of sec-utility (0,047 mol) in cyclohexane and 7.1 ml (0,047 mol) of tetramethylethylenediamine in 250 ml of tetrahydrofuran, maintaining the temperature -78oC.

At the end of the addition the mixture was stirred at -78oC for 0.5 h, then was treated at -70oC-sulfur dioxide, then gave the ability of the mixture to warm to room temperature. The mixture was dried in vacuum to dryness, and the residue was dissolved in water, was added with stirring to a chilled solution of hydroxylaminosulphate (15.2 g, 0,134 mol) and 15.4 ml of 35% sodium hydroxide (0,134 mol) and got the 10.1 g (yield 72%) of 2 - aminosulfonyl-6-sec-butyl-N,N-diethylbenzamide.

This substance (6,83 g, 0.22 mol) was dissolved in 100 ml of glacial acetic acid, the solution was heated under reflux for 13 h, and then evaporated to dryness. The residue is triturated with diethyl ether and after filtration was obtained 5.7 g (yield 83%) diethylammonium salt 4-second-Boticaria.

In the interaction of this salt (3.0 g, 0,096 mol) chlorocarbonylsulfenyl (1.13 ml) 0.012 mol) in toluene received 3,47 g (yield 100%) 2-phenylthiomethyl-4-second-Boticaria.

As a result of reactions (yield 87%) of 2-chloromethyl-4-sec-butyl saccharin.

Example 22P. To a solution of tetramethylethylenediamine (9.3 ml, 0,058 mol) in 340 ml of tetrahydrofuran was added at -78oC 52 ml of a 1.1 M solution of sec-utility (0,057 mol) in tetrahydrofuran. Then to the solution was added at -78oC solution of 2-propyl-N,N-diethylbenzamide (11,37 g, 0,052 mol) in 75 ml of tetrahydrofuran, after which the mixture was stirred for 15 min and then was added a solution of ethyl iodide (8,3 ml, 0.104 g mol) in tetrahydrofuran. The solution was stirred at -78oC for 1.5 h, and then cooled by adding dropwise a saturated solution of ammonium chloride at -78oC. were Then given the ability of the mixture to warm to room temperature, diluted with diethyl ether, washed first with diluted hydrochloric acid, then with water, saturated sodium bicarbonate solution, brine, and then dried to dryness and received 12,91 g of the crude product, which was chromatographically on a column of silica gel, elwira a mixture of 10% ethyl acetate/hexane, and received 3,23 g (25%) of 2-(3-pentyl)-N,N-diethylbenzamide in the form of a yellow oil.

Using the procedure described above in example 22A, the reaction between 2-(3-pentyl)-N,N-diethylbenzamide (3,05 g, 0,0115 mol), dissolved in tetrahydrofuran, and 10.5 ml of a 1.2 M solution of second-bushouse lithium salt was treated first with sulfur dioxide, and then the sodium salt of hydroxylaminosulphate and received of 1.97 g (yield 52%) of 2-amino-sulfonyl-6-(3-pentyl)-N, N-diethylbenzamide in the form of crystals pale yellow appearance, melting point 118-120oC (softening temperature 102oC) 1.84 g (0,0056 mol), which was cyclically heating at boiling under reflux in 22 ml of glacial acetic acid, and received 1.28 g (yield 70% ) diethylammonium salt of 4-(3-pentyl)-saccharin, the melting temperature of 107.5-109,5oC.

In the interaction of this salt (0,0037 mol) chlorocarbonylsulfenyl (0,74 ml, 0,0055 mol) in the presence of tetrabutylammonium bromide (116 mg, of 0.0004 mol) in 45 ml of toluene was received of 1.93 g of 2-phenylthiomethyl-4-(3-pentyl)-saccharin in the form of oil is pale-yellow, the interaction of which (1,93 g, 0,0037 mol) with chloride sulfuricum (0,59 ml, 0,0073 mol) in 37 ml of methylene chloride was obtained 1.2 g of 2-chloromethyl-4-(3-pentyl)-saccharin in the form of oil is pale yellow in color.

Examples 22D-22N. According to the method described in example 22A, replacing the used 2-methoxy-N, N-diethylbenzamide to the corresponding 2-R3-R4-substituted-N,N-diethylbenzamide, were obtained through the corresponding 2-phenyldimethylsilane subsequent 2-Gasometer-4-R3R4-substituted sa is alsharia in columns, entitled "TPL/Rast" and "Exit", shows the melting temperature, the solvent from which conducted recrystallization, and if these data were available. In all cases, the intermediate 2-phenyl-dimethylalanine immediately used in the next step without further characterization or purification.

Example 23. Using the procedure described in example 1, the reaction of saccharin (18.3 g, 0.1 mol) in 70 ml of 37% formalin in ethanol and received 3.58 g (yield 70%) 2-Oxymetazoline, the interaction of which (25 g, 0,117 mol) with tribromide phosphorus (63,3 g 0,234 mol) in diethyl ether was given to 29.8 g (92%) 2-bromoethylamine, melting point 155-157oC.

Example 24. To a solution of 6-nitrosourea (4 g, 0,0175 mol) in 240 ml of ethanol was added thallium ethylate (4.4 g, 0,0175 mol), the mixture was left to stand at room temperature for 1 h, cooled for 16 h, the precipitated precipitated solid is collected, dried and obtained 7.6 g (yield 100%) tallic salt of 6-nitrosourea. This product is suspended in 50 ml of dimethylformamide, and the mixture was treated with chlorocarbonylsulfenyl (of 3.07 g, 0,0194 mol), then was heated at ZoC for 5 h, left to stand at room temperature for 16 h, and then pouring remove salts of thallium. From the filtrate solvent was removed and the resulting solid pale yellow color homogenized with warm ethanol was again filtered, dried and obtained 4.6 g (yield 75%) of 6-nitro-2-phenyl-dimethylalanine, melting point 161-163oC. Using the procedure described above in example 17, were the interaction of the substance with chloride sulfuricum in methylene chloride and was obtained 3.7 g of 2-chloromethyl-6-nitrosourea.

Example 25A. A solution of 2-hydroxy-5-(1,1,3,3-TETRAMETHYLBUTYL)benzoic acid (49,8 g, 0,199 mol) in 200 ml of methanol was heated to 50oC, and then added to it dropwise 80 g of sulfuric acid, the rate of addition was such as to maintain the mixture at the boil. Then the mixture was heated under reflux for 11 hours, then cooled and distributed between water and ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, then brine, dried over sodium sulfate, evaporated to dryness and got to 48.6 g (yield 92%) of methyl ester of 2-hydroxy-5-(1,1,3,3-TETRAMETHYLBUTYL)benzoic acid.

This substance was dissolved in 250 ml of dimethylformamide and added to it first, 1,4-diazabicyclo [2,2,2] octane (40,4 g, 0.36 mol), and then dimethylthiocarbamate the Wali in a mixture of concentrated hydrochloric acid, water and ice and then extracted with ethyl acetate. The combined organic extracts were washed with diluted hydrochloric acid, then with sodium bicarbonate solution, brine, dried, evaporated to dryness and received 48,2 g (yield 76%) of methyl ester of 2-(N,N-dimethylthiocarbamate)-5-(1,1,3,3-TETRAMETHYLBUTYL)-benzoic acid, which was heated at 200oC for 15 h, then was cooled, dissolved in toluene, was chromatographically on a column of silica gel, elwira a mixture of ethyl acetate:toluene 1:9, and obtained 3.6 g (yield 14%) of the methyl ester of 2-(N,N-dimethyl-carbamido)-5-(1,1,3,3-Tetra-methylbutyl)-benzoic acid.

To a solution of this compound (0,025 mol) in 40 ml of methylene chloride was added with stirring, 80 ml of glacial acetic acid, and then 16 ml of water. The reaction mixture was cooled to 0oC and barbotirovany through her chlorine for 5 min, maintaining the temperature of the mixture from 5 to 24oC. Then the mixture was stirred for 30 min, concentrated in vacuo and the remaining solution was poured into ice-cold water. The mixture was extracted with ethyl acetate, the combined organic extracts were isolated product was obtained 6.8 g (yield 78%) of methyl ester of 2-chlorosulfonyl-5-(1,1,3,3-tetramethyl-butyl)benzoic acid.

the l of concentrated ammonium hydroxide. The resulting solution was stirred for 16 h, and then concentrated in vacuo, after which the concentrated solution was acidified to pH 3 with concentrated hydrochloric acid. The mixture was stirred for several hours, the separated solid was collected, washed with water, dried and obtained 9.0 g of 5-(1,1,3,3-TETRAMETHYLBUTYL)saccharin), melting point 213-215oC.

According to the method described in example 17, the reaction of saccharin (9.0 g, 0.30 mole) of thallium ethylate in ethanol, and then cooperated resulting salt of thallium with chlorocarbonylsulfenyl (3.33 g, 0,021 mol) in dimethylformamide and received USD 5.76 g (yield 66%) 2-phenylthiomethyl-5-(1,1,3,3-TETRAMETHYLBUTYL)saccharin, 3.3 grams (0,007 mol) which was treated 0,944 g chloride Sulfuryl in methylene chloride and was obtained 1 g (yield 41% ) 2 chloromethyl-5-(1,1,3,3-TETRAMETHYLBUTYL)saccharin.

Example 25B. Using the methodology described 25A, carried out the reaction of the ethyl ester of 2-hydroxy-6-methylbenzoic acid (15.5 g, 0,086 mol) of N,N-dimethylthiocarbamate (15.9 g, 0,129 mol) in the presence of 1,4-diazabicyclo[2.2.2]octane (19.3 g, 0,172 mol) in dimethylformamide and received 22.1 g (yield 96%) of ethyl ester of 2-(N,N-dimethylthiocarbamate)-6-methylbenzoic acid, chalance with silica gel and got the ethyl ester of 2-(N, N-dimethylcarbamate)-6-methylbenzoic acid in the form of oil red-brown color.

A solution of this ester (22,6 g, 0,0844 mol) in methylene chloride (170 ml) was treated with 340 ml of glacial acetic acid and 68 ml of water, cooling in a bath of dry ice/acetone, and then was barbotirovany through the reaction mixture for 10-15 minutes chlorine (gas). The reaction vessel was pumped out to remove excess chlorine and methylene chloride and the mixture was poured into water and divided the mixture between methylene chloride and water. The organic layer was dried, evaporated to dryness and obtained 19 g of ethyl ester of 2-chlorosulfonyl-6-methylbenzoic acid, the interaction of which (5 g, 0.019 mol) with concentrated ammonium hydroxide in tetrahydrofuran was received of 6.1 g (yield 67%) 4-methylcholine.

Using the procedure described in example 17, the product (10.1 g, 0,0512 mol) were transferred to a salt by reaction with thallium thallium ethylate (12.8 g, 0,0512 mol) in ethanol, and then in the interaction of salts of thallium with chlorocarbonylsulfenyl (6.7 g, 0,0427 mol) in dimethylformamide received 6.85 g (yield 50% ) 2 phenylthiomethyl-4-methylcholine.

The reaction of this compound (6.7 g, 0,021 mol) with chloride sulfuricum in methylene chloride was obtained 4.9 g (yield 95%) of 2-chloromethyl-4-methylsilicone quantities of pyridine was stirred for 24 h, and then evaporated to dryness in a vacuum. The residue was treated with methylene chloride to remove residual chloride tiomila and pyridine was again evaporated to dryness and received 87 g (yield 98%) of the corresponding acid chloride of bis-acid, with 44.8 g (0.18 mol) was dissolved in tetrahydrofuran and added dropwise to a solution of benzylamine (77,16 g to 0.72 mol) in tetrahydrofuran. The mixture was stirred at 40-45oC for 2 h, cooled, and precipitated precipitated solid was collected, washed with water. Dried and received 59 g (yield 84%) of N,N'-dibenzoylperoxide 3,3-dithiobisnitrobenzoic acid.

In the interaction of this compound (7.0 g, 0.018 mol) with chloride sulfuricum (of 10.25 g, 0,076 mol) in methylene chloride was obtained a mixture of 2-benzyl-2H-isothiazol-3-one and 5-chloro-2-benzyl-2H-isothiazol-3-one, which was mainly divided from each other by gomogenizirovannom in methylene chloride (which was dissolved solely the first connection). The insoluble substance was filtered and was chromatographically on a column of silica gel with methylene chloride. Thus, there was obtained 5-chloro-2-benzyl-2H-isothiazol-3-one, melting point 58-68oC.

A solution of this compound (10 g, 0,044 mol) in methylene chloride was cooled to 0o

To a solution of this compound (1.1 g, 0,0045 mol) in 8 ml of benzene was added 2-methoxyfuran (0.55 g, 0,0051 mol) and the solution was heated in a thick-walled bottle for reactions under pressure at 70oC for 1.5 h, and then cooled, the solid collected, washed with benzene, dried and obtained 2-benzyl-7-hydroxy-4-methoxybenzothiazole-3-one-1-oxide, melting point 235-237oC.

A mixture of this product (1.85 g, 0,006 mol), potassium carbonate (2,48 g, 0.018 mol) and methyl iodide (1.70 g, 0.012 mol) in acetone was heated under reflux for 1.5 h, then cooled and poured into water. Precipitated precipitated solid was isolated by filtration, washed with water, dried and received 1.70 g (yield 89%) of 2-benzyl-4,7-dimethoxybenzoate-C-he-1-oxide, 1.13 g (0,0035 mol) was oxidized in methylene chloride 3-chlormadinone acid (1,20 the camping 2-benzyl-4,7-dimethoxycoumarin (2,07 g, 0,0062 mol) moravcikova ammonium (1,37 g, 0.02 mol) and 1.5 g of catalyst (10% palladium on coal) in 80 ml of methanol was heated under reflux for 1 h, then was cooled, filtered, the filtrate is evaporated to dryness and got to 0.92 g (yield 57%) ammonium salt of 4,7-dimethoxycoumarin.

To this solution ammonium salt (1,11 g, 0,0042 mol) in dimethylformamide was added chloromethylthiazole (0,67 g, 0,0042 mol) and the solution was heated under reflux for 8 h, then the mixture was cooled and poured into ice-cold water. Separated solid was collected, washed with water, dried and obtained 0.50 g (yield 33%) 2-phenylthiomethyl-4,7-dimethoxycoumarin.

Carrying out the reaction between 2-phenylthiomethyl-4,7-dimethoxycoumarin (0.5 g, 0,0013 mol) and chloride sulfuricum in methylene chloride by the procedure described above in example 17, was given to 0.22 g (yield 58%) of 2-chloromethyl-4,7-dimethoxycoumarin.

Examples 26B and -26 C. Using a methodology similar to that described in example 26A, other derivatives of 2-chlorotriazine was prepared as follows.

Example 26B. In the interaction of 5-chloro-2-benzyl-2H-isothiazol-4-it (5.8 g, 0,024 mol) with 2-ethoxyphenol (3,76 g, 0,0335 mol) received 3,05 g (yield 40%) of 2-benzyl-4 ethoxy-7-oxybisethanol-C-he-is potassium (4,95 g, 0,0358 mol) in 125 ml of methyl ethyl ketone and 25 ml of dimethylformamide was obtained 7.0 g (yield 93%) of 2-benzyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]benzisothiazol-3-one-1-oxide, which was oxidized as described above, 3-chlormadinone acid in methylene chloride and was obtained 2-benzyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin. When dibenzylamine this compound (6.6 g, 0.16 mol) with arabinoxylan ammonia (3,34 g, 0,053 mol) in the presence of 6.4 g of catalyst (10% palladium on coal) in methanol was obtained ammonium salt of 4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin, and then carried out the reaction of this salt with chlorocarbonylsulfenyl (2.38 g, 0.015 mol) in 100 ml of dimethylformamide and received of 1.46 g (yield 21%) 2-phenylthiomethyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy] saccharin, melting point 73-75oC (from isopropanol). In the interaction of this product (1.4 g, 0,0029 mol) with chloride sulfuricum (0.4 g, 0,0029 mol) in methylene chloride was received of 1.16 g (yield 100% ) of 2-chloromethyl-4-ethoxy-7-[2-2(-methoxyethoxy)ethoxy]saccharin.

Example -26 C. When the interaction of 2-benzyl-7-hydroxy-4-methoxy-benzisothiazol-C-he-1-oxide (3.03 g, 0.01 mol) obtained in example 26A, with methyl 2-(2-methoxyethoxy)ethyl (2,01 g to 0.011 mol) in methyl ethyl ketone in the presence of potassium carbonate (2 g, 0.015 mol) poluchennoi acid (1.1 g, 0,0063 mol) in methylene chloride and was obtained 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin. When dibenzylamine of this product (0.25 g, 0,0006 mol) with arabinoxylan ammonia (0,13 g, 0,0021 mol) in the presence of 0.25 g of catalyst (10% palladium on coal) in methanol was obtained 0.21 g (yield 100%) of the ammonium salt of 4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin. The reaction of this ammonium salt (1.4 g, 0,004 mol) chlorocarbonylsulfenyl (0,63 g of 0.004 mol) in dimethylformamide was formed 2-phenylthio-methyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]-saccharin, the interaction of which with chloride sulfuricum in methylene chloride was received of 0.53 g (yield 35%) of 2-chloro-methyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin.

Example 27. A solution of 1.89 g (to 0.011 mol) Diethylaminoethanol sulfur (DAST) in 20 ml of methylene chloride was added to a suspension of 2-hydroxy-methylcholine (2,13 g, 0.01 mol) in 25 ml of methylene chloride, while maintaining the reaction mixture at a temperature of -78oC.

The reaction mixture was stirred at -78oC for 1 h, then was given the ability of the mixture to gradually warm to room temperature, stirred at this temperature for 16 h, then poured into ice-cold water. The organic layer was separated, washed in the of cetate and received 1.6 g (yield 74%) 2-hermeticaly, the melting temperature of 96-98oC.

Example 28A. To a solution of 4-methylcholine (0.5 g, 0,0025 mol) in tetrahydrofuran, cooled to -78oC in a bath of dry ice/acetone was added dropwise with stirring to 5.2 ml of 1.3 M solution terbutaline in tetrahydrofuran. The mixture was stirred at -78oC for 1 h, and then were treated for 1.5 h iodine stands (0.16 ml, 0,025 mol). The mixture was stirred for 1 h and 45 min, quickly cooled in 25 ml of 1 N hydrochloric acid, then the reaction mixture was added a base, an aqueous mixture was extracted with chloroform, and then acidified and extracted with ethyl acetate. The combined organic extracts washed with 10% sodium thiosulfate solution, then brine, dried over sodium sulfate, evaporated to dryness and received a product that, according to the spectrum of electron paramagnetic resonance (EPR), is a mixture containing 74% 4-acylcholine, and 21% 4,7-dimethylalanine.

Using the procedure described in example 17, spent the interaction of this crude product (0,47 g of 0.022 mol) chlorocarbonylsulfenyl (of 0.24 ml, 0,0028 mol) in toluene in the presence of tetrabutylammonium bromide, the product was chromatographically on column C and 20 fractions were obtained mixture of 0.07, containing mainly 4,7-dimethylfuran, which was rejected. After evaporation of the next 25 fractions were obtained and 0.37 g of 2-phenylthiomethyl-4-acylcholine, the interaction of which with chloride sulfuricum in methylene chloride was given to 0.29 g (yield 66%) of 2-chloromethyl-4-acylcholine.

Example 28B. Using the procedure described in example 28A, carried out the reaction of 4-methylcholine (10 g, 0,051 mol) with 86 ml of 1.18 M solution of sec-utility (0.10 mol) in tetrahydrofuran, the resulting solution was treated with iodine stands (4.5 ml 0,050 mol) and received 10,15 g (yield 89%) of 4-propylalanine, the interaction of which with chlorocarbonylsulfenyl (5,32 ml, 0,056 mol) in toluene in the presence of tetrabutylammonium bromide was formed 2-phenylthiomethyl-4-profilesharing (yield 65%) in the form of oil, then carried out the reaction of this substance (1.8 g, 0,0052 mol) with chloride sulfuricum (1.25 ml, to 0.016 mol) in methylene chloride and got to 0.94 g (yield 66%) of 2-chloro-methyl-4-propylalanine.

Example 29. Carried out the reaction between a substance (sample 0.07 g), obtained from the initial fractions during the chromatographic separation described in example 28A, and chloride sulfuricum (0.05 ml) in methylene chloride, the product was recrystallization from a mixture of cyclohexane uh is">

Examples 30A-30BK. Using a methodology similar to that described in example 4, substituting 2-chloromethyl-4-hariharan and sodium salt of 1-phenyl-tetrazole used there, in equimolar amount, respectively, of a suitable 2-halomethyl-4-R3-R4-substituted saccharin and the appropriate fragment of the LnR1received connection table.2. In the column entitled "X/base", the halogen contained in the 2-kilometerzahlen, and a base that was used to catalyze the reaction, i.e., or sodium or tallic salt LnR1reagent or added to the basic catalyst, i.e., potassium carbonate, triethylamine (TEA), ethyldiethanolamine (EDIPA) or sodium methylate. In the column entitled "Rast.", the above solvent used [DMF (dimethylformamide), THE (tetrahydrofuran), MDC (methylene chloride), MEK (methyl ethyl ketone or acetone] and in the column entitled "TPL/Rast. "given the melting point of the obtained substance and the solvent, which conducted the recrystallization. In table.2 and table.3-8 shows the following abbreviations for heterocyclic or other groups, R1one.

tetrazolyl, treas. triazolyl, Mor. morpholinyl, tadias. Tatlisu technique described in example 17 and substituting saccharin and methyl ester of 2-chloro-phenylthiourea acid used there, in equimolar amount, respectively, of a suitable 4-R3-R4-substituted saccharin and appropriate Cl-CHR2-S-R1the fragment was similarly obtained compounds are given in table.3, and in these compounds, n is 1, and L represents an-S-. In each case used tallic salt derivative of saccharin, and the reaction was carried out in dimethylformamide.

Example 32A. A solution of 2-(2,6-dichlorophenylthio)saccharin (0.28 g, 0,00067 mol) in 5 ml of methylene chloride was treated with stirring 3-chlormadinone acid (0.3 g, 0,0017 mol), then the mixture was stirred for 16 h, and then rapidly cooled 10% aqueous solution of sodium bisulfite. The reaction mixture was diluted with methylene chloride, salt was separated, the organic layer was washed successively with water, saturated sodium bicarbonate solution and a saturated solution of ammonium chloride, dried over sodium sulfate, evaporated to dryness, and the residue was chromatographically on a column of silica gel, elwira a mixture of methylene chloride:diethyl ether 10:1. Thus, there was obtained 0.1 g(yield 10%) 2-(-2,6-dichlorobenzenesulfonyl)saccharin, imaginal-sulfanilyl)saccharin (0.75 g, 0,0023 mol) was oxidized 3-chloro-adventurou acid (0.4 g, 0,0023 mol) in 50 ml of methylene chloride, and the product was recrystallization of a mixture of Acrylonitrile:ethanol 75:25 and got 2-(2-pyrimidinecarbonitrile)saccharin, the melting point of 225-227oC.

Example 33A. To a solution of 2-(5-mercapto-1,3,4-thiadiazole-2-altimeter)saccharin (0,345 g, 0.001 mol) and triethylamine (and 0.46 ml of 0.003 mol) in 2 ml of dimethylformamide was added the hydrochloride of 4-(2-chloroethyl)of the research (0,37 g, 0.002 mol). The reaction mixture was stirred at room temperature for 24 h, and then rapidly cooled, pouring into water, and extracted with ethyl acetate. The organic layer was washed with water, then brine, evaporated to dryness and the obtained yellow oil, which was transferred into chloroform and chromatographically on a column of silica gel, elwira with ethyl acetate. Thus was obtained 0,225 g (yield 49%) 2-(5-[2-(4-morpholinyl)-ethylthio]-1,3,4-thiadiazole-2-altimeter)saccharin, the melting point of 129-131oC.

Example 33B. Using the procedure described above in example 33A, carried out the reaction of 2-(5-mercapto-1,3,4-thiadiazole-2-altimeter)-saccharin (1,72 g of 0.005 mole) of the hydrochloride of 2-diethylaminoethylamine (1.44 g, 0.01 mol) in 10 ml of dimethylformamide in the presence of triethylamine (1,72 g 0,017 Melania 90,5-91,5oC (from ethyl acetate).

Example 33C. Using the method described in example 33A, carried out the reaction of 2-(5-mercapto-1,3,4-thiadiazol-2-altimeter)saccharin (0,69 g, 0.002 mol) of the hydrochloride of 1-(2-chloroethyl)piperidine (0.74 g, 0,004 mol) in 4 ml of dimethylformamide in the presence of 0.4 g of triethylamine was obtained 0.55 g (yield 60% ) 2-/5-[2-(1-piperidinyl)ethylthio]-1,3,4-thiadiazole-2-altimeter)saccharin, melting point 100,0-101,0oC (from ethyl acetate).

Example D. Using the method described in example 33A, carried out the reaction of 2-(5-mercapto-1,3,4-thiadiazole-2-altimeter)saccharin with the hydrochloride of 2-chloroethylamine in dimethylformamide in the presence of triethylamine and received 2-/5-[2-(diethylamino)ethylthio]-1,3,4-thiadiazole-2-altimeter/saccharin, melting point 93,0-94,5oC (from a mixture of cyclohexane:ethyl acetate).

Example 33E. Using the method described in example 33A, carried out the reaction of 2-(5-mercapto-1,3,4-thiadiazole-2-altimeter)saccharin (1,72 g of 0.005 mol) of the hydrochloride of 1-(2-chloroethyl)piperidine (1.84 g, 0.01 mol) in 10 ml of dimethylformamide in the presence of 2.4 ml of triethylamine and got a 1.08 g (yield 47% ) 2-/5-[2-1-/-piperidinylidene] -2-thioxo-1,3,4-thiadiazoline-3-ylmethyl)saccharin, melting point 89,0-92,0oC, in which 1,3,4-thiadiazole-2-ultimate-tetrazol-5-altimeter]saccharin (0,44 g, 0,0013 mol) in 10 ml of acetone was added chromic acid, obtained from the dilute sulfuric acid dihydrate sodium bichromate (agent Johnson), maintaining the reaction mixture at 0oC as long as the solution does not become permanently orange-brown color. The mixture was stirred at 0oC for 1 h, then at room temperature for 6 h, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, then brine, dried and evaporated to dryness, and the residue was chromatographically on a column of silica gel, elwira a mixture of 5-15% methanol - methylene chloride, and got to 0.29 g (yield 63%) 2-[1-/2-carboxymethyl/-1H-tetrazol 5-altimeter]saccharin, melting point 173-175oC.

Example 35. A solution of 2-[1-(3-AMINOPHENYL)-1H-tetrazol-5-altimeter]saccharin (1 g, 0,0026 mol) and succinic acid anhydride (0.26 g, 0,0026 mol) in 50 ml of dioxane was stirred at room temperature for 2 hours, heated under reflux for 6 h, then stirred at room temperature for two days, then was heated to boiling and added in a few hours a small amount of succinic acid anhydride as long as the analysis method Tonk who was gladly, was poured into diluted hydrochloric acid and ice water, and the solid deposited precipitates were collected, dried, recrystallization from a mixture of ethanol: acetonitrile 50:50 was obtained 0.5 g (yield 39%) 2-[1-/3-succinylamino/-1H-tetrazol-5-altimeter]saccharin, melting point 197-199oC.

Example 36. 5-nitro-2-/1-phenyl-1H-tetrazol-5-altimeter/saccharin (1 g, 0,0024 mol) was restored in 150 ml of tetrahydrofuran under a hydrogen pressure of 3.6 at in the presence of 3 spoons of Raney Nickel (washed before using tetrahydrofuran). At the end of recovery (approximately 5 h), the reaction mixture was filtered, the filter layer was washed with tetrahydrofuran and the filtrate is evaporated to dryness and received a cloudy yellow oil, which was transferred to ethanol and filtered. The product separated upon cooling was collected and received 0.4 g (yield 43%) of 5-amino-2-/1-phenyl-1H-tetrazol-5-altimeter/saccharin in the form of yellow crystals.

Example 37. A suspension of 5-amino-2-/1-phenyl-1H-tetrazol-5-altimeter/saccharin (0.4 g) in 25 ml of acetonitrile was treated with the acid chloride of acetic acid (between 6.08 g, 0.001 mol), the mixture was heated under reflux for 30 min, then was added a drop of acid chloride of acetic acid and which has tographically on a column of silica gel, elwira a mixture of ethylene chloride and ethyl acetate (95:5), and received 200 mg (43%) of 5-acetylamino-2-(1-phenyl-1H-tetrazol-5-altimeter)saccharin.

Example 38. The solution of sodium salt of 1-phenyl-5-mercaptotetrazole (5 g, of 0.025 mol) in 50 ml of methyl ethyl ketone was added dropwise with stirring to the heated solution of 3-chloro-1-jumprope in 300 ml of methyl ethyl ketone. The mixture was stirred at 40oC for 6 h, then left to stand at room temperature for two days, after which the reaction mixture is evaporated to dryness in a vacuum. The residue was dissolved in methylene chloride, the solution washed with water, and the aqueous extract was again extracted with methylene chloride. The combined organic extracts were dried, evaporated to dryness and the obtained yellow oil, which was chromatographically on a column of silica gel, elwira methylene chloride. Thus there was obtained 3.6 g (yield 75%) of 1-phenyl-5-/3-chlorpropyl/-1H-tetrazole in the form of oil pale yellow color. (In another experience of the same substance was obtained in the form of a solid crystalline substance of white color, melting point 33-34oC.)

This product (6.5 g, 0.014 mol) was dissolved in 100 ml of methyl ethyl ketone was added thereto sodium salt of thiophenol (1.7 g, 0.014 mol), a mixture of n is th methylene. The combined organic extracts were dried, evaporated to dryness and the obtained oil is pale yellow in color, which was chromatographically on a column of silica gel, elwira methylene chloride, and received of 3.85 g (yield 86%) of 1-phenyl-5-[3-(phenylthio)propylthio]-1H-tetrazole. (In another experience of the same substance was obtained in the form of white crystals with a melting point 57-59oC).

A solution of this product (3.8 g, 0.012 mol) in 100 ml of carbon tetrachloride was treated with N-chlorosuccinimide (1.5 g, 0.012 mol), the mixture was left to stand at room temperature for 1 h, then filtered, the filtrate is evaporated to dryness and obtained 4.3 g of 1-phenyl-5-[3-chloro-3-(phenylthio)propylthio]-1H-tetrazole.

This product (0.012 mol) and tallic salt of saccharin (4,58 g, 0.12 mol) dissolved in 75 ml of dimethylformamide, was heated at 50oC for 3 h and then left to stand at room temperature for 2 h, then was filtered and washed filter dimethylformamide. The combined filtrate was poured into water, the mixture was extracted with methylene chloride, the combined organic extracts were washed with brine, concentrated to dryness and the obtained oil is pale yellow in color, which was chromatographically on a column of silica gel, SS="ptx2">

This product (1 g, 0.002 mol) was dissolved in methylene chloride and oxidized 3-chlormadinone acid (0.34 g, 0.002 mol) using the procedure described in example 32A. Thus, there was obtained 0.8 g (yield 76%) of 2-[1-phenylsulfinyl-3-/1-phenyl-1H-tetrazol-5-iltil]propyl saccharin.

This product (1.6 g, of 0.003 mol) was heated at 120oC for 45 min in 130 ml of dimethyl ether of diethylene glycol, the mixture is then cooled and poured into water. Separated solid was collected, dried and dissolved in methylene chloride and the solution was chromatographically on a column of silica gel, elwira methylene chloride. Thus, there were obtained 1.2 g of TRANS-2-[3-/1-phenyl-1H-tetrazol-5-ylthio-/1-/propenyl] saccharin, melting point 191-193oC.

Example 39. Other 2-unsubstituted sacharine formula II, used as intermediates in the synthesis of compounds of formula I can be obtained as follows.

The reaction of 3-triftorperasin acid chloride tiomila leads to the formation of acid chloride of 3-triftorperasin acid, the interaction of which with diethylamino get 3-trifluoromethyl-N,N-diethylbenzamide. Using the procedure described in example 22A, carried out the reaction of this soy is the sodium salt of hydroxylaminosulphate and get 3-trifluoromethyl-2-aminosulfonyl-N,N-diethylbenzamide, when heated in glacial acetic acid is formed 7-trifluoromethyl-saccharin.

Similarly, the reaction of 4-cyclohexylbenzene acid chloride tiomila leads to the formation of acid chloride of 4-cyclohexylbenzene acid, the interaction of which with diethylamino receive a 4-cyclohexyl-N,N-diethylbenzamide. Using the procedure described in example 22A, carried out the reaction of this compound with second-butyllithium with subsequent interaction of the resulting lithium salt with sulfur dioxide and then with a sodium salt of hydroxylaminosulphate and receive a 4-cyclohexyl-2-amino-sulfonyl-N,N-diethylbenzamide, which when heated in glacial acetic acid is formed 6-cyclohexylaniline.

In the interaction of 6-aminocoumarin with the acid chloride of methansulfonate or chloride triftormetilfullerenov in methylene chloride in the presence of pyridine are formed, respectively, 6-methylsulfonylamino or 6-triftormetilfullerenov.

Diazotization of 6-aminocoumarin nitrous acid, and decomposing the resulting diazonium salts in the presence of cyanide copper (2) chloride or copper (2) and sulfur dioxide, chloride or copper (2) and alkaline salt of methylmercaptan ilmestymisajan or 6-cryptomaterial her. In the interaction of 6-chlorotriphenylmethane in situ with ammonia or methanesulfonamido are formed respectively 6-aminosulphonylphenyl and 6-methanesulfonylaminoethyl. In the oxidation of 6-methylthiopurine and 6-triftormetilfosfinov two molar equivalents of 3-chlormadinone acid receive, respectively, 6-methylsulfonylamino and 6-triftormetilfosfinov.

Hydrolysis of 6-cyanoalanine by heating with an aqueous solution of sodium hydroxide leads to the formation of saccharin-6-carboxylic acid. In the interaction of 6-cyanoaniline with a catalytic amount of sulfuric acid, which is carried out in ethanol solution when heated, get ethyl ester saccharin-6-carboxylic acid, the recovery of which the lithium borohydride is formed 6-oksimetildifenil. The oxidation of this compound with pyridine complex: chromium trioxide (2: 1) (reagent Collin) in methylene chloride receive 6-formicary, reductive amination of which ammonia and cyanoborohydride sodium leads to the formation of 6-aminoethylamino.

Reaction of each 2-unsubstituted saccharin, thus obtained, with chlorocarbonylsulfenyl in the presence of potassium tert-butylate and brough the scrap in methylene chloride leads to the formation of R4-2-unsubstituted sharenow formula I, below, where m and n are in each case equal to 0, R1is Cl, and R2and R3both represent hydrogen:

Example R4< / BR>
39A 7-CF3< / BR>
39B 6-cyclohexyl

39C 6-CH3SO2NH

39D 6-CF3SO2NH

39E 6-CN

39F 6-NH2SO2< / BR>
39G 6-CH3SO2NHSO2< / BR>
39H 6-CH3SO2< / BR>
39I 6-CF3SO2< / BR>
39J 6-HOOC

39K 6-HOCH2< / BR>
39 (L MODEL 6-OHC

39M 6-NH2CH2< / BR>
Example 40. Using the procedure described in example 4, substituting 2-chloromethyl-4-hariharan and sodium salt of 1-phenyltetrazole used there, in equimolar amount, respectively, of a suitable 2-chloromethyl-R4-saccharin, described above, and a suitable LnR1fragment, obtained compounds are given in table.4, in which R3in each case, unless otherwise noted, is hydrogen.

In connection 40N (a) R3is isopropyl. This compound is obtained by reaction of N, N-diethylcarbamoyl with the lithium salt of 2-bromo-5-methoxy-isopropylbenzene; interaction obtained (yield 79%) of N,N-diethyl-2-isopropyl-4-methoxybenzamide with second-butyllithium and subsequent interaction with duobus hanil-4-methoxy-6-isopropylbenzene in glacial acetic acid; the response obtained (yield 10%) diethylammonium salt of 4-isopropyl-6-methoxycoumarin with chlorocarbonylsulfenyl; 6-methoxycoumarin chloride sulfuricum and the response obtained (yield 88%) of 2-chloromethyl-4-isopropyl-6-methoxycoumarin with a sodium salt of 1-phenyl-5-mercaptotetrazole.

The results of biological tests.

Measurement of the inhibition constants, Kicomplex HLE inhibitor described Cha in Biochem. Pharmacol. 24, 2177-2185 (1975) for constants a truly reversible inhibition related to competitive inhibitors. However, the compounds of this invention do not form a truly reversible inhibitor complexes, and are consumed to some extent by the enzyme. Therefore, instead of measuring the Kicalculated K*iwhich is defined as the ratio of the koff/konthe rate of reactivation of the enzyme to the speed of inactivation of the enzyme. Measured values of koffand konand then calculate the K*i< / BR>
The rate of inactivation of the enzymatic activity (kon) is determined for the tested compounds, by measuring the dependence of the enzymatic activity of aliquots of the corresponding enzyme from time after addition of test compounds. Building dependency log fer is iraena as kobsln2/t1/2where t1/2represents the time required for the enzyme activity decreased by 50% Then the rate of inactivation is

konkoff/[J]

where [J] is the concentration of inhibitory compounds.

Similarly, define a constant reactivation, koffand then calculate the inhibition constant K*i/as

K*i= koff/kon< / BR>
The values obtained for konand K*ifor the specific derivatives of substituted saccharin are given in table. 5, these connections are marked with the numbers of examples in which the above receipt.

Examples 41A-41L. Additional examples of compounds of formula I where m is 0 and R2, R3and R4each represents a hydrogen were obtained from 2-(chloromethyl)saccharin [or, if specified, from 2-(methyl bromide)saccharin] in each example, the corresponding R1-Ln-H (except as noted examples), and these compounds are given in table.6.

Comments to the table.6:

A-Alkylation of 1-(2-chloroethyl)piperidine in dimethylformamide at room temperature 2-[/5-mercapto-1,3,4-thiadiazole-2-yl/thiomethyl]saccharin, obtained in turn by kondensatsionnom, exit 38% (melting point 204-206,5oC of 1,2-dichloroethane, yield 38%).

C From 2-(methyl bromide)saccharin, using as solvent ethanol, and as the Foundation of the sodium methylate.

D From 2-(methyl bromide)saccharin, using as solvent tetrahydrofuran.

E Oxidation of the corresponding sulfide.

G reconnection example 41F.

H Substitution of hydroxyl in the compound of example 41G on chlorine.

I Using as solvent acetonitrile, and as the Foundation of methyltriethoxysilane.

J Using as solvent dimethylformamide, and as the Foundation of the thallium ethylate.

L Using as solvent methyl ethyl ketone, and as the Foundation of potassium carbonate.

*Hydrochloric salt.

Examples 42A-Bu. Additional examples of compounds of formula I, where m is equal to 0 (with the exception of example 42B, where m is equal to 1), R2and R4represent hydrogen, and R3is isopropyl, were obtained from 2-chloromethyl-4-isopropylaniline (example 22E above) (or, if specified, from 2-methyl bromide-4-isopropylaniline) and in each example the corresponding R1-Ln
A: Using as solvent dimethylformamide, and as the Foundation of the triethylamine.

B: three-stage method: in the first stage of condensation tallic salt 4-isopropylaniline obtained from 4-isopropylaniline and ethylate thallium, 1-phenyl-5-(3-chloro-3-phenylthio-propyl)tetrazolo in dimethylformamide with a yield of 77% in the second stage of oxidation of the obtained 2[3-(1-phenyltetrazol-5-yl)-1-(phenylthio)propyl] -4-isopropylaniline metacompetencies acid with a yield of 87% and the third stage heat allocation received 2[3-(1-phenyltetrazol-5-yl)-1-(phenylthio)propyl]-4-isopropylaniline, yield 59%

C: the two-Stage method: first stage condensation of 2-(chloro-methyl)-4-isopropylaniline with mertiolate sodium, the second stage of oxidation of the obtained 2-(methylthio)-4-isopropylaniline.

D: Reaction with 1,1,3-triakistetrahedron-1,2,5-thiadiazole and bromide by tetrabutylammonium, using as solvent toluene.

E: Using as solvent dimethylformamide, and as the Foundation of sodium hydride.

F: Using as solvent methyl ethyl ketone, and as the Foundation of potassium carbonate.*Hydrochloric salt.

H: the two-Stage method: first with the release of 83% in the second stage, the condensation of the resulting 2-[(5-mercapto-1,3,4-thiadiazole-2-yl)-thiomethyl] -4-isopropylaniline hydrochloride with 4-(2-chloroethyl)the research in dimethylformamide using as the basis of triethylamine, exit 87%*Hydrochloric salt.

I: Using as solvent dichloromethane, and as the Foundation of databaseconnect.

J: Using as solvent acetonitrile, and as the Foundation of methyltriethoxysilane.

K: Alkylation of 2-[(5-mercapto-1,3,4-thiadiazole-2-yl)thiomethyl]-4-isopropylaniline (example 42H) the hydrochloride of 1-(2-chloroethyl)-piperidine using as a solvent of dimethylformamide, and as the basis of triethylamine.

L: Using as solvent ethanol, and as the Foundation of the sodium methylate.

M: Alkylation of 2-[(5-mercapto-1,3,4-thiadiazole-2-yl)thiomethyl]-4-isopropylaniline (example 42H) hydrochloride (2-chloroethyl)-dimethylamine in dimethylformamide using as the basis of triethylamine.*Salt of maleic acid.

N: Using as solvent ethanol, and as the Foundation of the sodium methylate.*Salt of maleic acid.

O: Using as solvent ethanol, and as the Foundation of the triethylamine. *Salt of maleic acid.

Q: the two-Stage method: in the first stage, the condensation of 2-(chloromethyl)-4-isopropylaniline with sodium azide in when the of storytale benzene or a mixture of benzene-dimethylformamide or benzene-tetrahydrofuran in the second stage cycloaddition obtain 2-(azidomethyl)-4-isopropylaniline with the corresponding acetylene, in this example, dimethyl ether acetylenedicarbonic acid, the reaction is carried out in the same solvent with or without heating.

T: the two-Stage method: in the first stage, the condensation of 2-(chloro-methyl)-4-isopropylaniline and 2-chloro-4-(4-thiomorpholine)phenol in acetonitrile using as the basis of methyltriethoxysilane, the yield of 74.7 per cent in the second stage of oxidation of the obtained 2-[2-chloro-4-(4-thiomorpholine)phenoxymethyl] -4-isopropyl-saccharin meta-chlormadinone acid with a yield of 38.5%

X: Using as solvent dimethylformamide, and as the Foundation of cesium carbonate.

AV: the two-Stage method: in the first stage, the condensation of 2-(chloromethyl)-4-isopropyl-saccharin and 2-benzyl-6-oxoferin in the methyl-ethylketone using as the base, potassium carbonate, yield 43% in the second stage dibenzylamine catalytic hydrogenation in the presence of palladium deposited on charcoal, in methanol containing muravlensky ammonium, exit 26%

AX: Using as solvent methyl ethyl ketone, and as the Foundation of the 0-utilitiesand potassium.

BB: the Oxidation of the compound of example 42AV one molar equivalent of meta-chlorbenzoyl acid.

BC: Okislyenii.

BJ: Using as solvent acetonitrile, and as the Foundation of sodium hydride.

BO: Using as solvent dimethylformamide, and as the Foundation of potassium carbonate.

BQ: the two-Stage method: in the first stage, the condensation of 2-(chloromethyl)-4-isopropyl-saccharin and benzyl ether of 2,6-dichloro-Z-oksibenzoynoy acid in dimethylformamide using as the basis of sodium hydride, in a second stage, dibenzylamine catalytic hydrogenation in the presence of palladium deposited on charcoal, in methanol containing acetic acid.

BT: Using as solvent tetrahydrofuran, and as the Foundation of the triethylamine.

Examples 43A-BV. Obtain 2-chloromethyl-4-isopropyl-6-methoxycoumarin.

To a solution of 300 ml of N,N,N',N'-tetramethylethylenediamine (TMEDA, 1,99 mole) in 4 l of anhydrous diethyl ether was added 1550 ml of sec-BuLi (1.3 M) and cooled the mixture in a nitrogen atmosphere -70oC. To this solution was added dropwise over 30 min a solution of 2-isopropyl-4-methoxy-N,N-diethylbenzamide (454 g, 1.82 mol) in 300 ml of anhydrous diethyl ether. Adding the temperature of the mixture maintained -60oC or below. After the addition the mixture was stirred at -70ooC. Then, to the mixture was added for 20 min at high pressure nitrogen through the cannula a solution of 200 g of SO2in 200 ml of dried diethyl ether, pre-cooled to -40oC.

Adding temperature of the reaction mixture is maintained below -40oC. Almost immediately stood out powdery precipitate white - abilityshipping. After addition the cooling bath was removed and the mixture was stirred at room temperature for 2 h, then was cooled to -5oC. Then, to the mixture was added dropwise over 15 min with continuous stirring 190 ml chloride Sulfuryl (2.36 mol), keeping the temperature below 10oC. the Mixture was stirred for 30 min at 0-5oC, insoluble white precipitate was filtered and washed with 2 l of anhydrous diethyl ether. After removal of the solvent at atmospheric pressure obtained chloride sulfonyl (dark crude oil) was dissolved in 1.4 l of tetrahydrofuran. The solution was cooled to -10oC and added to it the parts 540 ml of concentrated aqueous ammonia (28%) for 15 minutes adding the temperature was maintained 15oC or below. After paramasivan the roadways oil, which was dissolved in 6.0 liters of water and acidified 3 NHCl to pH 1. The obtained solid pale yellow color was filtered off, washed with 800 ml of water, dried in vacuum at 60oC for 18 h, then was recrystallization from a mixture of 800 ml of ethyl acetate and 3 l of hexane and received 429 l (yield 72%) of 2-amino-sulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide, melting point 122-125oC.

The solution of this diethylbenzamide (429,6 g, 1,31 mol) in 1.5 l of acetic acid was heated under reflux for 20 h, and then cooled to room temperature. The solvent was removed in vacuum. The oily residue was dissolved in 6 l of water and brought the pH of the solution 6NHCl to 1. The crude product was filtered off, washed with 2 l of water, dried in vacuum at 60oC for 18 h, recrystallization from a mixture of ethyl acetate/hexane and obtained 303 g (yield 91%) of 4-isopropyl-6-methoxycoumarin, melting point 188oC.

To a suspension of paraformaldehyde (24 g, 0.08 mol) and chloro-trimethylsilane (86,4 g, 1.6 mol) in 200 ml of 1,2-dichloroethane was added 0.8 ml of anhydrous tin tetrachloride and the resulting solution was stirred on a steam bath for 1 h Then transparent to the solution was added 4-isopropyl-6-methoxycoumarin (51,4 g, 0.2 mol) and the mixture was heated pool cue layer was separated, washed with 50 ml of 2N sodium hydroxide solution, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by crystallization from a mixture of ethyl acetate/hexane and obtained 57 g (yield 87%) of 2-chloromethyl-4-isopropyl-6-methoxycoumarin, melting point 151oC.

The examples 43A-CA compounds in which m is 0 (except for the connection example 43F, where m is equal to 1), R1is hydrogen, R3represents isopropyl, and R4is 6-metaxylem were obtained from 2-chloromethyl-4-isopropyl-6-methoxycoumarin and in each example the corresponding R1-Ln-H (except as noted examples), and these compounds are given in table.8.

Notes to table 8:

A: Using as solvent dimethylformamide and applying the sodium salt of 1-phenyltetrazol-5-thiol.

B: Using as solvent dichloromethane, and as the Foundation of the triethylamine.

C: Using as solvent dimethylformamide, and as the Foundation of the sodium methylate.

D: the two-Stage method: in the first stage, the condensation of 2-(chloro-methyl)-4-isopropyl-6-methoxycoumarin and of sodium azide in benzene or toluene in the presence of catalytic choicestvsomali-Kharin with the corresponding acetylene, in this example, phenylsulfonylacetate, the reaction is carried out in the same solvent with or without heating.

E: Using as solvent methyl ethyl ketone, and as the Foundation of potassium carbonate.*Hydrochloric salt.

F: three-stage pic about: in the first stage condensation tallic salt of 4-isopropyl-6-methoxycoumarin obtained from 4-isopropyl-6-methoxycoumarin and ethylate thallium, 1-phenyl-5-3-chloro-(3-phenylthiomethyl)-tetrazolo in dimethylformamide to yield 57% in the second stage of oxidation of the obtained 2[-3-(1-phenyltetrazol-yl)-1-(phenylthio)propyl] -4-isopropyl-6-methoxycoumarin meta-chlormadinone acid with a yield of 60.5% at the third stage of thermal selection is obtained 2-[3-(1-phenyltetrazol-5-yl)-1-(phenylthio)-propyl] -4-isopropyl-6-methoxycoumarin, yield 75%

I: Using as solvent dimethylformamide, and as the Foundation of sodium hydride.

K: Using as solvent acetonitrile, and as the Foundation of methyltriethoxysilane. *A mixture of geometric isomers (1:1).

AD: Using as solvent methyl ethyl ketone and applying the potassium salt of Z-phenyl-2-thioxo-2,3-dihydro-1,3,4-thiadiazole-5-thiol.

AH: COI is UYa as solvent acetone and applying potassium thiocyanate.

AW: Using as solvent dimethylformamide, and as the Foundation of diisopropylethylamine.

BB: Using as solvent acetonitrile, and as the Foundation of diisopropylethylamine.

BF: Using as solvent tetrahydrofuran, and as the Foundation of tert-butyl potassium.

BH: Using as solvent a mixture of acetonitrile and dimethylformamide, and as the Foundation of methyltriethoxysilane.

Example 44. A solution of 2-chloromethyl-4-ethyl-5,7-dimethoxycoumarin (example 22L, 0.4 g) and sodium salt of 1-phenyltetrazol-5-thiol (0.28 g) in 3 ml of dimethylformamide was heated at 110oC for 2 h, and then poured into water. After recrystallization of the resulting solid from a mixture of ethanol-water was obtained 2-(1-phenyltetrazol-yl)thiomethyl-4-ethyl-5,7-dimethoxycoumarin (0,44 g, yield 74%), melting point 162-164oC.

Example 45.

A. a Solution of 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide (example 26A, 1.5 g) and 1-methoxy-Z-trimethylsilylacetamide (d 0,885, 1,30 ml) was heated at 65oC during the night in the tube to work under pressure. Then were added to 0.74 ml of 1-methoxy-Z-trimethylsilylacetamide, and again heated solution in the tube at 65and out of volatile substances, and in conclusion, repeated addition and desorption at high vacuum. The oil is Golden-amber color was added dichloromethane, in a few hours this oil hardened. Received of 1.16 g (yield 68%) of 2-benzyl-6-hydroxy-1,2-benzisothiazol-(1H)-one-1-oxide.

B. a Solution of 2-benzyl-6-hydroxy-1,2-benzisothiazol-(1H)-3-one-1-oxide (3.75 g) 75-100 ml of methanol was added dropwise at room temperature to a solution of the magnesium salt of ortho-monongalia acid (8,14 g) 70-100 ml of water. For dissolving the resulting precipitate was added 200-250 ml of methanol and was stirred solution at room temperature over night. Then was added the same volume of water and the mixture was extracted with dichloromethane. The dichloromethane extract was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and drove away from it dichloromethane. A solution of the obtained solid (4,17 g) in dichloromethane was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, drove him dichloromethane and got a 3.87 g (yield 98%) of 2-benzyl-6-oxoferin.

C. a Mixture of 2-benzyl-6-oxoferin (0,86 g), 2-bromacil-2-methoxyethanol ether (d 1,347, 0.45 ml), potassium carbonate (1, 4 g), methyl ethyl ketone (50 ml) and dimetil. The resulting solid was collected, washed with water, dried and got to 0.92 g (yield 78%) 2 benzyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin, melting point 86-88oC.

D. a Mixture of 2-benzyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin (2,05 g) methanol (75-100 ml), moravcikova ammonium (1.10 g) and 1.0 g of catalyst (10% palladium on coal) was heated under reflux for 40 min, then cooled and filtered. From the filtrate drove volatile matter and received the ammonium salt of 6-[2-(2-methoxyethoxy)ethoxy]saccharin mixture which chlorocarbonylsulfenyl (0,79 g) and dimethylformamide was heated at 10oC for 8 h, then stirred at room temperature overnight and poured into 600 ml of water, cooled with ice. The mixture of water and saturated aqueous sodium chloride, dried over sodium sulfate and drove away from it dichloromethane. The residue (1.70 g) was chromatographically on a column of silica gel, elwira first with a mixture of dichloromethane-acetone (98:1), and then a mixture of dichloromethane-acetone (99:1), and obtained 0.96 g (yield 45%) of 2-phenylthiomethyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin.

E. To a solution of 0.96 g of 2-phenylthiomethyl-6-[2-(2-methoxyethoxy)-ethoxy]saccharin in dichloromethane was added dropwise at AC the mortar drove volatile compounds. Then added dichloromethane and again from solution drove volatile compounds. To the residue was added hexane and the mixture was stirred at room temperature overnight. The resulting solid white were collected, dried and got to 0.69 g (yield 89%) of 2-chloromethyl-6-[2-(2-methoxyethoxy)ethoxy] saccharin, melting point 113-115oC.

F. According to the method described in example 44, carried out the condensation of 2-chloromethyl-6-[2-(2-methoxyethoxy)ethoxy] saccharin (0.34 g) and sodium salt of 1-phenyltetrazol-5-thiol (0,19 g) in methyl ethyl ketone at 60oC. the Product (470 mg) was chromatographically on a column of silica gel using first dichloromethane and then a mixture of dichloromethane acetone (up to 97:3), and received 390 mg (yield 82%) of 2-(1-phenyltetrazol-5-yl)thiomethyl-6-[2-/2 - methoxyethoxy/ethoxy]saccharin in the form of butter.

Example 46. A solution of 2-(5-phenyl-1-tetrazolyl)thiomethyl-4-acylcholine (example 30AE, 0,020 g) and sodium salt of 1-phenyltetrazol-5-thiol (0,0026 g) in 1 ml of dimethylformamide was heated at 100oC for three days and then poured into water. After recrystallization of the solid substance from a mixture of ethanol - water received 0,012 g (yield 60%) of 2-(4-phenyl-5-thioxo-1-tetrazolyl)methyl-4-acylcholine, melting point 127-129oC.

,2 g) was aminosulfonyl sulfur dioxide, oxyamino-0-acid 5.6 g and got to 7.4 g (yield 63%) of 2-aminosulfonyl-4,5-dimethoxy-6-propyl-N, N-dimethylbenzamide, which was cyclically with a quantitative yield of 4-propyl-5,6-dimethoxycoumarin, when phenyldimethylsilane which chloromethyl-persulfide (1,42 ml) was received 4,07 g 2-phenylthiomethyl-4-propyl-5,6-dimethoxycoumarin, and then spent the reaction 3,59 g of this substance with a 2.12 ml chloride Sulfuryl and received 2,84 g (yield 97%) of 2-chloromethyl-4-propyl-5,6-dimethoxycoumarin.

B. following the procedure described in example 44, carried out the condensation of 2-chloromethyl-4-propyl-5,6-dimethoxycoumarin (0.6 g) and sodium salt of 1-phenyltetrazol-5-thiol (0.36 g) in 5 ml of dimethylformamide, the product was purified on a column of silica gel, elwira a mixture of ethyl acetate hexane (6:7), then triturated with hexane and was obtained 0.65 g (yield 76%) of 2-(phenyltetrazol-5-yl)thiomethyl-4-propyl-5,6-dimethoxycoumarin, melting point 145-146oC.

Example 48.

A. following the procedure described in example 22A was obtained 2-aminosulfonyl-4,5-dimethoxy-6-isopropyl-N, N-dimethylbenzamide (10,75 g) and cyclically his 4-isopropyl-5,6-dimethoxycoumarin (the melting point of 186-188oC from a mixture of diethyl ether in hexane), which (5 g) was phenyldimethylsilane chlorocarbonylsulfenyl (2,48 ml) and received 4,07 g 2-phenylthiomethyl-4-isopropyl-5,6-dimethoxycoumarin, the reaction with chlorine (yield 85%) melting point 117-119oC from a mixture of ethyl acetate hexane.

B. following the procedure described in example 44, carried out the condensation of 2-chloromethyl-4-isopropyl-5,6-dimethoxycoumarin (1,46 g) and sodium salt of 1-phenyltetrazol-5-thiol (0,92 g) in dimethylformamide (5 ml), the product has recrystallization from a mixture of ethanol and water was received of 1.05 g (yield 51%) of 2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-5,6-dimethoxycoumarin, melting point 69-71oC.

Example 49.

A. ethyl Mercaptan (43,9 g) was added under stirring to a suspension of aluminum chloride (62,74 g) in 500 ml of chloroform at 0oC. To the resulting solution was added over 30 min a solution of 4-isopropyl-6-methoxycoumarin (20,0 g) in 550 ml of chloroform. The resulting solution was heated at 60oC for 3-4 h, and then poured into ice water, acidified with hydrochloric acid. The resulting solid was filtered, washed with water, dried and received an 18.4 g (yield 97%) of 4-isopropyl 6-oxoferin.

C. By the method described in example 21, were phenyldimethylsilane 4-isopropyl-6-oxoferin (0,004 mol) chlorocarbonylsulfenyl (0,61 ml) and was obtained 0.32 g (yield 1%) 2-phenylthiomethyl-4-isopropyl-6-oxoferin, in which chloride sulfuricum (0.73 g) was obtained 2-chloromethyl-4-simera 44, carried out the condensation of 2-chloromethyl-4-isopropyl-6-oxoferin (0.3 g) and sodium salt of 1-phenyltetrazol-5-thiol (0.2 g) in 10 ml of dimethylformamide, the resulting product was chromatographically on evaporative column of silica gel, elwira a mixture of hexane in ethyl acetate (7:3) and received 0,3 (yield 67%) 2-/1-phenyltetrazol-1-yl/thiomethyl/4-isopropyl-6-oxoferin, melting point 188,5-189,5oC.

Example 50.

A. a Solution of 5.8 g of 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide (example 26A) and 3.76 g of 2-toxiferine in 40 ml of benzene was heated to 50oC. To the solidified reaction mixture was added 30 ml of benzene and heated it with a reflux condenser for 15 min, then at 70oC for 45 min, then cooled in the refrigerator overnight. The resulting solid pale yellow color was collected, washed with cold benzene, dried and received 3,05 g (yield 40%) of 2-benzyl-4-ethoxy-7-hydroxy-1,2-benzisothiazol-(1H/-3-one-1-oxide.

B. To a solution of 2-benzyl-4-ethoxy-7-hydroxy-1,2-benzisothiazol-(1H)-3-one-1-oxide (7.9 g) in 500 ml of dichloromethane and 31 ml of methanol was added with stirring meta-chlormadinone acid (8.6 g). Stirring is continued for several hours, then was added meta-chlormadinone acid (8.6 DOI. Solid (2,33 g) generated by repeated washing solution with water, collected, melting point 196 to 199oC. was also Collected solid (4,10 g) released during the washing dichloromethane layer with a saturated aqueous solution of sodium chloride, melting point 196 to 199oC. it Was found that both solids are 2-benzyl-4-ethoxy-7-oxoferin.

C. a Mixture of 2-benzyl-4-ethoxy-7-oxoferin (1.0 g), allyl bromide (0.36 g), potassium carbonate (0,62 g) and methyl ethyl ketone (20 ml) was heated at 80oC for 1 h and Then was added allyl bromide (0.36 g) and continued heating at 80oC for 1.5 h the Mixture was cooled and poured into water, cooled with ice (500 ml). The solid is collected and received at 1.08 g (yield 96% ) of 2-benzyl-4-ethoxy-7-allyloxycarbonyl, melting point 148-149oC.

D. a Mixture of 2-benzyl-4-ethoxy-7-allyloxycarbonyl (0.25 g) and triglyme was heated at 200oC for 20 min, thin layer chromatography were analyzed by the depth of the reaction was then heated at 200oC for 20 min, stirred overnight and poured into ice-cold water. The resulting sticky solid brown was dissolved in di is hatom sodium and drove away from it dichloromethane. The residue (0.29 grams) was chromatographically on a column of silica gel, elwira dichloromethane and a mixture of dichloromethane: acetone (up to 99:1), and received 90 mg (yield 36%) of 2-benzyl-4-ethoxy-6-allyl-7-oxoferin, the mass spectrum which showed the presence of the molecular ion with a mass 373.

E. a Mixture of 2-benzyl-4-ethoxy-6-allyl-7-oxoferin (2,45 g), potassium carbonate (2.76 g) and methyl iodide (1.84 g) in acetone was heated under stirring and at a temperature of 50oC for 2 h, then poured with stirring into ice-cold water (500 ml). The resulting sticky residue crystallized during the night. The solid was isolated and obtained 2.35 g (yield 92%) of 2-benzyl-4-ethoxy-6-allyl-7-methoxycoumarin, melting point 92-94oC.

F. According to the method described in part D of example 45, 2-benzyl-4-ethoxy-6-allyl-7-methoxycoumarin (2.35 g) was simultaneously dibenzylamine and was first made in the presence of moravcikova ammonium (1.51 g) and 1.25 g of catalyst (10% palladium on coal) 70 100 ml of methanol and received 1,94 g of ammonium salt of 4-ethoxy-6-propyl-7-methoxycoumarin, have phenyldimethylsilane in dimethylformamide by chlorocarbonylsulfenyl (0.95 g) and the product (yellow oil, 2.67 g) was purified by chromatographytandem on a column of silica gel, elwira with the ptx2">

G. According to the method described in part E of example 45, carried out the reaction of 2 phenylthiomethyl-4-ethoxy-6-propyl-7-methoxycoumarin (0.85 grams) with chloride sulfuricum (0,30 g) in dichloromethane, the product was purified hexane and got to 0.62 g (yield 89% ) of 2-chloromethyl-4-ethoxy-6-propyl-7-methoxycoumarin, melting point 131-133oC.

H. Using the method described in part F of example 45, carried out the condensation of 2-chloromethyl-4-ethoxy-6-propyl-7-methoxy-saccharin (0,62 g) and sodium salt of 1-phenyl-tetrazol-5-thiol (first used 0.36g, and after 3.5 h was added a small amount of salt, the total reaction time of 8 h oily product was extracted with dichloromethane, purified first by chromatographytandem on a column of silica gel, elwira dichloromethane, and then crystallization of the resulting oil (0,62 g, 71% yield) from ethanol and obtained 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-6-propyl-7-methoxycoumarin, melting point 110-111oC.

Example 51.

A. To a solution of 2.2 g of 4-ethyl-5,7-dimethoxycoumarin (example 22L) in 100 ml of tetrahydrofuran was added dropwise under stirring at a temperature of -78oC for 1 h with second-utility (0,87 M in cyclohexane, 20.4 ml). Stirring was continued at -78oC for 1 h, and the ability of the mixture to warm to room temperature and cooled it in water. To the mixture was added an aqueous solution of sodium hydroxide (0.5% of the 200 ml), then washed her 200 ml of ethyl acetate, acidified with concentrated hydrochloric acid and was extracted with 200 ml of ethyl acetate. The extract was washed with an aqueous solution of sodium thiosulfate (10% 50 ml) and saturated aqueous sodium chloride (50 ml), dried over sodium sulfate, drove him ethyl acetate and obtained 0.73 g (yield 32%) of 4-ethyl-5,7-dimethoxy-6-methylcholine.

B. Using the methodology described in example 21, were phenyldimethylsilane 4-ethyl-5,7-dimethoxy-6-methylcholine (0.6 g) chlorocarbonylsulfenyl (0,24 ml) and received 2-phenylthiomethyl-4-ethyl-5,7-dimethoxy-6-metalshark, the interaction of which with chloride sulfuricum was obtained 0.16 g (yield 22%) of 2-chloromethyl-4-ethyl-5,7-dimethoxy-6-methylcholine.

C. By the procedure described in example 44, carried out the condensation of 2-chloromethyl-4-ethyl-5,7-dimethoxy-6-methylcholine (0.17 g) and sodium salt of 1-phenyltetrazol-5-thiol (0,084 g) in 4 ml of dimethylformamide, the product was purified by chromatographytandem on evaporative column of silica gel, elwira a mixture of hexane in ethyl acetate (75: 25), and was obtained 0.15 g (yield 76%) of 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethyl-5,7-dimethoxy-6-methylcholine, melting point 44-46oC, then cooled and poured into water, cooled with ice (400 ml). The mixture was stirred overnight, the solid is collected and received of 0.58 g (yield 86%), 2-benzyl-4-ethoxy-7-(tert-butoxy-carbonyloxy)saccharin.

B. By the method described in example 45, spent two consecutive synthesegasbetriebe 2-benzyl-4-ethoxy-7-(tert-butoxycarbonylmethyl)saccharin (0.5 g, 6.5 g) arabinoxylan ammonia (0.25 g, 3,66 g) in the presence of catalyst (10% palladium on coal, 0.25 g and 2 g) in methanol with the formation of the ammonium salt of 4-ethoxy-7-(tert-butoxycarbonylmethyl)saccharin (0,44 g, 5,63 g); and then phenyldimethylsilane this salt chlorocarbonylsulfenyl (0.2 g, of 2.38 g) in dimethylformamide, followed by purification of the combined product (0,46 g, 6.42 per g) by chromatography on a column of silica gel (dichloromethane eluate mixture of dichloromethane-acetone 98:2) and received by 1.9 g (yield 40% ) 2-phenylthiomethyl-4-ethoxy-7-(tert-butoxycarbonylmethyl)saccharin.

C. By the method described in part E of example 45, carried out the reaction of 2-phenylthiomethyl-4-ethoxy-7-(tert-butoxycarbonylmethyl)-saccharin (1.9 grams) and chloride Sulfuryl (0.54 g) in dichloromethane p is XI)saccharin, melting point 117-119oC.

D. According to the method described in part F of example 45, carried out the condensation of 2-chloromethyl-4-ethoxy-7-(tertbutoxycarbonyl)-saccharin (1.42 g) and sodium salt of 1-phenyltetrazol-5-thiol (first 0,70 g, and after 6 h the reaction was added a small amount of salt, the total reaction time 8 h), the product (1.20 g) was extracted by dichloromethane, part of it (0,42 g) was purified by chromatography on a column of silica gel, elwira a mixture of dichloromethane-acetone (98: 2) and received 300 mg (71% yield) 2-/1-phenyltetrazol-5-yl(thiomethyl-4-ethoxy-7-)tert-butoxycarbonylmethyl/saccharin, melting point 110-112oC.

Example 53. A solution of 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-(tertbutoxycarbonyl)saccharin (example 52, of 0.47 g) in 5-10 ml triperoxonane acid and 5-10 dichloromethane was stirred at room temperature for 2 h, and then drove away from him, volatile substances, and then another three desirerable from it dichloromethane, and then drove away from him acetone. A solution of the oily residue in acetone (1 ml) was added to 100 ml of ice water containing concentrated hydrochloric acid (1 ml). The resulting solid was collected, washed with water and dried (0.34 g). The solution of this substance VI received 70 mg (yield 17%) of 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-carboxymethylcysteine, melting point 187-189oC.

Example 54.

A. 1,2-dimethoxy-4-isopropylbenzene- (31 g) bromisovali N-bromosuccinimide on kieselguhr at tetrachloride methane according to the method Hisatoshi and others (Bulletin of the Chemical Society of Japan, I. 32, S. 591-593, 1989) to obtain 5-bromo-1,2-dimethoxy-4-isopropylbenzene, when litvinovii which n-butyllithium in diethyl ether was formed 5-Li, 1,2-di-methoxy-4-isopropylbenzene, then this compound was diethylaminocarbonylmethyl in the same solvent and obtained 15.2 g of 2-isopropyl-4,5-dimethoxy-N,N-diethylbenzamide in the form of a viscous oil.

B. By the method described in example 43, spent amidosulfuron this 2-isopropyl-4,5-dimethoxy-N,N-sulfuricum and concentrated ammonia 4.5 g 2 isopropyl-4,5-di-methoxy-6-aminosulfonyl-N,N-diethylbenzamide, melting point 181-182oC, when the cyclization in which acetic acid was obtained 2.86 g of 4-isopropyl-6,7-dimethoxycoumarin, melting point 210-212oC.

C. To a solution of 4-isopropyl-6,7-dimethoxycoumarin (0.5 g) in 3 ml of dimethylformamide was added 0.5 ml of diisopropylethylamine, was heated at 80oC for 16 h, diluted with ethyl acetate, washed with an aqueous solution of sodium carbonate, 3N hydrochloric Ki the current was purified by chromatographytandem on evaporative column of silica gel using as eluent dichloromethane and was obtained 0.35 g of 2-phenylthiomethyl-4-isopropyl-6,7-dimethoxycoumarin, then this substance were chlorinated chloride sulfuricum (0.1 ml) in dichloromethane (3 ml), the product was purified by rubbing with hexane and was obtained 0.3 g of 2-chloromethyl-4-isopropyl-6,7-dimethoxycoumarin. condensation of 2 chloromethyl-4-isopropyl-6,7-dimethoxycoumarin.

D. Using the methodology described in example 44, carried out the condensation of 2-chloromethyl-4-isopropyl-6,7-dimethoxycoumarin (0,0095 g) and sodium salt of 1-phenyltetrazol-5-thiol (0,120 g) in 2 ml of acetonitrile, the product was purified by crystallization from ethanol and obtained 0,099 g (yield 70%) of 2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-6,7-dimethoxy-6-methylcholine, melting point 169-171oC.

Example 55.

A. According to the methods described in parts D and E of example 45, spent dibenzylamine 2-benzyl-4-ethoxy-7-oxoferin (part B of example 50) arabinoxylan ammonia in the presence of a catalyst (palladium on coal) in methanol and received ammonium salt of 4-ethoxy-7-oxoferin, which was phenyldimethylsilane chlorocarbonylsulfenyl in dimethylformamide to 2-phenylthiomethyl-4-ethoxy-7-oxoferin, and then carried out the reaction of this compound with 4-ethoxy-7-oxishare.

B. By the method described in part F of example 45, carried out the condensation of 2-chloromethyl-4-ethoxy-7-oxishare from ethanol and obtained 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-oxoferin, melting point 178-180oC.

Example 56. A mixture of 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-hydroxy-saccharin (example 55, 0.5 g), the acid chloride dimethylcarbinol acid (0,14 ml, 0.16 g), diazabicyclo (0.27 g) and N,N-dimethylacetamide (20 ml) was heated at 80oC for 4-5 h, then cooled and poured with stirring into ice-cold water (400 ml). The resulting solid was chromatographically on a column of silica gel, elwira dichloromethane and a mixture of dichloromethane acetone 98: 2, and got the first 2-(4-phenyl-5-thioxo-1-tetrazolyl)methyl-4-ethoxy-7-dimethylaminocarbonylmethyl (melting point 172-173oC after recrystallization from ethanol), and then 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-dimethylaminocarbonylmethyl (melting point 145-146oC after homogenization in diethyl ether).

Example 57. 2-(1-phenyltetrazol-5-ID)thiomethyl-4-isopropyl-5,6-dimethoxycoumarin (0,48 g) was added under stirring and the temperature at 0oC to a solution of aluminum chloride (0.4 g) and ethyl mercaptan (0.15 ml) in 3 ml of chloroform. At the end of the addition the mixture was stirred at room temperature for 18 hours Then the reaction mixture was passed through silica gel, elwira a mixture of ethyl acetate geekstogo oil; the structure of this compound was confirmed methods13With NMR and proton magnetic resonance data of mass-spektrometricheskogo analysis and method nuclear amplification. The latter method showed 19% of the signal gain of protons metoxygroup and 10% of the signal amplification of the C-7 proton.

Example 58. (The overall composition for tablets). Ingredients wt.

Connection examples 41-57 32-62

Dezintegriruetsja substance 28-36

Binder 10-20

Lubricating substance 0,1-0,5

Other fillers 2-5

Notes. Dezintegriruetsja substance may be represented by various starches. A binder can be represented by different cellulose. Grease is a talc, silica and magnesium stearate.

Example 59. Ingredients mg/tablet:

The compound of example 57 150

Lactose, monohydrate 100

Hydroxypropylcellulose 50

Polyvinylpyrrolidone 20

Magnesium stearate 2

Example 60. Ingredients mg/tablet:

The compound of example 50 140

The rest of the ingredients are the same as those in example 59.

The results of biological tests.

In the study of inhibition of elastase using the elastase Leone from 0,024 nM (example 43 AL) to 1000 nM (example 42 (D).

1. A derivative of 2-substituted saccharin General formula I

< / BR>
where L is-O-, -S-, -SO - or-SO2-;

m and n are 0 or 1;

R1phenyl, substituted 1-[4-(lower alkyl)-piperazine-1-yl]-carbonyl, 4-morpholinylcarbonyl, formyl, (lower alkoxy)-carbonyl, 4-teamorganization or S-dioxide, hydroxy-(lower alkyl), halogenated lower alkyl, 4-morpholinyl-(lower alkyl)-aminocarbonyl, 4-morpholinyl-(lower alkoxy)-carbonyl, 1-[4-(lower alkyl)-piperazine-1-yl)-sulfonium, 4-morpholinyl-(lower alkoxyl), di-(lower alkyl)-amino-(lower alkyl)-aminosulfonyl or N-(lower alkyl)-derived, (lower alkyl)-sulphonium, 4,5-dihydrooxazolo-2-yl, (lower alkyl)-tetrazol-5-yl, 4-morpholinylcarbonyl, nitrophenyl-athropos, carboxyla or di-(lower alkyl)-fosforom, or is any specified group in combination with the substitution of the phenyl by halogen, lower alkoxyl or nitrogroup, or a heterocycle selected from pyridazin-3-yl, 4-pyrone-3-yl, quinoline-8-yl, 1,3,4-oxadiazol-2-yl, coumarin-7-yl, saccharin-6-yl, imidazol-1-yl, thiazol-2-yl, 2-thioxo-2,3-dihydro-1,3,4-oxadiazol-3-yl, 1,2,5-thiadiazole-3-yl, 2-thioxo-2,3-dihydro-1,3,4-thiadiazole-3-yl, 2 thioxo-2,3-dihydro-1,3,4-thiadiazole-5-yl, 1,2,3-triazo the ILA, pyridyl, 1,1,3-triakistetrahedron-1,2,5-thiadiazole-2-yl, 6,7-dihydro-1H-1,2,4 - triazolo-[3,4-b] [1,3]thiazin-3-yl, 2,5-dioxopiperidin-1-yl, 3-indolyl, oxazol-2-yl, thiazol-4-yl, 2,3-dihydro-2-oxo-5-phenyl-1,3,4-thiadiazole-3-yl, 2,3-dihydro-2-oxo-5-phenyl-1,3,4-oxadiazol-3-yl, 6-oxo-1,2-dihydro-1,2,4-triazine-1-yl, 1,2,3-triazine-1-yl and 1-indolyl, or specified a heterocycle substituted on any available nitrogen atom by lower alkyl, hydroxy-(lower alkyl), 2-, 3 - or 4-pyridinyl, (lower alkoxy)-carbonyl or phenyl, or said heterocycle substituted on any available carbon atom by lower alkyl, cycloalkylation, (lower alkyl)-tigraphy, 1-piperidinyl-(lower alkyl)-tigraphy, (lower alkoxy)-carbonyl, cyano, hydroxy-(lower alkyl), phenylsulfonyl, halogen, carboxyla or its salt with an alkali metal, fullam, trifluoromethyl, 2-benzothiazolyl, (lower alkyl)-sulphonium, aminocarbonyl, benzyl, 4-morpholinyl, pyridinyl, pyrazinium, (lower alkoxy)-carbonyl-(lower alkyl), 1-piperidinylcarbonyl, benzyloxypropionic, hydroxyl, benzoyl, or benzoyl, substituted lower alkoxyl or halogen, or phenyl, or phenyl substituted lower alkoxyl, trifluoromethyl, (lower alkoxy)-p is-tetrazolyl), 5-oxo-1-tetrazolyl, 5-thioxo-1-tetrazolyl, 2-(1,3,4-thiadiazolyl) or 1,2,3-triazole-1-yl, substituted on any available carbon atom of the di-(lower alkyl)-amino-(lower alkyl), 4-morpholinyl-(lower alkyl)-amino group, cyano, 1-piperidinyl-(lower alkyl), phenylsulfonyl, toluensulfonyl, tri-(lower alkyl)-Sillam, carboxyla or its salt with an alkali metal, trifluoromethyl, (lower alkyl)-sulphonium, piridinium, di-(lower alkyl)-aminosulfonyl, 1-piperidinylcarbonyl, 4-morpholinyl-(lower alkyl) or phenyl, substituted (lower alkoxy)-carbonyl, or when R4is carboxy-(lower alkoxyl), (lower alkoxy)-carbonyl-(lower alkoxyl) or di-(lower alkyl)-aminocarbonylmethyl, the heterocycle is a 1-phenyltetrazol-5-yl, or, when L is-O-, and n is 1, R1- cycloheptatrien-2-yl, or when L is-S-, and n is 1, R1cyano-or (lower alkoxy)-thiocarbonyl, or, when L is-SO2-, n is 1, R1lower alkyl or trifluoromethyl;

R2hydrogen;

R3hydrogen, primary or secondary lower alkyl or lower alkoxyl;

R4hydrogen or 1 to 3 substituent selected from lower alkyl, hydoxyl, lower and is of IMT-(lower alkoxyl) or di-(lower alkyl)-aminocarbonylmethyl, provided that (1) when n is 0, R1can only be a heterocycle, and CHR2can only be linked to a ring nitrogen atom of the radical R1and (2) when m is 0, n is 1, L is-O-, -S - or-SO2-, and R2R3and R4is hydrogen, R1may not be substituted by phenyl.

2. Connection on p. 1, where L represents-O - or-S-, m is 0, n is 0 or 1, and R2the hydrogen.

3. Connection on p. 1, where R3hydrogen, methyl, ethyl, propyl, isopropyl, sec-butyl, methoxy, ethoxyl or isopropoxy, and R4is hydrogen, 5-(1,1,3,3-TETRAMETHYLBUTYL), 6-hydroxy, 7-hydroxy, 5-methoxy, 6-methoxy, 7-methoxy, 5,6-dimethoxy, 5,7-dimethoxy, 6,7-dimethoxy, 7 carboxymethoxy, 7-(tert-butoxycarbonyl)methoxy, 7-dimethylaminocarbonylmethyl, 6-propyl-7-methoxy, 5,7-dimethoxy-6-methyl or 5-hydroxy-6-methoxy.

4. Connection on p. 3, where L represents-O-, n is 1 and R1substituted phenyl chosen from 2-formyl-4-nitrophenyl, 2-oxymethyl-4-nitrophenyl, 2-chloromethyl-4-nitrophenyl, 4-chloromethyl-2-nitrophenyl, 4-(4-nitrophenylazo)phenyl, 2,4-dichloro-3-(4-methyl-1-piperazinylcarbonyl)phenyl, 4-[(4-methylpiperazin-1-yl)carbonyl]phenyl, 2,4-dichloro-6-(4-morpholinylcarbonyl)phenyl, 2-chloro-4-(4-morpholinylcarbonyl)phenyl, 2-methoxycarbonyl-5-methoxyphenyl, 2-ftphome)phenyl, 4,6-debtor-4-(4-morpholinylcarbonyl)phenyl, 4,5-debtor-4-(4-morpholinylcarbonyl)phenyl, 4-fluoro-2-(4-morpholinylcarbonyl)phenyl, 2,5-debtor-2-(4-morpholinylcarbonyl)phenyl, 3-[2-(4-morpholinyl)ethylaminomethyl] phenyl, 2,4-dichloro-3-[2-(4-morpholinyl)etoxycarbonyl] phenyl, 3-[2-(4-morpholinyl)ethoxy] phenyl, 3-{ 2-[(dimethylamino)ethyl]methylaminomethyl}phenyl, 2,4-dichloro-4-carboxyphenyl, 3-[2-(4-morpholinyl)etoxycarbonyl]phenyl, 2,4-dichloro-3-[2-(4-morpholinyl)ethylaminomethyl]phenyl, 4-(4-morpholinylcarbonyl)-3-triptoreline, 2.5-debtor-4-(4-morpholinylcarbonyl)phenyl, 2,6-dichloro-4-(4,5-dihydrooxazolo-2-yl(phenyl), 2,6-dichloro-4-(2-methyltetrazol-5-yl)phenyl, 3,5-debtor-4-(4-morpholinylcarbonyl)phenyl, 3,5-debtor-4-(4-morpholinylcarbonyl)phenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,4-dichloro-3-[2-(4-morpholinyl)etoxycarbonyl] phenyl, 2-diethylphosphonate, 2.5-debtor-4-(4-methyl-1-piperazinylcarbonyl)phenyl, 3-[(4-methylpiperazin-1-yl)sulfonyl]phenyl, 2,6-debtor-4-(4-methyl-1-piperazinylcarbonyl)phenyl or 2,3,5-Cryptor-4-(4-morpholinylcarbonyl)phenyl.

5. Connection on p. 4, where R1phenyl substituted by fluorine and 4-morpholinylcarbonyl.

6. Connection on p. 5, where R1- 2,3,5-Cryptor-4-(4-morpholinylcarbonyl)phenyl, R3isopropyl, and Rcycle, selected from 5,7-dichlorohydrin-8-yl, 2-methyl-4-pyrone-3-yl, 6-oxymethyl-4-pyrone-3-yl, 4,5-dichloropyridazin-3-yl, 2-ethyl-4-pyrone-3-yl, 3-anilkumar-7-yl, 4-anilkumar-7-yl, 6-chloro-4-triptorelin-7-yl, 4-methylcoumarin-7-yl, 3-(benzothiazol-2-yl)coumarin-7-yl, saccharin-6-yl, 4-(4-morpholinyl)-1,2,5-thiadiazole-3-yl, 4-ethoxycarbonylmethoxy-5-yl, 2,5-dioxopiperidin-1-yl, 2-methyl-4,5-di(oxymethyl)-3-pyridyl, 5-methoxycarbonylamino-3-yl, 1-methyl-2-ethoxycarbonylmethyl-3-yl, 2-phenyl-5-methylthiazole-4-yl or 2-methyl-5-phenylthiazol-4-yl.

8. Connection on p. 3, where L is-S-, n is 1 and R1a heterocycle or substituted heterocycle selected from 5-(2-diethylaminoethyl)-1,3,4-thiadiazole-2-yl, 5-[2-(4-morpholinyl)ethylamino] -1,3,4-thiadiazole-2-yl, 5-[2-(4-morpholinyl)ethyl] -1,3,4-thiadiazole-2-yl, 5-[2-(1-piperidinyl)ethyl] -1,3,4-thiadiazole-2-yl, 5-phenyl-1,3,4-oxadiazol-2-yl, 4-(ethoxycarbonylmethyl)thiazole-L-yl, 5-(2-furyl)-1,3,4-oxadiazole 2-yl, 5-benzyl-1,3,4-oxadiazol-2-yl, 5-hydroxy-6-methyl-6,7-dihydro-1H-1,2,4-triazolo[3,4-b] [1,3]triazine-3-yl, 5-(3-pyridyl)-1,3,4-oxadiazol-2-yl, 5-(4-triptoreline)-1,3,4-oxadiazol-2-yl, 5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl, 5-(4-pyridyl)-1,3,4-oxadiazol-2-yl, 5-(pyrazinyl)-1,3,4-oxadiazol-2-yl, 5-(2-pyridyl)-1,3,4-thiadiazole-2-yl, 5-(3-furyl)-1,3,4-oxadiazol-3-yl, 5-(2-pyridyl)-1,3,4-oxadiazol-2-yl, 3-phenyl-2-thioxo-2,3-dihydro-1,3,4-thiadiazole-5-yl, 5-(3,5-acid)-1,3,4-oxadiazol-2-yl, 5-(4,5-acid)-1,3,4-oxadiazol-2-yl, 4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine-3-yl, 5-(4-pentyloxide)-1,3,4-oxadiazol-2-yl, 5-{4-[2-(2-methoxyethoxy)ethoxy]phenyl}-1,3,4-oxadiazol-2-yl, 5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl, 5-(2,5-acid)-1,3,4-oxadiazol-2-yl, 5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl or 5-phenyloxazol-2-yl.

9. Connection on p. 3, where n 0, and R1a heterocycle or substituted heterocycle selected from 4,5-dicyanoimidazole-1-yl, 1,1,3-triakistetrahedron-1,2,5-thiadiazole-2-yl, 4,5-di(methoxycarbonyl)-1,2,3-triazine-1-yl, 5-phenylsulfonyl-1,2,3-triazole-1-yl, 4-(trimethylsilyl)-5-phenylsulfonyl-1,2,3-triazole-1-yl, 4-carboxy-1,2,3-triazole-1-yl, 4-phenylsulfonyl-1,2,3-triazine-1-yl, 4-ethylsulfonyl-5-isopropyl-1,2,3-triazine-1-yl, 4-isopropyl-5-ethylsulfonyl-1,2,3-triazine-1-yl, 4,5-di(aminocarbonyl)-1,2,3-triazine-1-yl, 4,5-dicarboxy-1,2,3-triazine-1-yl, 4-(trimethylsilyl)-5-dimethylaminomethyl-1,2,3-triazole-1-yl, 4-trimethylsilyl-1,2,3-triazole-1-yl, 4-phenylsulfonyl-5-trimethylsilyl-1,2,3-triazole-1-yl, 2-benzoyl-4,5-dibromomethane-1-yl, 2-thioxo-2,3-dihydro-1,3,4-oxadiazol-3-yl, 2-thioxo-2,3-dihydro-5-(2-pyridyl)-1,3,4-tiade the-triazole-1-yl, 4,5-dicyano-1,2,3-triazole-2-yl, 4,5-di(tert-butylsulfonyl)-1,2,3-triazole-1-yl, 4,5-di(1-piperidinylcarbonyl)-1,2,3-triazole-1-yl, 4,5-di(trifluoromethyl)-1,2,3-triazole-1-yl, 4,5-di(1-piperidinylcarbonyl)-1,2,3-triazole-2-yl, 3-benzyloxy-4,5-dihydro-5-oxo-1,2,4-oxadiazol-4-yl, 1,2,5-thiadiazole-3-yl, 2-(4-methoxybenzoyl)indol-1-yl or 2-methyl-3-(2,6-dichlorobenzoyl)indol-1-yl.

10. The pharmaceutical composition exhibiting inhibitory activity against elastase, containing an effective amount of the active ingredient on the basis of the derived saccharin and pharmaceutically acceptable additives, characterized in that as a function of saccharin it contains a compound of formula I under item 1.

11. The composition according to p. 10, characterized in that it contains as a particular derived saccharin compound according to any one of paragraphs.2 9.

 

Same patents:

The invention relates to racemic mixtures and (S)-4-[(2-benzothiazolyl)methylamino]--[(3,4-differience)methyl]-1-piperazineethanol, which can be represented by formula

< / BR>
and its pharmaceutically acceptable acid additive salts (salts of acid incorporation)

The invention relates to new derivatives of sulfamethoxypyrazine and herbicides containing them as active ingredients

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

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

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

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

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

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

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

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

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The invention relates to novel condensed heterocyclic compounds or their salts

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective

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The invention relates to new 2-sharonlee heterocyclic carboxylates, inhibiting the enzymatic activity of proteolytic enzymes, containing compositions, to a method of their use for the treatment of diseases associated with degeneration of the tissues, and to a method of production thereof
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