Omega-amides of n-arylsulfonyl-amino acids

 

(57) Abstract:

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

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

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

moreover, in formulas IIc and IId, R8means H or halogen, R9means H, or R3means -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)about-N(R4)-R5and R9has the above values, means the integer 2 and R4and R5together with the ring amino group form a 4-7-membered ring, in which one atom wait-CH=CH-. The compounds I are inhibitors of matrix metalloprotease and can be used in medicine. 3 C.p. f-crystals, 3 tables.

The invention relates to omega-Amida N-arylsulfonamides, how they acquire and use them as medicines.

In applications EP 0606046, WO 95/35276 and WO 96/27583 described arylsulfonamides acids and their action as inhibitors of matrix metalloproteinases. Special arylsulfonamides acids serve as intermediates for obtaining thrombin inhibitors (EP 0468231) and inhibitors alsoreported (EP 0305947). In the application EP 0757037 also described the effect of derivative sulfonylamino as inhibitors of metalloproteinases.

When searching for active compounds for the treatment of diseases of the connective tissues, it was shown that proposed according to the invention sulphonilecarbomide acids are strong inhibitors of matrix metalloproteinases. Particular importance is attached to the braking stromelysin (MMP-3) and neutrophil collagenase (MMP-8), since both enzymes are involved in the degradation of proteoglycans as important components of cartilage tissue (A. J. Fosang, etc. J. Clin. Invest., 98 (1996), 2292-2299). Equal to the Pnom destruction and construction components of the matrix. For example, MMP-1 (collagenase-1) performs a vital function because it is involved in the breakdown of natural collagen, in particular, where are the morphogenetic changes. Medical biologically active substances, which, although able to inhibit MMP-3 and MMP-8, but remain inactive with respect to MMP-1, thus are preferred. Especially preferred from the standpoint of human health or animal may be the biologically active substance, which, along with moderate inhibition of MMP-3 and -8 does not have or has only a weak effect on MMP-1. Therefore, the invention relates to a compound of the formula I

and/or a stereoisomeric form of the compounds of formula I and/or physiologically acceptable salts of the compounds of formula I, and R' means

1. phenyl,

2. phenyl, which one - or twofold substituted

2.1 (C1-C6)-alkyl, a linear, cyclic or branched,

2.2 hydroxy-group,

2.3 (C1-C6)-alkyl-C(O)-O-,

2.4 (C1-C6)-alkyl-O-,

2.5 (C1-C6)-alkyl-O- (C1-C4)-alkyl-O-,

2.6 halogen,

2.7-CF3

2.12 methylenecyclopropane,

2.13 R4-(R5)N-C(O)-

2.14 R4-(R5)N - or

2.15 a heterocycle of the following groups:

isoxazolidine, morpholine, isothiazolin, thiomorpholine, pyrazolidine, imidazolidine, piperazine, azetidine, pyrrole, pyrrolin, pyrrolidine, pyridine, azepine, piperidine, oxazole, isoxazol, imidazole, pyrazole, thiazole, isothiazol, diazepin, thiomorpholine, pyrimidine and piratin, which is unsubstituted or substituted with the substituents described with 2.1 through 2.14, or

3. heteroaromatic group, of the following from 3.1 to 3.15 groups, which is unsubstituted or substituted as described in 2.1 through 2.14,

3.1 pyrrol,

3.2 pyrazole,

3.3 imidazole,

3.4 triazole,

3.5 thiophene,

3.6 thiazole,

3.7 oxazol,

3.8 isoxazol,

3.9 pyridine,

3.10 pyrimidine,

3.11 indole,

3.12 benzothiophen,

3.13 benzimidazole,

3.14 benzoxazol or

3.15 benzothiazole,

R2, R4and R5are the same or different and signify

1. a hydrogen atom,

2. (C1-C6)-alkyl-,

3. BUT-C(O)-(C1-C6)-alkyl-,

4. the AET integer null, 1 or 2, or

5. picolyl or

6. R4and R5together with the ring amino group form a 4-7-membered ring, in which, if necessary, one of the carbon atoms replaced by-O-, -S - or-NH-,

R3means

1. -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen atom to which they are bound, form a residue of formula IIA, IIb or IIE

moreover, in formulas IIA, IIb and IIE

q means the integer zero, 1 or 2 and

r is the integer zero or 1,

Z denotes the carbon atom, nitrogen, oxygen, or sulfur, or a covalent bond, and

R8means a hydrogen atom or values described for R1under 2.1 to 2.14,

2. -(C1-C4)-alkyl-C(O)-Y

where Y represents the formula IIC or IId

moreover, in formulas IIC and IId

R8means a hydrogen atom or has the meaning set forth for R1under 2.1 to 2.14 and

R9means 2.1 hydrogen atom

2.2 (C1-C6)-alkyl-,

2.3 BUT-C(O)-(C1-C6)-alkyl-,

2.4 phenyl- (CH2)n- where the phenyl is not substituted or mono - or doubly

substituted, as ooll or

3. -(C1-C4)-alkyl-C(O)N(R9)-(CH2)o-N(R4)-R5and R9has the above values, means the integer 2, 3, 4 or 5 and

R4and R5have the above values,

And means

a) covalent bond,

b) -O-,

c) -CH=CH - or

d) -CC-,

B means

(a) -(CH2)m-, where m indicates an integer zero, 1, 2, 3,

4, 5 or 6,

b) -O-(CH2)pwhere R denotes an integer from 1 to 5, or

c) -CH=CH -

X is-CH=CH-, an oxygen atom or a sulfur atom.

Preferred is a compound of formula I, where R’ means

1. phenyl or

2. phenyl, which is substituted once

2.1 (C1-C6)-alkyl, where alkyl is a linear, cyclic or branched,

2.2-HE,

2.3 (C1-C6)-alkyl-C(O)-O-,

2.4 (C1-C6)-alkyl-O-,

2.5 (C1-C6)-alkyl-O-(C1-C4)-alkyl-O-,

2.6 halogen,

2.7-CF3or

2.8 R4-(R5)N-, R2, R4and R5are the same or different and signify

1. Ethnography form a 4-7-membered ring, in which, if necessary, one of the carbon atoms replaced by-O-, -S - or-NH-,

R3means

1. -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen atom to which they are bound, form a residue of formula IIA and formula IIA

q denotes an integer of zero or 1 and

Z means a carbon atom, a nitrogen, oxygen or sulfur and

R8means a hydrogen atom or values described for R1under 2.1 to 2.8,

2. -(C1-C4)-alkyl-C(O)-Y, where

Y means the remainder of the formula IIC or IId, and in formulas IIC and IId

R8means a hydrogen atom or has the meaning set forth for R1under 2.1 to 2.8 and

R9means a hydrogen atom or

3. -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)o-N(R4)-R5and

R9means a hydrogen atom,

on means the integer 2 or 3 and

R4and R5are the same or different and signify

1. a hydrogen atom,

2. (C1-C6) -alkyl or

3. R4and R5together with the ring amino group form a 4-7-membered ring, in which case the neo is SS="ptx2">

In means

(a) -(CH2)m- where m is the integer zero, 1 or 2,

b) -O-(CH2)pwhere R denotes an integer of 1 or 2, and

X is-CH=CH-.

In addition, preferred is a compound of formula I, where

R’ means

1. phenyl or

2. phenyl, which is substituted once

2.1 chlorine,

2.2 bromine,

2.3 fluorine,

2.4 pyrrolidino or

2.5 morpholine,

R2means a hydrogen atom,

R3means

1. -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen atom to which they are bound, form a residue of formula IIA and formula IIA

q denotes an integer of zero or 1,

Z means a carbon atom and

R8means a hydrogen atom, chlorine, bromine or fluorine,

2. - (C1-C4)-alkyl-C(O)-Y, where

Y means the remainder of the formula IIC or IId, and in formulas IIc and IId

R8and R9indicate each a hydrogen atom or

3. -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)o-N(R4)-R5and

R9means a hydrogen atom,< and independently from each other mean

1. a hydrogen atom,

2. phenyl or

3. morpholine,

A represents a covalent bond or-O-,

In the mean covalent bond and

X is-CH=CH-.

Particularly preferred are the following compounds: 2-(biphenyl-4-sulfonylamino)-4-(naphthalene-1-yl-carbarnoyl)-butyric acid, 2-(biphenyl-4-sulfonylamino)-4-(naphthalene-2-yl-carbarnoyl)-butyric acid, 2-(biphenyl-4-sulfonylamino)-4-(2-phenylmenthylcarbamate)-butyric acid, 2-(4’-chlorobiphenyl-4-sulfonylamino)-4-(3-morpholine-4-yl-propellerblades)-butyric acid, triptorelin 4-(3-(4-(biphenyl-4-sulfonylamino)-4-carboxymethylamino)-propyl)-4-morpholine, 2-(biphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 5-(2,3-dihydroindol-1-yl)-5-oxo-2-(4’-pyrrolidin-1-yl-biphenyl-4-sulfonylamino)-pentane acid, 2-(4’-chlorobiphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 2-(4’-bromobiphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 2-(4’-chlorobiphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 2-(4’-bromobiphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxo-2-(4’-PIR is enyl-4-sulfonylamino)-5-oxopentanoic acid.

The expression "R4and R5together with the ring amino group form a 4-7-membered ring and/or one of the carbon atoms replaced by-O-, -S - or-NH-" refers to the residue produced, for example, from isoxazolidine, research, isothiazolinone, thiomorpholine, pyrazolidine, imidazolidine, piperazine, azetidine, pyrrole, pyrroline, pyrrolidine, pyridine, azepine, piperidine, pyrazole or diazepine. By "halogen" refers to fluorine, chlorine, bromine or iodine. By "alkyl" is understood hydrocarbon residue, a hydrocarbon chain which may be linear or branched.

Source substances for chemical transformations known or can be easily obtained by known literature methods.

The invention relates also to a method for obtaining compounds of formula I and/or stereoisomeric forms of the compounds of formula I and/or physiologically acceptable salts of the compounds of formula I, characterized in that (as described in method A, see examples)

a) aminocarbonyl acid of the formula II

where R11means a hydrogen atom or customary in the chemistry of peptides ester protective group, s indicates an integer zero, 1, 2 or 3, R10mean residue OR12where R12the>means the residue-N(R6)-R7where R6and R7defined in formula I, is subjected to the interaction with the derived sulfonic acids of the formula III

where R’, X, a and b defined in formula I and Y represents a halogen atom, imidazolyl or or13where R13represents a hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl, which, if necessary, replaced,

in the presence of a base or, if necessary, the drying means to form compounds of formula IV

where R’, A, X, B, R2, s, R10and R11have the above values,

and then possibly present in the residue R10the protective group R12in the presence of the protective group R11otscheplaut and then enter the balance-N(R6R7by corresponding, known from the chemistry of peptides, activation of the carboxyl group, otscheplaut existing protective group, R11and get the connection formula I, or (as described in methods b and C, see examples)

b) the amino acid anhydride of the formula V

in which R13means a hydrogen atom and R14is a well-known of the chemistry of peptides N-protective g is a group, for example, phthalimidopropyl, and s are defined above, is subjected to the interaction with the primary or secondary residue-N(R6)-R7disclosure of the cycle before the formation of the intermediate product of formula VI

where R13, R14, s, R6and R7have the above values,

moreover, this disclosure cycle depending on the protective group and the reaction conditions (cf X. Huang, X. Luo, Y. Roupioz, J. W. Keillor, J. Org. Chem., 1997, 62, 8821-8825), as a rule, goes regioselective, resulting isomers of formula VI, which in the regioselective formation of a mixture of isomers can be enriched by crystallization or chromatography; then present protective groups R13and/or R14otscheplaut with the release of amines and then produce N-sulfonation derivative of sulfonic acids of the formula III, as described under a), which leads to the product of formula I, or

(C) a compound of the formula I obtained according to methods a) or b), which because of its chemical structure occurs in enantiomeric forms, isolated in the form of pure enantiomers by salt formation with enantiomerically pure acids or bases, by chromatography on chiral stationary phases or through the formation of production is x the diastereomers and removal of the chiral auxiliary groups or

d) compound of formula I obtained by the method (a), (b) or (C) or isolated in free form or, in the case of acidic or basic groups is converted into a physiologically acceptable salt.

Suitable protective groups are preferred N-protective group used in the chemistry of peptides, for example protective groups, urethane type, benzyloxycarbonyl (Z), tert-butyloxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc) or amides of the acids, in particular formyl, acetyl or TRIFLUOROACETYL, as well as alkyl, for example benzyl.

As the original products to obtain derivatives of sulfonic acids of the formula III preferably suitable sulfonic acids or their salts of the formula VII, for example

and R15means the residue described for R1under 2.1 to 2.14. Derivatives of sulfonic acids of the formula III, which as R15contain secondary or cyclic amine type-N(R4)-R5preferably and high output are catalyzed by Pd substitution basalganglia, preferably bromide, a secondary amine in accordance with openam chlorosulfonic acid. And sulfochloride function due to the guiding action of the amino group is preferably directed into the desired para-position.

Preferably the used catalyst dichlorobis(trailerteen)palladium(II) can be obtained similarly R. F. Heck in "Palladium Reagents in Organic Syntheses", Academic Press, London (1985), page 18, on the basis of three-on-tolylphosphino, palladium chloride(II) and LiCl in methanol.

To obtain arylsulfonic acids of formulas VIIa and VIIb are preferable method of sulfating, described in Houben-Weyl "Methods der Organischen Chemie", volume 9, pages 540-546, concentrated sulfuric acid, if necessary in the presence of a catalyst, sulfur trioxide and the products of its accession or halogencontaining, such as chlorosulfonic acid. Especially in the case of simple diphenyl ether of the formula VIIb reliable is the use of concentrated sulfuric acid and acetic anhydride as solvent (compare C. M. Suter, J. Am. Chem. Soc., 53 (1931), 1114) or interaction with excess chlorosulfonic acid (J. P. Bassin, R. Cremlyn and F. Swinbourne; Phosphorus, Sulfur and Silicon 72 (1992), 157). Sulfonic acids according to formula VIIc, or VIId VIIe can be obtained in a known manner, in which the corresponding arylalkylamine expose the thief, moreover, the interaction can be accelerated in the presence of salts of tetraalkylammonium, such as tetrabutylammonium.

As derivatives of sulfonic acids according to the formula III, in particular, are used in the acid chlorides of sulfonic acids. To obtain the corresponding sulfonic acids, also in the form of their salts, such as salts of sodium, ammonium or pyridinium, in a known manner is introduced into the reaction pentachloride phosphorus or thionyl chloride in the absence or in the presence of a solvent, such as trichloride phosphorus, or an inert solvent such as methylene chloride, cyclohexane or chloroform, usually at the reaction temperature from 20 ° C to boiling point of the used reaction medium. Preferably conduct direct sulfochlorinated corresponding aromatic compounds chlorosulfonic acid, sulfurylchloride or pyrosulfuric (Houben-Weyl, Methods der Organischen Chemie, volume 9 (1995), pp. 572-579).

The interaction of derivatives of sulfonic acids of the formula III with an amino acid of formula II according to the options method a) or b) preferably proceeds by reacting the Schotten's-Bauman. As a reason it is particularly applicable hydroxides of alkali metals, such as hydroxide NAT is whether mixing or not mixing with the water solvent, such as tetrahydrofuran (THF), acetone, dioxane or acetonitrile, and the reaction temperature typically support 10 to 50C. For the case when the reaction is carried out in anhydrous medium, are used primarily tetrahydrofuran or methylene chloride, acetonitrile or dioxane in the presence of a base, such as triethylamine, N-methylmorpholine, N-ethyl - or diisopropylethylamine, possibly in the presence of N,N-dimethylaminopyridine as a catalyst.

In another embodiment, especially when using the polar of the original product, which is present in unprotected form, the amino acids of formula II can first use cilleruelo agent, such as batrineteasinguratatea (BSTFA), translate in Siciliano form and then subjected to interaction with derivatives of sulfonic acids to form compounds of formula IV.

Obtaining physiologically acceptable salts of the compounds of the formula I is capable of salt formation, including their stereoisomeric forms, carried out by known methods. Carboxylic acids form with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholate, and ammonia or organic bases, for example 2-amino-2-(hydroxymethyl)-1, the slots, can be lysine, ornithine or arginine, sustainable alkaline salts, alkaline earth metal or, if necessary, substituted ammonium salt. Salts of the compounds of formula I which is formed with the aforementioned organic bases have a high solubility. If the compounds of formula I contain basic groups, can be obtained with a strong acid resistant additive salts of acids. These include both inorganic and organic acids, such as hydrochloric, Hydrobromic, sulfuric, phosphoric, methansulfonate, benzolsulfonat, para-toluensulfonate, 4-bromobenzophenone, acetic, oxalic, tartaric, triftormetilfullerenov, cyclohexanesulfonyl, amber or triperoxonane acid.

The invention relates also to medicines, different active content of at least one of the compounds of formula I and/or physiologically acceptable salts of the compounds of formula I and/or, if necessary, stereoisomeric forms of the compounds of formula I together with a pharmaceutically suitable and physiologically acceptable carrier, additive and/or other biologically active or auxiliary substances.

Takih diseases, on the processes which have an impact matrix-otsepleniya metalloproteinases. These include degenerative joint diseases such as osteoarthritis, rheumatoid arthritis, spondylosis, degenerative cartilage after joint trauma or immobilization of the joints, for example after lesions of the meniscus or nadkarni Cup or torn ligaments. Next, these include diseases of connective tissues, such as collagenoses, periodontal disease, which can lead to tooth loss, impaired wound healing and chronic diseases of the musculoskeletal system, such as inflammatory, due to immunological or metabolic acute and chronic skin lesions, arthropathies, myalgias and disturbances of bone metabolism (osteoporosis). Medical introduction compounds of the formula I according to the invention may be indicated for diseases of the blood vessels, such as blockage of the blood vessels, atherosclerotic plaques, or aneurysms, especially when threatening rupture, for example, when the stenosis of any pathogenesis. Further, the compounds of formula I are suitable for the treatment of inflammations, wounds and ulcers, particularly on the skin, cancer, in particular, to block or suspension whom shock, periodontal disease, periodontitis are the medical applications of the proposed connections.

Medicinal product according to the invention are usually administered orally or parenterally. But it is also possible rectal or transdermal application.

The invention relates also to a method for producing a medicinal product, which is characterized in that at least one compound of formula I with a pharmaceutically suitable and physiologically acceptable carrier and, if necessary, with other suitable active substances, additives or auxiliary substances are transferred into a suitable form for the application.

Suitable solid or galenovye forms of application are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, and preparations with prolonged release of the active substance, upon receipt of which are conventional tools such as the media, the spray means, binder, coating, swelling, internal or external lubricants, flavoring agents, sweetening tools and solubilisate and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable fats, such as fish oil, sunflower, peanut or sesame oil, polyethylene glycol and the solvent, as well as sterile water and mono - or polynuclear alcohols, such as glycerin.

Preferably the pharmaceutical drugs and get injected in dosage units, each unit contains as an active ingredient a certain dose of proposed compounds of formula I. In the case of solid dosage units such as tablets, capsules, coated tablets or suppositories, this dose can contain up to about 1000 mg, preferably each approximately 50 to 300 mg, and in the case of injection solutions in ampoules to about 300 mg, preferably about 10 to 100 mg.

For the treatment of adult weighing about 70 kg patient, depending on the activity of the compounds according to formula I, the daily dose is from about 20 to 1000 mg of active substance, preferably from about 100 to 500 mg depending on the condition, however, may also be higher or lower daily doses. Receiving daily doses can be performed once in the form of an individual dosage unit or Nickolaevna, which is the basis of the invention, identified by nuclear resonance and mass spectroscopy, and in the case of Regio - or diastereoisomeric forms for unambiguous confirmation of the structure along with1H and13- Used multidimensional NMR methods. Spectra 1H-NMR spectrum taken at 400 MHz device (Bruker, usually with tetramethylsilane was (TMS) as internal standard and at room temperature (RT). The final product was determined, generally, by mass spectroscopy (FAB-, ESI-MS, positive or negative ionization). Temperature data are given in degrees Celsius, CT means room temperature (22 to 26OC). The used abbreviations are either explained or correspond to the usual notation.

Examples of obtaining

Method (A)

Example 5. Triptorelin 4-(3-(4-(biphenyl-4-sulfonylamino)-4-carboxymethylamino)-propyl)-4-morpholine

Step 1: sulfonation glutamyl-tert-butyl ether

3 g (0,0148 mole) of L-Glu-O-tert-VI was dissolved in 29.5 ml of 0.5 N. NaOH and 250 ml of tetrahydrofuran (THF), cooled in an ice bath to 0 C and at the same time (while maintaining pH 8.5) was added dropwise in about 30 minutes the solution 4,476 g (0,0177 mole) biphenyls the Oh temperature and the end of the reaction is determined by thin-layer chromatography (TLC). Remove the THF under reduced pressure, extracted once with diethyl ether, acidified with 1 N. Hcl to a pH of 1.5, the product is repeatedly extracted with ethyl acetate, and dried to remove the solvent under reduced pressure. Remains 2,89 g of product, which can undergo further transformation without further purification.

Stage 2: conversion into amide

0.25 g (0,596 mmole) of the product from step 1 was dissolved in 50 ml of absolute THF, are added 0,119 g (to 0.63 mmole) of EDC (hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) and 0,0845 g (0.55 mmole) of hydrate of 1-hydroxybenzotriazole, stirred for 30 minutes, then carefully add 0,268 ml (1,79 mmole) of N-(3-aminopropyl)-research and stirred for further 8 hours. Mixed with water, acidified with 1 N. Hcl to pH 2, extracted several times with ethyl acetate, washed with dilute NaCl, dried and evaporated. Output 250 mg. Further purification can be effected by chromatography on silica gel using dichloromethane/methanol, 9:1.

Stage 3: removal of protective groups

0.11 g of the product from step 2 was dissolved in 5 ml triperoxonane acid and 5 ml dichloromethane and stirred in the atmosphere of inert gas until the end of the reaction (TLC control) for about 3 hours at room those which 1 g of compound of example 5 in the form of triptoreline.

Method)

Example 6. 2-(Biphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid

Stage 1: the interaction phthaloyl-L-glutaminolytic with dihydroindole

1.5 g (0,0058 mole) phthaloyl-L-glutaminolytic dissolved in 15 ml of absolute dioxane and within 10 min added dropwise a solution of 0,813 ml (0,0073 mole) of dihydroindole in 15 ml of dioxane. Heat up the end of the reaction (approximately 5 hours, TLC control) to 40 ° C, evaporated, extracted several times under reduced pressure, dichloromethane. Yield 2.7 g (product contains about 15 mol.% dioxane).

Stage 2: removal of protective groups

2,43 g of the product from step 1 was dissolved in 30 ml of ethanol and added to 0.39 ml (0,0080 mole) of hydrazine hydrate is added. Stirred for 3 hours at 80 ° C, evaporated under reduced pressure to dryness, mix the residue with 50 ml of 25% aqueous acetic acid and heated for about 10 min up to 80C. Then cooled in a water bath and the precipitation is sucked off, again mixing the precipitate with acetic acid and repeat the operation. The remaining balance falicitated drop. The purified filtrate is evaporated and obtain 0.7 g of product.

Stage 3: introduction N-arylsulfonyl residue

Nie 20 min added dropwise a solution of 0.61 g (0,0024 mole) of beenincorporated, dissolved in 50 ml of THF. Stirred at RT until completion of the reaction (approximately 6 to 8 hours, TLC control), once extracted with diethyl ether, acidified with 1 N. Hcl to a pH of 1.5, the product is extracted several times with ethyl acetate, dried and evaporated under reduced pressure. After drying remained at 0.42 g of the product of example 6.

Method (C)

Example 8. 2-(4’-Chlorobiphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid

Stage 1: the interaction of Cbz-Glu-anhydride and 2,3-dihydro-1H-indol

5 g is 0.019 mole) of L-Cbz-glutaminolytic together with 2,56 ml (this corresponds to is 0.023 mole) of 2,3-dihydro-1H-indole are dissolved in 100 ml of absolute dimethyl sulfoxide and stirred for 30 min at room temperature (RT), and another 30 min at 40C until the end of the reaction (TLC control). Mix make into water, extracted several times with ethyl acetate, the organic phase is washed with 1 N. Hcl and saturated NaCl solution, dried and evaporated. Output 7,07,

Stage 2: removal bz(carbobenzoxy)-protective group

6.8 g (0,018 mole) of the product from step 1 for 30 min, dissolved in 60 ml of 33% solution NWG/acetic acid and stirred until the reaction at RT (about 15 hours, TLC control). Polucen is with methanol/water (10:1), the product is filtered, dried, and again stirred in THF. After extraction and drying under reduced pressure remains to 2.13 g of crystalline hydrobromide with a purity of 98% (after HPLC).

Reductive cleavage of the protective group analogously to example 12, step 4 gives the hydrochloride of 2-amino-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid with a yield of 85%.

Stage 3: 2-(4’-chlorobiphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid

0.33 g (1 mmol) of product from step 2 was dissolved in 60 ml of THF/water (1:1) and using the device for titration and 0.5 N. set NaOH pH 12. At constant pH for about 45 min added dropwise a solution of 0,345 g (1.2 mmole) of 4’-chlorobiphenyl-4-sulphonylchloride dissolved in 30 ml of THF. Stirred for further 2 hours at pH 12 (TLC control), is mixed with 0.1 G. Hcl to pH 2, extracted several times with ethyl acetate, washed with water, dried and evaporated. Output 0,395 g, melting point C and purity of more than 92%.

Defined as a mixture of 4-chlorophenylsulfonyl acid may be removed by chromatography or precipitation.

Example 12. 5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxo-2-(4’-pyrrolidin-1-yl-biphenyl-4-sulfonylamino)-pentane klya) pyrrolidine and 6.2 g (0,0642 mol) tert-butanolate sodium are suspended in 600 ml of toluene and added 900 mg of catalyst dichlorobis(trailerteen)palladium (II). Heated for 8 hours under reflux, cooled, mixed with water/ethyl acetate, the organic phase is washed with water, dried over sodium sulfate and evaporated. The residue is dissolved in about 300 ml tert-butyl methyl ether and the addition of 50 ml of 1 N. ethereal Hcl precipitated hydrochloride of the product. Yield 6.0 g, melting point above 125C (decomposition).

Stage 2: 4’-pyrrolidin-1-yl-biphenyl-4-sulphonylchloride

6 g (is 0.023 mole) of the product from step 1 with cooling and under a protective gas portions contribute in 11 ml of chlorosulfonic acid and 3.5 hours heated to 60C. The solution was poured on ice, adjusted the suspension by the addition of solid sodium carbonate to pH 8, the precipitated product is sucked off and dried under reduced pressure. Output 7 g, melting point above C (decomposition).

Stage 3: interaction of Z-Glu-anhydride with 5-fluoro-2,3-dihydro-1H-indol

8.8 g (0,0334 mol L-Z-glutaminolytic with 5.5 g (0,04 mole) of 5-fluoro-2,3-dihydro-1H-indole are dissolved in 150 ml of absolute dimethyl sulfoxide and stirred at RT until completion of the reaction (approximately 3 hours, TLC control). Mix make into water, extracted several times with ethyl acetate and the organic phase is washed with 1 N. 13 g (0,0325 mole) of the product from step 3 is dissolved in 450 ml of methanol and 33 ml of 1 N. HCl, add on the tip of a spatula palladium and hydronaut at 40 bar and 60 SECONDS before the end of the reaction (TLC control). After filtration and evaporation the crude product is extracted with boiling under reflux THF, remaining after cooling, the solid hydrochloride is filtered off and dried under reduced pressure. The output of 7.1 g, melting point above S.

Stage 5: 5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxo-2-(4’-pyrrolidin-1-yl-biphenyl-4-sulfonylamino)-pentane acid

0,303 g (1 mmol) of product from step 4 was dissolved in 60 ml of THF/water (1:1) and using taraudage device (model 686, firm Metrohm) and 0.5 N. NaOH establish a pH of 12.0. When maintaining a constant pH for about 45 min added dropwise a solution of 0.39 g (1.2 mmole) of the product from step 2 is dissolved in 40 ml of THF. Stirred for further 2 hours at pH 12 (TLC control), is mixed with 0.1 G. Hcl to pH 2, extracted several times with ethyl acetate, washed with water, dried and evaporated. The product was then purified by chromatography on silica gel (dichloromethane/methanol, 95:5). Output 0,393 g, melting point S.

Method D)

Example 15. Trometamina salt of 2-(4’-chlorobiphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid

of 104.5 g (0,21 lamina (2-amino-2-(hydroxymethyl)-1,3-propane diol, TRIS), dissolved in 100 ml of water. Mix a short time heated to boiling and filtered hot. Transparent filtrate is left to warm up to CT, while falls salt. It is sucked off and washed twice in 150 ml of ethanol/water in a ratio of 9:1 and dried in a desiccator. Output for 93.9 g (72%) tromethamine salt.

Example 16. 2-(4’-Chlorobiphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoate-Tris(2-hydroxyethyl)-ammonium

0.05 g of product from example 8 was dissolved in 3,18 g of acetone, was added 0.01 g of triethanolamine, the solution is filtered and placed in an open Erlenmeyer flask in the TLC chamber, the bottom of which is about 1 cm covered tert-butylmethylamine ether. Crystal formation occurs within 10 hours and was completed in 4-5 days. The solution is decanted and the product is dried under reduced pressure. Yield 0.06 g, melting point 120C.

Examples 1 through 5 of table 1 obtained by the method (A), examples 6 and 7 on the way In) and examples 8 through 14 on the way). The original product, it is necessary to incorporate lateral arylsulfonyl circuit of example 13 (4’-morpholine-4-yl-biphenyl-4-sulphonylchloride) is obtained analogously to method (C), stage 1.

Pharmacological prima neutrophil collagenase man

Both enzyme - stromelysin (MMP-3) and neutrophil collagenase (MMP-8) were prepared according to Ye and others (Biochemistry, 31 (1992), page 11231-11235) or Weithmann, etc. (Inflamm Res, 46(1997), 246-252). To measure the inhibitory effect on the enzymatic activity were incubated with 70 μl of buffer solution and 10 μl of an enzyme solution with 10 ál of 10% (vol./about.) aqueous solution of dimethyl sulfoxide for 15 minutes. After addition of 10 µl of 10% (vol./about.) aqueous solution of dimethyl sulfoxide, which contains 1 mmol/l substrate, for an enzymatic reaction was monitored by fluorescent spectroscopy (328 nm (vosb)/393 nm(em)).

Enzymatic activity was defined as the addition of extinction per minute. In table 2 the values of the IC50were measured as the concentration of inhibitor that every time lead to a 50% increase inhibition of the enzyme. Buffer solution contains 0.05% Brij (Sigma, Deisenhofen, Germany) and 0.1 mol/l of piperazine-N,N’-bis[2-econsultancy acid]/NaOH, 0.1 mol/l NaCl, 0.01 mol/l CaCl2and 0.1 mol/l of piperazine-N,N’-bis[2-econsultancy acid] (pH 6.5).

The enzyme solution contains 5 g/l obtained by Ye and other enzymatic domain. The substrate solution contains 1 mmol/l fluorogenic substrate (7-methoxycoumarin-4-yl>P CLASS="ptx2">

Determination of the water solubility of the free 2-(4’-chlorobiphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid according to example 8 and its tromethamine salt according to example 15

1. The materials used

1.1 analyte

a) the compound according to example 8; 2-(4’-chlorobiphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid,

b) the compound according to example 15; trometamina salt of 2-(4’-chlorobiphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid.

1.2 Reagents

water: deionized, acetonitrile: LiChrosolv (Merck), diethylamin: synthesis (Merck), acetic acid: concentrated and 1 N. (Merck).

2. The experiment

2.1 2-(4’-Chlorobiphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid

In an Erlenmeyer flask with a capacity of 100 ml were placed about 50 mg verifiable substance according 1.1 (a). After adding 10 ml of water was stirred at 25C. After 2 hours and after 3 hours, aliquots were taken and centrifuged. 1 ml of sample was diluted in mobile phase to 10 ml the Concentration of the active component was determined using HPLC according to sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid

In an Erlenmeyer flask with a capacity of 100 ml were placed approximately 800 mg tromethamine salt according 1.1 (b). After adding 10 ml of water was stirred at 25C. After 2 hours and after 3 hours, aliquots were taken and centrifuged. 1 ml of sample was diluted in mobile phase to 100 ml Concentration of the active component was determined using HPLC with respect to an external standard. Repetition of the experiment.

3. Analysis

Tool: device Gynkotek HPLC

Column: stationary phase: ChiraDex 5 μm, Merck

Dimensions: 250 mm x 4.0 mm

Mobile phase: acetonitrile 440 ml; water 560 ml; diethylamin

ml; pH 6.4 with acetic acid.

Injection volume: 10 ál

Current: 0.8 ml/min

The column temperature: 40C

Definition: UV at 261 nm

5. Results see table 3

Time-dependent difference in the values of the solubility of 2-(4’-chlorobiphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid may be associated with the phenomenon of saturation/saturation. As a result, the selected value obtained after 3 hours.

Solubility in water tromethamine salt of 2-(4’-chlorobiphenyl-4-solidnoi 2-(4’-chlorobiphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid.

1. Omega-amides of N-arylsulfonyl-amino acids of formula I

and/or a stereoisomeric form of the compounds of formula I and/or physiologically acceptable salt of the compounds of formula I,

where R1means 1. phenyl,

2. phenyl, substituted once 2.6. halogen, 2.15. the rest of the heterocycle of the following groups: morpholine, pyrrolidine,

R2means a hydrogen atom,

R3means

1. -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen to which they are bound, form a residue of formula IIa, IIe

where q=0 or 1;

Z means a carbon atom or a covalent bond;

R8means a hydrogen atom or halogen,

2. -(C1-C4)-Alkyl-C(O)-Y, where Y means the remainder of the formula IIc or IId

where R8means a hydrogen atom or halogen;

R9means 2.1 hydrogen atom

3.-(C1-C4)-Alkyl-C(O)-N(R9)-(CH2)about-N(R4)-R5and R9has the above meanings; on=2;

R4and R5together with the ring amino group form a 4-7-membered ring in which one carbon atom is replaced by-O-; And means (a) covalent tie is characterized in that what R1means 1. phenyl or 2. phenyl, substituted once by halogen; R2means a hydrogen atom; R3means 1. -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen to which they are bound, form a residue of formula IIa

where q=0 or 1;

Z means a carbon atom;

R8means a hydrogen atom or halogen,

2. -(C1-C4)-Alkyl-C(O)-Y, where Y means the remainder of the formula IIc or IId

where R8means a hydrogen atom or halogen;

R9means a hydrogen atom or

3. -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)about-N(R4)-R5and R9means a hydrogen atom, o=2; R4and R5together with the ring amino group form a 4-7-membered ring in which one carbon atom is replaced by-O-; And means (a) a covalent bond; B means (a) -(CH2)m-, where m=0.

3. The compound of formula I under item 1, characterized in that it is a compound from the group comprising 2-(biphenyl-4-sulfonylamino)-4-(naphthalene-1-yl-carbarnoyl)-butyric acid, 2-(biphenyl-4-sulfonylamino)-4-(naphthalene-2-yl-carbarnoyl)-butyric acid, 2-(biphenyl-4-sulfonylamino)-4-(2-phenylalanyl acid, triptorelin 4-(3-(4-(biphenyl-4-sulfonylamino)-4-carboxy-Butylimino)-propyl)-4-morpholine, 2-(biphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 5-(2,3-dihydroindol-1-yl)-5-oxo-2(4'-pyrrolidin-1-yl-biphenyl-4-sulfonylamino)-pentane acid, 2-(4'-chloro-biphenyl-4-sulfonylamino)-5-(2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 2-(4'-bromo-biphenyl-4-sulfonylamino)-5-(2,3-dihydro-indol-1-yl)-5-oxopentanoic acid, 2-(4'-chloro-biphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxopentanoic acid, 2-(4'-bromo-biphenyl-4-sulfonylamino)-5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxo-pentane acid, 5-(5-fluoro-2,3-dihydroindol-1-yl)-5-oxo-2-(4'-pyrrolidin-1-yl-biphenyl-4-sulfonylamino)-pentane acid and 5-(5-fluoro-2,3-dihydroindol-1-yl)-2-(4'-morpholine-4-yl-biphenyl-4-sulfonylamino)-5-oxopentanoic acid.

4. The compound of formula I under item 1, characterized in that it is a salt of 2-amino-2-(hydroxymethyl)-1,3-propane diol, trimethylamine salt, salt of triethylamine, ethanolamine salt or the salt of triethanolamine.

 

Same patents:

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

The invention relates to new derivatives of 2-aminopyridine F.-ly (1) where denotes unsubstituted or substituted phenyl, pyridyl, thienyl, thiazolyl, hinely, cinoxacin-2-yl or Antonelliana derivatives; D is unsubstituted or substituted phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, hinely, triazolyl, oxazolyl, isoxazolyl or Antonelliana derivatives, provided that C and D are not simultaneously have the following values: S - phenyl, and D is phenyl, S - phenyl, and D - pyridyl, With - pyridyl and D - phenyl, - pyridyl and D - pyridyl; R1- R4- hydrogen, NO2or NH2

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

The invention relates to new derivatives of phenyl - and aminobenzenesulfonamide formula

< / BR>
where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

The invention relates to new derivatives oksiminoalkil acid of the formula (I), where R1is oxazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl, teinila, furil; thiazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl; unsubstituted chinoline and so on; X represents a bond or the group-NR6- where R6represents hydrogen or C1-4alkyl; n represents an integer from 1 to 3; Y represents an oxygen atom or the group-NR7- where R7is hydrogen; ring a represents a benzene ring, optionally substituted by one or two1-4alkoxy; p is an integer from 1 to 3; R2represents phenyl, optionally substituted lower alkyl, halogen, and so on; unsubstituted furyl; unsubstituted pyridyl; pyridinyl-1-oxide; q is an integer from 0 to 6; m represents 0 or 1; R3represents a hydroxy-group, lower alkoxy or-NR9R10where R9and R10represent identical or different groups selected from hydrogen, lower alkyl and lower alkylsulfonyl; R4and R5represent identical or different groups selected from hydrogen or

The invention relates to thiosulfonate formulas

< / BR>
< / BR>
or

< / BR>
< / BR>
< / BR>
where R1represents a radical having a length greater than the saturated chain of four carbon atoms, and shorter than the saturated chain from eighteen carbon atoms, and in rotation around the axis passing through the position 1, associated with the SO2and position 4 6-membered ring or through position 1, associated with the SO2group and associated with the Deputy position 3 or 5 of the 5-membered ring, defines a three-dimensional volume, the largest size in which the width is approximately one phenyl ring up to three phenyl rings in a direction transverse to the axis of rotation; R2means hydrido,1-C6alkyl, phenyl-C1-C4alkyl, heteroaryl-C1-C4alkyl, C2-C4alkyl substituted amino; C2-C4alkyl, substituted monosubstituted amino or disubstituted amino, where-C6) alkyl, C5-C8cycloalkyl and C1-C6alkylsulphonyl, or where two of the substituent and the nitrogen to which they are attached, together form pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, thiomorpholine, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, and other pyrimidinyl

The invention relates to new carboxamides f-ly 1, where E-N, G-H, lower alkyl, lower alkylene COOH, COO-lower alkyl, lower alkanoyl, lower alkanoyloxy, lower alkoxy, aryl-lower alkoxy, СОNH2and others, M-H, lower alkyl, lower alkenyl, aryl, heteroaryl, cycloalkyl, L-H, lower alkyl, aryl, cycloalkyl, or M and L together with the atoms to which they are linked, form a group - N (het), or E and G spot form a methylene or carbonyl group, and M represents H, lower alkyl, lower alkenyl, aryl, heteroaryl, cycloalkyl, L-H, lower alkyl, aryl , cycloalkyl, A-H, alkyl, aralkyl, Q represents a group of formula Q1or Q2T-CH2or Oh, R6and R7- H, cerboneschi alkoxy, HE

-aminocarbonyl acids possessing antiarrhythmic and antifibrillatory activity" target="_blank">

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

The invention relates to new derivatives phenylbenzimidazol formula I listed in the description, in which R1and R2identical or different, represent a hydrogen atom or a halogen or an alkyl radical, possibly halogenated, and R3and R4identical or different, represent alkyl, C1- C4or can form together with the nitrogen atom to which they are linked, a cycle of morpholino
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