Derivatives of phosphinic and phosphonic acids, method for their production and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to derivatives of phosphinic and phosphonic acids of the formula (I)

where R1means unsubstituted or substituted phenyl, -O-(C1-C6)-alkyl, R2means hydrogen, RR3mean hydrogen, alkyl, unsubstituted or substituted phenyl, COOH group or - (CH2)2-CH(COOH)-NH-SO2-C6H4-C6H4-Cl(n), t stands for an integer of 1-4, And is a covalent bond, X is a group-CH=CH -, - group,- (CH2)about- where is 0,1,2 or 3, Y1and Y2mean-OH, -(C1-C4)-alkyl, -O-(C1-C4)-alkyl, and/or their stereoisomeric forms and/or physiologically acceptable salts. The compounds of formula (I) have activity against metalloproteinases and can find application in medicine. 4 C. and 3 h.p. f-crystals, 3 tables.

The invention relates to new derivatives sulfonylmethane and phosphonic acids, method for their production and their use as pharmaceuticals.

In the application for the European patent EP 0606046, International applications WO 95/35276 and WO 96/27583 describes arylsulfonamides acids and their action as an inhibitor products to obtain inhibitors of thrombin (European patent EP 0468231) and inhibitors aldozoreduktaza (European patent EP 0305947). In the application for the European patent EP 0757037 also describes the effect of derivative sulfonilmocevinnah acids as inhibitors of metalloproteinases. Next arylsulfonyl the group has been proven as an effective protective group for amino group-aminocarbonyl acids (R. Roemmele, H. Rapoport, J. Org. Chem., 53, 2367-2371 (1988)).

When searching for an effective compounds for the treatment of diseases of the connective tissue at the present time, it is shown that the proposed according to the invention derived sulfonylmethane and-phosphonic acids are strong inhibitors of metalloproteinases. With particular importance attached to the inhibition stromelysin (matrix metalloproteinase 3), neutrophil collagenase (MMP-8) and aggrecanases, because these enzymes are largely involved in the destruction of proteoglycans as important parts of the cartilage tissue (A. J. Fosang and al., J. Clin. Invest., 98, 2292-2299 (1996)).

Pathological loss of aggrecan, the main proteoglycan of cartilage, includes proteolytic cleavage in his interglobular domain. Analyses of amino acid sequences proteoglycan metabolites isolated from synovial fluid of patients who suffer damages the district heating preferably occurs between amino acids Glu373and A1A374in interglobular domain of human aggrecan (Lohmander and al., Arthritis Rheum., 36, 1214-1222 (1993)). The proteolytic activity responsible for this cleavage, still have not been able to identify. It is denoted as “aggrecanases” and it can be related to the family of metalloproteinases.

The first evidence for the expression MT-MMP in human cartilage ( and al., Arthritis Rheum., 40, 704-709 (1997)), associated with the discovery that the catalytic domain of this enzyme cleaves the restriction site “aggrecanases in recombinant aggrecan-fused protein rAgglmut( and al., Biochem. J., 333, 159-165 (1998)), has led to the testing described here are strong inhibitors of matrix metalloproteinases in relation to their actions against activity “aggrecanases”. At the same time using different methods of analysis were able to show that the derivative sulfonylmethane and-phosphonic acids are also strong inhibitors of activity “aggrecanases”.

The invention relates therefore to the compound of 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 R1means:

authorized (C1-C6) -alkyl,

2.2. by hydroxyl,

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,

2.8. -CN,

2.9. -NO2,

2.10. BUT-C(O)-,

2.11. (C1-C6)-alkyl-O-C(O)-,

2.12. methylenecyclopropane,

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

2.14. R4(R5)N - or

2.15. the remainder of heteroaromatic compounds from the group 3.1-3.16;

3. the remainder of heteroaromatic compounds from the following group 3.1-3.16, unsubstituted or substituted as described in paras.2.1-2.15:

3.1. pyrrol,

3.2. pyrazole,

3.3. imidazol,

3.4. triazole,

3.5. thiophene,

3.6. the thiazole,

3.7. oxazol,

3.8. isoxazol,

3.9. pyridine,

3.10. the pyrimidine,

3.11. pyrrolidin,

3.12. indole,

3.13. benzothiophen,

3.14. the benzimidazole,

3.15. benzoxazol or

3.16. benzothiazole; or

4. -O-(C1-C6)-alkyl;

R2, R4and R5are the same or different-C6)-alkyl-,

4. phenyl-(CH2)n- where the phenyl is not substituted or mono - or

doubly substituted, as described in paras.2.1-2.15, or substituted-NH-C(O)-(C1-C3)-alkyl, and n means an integer of 0, 1 or 2, or

5. picolyl, or

6. R4and R5together with the ring amino group form a 4-7-membered cycle, where one of the carbon atoms may be replaced by-O-, -S - or-NH -, or two adjacent carbon atom 4-7-membered cycle are part of the benzyl residue;

R and R3are the same or different and mean:

1. a hydrogen atom,

2. (C1-C10)-alkyl-, where the alkyl is not substituted, or one hydrogen atom of the alkyl residue is replaced by a group-HE,

3. (C2-C10)-alkenyl-where alkenyl is a linear or branched,

4. R2-O-(C1-C6) -alkyl-,

5. R2-S(O)n-(C1-C6)-alkyl-, and n have the above meaning,

6. R2-S(O)(=NH)-(C1-C6)-alkyl,

7. the remainder of the formula (A)

where n means an integer of 0, 1 or 2, and W means nitrogen atom, oxygen or sulfur;

8. phenyl-(CH2)m-, where m indicates an integer 0, 1, 2, 3, 4�ukratko substituted;

8.1. as described in paras. 2.1-2.15,

8.2. -O-(CH2)m-phenyl, where the phenyl is not substituted or mono - or doubly substituted, as described in paras.2.1-2.15, and m means an integer 0, 1, 2, 3, 4, 5 or 6;

8.3. -C(O)-(CH2)m-phenyl, where phenyl is specified in paragraph 8.2 value;

9. heteroaryl-(CH2)m- where heteroaryl is specified in paras.3.1-3.16 the value of m has the above meaning and/or one atom of hydrogen (CH2)m-chain replaced by a group-HE and heteroaryl not substituted, or one - or twofold substituted:

9.1. as described in paras.2.1-2.15,

9.2. -CH(O)

9.3. -SO2-phenyl, where the phenyl is not substituted or is specified in paragraph 8.2. the value

9.4. -O-(CH2)m-phenyl;

10. -(CH2)m-P(O)(OH)-(C1-C3)-alkyl, where m has the above meaning;

11. typical amino acid residue or

12. R6-C(O)-(C1-C6)-alkyl, where R6means:

1. a hydrogen atom,

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

3. phenyl, where the phenyl is not substituted or substituted as described in paras.2.1-2.15,

4. heteroaryl where heteroaryl is specified in paras.3.1

5. HE,

6. -OR2where R2has the above meaning,

7. -NR4-(R5), where R4and R5have the above meaning,

8. heteroaryl-(CH2)m-NH-, where heteroaryl is specified in paras.3.1-3.16 value and/or substituted, as described in paras.2.1-2.15, and m has the above meaning,

9. R4-(R5)N-NH-, where R4and R5have the above meaning,

10. BUT-C(O)-CH(R3)-NH-, where R3has the above meaning,

13. - (CH2)p-N(R9)(R10), where p denotes an integer of 0, 1, 2, 3 or 4; R9and R10are the same or different and mean:

1. a hydrogen atom,

2. phenyl-(CH2)m- where the phenyl is not substituted or mono - or doubly substituted, as described in paras.2.1-2.15, and m means an integer of 0, 1, 2 or 3;

3. Rx-C(O)-, where Rxmeans:

3.1. (C1-C6)-alkyl-,

3.2. (C2-C6)-alkenyl-,

3.3. phenyl-(CH2)m- where the phenyl is not substituted or mono - or doubly substituted, as described in paras.2.1-2.15, and m means an integer of 0, 1, 2 or 3;

3.4. heteroaryl-(CH2)m- where heteroaryl is specified in paras.3.1-3.16 value and/or C is ieuconoe value

5. Rx-CH(NH2)-C(O)-, where Rxhas the above meaning,

6. R8-N(R7)-C(O)-, where R8means:

6.1. a hydrogen atom,

6.2. (C1-C6)-alkyl-,

6.3. phenyl-(CH2)m- where the phenyl is not substituted or mono - or doubly substituted, as described in paras.2.1-2.15, and m means an integer of 0, 1, 2 or 3; or

6.4. heteroaryl-(CH2)m- where heteroaryl is specified in paras.3.1-3.16 value and/or substituted, as described in paras.2.1-2.15, and m means an integer of 0, 1, 2 or 3,

and where R7means a hydrogen atom or a (C1-C6)-alkyl-, or

where R7and R8together with the nitrogen atom to which they are bound, form a 4-7-membered cycle and the cycle is not substituted, or one atom of carbon in the cycle is replaced by-O-, -S - or-NH-;

7. Rx-SO2- where Rxhas the above meaning,

8. Rx-NH-C(=NR7)-, where Rxand R7have the above value or mean:

8.1. (C1-C6)-alkyl-C(O)-,

8.2. -NO2or

8.3. -SO2-(CH2)q-phenyl, where the phenyl is not substituted or mono - or doubly substituted, as described in paras.2.1-2.15, and q indicates an integer of 0, 1, 2 or 3;

9. -SO

10. the residue of formula (IIp)

where m means an integer of 0, 1, 2 or 3 and W means nitrogen atom; or

R9and R10together with the nitrogen atom to which they are bound, form a loop of the partial formulae (IIA) to (IIn)

or

and r is an integer of 1 or 2, R11means balance, as specified in paras.2.1-2.15, and R7and m have the above meaning;

14. HE,

15. =O or

16. (C1-C6)-alkyl; or

the residue-C(R)(R3)- means-NH - or-NR2- where R2has the above value, and

t denotes an integer of 1, 2, 3 or 4; or

R2and R3together form a cycle with ekzoticheskim the remainder of phosphinic or phosphonic acid partial formula (II)

where r is the integer 0, 1, 2 or 3 and/or one of the carbon atoms in the cycle is replaced by-O-, -S - or -(R7)N-, where R7means:

1. a hydrogen atom,

2. (C1-C6)-alkyl,

3. phenyl, where the phenyl is not substituted or substituted, as described in paras.2.1-2.15,

4. benzyl, where the benzyl not znachenie; and/or the carbon atoms in the cycle of partial formulas (II) one - or multi-substituted (C1-C6)-alkyl, phenyl, phenyl group-(CH2)mor group, BUT-;

U mean-SO2- or-CO-;

Y1and Y2are the same or different and independently from each other mean:

(a) a hydrogen atom,

b) HE,

b) -(C1-C4)-alkyl, where alkyl is a linear or branched,

g) -(CH2)u-phenyl, where u denotes 0 or 1,

e) -O-(C1-C4)-alkyl, where alkyl is a linear or branched, or

e) -O-(CH2)s-phenyl, where s denotes 0 or 1;

And means:

a) covalent bond,

b) -O-,

in) -CH=CH - or

d) SS-;

In means:

(a) -(CH2)o- where denotes the integer 0, 1, 2, 3, or 4

b) -O-(CH2)p-, where p denotes an integer of 1-5, or

in) -CH=CH-; and

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

Preferred is a compound of formula (I), and

R1means:

1. phenyl; or

2. phenyl, substituted once

2.1. (C1.3. -C(O)-HE,

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

2.5. pyrrolidino,

2.6. halogen or

2.7. -CF3;

or

3. -O-(C1-C6)-alkyl;

R2, R4and R5are the same or different and mean a hydrogen atom or a (C1-C6)-alkyl;

R means a hydrogen atom;

R3means:

1. (C1-C6)-alkyl-, where the alkyl is a linear, branched or cyclic, and/or one hydrogen atom of the alkyl residue substituted by a group-HE;

2. R2-S(O)n- (C1-C6)-alkyl-, where R2means (C1-C6)-alkyl or phenyl-(CH2)nand n means an integer of 0 or 1;

3. -(CH2)m- phenyl, where the phenyl is not substituted or mono - or doubly substituted, as described in paras.2.1-2.15, and/or one atom of hydrogen,- (CH2)m-chain replaced by a group-HE, and m means an integer of 1, 2, 3, 4 or 5;

4. -(CH2)m-heteroaryl where heteroaryl has specified in paragraphs.3.3, 3.5, 3.6, 3.9 or 3.11 value and/or substituted, as described in paras.2.1-2.15, and/or one atom of hydrogen,- (CH2)m-chain replaced by a group-HE, and m means an integer of 1, 2, 3 or 4;

5. the feature is about 0, 1 or 2 and where R9and R10are the same or different and mean a hydrogen atom or-SO2-(CH2)q-phenyl-phenyl, where the phenyl is not substituted or mono - or doubly substituted, as described in paras.2.1-2.15, and q indicates an integer of 0, 1, 2 or 3; or

7. R6-C(O)-, where R6means:

7.1. HE,

7.2. R2O-, where R2has the above value, or

7.3. R4-(R5)N-, where R4and R5have the above meaning;

8. a hydrogen atom;

9. -HE;

10. =O; or

11. (C1-C6)-alkyl; or

the residue-C(R)(R3means-NH - or-NR2- where R2has the above value, and

t denotes an integer of 1, 2, 3 or 4;

U mean-SO2-;

Y1means-HE;

Y2means:

a) -O-(C1-C4)-alkyl, where alkyl is a linear or branched,

b) HE, or

b) -(C1-C4)-alkyl, where alkyl is linear or branched;

A represents a covalent bond or-O-;

In the mean covalent bond or -(C1-C4)-alkyl; and

X is-CH=CH-.

Especially preferred is n-halogen;

R2means a hydrogen atom;

R means a hydrogen atom;

R3means:

1. (C1-C4)-alkyl-,

2. phenyl, where the phenyl is not substituted or mono - or doubly substituted by a group-CF3or-COOH;

3. a hydrogen atom;

4. HE or

5. -NH-SO2-phenyl-phenyl, where the phenyl is not substituted or substituted with halogen;

t denotes an integer of 1, 2, 3 or 4;

U mean-SO2-;

Y1and Y2mean-HE or-O-CH3;

And means covalent bond;

In the mean covalent bond or -(CH2)o- where o is 1, 2 or 3; and

X is-CH=CH-.

Particularly preferred compounds:

(R)-[1-(4’-chlorodiphenyl-4-sulfonylamino)-2-methylpropyl]phosphonic acid;

dimethyl [3-(4’-chlorodiphenyl-4-sulfonylamino)-1-hydroxy-3-(4-triptoreline)propyl]phosphonic acid or [1-(4’-chlorodiphenyl-4-sulfonylamino)-3-methylbutyl]phosphonic acid.

Under the expression “R4and R5together with the ring amino group form a 4-7-membered cycle and/or one of the carbon atoms replaced by-O-, -S - or-NH -,” see the remains produced, for example, from the Ola, thiazole, isothiazole, diazepine, thiomorpholine, pyrimidine or pyrazine. The term “halogen” refers to fluorine, chlorine, bromine or iodine. The term “alkyl” or “alkenyl” understand hydrocarbon residues, carbon chain which is linear or branched. Cyclic alkyl residues are, for example, 3-6-membered monocycle as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Next, alkeline residues may contain several double bonds.

-Amino acids meet the following General structural formula:

-Amino acids differ from each other in the residue R, which in the framework of the present invention is designated as the “natural balance” of amino acids.

Source substances for chemical transformations known or they can get well-known from the literature methods. Used as starting substances for the synthesis proposed according to the invention compounds aminophosphine and phosphonic acid, if in case they are not commercially available, synthesized by known methods (R. S. Rogers, M. K. Stern, Synlett, 708 (1992); P. P. Giannousis, P. A. Bartlett, J. Med. Chem., 30, 1603 (1987); J. P. Genet, M. Uziel, A. M. Touzin, S. Roland, S. Thorimbert, S. Tanier, Tetrahedron Lett., 33, 77 (1992); E. K. Baylis, the Basis of formulas (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:

a) aminophosphines or phosphonic acid of the formula (III)

where R2, Y1, Y2R and R3are specified in the formula (I) is administered in cooperation with the derived sulfonic acids

or a carbonyl derivative of formula (IV)

where R1And, X, U and V have specified in the formula (I) value, and Z means a halogen atom, imidazolyl or8where R8represents a hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl, possibly substituted,

in the presence of a base or, if necessary, drying means for obtaining the compounds of formula (I); or

b) ether aminophosphines or phosphonic acid of the formula (V)

where R2, R3, t, Y2and R8have the above meaning,

enter into interaction with the derived sulfonic acids or carbonyl derivative of formula (IV) to obtain the compounds of formula (VI)

and the compound of formula (VI) by removal of residue R8, preferably in the presence of base or acid, is converted into a compound of formula (I); or

C) the compound of formula (VII) is between the compound of formula (VIII)

and the compound of formula (VIII) by reacting with the compound of the formula (IV) is transferred to the compound of formula (IX)

and then the compound of formula (IX) by removal of the protective group E and remainder R8using a suitable chip off the reagent is transferred to a compound of formula (I); or

g) obtained according to the methods a), b) or C) a compound of formula (I), which because of its chemical structure is in enantiomeric forms, by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the resulting diastereomers and removal of the chiral auxiliary groups, separated into pure enantiomers; or

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

As a suitable protective group for this purpose use is preferably conventional in the chemistry of peptides N-protective group, for example a protective group of the urethane type, benzyloxyethyl, in particular formyl, acetyl or TRIFLUOROACETYL, and alkyl type, for example benzyl.

As compounds of the formula (III) in which R2means a hydrogen atom and R3represents a characteristic amino acid residue, preferably using characteristic remains of the following naturally occurring-amino acids as glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and aspartic acid. As compounds of the formula (III) in which R2means a hydrogen atom and R3represents a characteristic amino acid residue, preferably using characteristic residues, for example, the following, which is not found in nature, amino acids as 2-aminoadenosine acid, 2-aminobutyric acid, 2,4-diaminopentane acid, 2-aminoadamantane acid, 2,3-diaminopropionic acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminofilina acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolinate acid, hydroxylysine, sarcastically, 3-hydroxyproline, allowedactions, 3-(2-naphthyl)alanine, 3-(1-nafcillin), homophenylalanine, homocysteine, homocysteinemia acid, homotrimer, cysteine acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, citrulline, phosphinotricin, 4-forfinally, 3-forfinally, 2-forfinally, 4-chlorophenylalanine, 4-nitrovanillin, 4-aminophenylalanine, cyclohexylamine, 5-percription, 5-methoxytryptophol, methioninamide, methanesulfonic or possibly substituted NH2-NH-CONH2. In the case of naturally occurring, however, it is also not naturally occurring amino acids, which contain the side chain R3functional group as the amino, hydroxyl, carboxyl, mercaptopropyl, guanidyl, imidazolyl or indolyl, this group can also be protected.

In the case of the imidazole residue in R3for example, used for education sulfonamida derived sulfonic acids of the formula (IV) is used as a protective group of the imidazole nitrogen, which can again be split in particular in the presence of bases like sodium hydroxide solution.

To obtain the compounds of formula (I) in which R2and R3together form a cycle of partial structure (I is ostrovul acid, piperazine-2-phosphonic acid or hexahydropyridine-3-phosphonic acid, and in particular the nitrogen atom in position 4 of the piperazine-2-phosphonic acid may be substituted by a protective group Z, for example by benzyloxycarbonyl or tert-butyloxycarbonyl, as described in the variant of the method), or the remainder R7.

As the original products to obtain derivatives of sulfonic acids of the formula (IV) are preferably sulfonic acids or their salts of the formula (X), for example:

and R9means specified in paras. 2.1-2.15 residue.

To obtain arylsulfonyl formula (Ha) and (b) preferably use described in Houben-Vayle “Methods of organic chemistry”, T. 9, S. 450-546, methods of sulfonation with concentrated sulfuric acid, if necessary, in the presence of a catalyst, sulfur trioxide and its products attach or halogenocarboxylic as chlorosulphonate. Especially in the case of diphenyl ether of the formula (b) is a useful use of concentrated sulfuric acid and acetic anhydride as solvent (see C. M. Suter, J. Am. Chem. Soc., 53, 1114 (1931)), or were is facility according to the formula (XC), (Xd) or (Heh) you can get itself in a known manner, in the case of which the corresponding arylalkylamine enter into interaction with sulfites as sodium sulfite or ammonium sulfite, aqueous or aqueous-alcoholic solution, and the interaction can be accelerated in the presence of tetralone-ammonium salts, as tetrabutylammonium.

As derivatives of sulfonic acids according to the formula (IV) in particular find application anhydrides of sulfonic acids. To obtain the corresponding sulfonic acids, also in the form of their salts, as sodium, ammonium or pyridinium salts, in a known manner enter into interaction with pentachloride phosphorus or thionyl chloride without solvent or in the presence of a solvent, as oxytrichloride phosphorus, or an inert solvent like dichloromethane, cyclohexane or chloroform, in General, when the reaction temperatures are from 20°C. up to the boiling point of the used reaction medium.

The interaction of derivatives of sulfonic acids of the formula (IV) with aminophosphonate acids of formula (III), (V) or (VII), according to the options method a), b) or C) preferably proceeds by reacting the Schotten's-Bauman. As grounds for this purpose, especially p. the alkali metals and amines. The interaction occurs in water and/or mixing or not mixing with the water solvent as tetrahydrofuran (THF), acetone, dioxane or acetonitrile, and the reaction temperature support, in General, in the range from -10°C to 50°C. In the case of carrying out the reaction in an anhydrous environment is used primarily tetrahydrofuran or dichloromethane, acetonitrile or dioxane in the presence of a base like triethylamine, N-methylmorpholine, N-ethyl - or diisopropylethylamine, possibly in the presence of N,N-dimethylaminopyridine as a catalyst.

According to other variants aminocarbonyl acid of formula (III), (IV) or (VII) first using cilleruelo funds as bis-trimethylsilyltrifluoroacetamide (BSTFA), you can translate in their Siciliano form and then enter into interaction with derivatives of sulfonic acids to obtain the compounds of formula (I).

Physiologically acceptable salts capable of salt formation of compounds of formula (I), including their stereoisomeric forms, get itself known. Phosphonic or phosphinic acid reagent of the main character as hydroxides, carbonates, bicarbonates, alcoholate, and also ammonia or with organic bases, such as, naprimer, for example, lysine, ornithine or arginine, form stable alkali metal salts, alkaline earth metal or perhaps substituted ammonium salt. If the compounds of formula (I) contain basic groups, using strong acids can also be obtained a stable salt accession acids. This is used as inorganic and organic acids as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, benzosulfimide, p-toluensulfonate, 4-bromobenzonitrile, cyclohexanedicarboxylate, triftormetilfullerenov, acetic acid, oxalic acid, tartaric acid, succinic acid or triperoxonane acid.

The invention relates also to medicines, characterized in that they contain an effective amount 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 and auxiliary substances.

On the basis of pharmacologic is of deseases, the course which involved a strong destructive activity matrix enzymes, as metalloproteinases or aggrecanases. These diseases include degenerative joint diseases like osteoarthritis, spondylosis, atrophy of cartilage after joint injuries or prolonged immobilization of the joints after injury meniscus or kneecap or torn ligaments. Further, these are also diseases of connective tissue, as collagenoses, periodontal disease, impaired wound healing, and chronic diseases of the musculoskeletal system as inflammatory, immunologically or metabolically due to acute and chronic skin lesions of rheumatic or gouty origin, arthropathies, myalgias and disturbances of bone metabolism. Further, the compounds of formula (I) are suitable for the treatment of ulceration, atherosclerosis and stenosis. The compounds of formula (I), further suitable for the treatment of inflammation, cancer, metastasis of tumors, cachexia, anorexia and septic shock. Proposed according to the invention the drug is administered, in General, oral or parenteral. It is also possible rectal or percutaneous introduction.

The invention otnoenie formula (I) together with a pharmaceutically suitable and physiologically acceptable carrier and, if necessary, other suitable biologically active substances, additives or auxiliary substances brought to a suitable form of application.

Suitable solid or galenovye forms of the compositions 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 biologically active substances, upon receipt of which use conventional tools, as media, parafora, binder, means for coating, contributing to the swelling means giving lubricity (tablets) of the substance or lubricants, flavorings, sweeteners tools and agents of dissolution. As commonly used excipients should indicate magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oil, as fish oil, sunflower oil, peanut oil or sesamol, polyethylene glycol and solvents such as, for example, sterile water and one - or polyhydric alcohols as glycerol.

The pharmaceutical preparation of the component contains a number of proposed according to the invention the compounds of formula (I). In the case of a solid single doses as tablets, capsules, coated tablets or suppositories, this quantity may be up to about 1000 mg, but preferably approximately from 50 to 300 mg, and in the case of injection solutions in the form of ampoules up to about 300 mg, but preferably about 10 to 100 mg.

For the treatment of adult patients weighing approximately 70 kg, depending on the effectiveness of the compounds according to formula (I), shows a daily dose of from about 20 mg to 1000 mg of biologically active substances, preferably about 100-500 mg Under certain conditions, however, you can also enter a higher or lower daily doses. The daily dose can be administered by a single dose in a single dose or, however, as several smaller doses, and by repeated administration of divided doses at certain intervals of time.

1H-NMR spectra were taken on the device 400 MHz (Bruker) or on the device 200 MHz firm Varian, usually with tetramethylsilane was (TMS) as internal standard and at room temperature (RT). Used solvents are indicated in each case. Target products, usually determined using methods of mass spectrometry (mass spray (ESI)); in each case, identified the main peaks. The temperature data are in degrees Celsius, RT means room temperature (22°C-26°C). Abbreviations are either explained or correspond to the customary.

Example 1

(R)-[1-(4’-Chlorodiphenyl-4-sulfonylamino)-2-methylpropyl] phosphonic acid

250 mg (1.6 mmol) of (R)-(1-Amino-2-methylpropyl)phosphonic acid are dissolved in 6 ml of 1 M NaOH and 6 ml of tetrahydrofuran. Then add 560 mg (1,96 mmol) 4-chlorodiphenyl-4’-sulphonylchloride and stirred at a temperature of 22°C during the night. The reaction mixture was concentrated, acidified with 2 M hydrochloric acid and extracted with ethyl acetate. Formed as a by-product 4-chlorodiphenyl-4’-acid precipitates and is separated. After drying and concentration of an ethyl acetate phase get a solid substance.

Yield: 136 mg (21%); molecular weight: 403,83;

1H-NMR (in DMSO-d6(hexacyanometallate)), (M. D.): 10,8 (ush. with 2N); 7,91, 7,82, 7,76, 7,63, 7,56 (5 d, N); a 3.06 (m, 1H); to 1.98 (m, 1H); 0,87, 0,80 (DD, 6N);

mass spectrometry (ESI, M+Na+): 425,9.

Example 2

Monotropy ester (R,S)-[1-(4’-chlorodiphenyl-4-sulfonylamino)-1-phenylmethyl]fastnot in 6 ml of 2 M NaOH solution and 10 ml of tetrahydrofuran. Then add 1.44 g (5,01 mmol) 4-chlorodiphenyl-4’-sulphonylchloride and stirred at a temperature of 22°C during the night. The formed precipitate was separated and distributed in a hot mixture of water with ethyl acetate. After acidification with hydrochloric acid to pH 1 to 2 ethylcatechol phase is separated and concentrated. Get a solid substance.

Yield: 610 mg (34%); molecular weight: 465;

1H-NMR (in DMSO-d6) (M. D.): 8,66 (ush. s, 1H); EUR 7.57 (m, N); 7,16 (m, 2H); 7,01 (m, 3H); 4,58 (DD, 1H); of 3.85 (m, 2H); 1,11 (m, 3H);

mass spectrometry (FAB; M+M+Na+): 466,0; 488,0.

Example 3

(R,S)-[(4’-Chlorodiphenyl-4-sulfonylamino)phenylmethyl]phosphonic acid

320 mg (0.69 mmol) of monoethylene ether obtained in example 2, is dissolved in 6 ml dichloromethane and at a temperature of 0°C is mixed with a 0.36 ml (2,75 mmol) trimethylsilylpropyne. After incubation for 4 h at room temperature, the reaction mixture is evaporated to dryness in a rotary evaporator and the remaining residue is treated with water. A solid substance was separated and the aqueous phase is subjected to drying by freezing.

Exit; 257 mg (80%); molecular weight: 436,8 g/mol;

1H-NMR (in DMSO-d6) (M. D.): 7,6 (m, 8H); to 7.2 (m, 2H); 7,0 (m, 3H); is levonline)-2-(1H-indol-3-yl)ethyl]phosphonic acid

150 mg (0,274 mmol) of the corresponding complex of diethyl ether are dissolved in 4 ml dichloromethane and at room temperature is mixed 0.11 ml (0.82 mmol) of trimethylsilylpropyne. After 3 h, the reaction mixture is evaporated to dryness in a rotary evaporator, the remaining residue is treated with diisopropyl ether and the solid is filtered off.

Yield: 42 mg (33%); molecular weight: 490,92;

1H-NMR (in DMSO-d6) (M. D.): 10,4 (s, 2H); 7,9, 7,68, 7,55 (3 d, 5H); 7,3, 6,9 (2 m, 8H); 3,7 (m, 1H); 3,2-2,6 (2m, 4H);

mass spectrometry (ESI+): 491,0.

Example 5

(R,S)-[1-(4’-Chlorodiphenyl-4-sulfonylamino)ethyl]phosphonic acid

To 178 mg (1.4 mmol) of (R,S)-1-aminoethylphosphonic acid in 30 ml of acetonitrile under nitrogen atmosphere add 733 mg (2.8 mmol) of N,O-bis-trimethylsilyl-trifurcated and within 2 h refluxed. After cooling to a temperature of 15°C add 490 mg (1.7 mmol) of 4’-chlorodiphenyl-4-sulphonylchloride in 15 ml of acetonitrile. Stirred for 3 h at room temperature, concentrated, mixed with methanol and again concentrated. The remainder chromatographic on silica gel using mixtures of dichloromethane with methanol in the ratio of 75:25 and 1% acetic acid.

mass spectrometry (ESI-): 374,1.

Example 6

(R,S)-[1-(4’-Chlorodiphenyl-4-sulfonylamino)-3-methylbutyl]phosphonic acid

To 222 mg (1 mmol) of the hydrochloride of (R,S)-1-amino-3-methylbutyrate acid in 30 ml of acetonitrile under nitrogen atmosphere add 516 mg (2 mmol) N,O-bis-trimethylsilyl-trifurcated and within 2 h refluxed. After cooling to a temperature of 15°C add 345 mg (1.2 mmol) of 4’-chlorodiphenyl-4-sulphonylchloride in 15 ml of acetonitrile. Stirred for 3.5 h at room temperature, concentrated, mixed with methanol and concentrated. The remainder chromatographic when using reversed phase18(RP18) using a mixture of acetonitrile with water (containing 0.1% triperoxonane acid) with gradient

acetonitrile from 10% to 100%.

Yield: 75 mg (18%); molecular weight: 417,85;

mass spectrometry (SI-): 416,1.

Specified in the following table 1 connection receive according to the methods of examples 1-6.

The drugs examples

Receipt and determination of enzyme catalytic activity is 3) and neutrophil collagenase (MMP-8) - receive according to Ye and others (Biochemistry, 31, 11231-11235 (1992)). To determine enzyme activity or action inhibitor of the enzyme 70 μl of buffer solution and 10 μl of an enzyme solution with 10 ál of 10% (volume/volume) aqueous solution of dimethyl sulfoxide, which, if necessary, contains an inhibitor of the enzyme, incubated for 15 minutes After adding 10 ál of 10% (volume/volume) aqueous solution of dimethyl sulfoxide containing 1 mmol/l of substrate, the enzyme reaction is monitored by fluorescence spectroscopy (328 nm (ex)/393 (em)).

Enzyme activity present in the form of increased extinction coefficient per minute. Listed in the table 2 values IR50defined as the concentration of inhibitor, which, respectively, lead to a 50% increase inhibition of the enzyme.

Buffer solution contains 0.05% Brij (Sigma, Deisenhofen, Germany) and 0.1 mol/l Tris/HCl, 0.1 mol/l NaCl, 0,01

mol/l CaCl2and 0.1 mol/l of piperazine-N,N’-bis[2-econsultancy] (pH 6.5).

The enzyme solution contains 5 mg/ml of one of the received according to Ye and other domains of the enzyme. The substrate solution contains 1 mmol/l fluorogenic substrate (7-methoxycoumarin-4-yl)acetyl-Pro-Lu-Gly-Lu-3-(2’,4’-dinitrophenyl)-L tion of the enzyme activity of the catalytic domain aggrecanases when using cells chondrosarcoma rats

To generate the still unidentified activity “aggrecanases used cell chondrosarcoma rats (RCS) (Lark and al., J. Biol. Chem., 270, 2550-2556 (1995)). Was carried out by seeding these cells on 96-well plates to cell cultures, pre-coated with poly-L-lysine (80,000 cells per well). After stimulation RCS cells with 0.67 µmol retinova acid and time of incubation 47 h at 37°C and 5% CO2these cells generate activity “aggrecanases”. The compound (1) as the test substance then pre-incubated for 1 h in containing “aggrecanases the supernatant of the cell culture before the introduction in the supernatant of cell culture RCS-cells 5 μg eukaryotic rAgglmutto detect cracking activity “aggrecanases” ( and al., Biochem. J., 333, 159-165 (1998); and Hughes and al., J. Biol. Chem., 272, 20269-20274 (1997)). After incubation for 4 h, the cell culture supernatant was collected and determined generated by the activity “aggrecanases” cleavage products rAgglmut-fused proteins by gel electrophoresis on polyacrylamide gel with sodium dodecyl sulfate and by Western blot analysis using monoclonal antibody BC-3 (Hughes and al., Biochem. J., 305, 799-804 (1995)). Actually the e defined split rAgglmutthe more effective of the tested compound of the formula (I).

Listed in the table 3 values IR50defined as inhibiting concentration, which, respectively, lead to a 50% increase inhibition of the enzyme aggrecanases.

1. Derivatives of phosphinic and phosphonic acids of the formula (I)

where R1means phenyl which may be substituted with halogen or pyrrolidino,

or-O-(C1-C6)-alkyl;

R2means a hydrogen atom;

R and R3are the same or different and mean a hydrogen atom, a linear or branched alkyl which can be substituted by indolium, phenyl which may be substituted by groups CF3or COOH, COOH group or

t denotes an integer of 1, 2, 3, 4;

And means covalent bond;

X is the group-CH=CH-;

In means a group -(CH2)about- where on means 0, 1, 2 or 3;

U mean-SO2- or-CO-;

Y1and Y2are the same or different and independently from each other mean-OH, -(C1-C4)-alkyl, which may be linear or branched, or-O-(C1-C4)-alkyl,CI acceptable salt.

2. The compound of formula (I) under item 1, wherein R1means phenyl which may be substituted with halogen or pyrrolidino, or-O-(C1-C6)-alkyl, R2means a hydrogen atom, R denotes a hydrogen atom, R3means a hydrogen atom, a linear or branched (C1-C6)-alkyl which can be substituted by indolium, phenyl which may be substituted by groups CF3or COOH, COOH group or

t denotes an integer of 1, 2, 3 or 4;

U mean-SO2-;

Y1means-HE;

Y2means-OH, -(C1-C4)-alkyl, which may be linear or branched, or-O-(C1-C4)-alkyl, which may be linear or branched;

And means covalent bond;

In means -(C1-C4)-alkyl;

X is-CH=CH-.

3. The compound of formula (I) under item 1 or 2, characterized in that the

R1means phenyl, which is substituted once by halogen;

R2 means a hydrogen atom;

R means a hydrogen atom;

R3means a hydrogen atom, a linear or branched (C1-C4)-alkyl, phenyl, which may be the P>U mean-SO2-;

Y1and Y2mean-HE or-O-CH3;

And means covalent bond;

In means -(CH2)about- where o is 1, 2 or 3;

X is-CH=CH-.

4. The compound of formula (I) under item 1, which represents the (R)-[1-(4’-chloro-diphenyl-4-sulfonylamino)-2-methylpropyl]-phosphonic acid; dimethyl [3-(4’-chloro-diphenyl-4-sulfonylamino)-1-hydroxy-3-(4-trifluoromethyl-phenyl)propyl] phosphonic acid; [1-(4’-chloro-diphenyl-4-sulfonylamino)-3-methyl-butyl]phosphonic acid or monotropy ester (R,S)-[1-(4’-chloro-diphenyl-4-sulfonylamino)-1-phenylmethyl]phosphonic acid.

5. The compound of formula (VI)

where R1, A, X, B, U, Y2, t, R2and R3have the meanings specified for compounds of formula (I) p. 1;

R8means hydrogen or (C1-C6)-alkyl,

and/or its stereoisomeric forms and/or physiologically acceptable salts.

6. The method of obtaining the compounds of formula (I) according to any one of paragraphs.1-5, characterized in that the ether aminophosphines or phosphonic acid of the formula (V)

where R2, R3, t, Y2and R8have listed in paragraph 5 values

to obtain the compounds of formula (VI)

and the compound of formula (VI) by removal of residue R8,

preferably in the presence of base or acid, is converted into a compound of formula (I), if necessary, the resulting compound of formula (I), which because of its chemical structure is in enantiomeric forms, by salt formation with enantiomerically pure acids or bases, by chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, the subsequent separation of the resulting diastereomers and removal of the chiral auxiliary groups, separated into pure enantiomers or the resulting compound of formula (I) or isolated in free form or, in the case of acidic or basic groups is converted into a physiologically acceptable salt.

7. Pharmaceutical composition having inhibitory activity against metalloproteinases and containing an effective amount of at least one of the compounds of formula (I) according to any one of paragraphs.1-5 together with a pharmaceutically suitable and physiologically acceptable carrier or additive.

The UP> mean (CH2)2-CH(COOH)-NH-SO2-C6H4-C6H4-Cl(n), and the compounds dimethyl [3-(4’-chloro-diphenyl-4-sulfonylamino)-1-hydroxy-3-(4-trifluoromethyl-phenyl)propyl] phosphonic acid and [1-(4’-chloro-diphenyl-4-sulfonylamino)-3-methyl-butyl]phosphonic acid".

 

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