DE19542189A1 - New cyclic alpha-imino:hydroxamic acid derivatives - Google Patents

Abstract

N-Sulphonyl cyclic alpha -iminohydroxamic acid derivatives of formula (I) and their stereoisomers and salts are new. R<1> = R<5>-C6H4-X-C6H4-A-, 5-, 6-, 7- or 8-isoquinolinyl, Z-p-C6H4-A-, a tricyclic group of formula (a), a heterocyclic group of formula (b) (in which one C atom is optionally replaced by Y), a benzazole group of formula (c), naphthyl (optionally substituted by 1-3 groups R<5>) or R; R = phenyl substituted by R<2>, R<3> and R<4>; R<2>-R<5> = H, 1-10C alkoxy, OH, COOH, 3-6C cycloalkyl, (3-6C) cycloalkyl-O-(1-4C) alkyl, halogen, CN, NO2, CF3, OR<13>, OAr, OCOR<13>, OCOAr, NR<8>R<9>, COOR<13>, CONR<8>R<9>, CONR<14>R<15>, guanidino or OCH2O (bonded to adjacent C); m, n = 0-2, provided that: (i) m+n = 1-3 and R<1> is other than R; (ii) m and n are different and R<1> = R; or (iii) m = n = 1, R<1> = R and R<2>-R<4> (as substituents in formula (I), rather than in R) and R<5> are other than H; Z = pyrrolyl, triazolyl, pyrazolyl, dihydropyrazolyl, imidazolyl, pyrrolinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, tetrazolyl, thiazolyl, thiazolinyl, thiazolidinyl, phenyl, pyridinyl, thienyl, oxazolyl, isoxazolyl, thiadiazolyl, morpholinyl, pyrimidinyl, pyrazinyl, piperazinyl or a group (b) in which A = a bond and one C atom is replaced by Y; p = 1 or 2; R<12> = H, halo, OH, 1-5C alkyl or 1-5C alkoxy; Ar = phenyl substituted by 1 or 2 R<5>; R<8> = H, benzyl or 1-4C alkyl; R<9> = H, benzyl, COR<13>, OCOR<13> or 1-4C alkyl; NR<14>R<15> = pyrrolidino, piperidino, morpholino or piperazino; R<13> = phenyl, benzyl, 1-6C alkyl or 3-6C cycloalkyl; X = a bond, O, S, SO, SO2, CO, -C(OH)-(sic) or NR<10>; R<10> = H or 1-4C alkyl; Y = O, S or NR<11>; R<11> = H, 1-6C alkyl, phenyl, benzyl, COR<13>, COOR<13> or substituted phenyl; A = (CH2)q or CH=CH; and q = 0-4.

Description

The invention relates to cyclic N-substituted α-iminohydroxamic acids, Process for their preparation and use thereof as a medicament.

EP 0 606 046 describes some arylsulfonamido-hydroxamic acid derivatives described and their effect as matrix metalloproteinase inhibitors.

In pursuit of more effective compounds for the treatment of To find connective tissue diseases, it has now been found that the Iminohydroxamic acid derivatives inhibitors of Metalloproteinases are.

The invention relates to a compound of formula I.

and / or an optionally stereoisomeric form of the compound of formula I and / or a physiologically tolerable salt of the compound of formula I, in which case i)
R¹ for

• a) a radical of formula II
• b) a radical of the formula III
• c) a radical of the formula IV
• d) a radical of the formula VI where Z
  1) pyrrole,
  2) triazole,
  3) pyrazole,
  4) dihydropyrazole,
  5) imidazole,
  6) pyrroline,
  7) pyrrolidine,
  9) pyrazolidine,
  10) imidazoline,
  11) imidazolidine,
  12) piperidine,
  13) tetrazole,
  14) thiazole,
  15) thiazoline,
  16) thiazolidine,
  17) benzene,
  18) pyridine,
  19) thiophene,
  20) oxazole,
  21) isoxazole,
  22) thiadiazole,
  23) morpholine,
  24) pyrimidine,
  25) pyrazine,
  26) piperazine or
  27) a radical of the formula VII where p is 1 or 2 and a carbon atom is Y,
• e) a radical of the formula VIII where o is 1 or 2,
• f) a radical of formula VIII, wherein a carbon atom of Ring system has the meaning Y,
• g) a radical of the formula IX wherein R¹²
  1) hydrogen atom,
  2) halogen,
  3) hydroxyl,
  4) (C₁-C₅) alkyl or
  5) means (C₁-C₅) alkoxyl,
• h) naphthyl or
• i) naphthyl, mono- or trisubstituted by R⁵, and

n stands for zero, 1 or 2,
m stands for zero, 1 or 2, the sum of n and m being 1, 2 or 3, and
R², R³, R⁴ and R⁵ are the same or different and are for

• a) hydrogen atom, or
• b) the meaning of R¹ for case ii), point 2.1. until 2.19., or

where in case ii)
R¹ for

• 1) phenyl or
• 2) Phenyl mono- to trisubstituted by
  • 2.1. (C₁-C₁₀) alkoxyl,
  • 2.2. -OH,
  • 2.3. -COOH,
  • 2.4. (C₃-C₆) cycloalkyl,
  • 2.5. (C₃-C₆) cycloalkylO- (C₁-C₄) alkyl,
  • 2.6. Halogen,
  • 2.7. -CN,
  • 2.8. -NO₂,
  • 2.9. -CF₃,
  • 2.10. -O-R¹³,
  • 2.11. -O-phenyl, mono- or disubstituted by R⁵,
  • 2.12. -OC (O) -R¹³,
  • 2.13. -OC (O) -phenyl, mono- or disubstituted by R⁵,
  • 2.14. -NR⁸R⁹, where R⁸ is hydrogen, benzyl or (C₁-C₄) alkyl, and wherein
    R⁹ 1) hydrogen atom,
    2) benzyl,
    3) -C (O) -R¹³,
    4) -OC (O) -R13 or
    5) means (C₁-C₄) alkyl,
  • 2.15. -C (O) -O-R¹³,
  • 2.16. -C (O) -NR⁸R⁹, where R⁸ and R⁹ as under 2.14. are defined
  • 2.17. -C (O) -NR¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ together with the N atom to which they are attached, one
    1) pyrrolidine residue,
    2) piperidine residue,
    3) morpholine residue or
    4) form piperazine residue,
  • 2.18. -NC (NH) -NH₂, or
  • 2.19. adjacent carbon atoms in the ring contain the radical -O-CH₂-O-, and where
    R¹³ 1) phenyl,
    2) benzyl,
    3) (C₁-C₆) alkyl or
    4) (C₃-C₆) cycloalkyl, and

n means zero, 1 or 2 and
m is zero, 1 or 2, and the meaning of n and m is not the same, and
R², R³, R⁴ and R⁵ are the same or different and are for

• a) hydrogen atom, or
• b) the meaning of R¹ for case ii), point 2.1. until 2.19. have, or

where in case iii)
R¹ is as defined for case ii),
n 1 means
m means 1 and
R², R³, R⁴ and R⁵ are the same or different and the meaning of R¹ for case ii), points 2.1. to 2.19., and
X for

• a) a covalent bond,
• b) -O-,
• c) -S-,
• d) -S (O) -,
• e) -S (O) ₂-,
• f) -C (O) -,
• g) -C (OH) - or
• h) -N (R¹⁰) -, in which R¹⁰ represents hydrogen atom or (C₁-C₄) alkyl, stands, and

Y for

• a) -O-,
• b) -S- or
• c) -N (R¹¹) -, wherein R¹¹
  1) hydrogen atom,
  2) (C₁-C₆) alkyl,
  3) phenyl,
  4) benzyl,
  5) -C (O) -R¹³,
  6) -C (O) -O-R¹³ or
  7) substituted phenyl,
  stands, and

A for

• a) - (CH₂) _q -, where q is zero, 1, 2, 3 or 4, or
• b) -CH = CH- stands.

Preferred is a compound of formula I and / or a physiologically acceptable salt of the compound of formula I and / or an optionally stereoisomeric form of the compound of formula I, wherein
R 1 in the case i) represents a radical of the formula II,
R¹ for case ii) represents morpholinyl, phenyl or phenyl, mono- to trisubstituted by methoxy, or
R¹ for case iii) is phenyl, mono- to trisubstituted by methoxy, and
A represents a covalent bond,
X represents oxygen atom, and
R², R³, R⁴ and R⁵ are the same or different and are for

• a) hydrogen atom,
• b) methoxy or
• c) -O-CH₂-O- stand.

The compounds are particularly preferred 2- (4-phenoxybenzenesulfonyl) -1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid, 2- (morpholinosulfonyl) -1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid, 1- (4- Methoxybenzenesulfonyl) indoline-2-hydroxamic acid, 2- (4-methoxybenzenesulfonyl) - 6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid and 2- (4-methoxybenzenesulfonyl) -6,7-methylenedioxy-1,2,3,4-tetrahydroisoc-hinolin-3- hydroxamic acid.

The term halogen means fluorine, chlorine, bromine or iodine. The term alkyl or alkoxyl is understood to mean residues thereof Carbon chain can be straight-chain, branched or cyclic. Cyclic Alkyl radicals are, for example, 3- to 6-membered monocycles such as cyclopropyl, Cyclobutyl, cyclopentyl or cyclohexyl.

To the "radical of formula VII or VIII, wherein a carbon atom has the meaning Y has "include, for example, isoxazolidine, morpholine, isothiazolidine, Thiomorpholine, pyrazolidine, imidazolidine or piperazine.  

Suitable physiologically acceptable salts of the compound of formula I are for example alkali, alkaline earth and ammonium salts including those of organic ammonium bases or basic amino acids.

The invention also relates to a method for producing the compound of Formula I and / or a physiologically acceptable salt of the compound of Formula I and / or an optionally stereoisomeric form of the compound of Formula I, which is characterized in that one

• a) an imino acid of the formula XII wherein radicals R², R³ and R⁴, as well as n and m as defined in formula I, are reacted with a (C₁-C₄) alcohol or a benzyl alcohol to give the compound of the formula XIII, wherein R _{x is} (C₁-C₄) alkyl or benzyl, or
• b) a compound of the formula XIII prepared by process a) with the compound of the formula XIV, in which R _z denotes chlorine atom, imidazolyl or -OH, in the presence of a base, to give a compound of the formula XV, wherein R¹, R², R³, R⁴, n and m are as defined in formula I and R _{x is} as defined in formula XIII, or
• c) a compound of the formula XIII prepared by process a) with a Base reacted and then with a compound of formula XIV a compound of formula XV, or
• d) reacting a compound of formula XII with a compound of formula XIV to a compound of formula XVI wherein R¹, R², R³, R⁴, n and m are as defined in formula I, or
• e) converting a compound of the formula XV into a compound of the formula XVI, or
• f) converting a compound of the formula XV prepared by process b) or c) with the hydroxylamine of the formula XVII (XVII) H₂N-OR _y in which R _{y is a} hydrogen atom or an oxygen protecting group, converted to the compound of the formula I and optionally splitting off the oxygen protecting group, or
• g) a compound of the formula XVI prepared by process d) or e) with the hydroxylamine of formula XVII to the compound of formula I. implements, or
• h) a compound of the formula I prepared by process f) or g), which occurs in enantiomeric forms due to its chemical structure, by salt formation with enantiomerically pure acids or bases, Chromatography on chiral stationary phases or derivatization using Chiral enantiomerically pure compounds such as amino acids, separation of the diastereomers thus obtained, and cleavage of the chiral Separates auxiliary group into the pure enantiomers, or
• i) the compound of the formula I prepared by processes f), g) or h) either isolated in free form or in the presence of acid or basic groups, if necessary in physiologically acceptable Converts salts.

The reaction in process step f) is carried out under normal conditions in a suitable solvent.

The implementation according to process step a) takes place in the case of (C₁-C₄) - Alcohols in the presence of HCl gas or thionyl chloride under usual Reaction conditions. The preparation of the corresponding benzyl ester Formula XIII takes place in benzene or toluene with the corresponding alcohol as well an acid such as p-toluenesulfonic acid. Tertiary butyl esters can be, for example Produce using known processes with isobutene and sulfuric acid.  

The reaction in process step b) is carried out in the presence of a basic compound such as N-methylmorpholine (NMM), N-ethylmorpholine (NEM), Triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, collidine, imidazole or sodium carbonate in solvents such as tetrahydrofuran (THF), Dimethylformamide (DMF), dimethylacetamide, dioxane, acetonitrile, toluene, Chloroform or methylene chloride, or in the presence of water. The sulfonic acid chlorides of the formula XIV are preferred in the presence of NMM used in THF.

The reaction in process step c) is carried out in the presence of a base such as KOH, LiOH or NaOH.

The reaction according to process step d) takes place in an aqueous organic Solvent system, preferably in THF and water in the presence of one Base such as sodium carbonate and the compound of formula XIV. Furthermore, the Reaction without solvent with or without base under reduced pressure, as achieved by an oil pump.

The saponification of the compound of formula XV to the compound of Formula XVI (process step e)) is, for example, basic, preferred acidic or in the case of the benzyl derivatives by hydrogenolysis. In the case of basic saponification it is necessary to treat the carboxylic acid with a other acid e.g. B. dilute hydrochloric acid, from the carboxylic acid salt release.

In the reaction according to process step g), the carboxylic acids are the Formula XVI activated. Activated carboxylic acids are, for example, acylhalo genides, acyl azides, mixed anhydrides and carbonates. Are preferred Acyl chlorides or fluorides, mixed anhydrides and carbonates Pivaloyl chloride, ethyl, isopropyl or isobutyl chloroformate; Most active like Cyanoethyl, o- or p-nitrophenyl, succinimido or phthalimido, as well as the  through the coupling reagents such as diisopropylcarbodiimide (DIC), carbonyldi imidazole (CDI), dicyclohexylcarbodiimide (DCC) or benzotriazolyltetramethyl uronium tetrafluoroborate (TBTU), optionally with the addition of Hydroxybenzotriazole (Hobt) or Oxohydroxybenzotriazin (HOObt) activated carboxylic acids.

The starting products and reagents used can either be after known methods are prepared or are commercially available.

If the compound of formula I in diastereoisomeric or enantiomeric form occurs and occurs in the selected synthesis as its mixtures, succeeds Separation into the pure stereoisomers either by chromatography an optionally chiral carrier material, or, if the racemic Compound of formula I is capable of salt formation by fractional Crystallization with an optically active base or acid as an auxiliary formed diastereomeric salts. As chiral stationary phases for the Separation of enantiomers by thin layer or column chromatography For example, modified silica gel carriers (so-called pirkle phases) are suitable as well as high molecular carbohydrates such as triacetyl cellulose. For analytical Purposes are after corresponding derivatization known to the person skilled in the art, also gas chromatographic methods on chiral stationary phases applicable. For the enantiomer separation of the racemic carboxylic acids with an optically active, usually commercially available base such as (-) - Nicotine, (+) - and (-) - phenylethylamine, quinine bases, L-lysine or L- and D-arginine formed the differently soluble diastereomeric salts that the more soluble component is isolated as a solid, the more soluble one Diastereomer separated from the mother liquor, and from the thus obtained diastereomeric salts obtained the pure enantiomers. In principle in the same way you can the racemic compounds of formula I, the one contain basic group such as an amino group, with optically active acids, such as (+) - camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L-lactic acid  and convert (+) and (-) - mandelic acid into the pure enantiomers. Also can be chiral compounds containing alcohol or amine functions, with appropriately activated or possibly N-protected enantiomerically pure amino acids in the corresponding esters or amides, or vice versa chiral carboxylic acids with carboxy-protected enantiomerically pure Amino acids in the amides or with enantiomerically pure hydroxycarboxylic acids like lactic acid, convert into the corresponding chiral esters. Then can the chirality of the amino acid or introduced in enantiomerically pure form Alcohol residue can be used to separate the isomers by using a Separation of the diastereomers now present by crystallization or Chromatography on suitable stationary phases and then the carried away chiral part of the molecule cleaves again by suitable methods.

Acidic or basic products of the compound of formula I can be in the form of their Salts or in free form. Pharmacological are preferred compatible salts, e.g. B. alkali or alkaline earth metal salts or hydrochlorides, Hydrobromides, sulfates, hemisulfates, all possible phosphates and salts of Amino acids, natural bases or carboxylic acids.

Hydroxylamine can be obtained in free form, from hydroxylamine salts and one suitable base in solution or in O-protected form or in each case in Form of its salts can be used. The production of free hydroxylamine is known from the literature and can be used, for example, in alcoholic solution. The use of the hydrochloride together with alcoholates is preferred such as sodium methoxide, potassium hydroxide or potassium t-butoxide.

O-protected hydroxylamine derivatives preferably contain mild Protective groups that can be split off under conditions. Are particularly preferred here Protecting groups of the silyl, benzyl and acetal type. Are particularly suitable the O-trimethylsilyl, O-tertiary-butyldimethylsilyl, O-benzyl, O-tertiary butyl and O-tetrahydropyranyl derivative.  

Starting compounds and intermediates used in the manufacture of Compound of formula I can be used, if functional Groups such as hydroxyl, thiol, amino or carboxyl, e.g. B. in the radicals R¹, R², R³, R⁴ or R⁵ are included, used in a suitably protected form.

The introduction of protective groups is necessary in all cases where in a desired chemical reaction on other than that Reaction centers undesirable side reactions are expected (T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991).

The protective groups used can be before or after the implementation of the Compound of formula XII to be split off to the compound of formula I.

The following can be used in particular as auxiliaries and bases: Hobt, HOObt, N-hydroxysuccinimide (HOSu), TEA, NMM, NEM, DIPEA, imidazole. Preferred solvents for the reaction are: dichloromethane (DCM), THF, Acetonitrile, N, N-dimethylacetamide (DMA), DMF and N-methylpyrrolidone (NMP). The preferred temperatures are between -78 ° C and + 90 ° C, depending on Boiling temperature and type of solvent used. Particularly preferred is the temperature range from -20 to + 30 ° C.

The production of physiologically compatible salts from those capable of salt formation Compounds of formula I, including their stereoisomeric forms, takes place in a manner known per se. The carboxylic acids and hydroxamic acids form with basic reagents such as hydroxides, carbonates, hydrogen carbonates, Alcoholates and ammonia or organic bases, for example Trimethyl- or triethylamine, ethanolamine or also basic amino acids, about lysine, ornithine or arginine stable alkali, alkaline earth or, if appropriate substituted ammonium salts. If the compounds of the formulas I are basic Has groups, can also be stable with strong acids Prepare acid addition salts. Both inorganic and  organic acids, such as hydrogen chloride, hydrogen bromide, sulfur, Phosphorus, methanesulfone, benzenesulfone, p-toluenesulfone, 4-bromobenzene-sulfone, Cyclohexylamido sulfone, trifluoromethyl sulfone, vinegar, oxal, wine, amber or Trifluoroacetic acid in question.

The invention also relates to medicinal products characterized by an effective one Content of at least one compound of formula I and / or one physiologically acceptable salt of the compound of formula I and / or optionally stereoisomeric form of the compound of formula I, wherein the R¹, R² and R³ are as defined in formula I, together with a pharmaceutically suitable and physiologically compatible carrier, Additive and / or other active and auxiliary substances.

Due to the pharmacological properties, the Compounds according to the invention for the prophylaxis and therapy of all such Diseases, on the course of which an increased activity of matrix-degrading Metalloproteinases is involved. These are diseases of the Connective tissue such as collagenosis, periodontal diseases, wound healing disorders and chronic musculoskeletal disorders such as inflammatory, immunological or metabolic acute and chronic Arthritis, arthropathy, myalgia and disorders of bone metabolism. This also includes degenerative joint diseases such as Osteoarthrosis, spondylosis, cartilage loss after joint trauma or prolonged immobilization of the joints after meniscus or patella injuries or Torn ligaments. The compounds of the formula I are also suitable for treatment ulceration, atherosclerosis and stenosis. Furthermore, they suppress Compounds of Formula I clearly have the cellular tumor necrosis factor Generation and are therefore suitable for the treatment of inflammation, Cancer, tumor metastasis, cachexia, anorexia and septic shock.  

The invention also relates to a method for producing a medicament, characterized in that at least one compound of the formula I with a pharmaceutically suitable and physiologically compatible carrier and optionally other suitable active ingredients, additives or auxiliaries in one brings suitable dosage form.

Suitable solid or galenical forms of preparation are, for example Granules, powders, coated tablets, tablets (micro) capsules, suppositories, syrups, Juices, suspensions, emulsions, drops or injectable solutions as well Preparations with protracted release of active ingredients, which are common in their manufacture Auxiliaries, such as carriers, explosives, binders, coating, swelling, sliding or Lubricants, flavors, sweeteners and solubilizers, Find use. Magnesium is a commonly used auxiliary carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, Milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, Polyethylene glycol and solvents such as sterile water and one or polyhydric alcohols such as glycerin.

The pharmaceutical preparations are preferably in dosage units manufactured and administered, each unit as an active ingredient contains certain dose of the compound of formula I according to the invention. At solid dosage units such as tablets, capsules, coated tablets or suppositories, this dose can be up to about 1000 mg, but preferably about 50 to 300 mg and for ampoule injection solutions up to about 300 mg, preferably but about 10 to 100 mg.

For the treatment of an adult patient weighing approximately 70 kg, daily doses of approximately 20 mg to 1000 mg of active ingredient, preferably approximately 100 mg to 500 mg, are indicated, depending on the effectiveness of the compounds according to formula I. Under certain circumstances, however, higher or lower daily doses may also be appropriate. The daily dose can be administered either by single administration in the form of a single dosage unit or else several smaller dosage units, or by multiple administration of divided doses at certain intervals.
1 H-NMR spectra were recorded on a 200 MHz device from Varian, usually with tetramethylsilane (TMS) as the internal standard and at room temperature (RT). The solvents used are given in each case. End products are usually determined by mass spectroscopic methods (FAB-, ESI-MS). Temperatures in Celsius degrees, RT means room temperature (22-26 ° C). Abbreviations used are either explained or correspond to the usual conventions.

General working instructions Tic benzyl ester p-toluenesulfonate (Tic: 1,2,3,4-tetrahydroisoquinoline-3 carboxylic acid)

1 mol of Tic (free amino acid), 10 mol of benzyl alcohol and 1 mol of p-toluenesulfonic acid monohydrate are dissolved or suspended in 1.2 l of toluene and heated under reflux on a water separator. After the reaction has ended, the solvent is evaporated off, the solid, crystalline residue is taken up several times in diethyl ether and filtered off with suction and then dried in an oil pump vacuum.
Yield: quantitative.
1 H-NMR: (200 MHz, δ in ppm, DMSO-d₆) 9.7 (s, br., 2 H, prot.NH), 7.5-7.25 (2m, 7H, aromatic), 7 , 1 (d, 2H, aroma p-TsOH), 5.3 (s, 2H, CH₂ benzyl); 4.7 (dd, 1H, CHα); 4.4 "d", 2H, CH₂); 3.4-3.1 (m, 2H, CH₂); 2.3 (s, 1H, CH₃ p-TsOH).

Tic sulfonation

0.1 mol of Tic solution (free amino acid 17.7 g) in 50 ml of 2 N aqueous NaOH finely powdered sulfonic acid chloride (105 mmol) was added at 0 ° C., followed of 14.2 g (110 mmol) of diisopropylethylamine and 50 ml of acetone or THF. After The ice bath is removed for 10 minutes and the more or less homogeneous solution stirred for a further 6 h at RT. The reaction mixture is then concentrated, mixed with 300 ml of ethyl acetate and acidified with 4 N HCl. The organic Phase is separated off, the aqueous phase is washed twice with 50 ml each Extracted ethyl acetate. The combined organic phases are with shaken out saturated NaCl solution and dried over sodium sulfate. After the solvent has been distilled off, the sulfonated remains Tetrahydroisoquinoline carboxylic acid as an oily or solid residue, which in in some cases purified by recrystallization from ethyl acetate / petroleum ether can be, but often also sufficiently pure for further implementation is.

example 1 2- (4-phenoxybenzenesulfonyl) -1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid 1a: 2- (4-phenoxybenzenesulfonyl) -1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid methyl ester

A solution of 1.92 g (0.01 mol) of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester and 2.7 g (0.01 mol) of 4-phenoxybenzenesulfonic acid chloride in 50 ml of absolute THF are in the presence of 1.7 ml (0.01 mol) of N-ethylmorpholine heated under reflux for 8 h. After removing the solvent, the residue is taken up in dichloromethane and shaken out successively with 5% citric acid, 5% sodium bicarbonate solution and 2 × with water. Drying over sodium sulfate and concentrating the organic phase gives the ester, which is reacted further without purification.
Yield: 4.0 g (95% of theory).

1b: 2- (4-phenoxybenzenesulfonyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

A solution of 4.0 g (9.5 mmol) of the ester (1a) in 50 ml of isopropanol is stirred for 24 hours at RT after addition of 9.5 ml of 1N sodium hydroxide solution. It is then acidified with 1N hydrochloric acid and the mixture is evaporated to dryness in vacuo. The residue is taken up in toluene, extracted with 5% citric acid and, after drying the organic phase over sodium sulfate, evaporated in vacuo.
Yield: 3.4 g of carboxylic acid 1b (83% of theory).
1 H NMR (DMSO-d₆): 12.8 (s, 1H, COOL); 7-7.85 (m, 13H, aroma); 4.8 (t, 1H-C (3)); 4.58; 4.45 (AB, 2H-C1); 3.08 (2H-C (4)).

1c: 2- (4-phenoxybenzenesulfonyl) -1,2,3,4-tetrahydroisoquinoline-3- hydroxamic acid

3.4 g (8.3 mmol) of carboxylic acid 1b are dissolved in 30 ml of DMF and successively at -20 ° C. with 1.4 g (12 mmol) of N-ethylmorpholine and 1.13 g (8.3 mmol) of isobutyl chloroformate transferred. After an activation time of 30 min, 4.37 g (41.5 mmol) of O-trimethylsilylhydroxylamine are added and stirring is continued for 4 h at RT. After adding 250 ml of ethyl acetate and 500 ml of water, it is acidified with citric acid. After separating the organic phase and shaking the aqueous phase 4 times, the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. Recrystallization from toluene / ethyl acetate (1: 1) gives the hydroxamic acid 1.
Yield: 2.9 g (82% of theory) Melting point: 164-166 ° C (decomposition).
1 H NMR: (DMSO-d₆) 10.75, 8.91 (2s, 2H, NHOH); 7.83-7.1 (m, 13H, aroma); 4.6, 4.5 (dd, 2H-C1); 4.41 (t, 1H-C3); 2.85, 2.9 (2s, 2H-C4).

Example 2 2- (morpholinosulfonyl) -1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid- 2a: 2- (morpholinosulfonyl) -1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid methyl ester

To a solution of 4.8 g (0.025 mol) of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester and 2.9 g (0.025 mol) of N-ethylmorpholine are added 4.2 g (0.025 mol) of morpholine with stirring. N-sulfonic acid chloride added dropwise in 20 ml of THF. After stirring at RT for 2 h, the reaction is heated to reflux after 2 h to complete. After treatment of the CHCl₃-enriched reaction solution with 5 percent citric acid, 5 percent NaHCO₃ solution and water, the organic phase is dried over Na₂SO₄ and concentrated to dryness.
Yield of ester (2a): 7.5 g (92% of theory).

2b: 2- (morpholinosulfonyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

Reaction of 7.5 g (0.023 mol) 1b analogously to 2a.
Yield of carboxylic acid 2b: 6.7 g (93% of theory)

2c: 2- (morpholinosulfonyl) -1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid -

2.3 g (7.5 mmol) of carboxylic acid 2b are dissolved in 40 ml of absolute THF and successively at -20 ° C. with 1.2 g (12 mmol) of N-methylmorpholine and 1.1 g (7.5 mmol) Isobutyl chloroformate added. After 30 min, 3.9 g (37.5 mmol) of O-trimethylsilylhydroxylamine are added and the mixture is stirred at RT for a further 5 h. After adding 200 ml of water, it is acidified with dilute HCL and shaken out several times with dichloromethane. The collected organic phases are dried over Na₂SO₄ and evaporated in vacuo. The oil obtained is chromatographed on silica gel 60 under pressure using ethyl acetate / dichloromethane (1: 1) as the mobile phase. Recrystallization of the product fractions from ethyl acetate gave crystalline hydroxamic acid 2c.
Yield: 1.4 g (55% of theory) Melting point: 164-165 ° C (decomposition).
1 H NMR: (DMSO-d₆) 10.65, 8.9 (2s, 2H, NHOH); 7.2 (s, 4H, aroma); 4.65, 4.5 (AB, 2H-C1); 4.38 (t, 1H-C3); 3.65, 2.9 (4HCH₂CH₂; 2H-C4)

Example 3 1- (4-methoxybenzenesulfonyl) indoline-2-hydroxamic acid 3a: 1- (4-methoxybenzenesulfonyl) indoline-2-carboxylic acid

1 g (6.1 mmol) of indoline-2-carboxylic acid and 2.5 g (12.2 mmol) of 4-methoxybenzene sulfonyl chloride are at 50 ° C and 0.02 mbar for 4 hours (h) in a Kugelrohr with constant slow turning leave. The brownish, crystalline product is then taken up in sodium carbonate solution and extracted twice with diethyl ether. The aqueous phase is acidified with 6N HCl and extracted four times with ethyl acetate. After being shaken out with saturated NaCl solution, the combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. Remaining solvent residues are removed in an oil pump vacuum.
Yield: 1.34 g, (65% of theory).
1 H NMR: (DMSO-d₆) 7.8; 7.1 (2d, 4H, aroma p-TsOH); 7.4-7.0 (m, 4H, aroma); 4.9 (dd, 1H, CHα); 3.8 (2, 3H, OMe); 3.4-2.9 (2 dd, 2H, CH₂).

3b: 1- (4-methoxybenzenesulfonyl) indoline-2-hydroxamic acid

1.3 g (3.9 mmol) of 1- (4-methoxybenzenesulfonyl) indoline-2-carboxylic acid according to Example 3a are dissolved in 10 ml of N, N-dimethylacetamide (DMA) and successively at -20 ° C. with 0, 37 ml (1 equivalent) of chloroformate and 0.81 ml of N-methylmorpholine were added. After an activation time of 30 minutes (min), 3.8 ml (19.5 mmol) of O-trimethylsilylhydroxylamine are added and stirring is continued for 4 h at RT. After dilution with ethyl acetate, it is acidified with citric acid and, after the aqueous phase has been separated off, washed with saturated NaCl solution. The organic phase is dried over sodium sulfate, filtered off and evaporated under reduced pressure. The oil obtained is chromatographed on silica gel 60 under pressure using dichloromethane / ethyl acetate / acetic acid 5.5 / 3.5 / 1 as the mobile phase. Product fractions (with a positive iron (III) chloride reaction) are combined and evaporated. The crystalline product is then mixed with diethyl ether and freed from solvent residues under reduced pressure.
Yield: 400 mg (33% of theory). Melting point: 142 ° C.
1 H NMR: (DMSO-d₆) 10.9 and 9.1 (2s, 2H, NHOH); 7.8; 7.1 (2d, 4H, aroma p-TsOH); 7.4-7.0 (m, 4H, aroma); 4.6 (dd, 1H, CHα); 3.8 (s, 3H, OMe), 3.2-2.8 (2 dd, 2H, CH₂) ESI-MS: M + H 349.

Example 4 2- (4-methoxybenzenesulfonyl) -6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline-3- hydroxamic acid 4a: 2- (4-methoxybenzenesulfonyl) -6,7,8-trimethoxy-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid

The benzyl ester is prepared according to the general working instructions. 1.2 g (3.05 mmol) of the benzyl ester are used for the sulfonation. This is dissolved in 20 ml THF and at 0 ° C with 0.63 g (3.05 mmol) 4-methoxybenzenesulfonyl chloride added. After adding 0.32 ml  N-methylmorpholine is stirred at 0 ° C to room temperature overnight. Then it is mixed with 20 ml of ethyl acetate and with 10 percent Sodium carbonate solution and saturated NaCl solution shaken out. The organic phase is dried over sodium sulfate, filtered and under evaporated under reduced pressure. The remaining residue is on silica gel 60 chromatographed with ethyl acetate / petrol ester / glacial acetic acid 20/10/1 under pressure. Pure product fractions (600 mg) are combined and after concentration hydrogenated directly with 100 mg 10% Pd / C in 50 ml ethanol. After completing the Reaction, the catalyst is separated off and the remaining solution under evaporated under reduced pressure. 330 mg (66% of theory) are obtained.

4b: 2- (4-methoxybenzenesulfonyl) -6,7,8-trimethoxy-1,2,3,4- tetrahydroisoquinoline-3-hydroxamic acid

330 mg (0.75 mmol) of the carboxylic acid from Example 4a are dissolved in 15 ml of THF and successively at -20 ° C. with 0.07 ml (0.75 mmol) of ethyl chloroformate and 0.15 ml (1.5 mmol) N-methylmorpholine (NMM) added. After 30 min at this temperature, 0.474 ml of O-trimethylsilylhydroxylamine (3.75 mmol) is added. After 6 h at RT, 30 ml of ethyl acetate are added and the mixture is shaken with 20 percent aqueous citric acid and saturated NaCl solution. After drying the organic phase over sodium sulfate and evaporation under reduced pressure, 290 mg of a light, viscous oil remain, which becomes crystalline on treatment with diethyl ether.
1 H NMR: (DMSO-d₆) 10.7; 8.8 (2s, 2H, NHOH); 7.7; 7.0 (2d, 4H, ar. Sulfonate); 6.6 (s, 1H, ar.); 4.4 (m, 2H, CHα, CH₂β); 3.8 (m, approx. 10H, OMe, CH₂); 2.7 (m, 2H, CH₂) ESI-MS: M + H 453.

Example 5 2- (4-methoxybenzenesulfonyl) -6,7-methylenedioxy-1,2,3,4-tetrahydroisoc-hinolin-3- hydroxamic acid

The preparation of the corresponding carboxylic acid benzyl ester from the carboxylic acid corresponds to the general working instructions. For sulfonation or benzyl ester cleavage, the procedure is analogous to Example 4a. The free, sulfonated carboxylic acid is reacted as described under 4b. The product is obtained in crystalline form after treatment with diethyl ether.
Yield: 140 mg, 57% of theory. Theory; Melting point 166 ° C.
1 H NMR: (DMSO-d₆) 10.7; 8.8 (2s, 2H, NHOH); 7.7; 7.0 (2d, 4H, ar. Sulfonate); 6.8; 5.9 (2d, 4H, ar, CH₂); 4.4 (m, 3H, CHα, CH₂β); 3.8 (s, 3H, OMe); 2.7 (m, 2H, CH₂) ESI-MS: M + H 407.

Example 6 Determination of the enzymatic activity of the catalytic domain of the human stromelysins and neutrophil collagenase

The two enzymes are presented according to Ye et al. (Biochemistry 31 (1992) Pages 11231 to 11235). For measuring enzyme activity or Enzyme inhibitor effect with 70 ul buffer solution and 10 ul enzyme solution 10 ul of a 10 percent (v / v) aqueous dimethyl sulfoxide solution, the optionally containing the enzyme inhibitor incubated for 15 minutes. After Addition of 10 μl of a 10 percent (v / v) aqueous dimethyl sulfoxide solution, which contains 1 mmol / l of the substrate becomes the enzyme reaction Followed by fluorescence spectroscopy (328 nm (ex) / 393 nm (em)). The enzyme activity is shown as the increase in extinction / minute. In the Tab. 1 IC values listed are determined as that Inhibitor concentration that leads to 50 percent inhibition of the enzyme. The buffer solution contains 0.1 mol / l Tris / HCl, 0.1 mol / l NaCl, 0.01 mol / l CaCl₂ and 0.05% Brÿ (Sigma, Deisenhofen, Germany). The enzyme solution contains 5 µg / ml of one of those shown by Ye et al Enzyme domains. The substrate solution contains 1 mmol / l of the fluorogenic Substrates (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ′, 4′- dinitrophenyl) -L-2,3-diaminopropionyl-Ala-Arg-NH₂ (Bachem, Heidelberg, Germany).  

Table 1

Claims (14)

1. Compound of formula I. and / or an optionally stereoisomeric form of the compound of formula I and / or a physiologically tolerable salt of the compound of formula I, in which case i)
R¹ for

• a) a radical of formula II
• b) a radical of the formula III
• c) a radical of the formula IV
• d) a radical of the formula VI where Z
  1) pyrrole,
  2) triazole,
  3) pyrazole,
  4) dihydropyrazole,
  5) imidazole,
  6) pyrroline,
  7) pyrrolidine,
  9) pyrazolidine,
  10) imidazoline,
  11) imidazolidine,
  12) piperidine,
  13) tetrazole,
  14) thiazole,
  15) thiazoline,
  16) thiazolidine,
  17) benzene,
  18) pyridine,
  19) thiophene,
  20) oxazole,
  21) isoxazole,
  22) thiadiazole,
  23) morpholine,
  24) pyrimidine,
  25) pyrazine,
  26) Piperazine
  27) a radical of the formula VII where p is 1 or 2 and a carbon atom is Y,
• e) a radical of the formula VIII where o is 1 or 2,
• f) a radical of the formula VIII in which one carbon atom of the ring system has the meaning Y,
• g) a radical of the formula IX wherein R¹² 1) hydrogen atom,
  2) halogen,
  3) hydroxyl,
  4) (C₁-C₅) alkyl or
  5) means (C₁-C₅) alkoxyl,
• h) naphthyl or
• i) naphthyl, mono- or trisubstituted by R⁵, and

n stands for zero, 1 or 2,
m stands for zero, 1 or 2, the sum of n and m being 1, 2 or 3, and
R², R³, R⁴ and R⁵ are the same or different and are for

• a) hydrogen atom, or
• b) the meaning of R¹ for case ii), point 2.1. to 2.19., or

where in case ii)
R¹ for

• 1) phenyl or
• 2) Phenyl mono- to trisubstituted by
  • 2.1. (C₁-C₁₀) alkoxyl,
  • 2.2. -OH,
  • 2.3. -COOH,
  • 2.4. (C₃-C₆) cycloalkyl,
  • 2.5. (C₃-C₆) cycloalkyl-O- (C₁-C₄) alkyl,
  • 2.6. Halogen,
  • 2.7. -CN,
  • 2.8. -NO₂,
  • 2.9. -CF₃,
  • 2.10. -O-R¹³,
  • 2.11. -O-phenyl, mono- or disubstituted by R⁵,
  • 2.12. -OC (O) -R¹³,
  • 2.13. -OC (O) -phenyl, mono- or disubstituted by R⁵,
  • 2.14. -NR⁸R⁹, wherein R⁸ is hydrogen, benzyl or (C₁-C₄) alkyl and wherein
    R⁹ 1) hydrogen atom,
    2) benzyl,
    3) -C (O) -R¹³,
    4) -OC (O) -R13 or
    5) means (C₁-C₄) alkyl,
  • 2.15. -C (O) -O-R¹³,
  • 2.16. -C (O) -NR⁸R⁹, where R⁸ and R⁹ as under 2.14. are defined
  • 2.17. -C (O) -NR¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ together with the N atom to which they are attached, one
    1) pyrrolidine residue,
    2) piperidine residue,
    3) morpholine residue or
    4) form piperazine residue,
  • 2.18. -NC (NH) -NH₂, or
  • 2.19. adjacent carbon atoms in the ring contain the radical -O-CH₂-O- means, stands and

R¹³ 1) phenyl,
2) benzyl,
3) (C₁-C₆) alkyl or
4) (C₃-C₆) cycloalkyl, and
n means zero, 1 or 2,
m is zero, 1 or 2, and the meaning of n and m is not the same, and
R², R³, R⁴ and R⁵ are the same or different and are for

• a) hydrogen atom, or
• b) the meaning of R¹ for case ii), point 2.1. to 2.19, have, or

where in case iii)
R¹ is as defined for case ii),
n 1 means
m means 1 and
R², R³, R⁴ and R⁵ are the same or different and the meaning of R¹ for case ii), points 2.1. to 2.19, and
X for

• a) a covalent bond,
• b) -O-,
• c) -S-,
• d) -S (O) -,
• e) -S (O) ₂-,
• f) -C (O) -,
• g) -C (OH) - or
• h) -N (R¹⁰) -, in which R¹ bedeutet represents hydrogen atom or (C₁-C₄) alkyl, and

Y for

• a) -O-,
• b) -S- or
• c) -N (R¹¹) -, wherein R¹¹
  1) hydrogen atom,
  2) (C₁-C₆) alkyl,
  3) phenyl,
  4) benzyl,
  5) -C (O) -R¹³,
  6) -C (O) -O-R¹³ or
  7) substituted phenyl,
  stands, and

A for

• a) - (CH₂) _q -, where q is zero, 1, 2, 3 or 4, or
• b) -CH = CH- stands.

2. A compound of formula I according to claim 1 and / or a physiologically acceptable salt of the compound of formula I and / or an optionally stereosiomeric form of the compound of formula I, wherein
R1 represents a radical of the formula II in the case i),
R¹ for case ii) represents morpholinyl, phenyl or phenyl, mono- to trisubstituted by methoxy, or
R¹ for the case iii) represents phenyl, mono- to trisubstituted by methoxy, and
A represents a covalent bond,
X represents oxygen atom, and
R², R³, R⁴ and R⁵ are the same or different and are for

• a) hydrogen atom,
• b) methoxy or
• c) -O-CH₂-O- stand.

3. A compound of formula I according to claims 1 or 2, wherein 2- (4-phenoxybenzenesulfonyl) -1,2,3,4-tetrahydroisoquinoline-3-hydroxam- acid or 2- (morpholinosulfonyl) -1,2,3,4-tetrahydroisoquinoline-3- hydroxamic acid, 1- (4-methoxybenzenesulfonyl) indoline-2-hydroxamic acid, 2- (4-methoxybenzenesulfonyl) -6,7,8-trimethoxy-1,2,3,4-tetrahydroiso quinoline-3-hydroxamic acid and 2- (4-methoxybenzenesulfonyl) -6.7- methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid is used. 4. A process for the preparation of the compound of formula I according to claim 1, characterized in that

• a) an imino acid of the formula XII wherein the radicals R², R³ and R⁴, as well as n and m as defined in formula I, are reacted with a (C₁-C₄) alcohol or a benzyl alcohol to give the compound of the formula XIII, wherein R _{x is} (C₁-C₄) alkyl or benzyl, or
• b) a compound of the formula XIII prepared by process a) with the compound of the formula XIV, wherein R _{z represents} chlorine atom, imidazolyl or -OH, in the presence of a base to form a compound of formula XV wherein R¹, R², R³, R⁴, n and m are as defined in formula I and R _{x is} as defined in formula XIII, or
• c) reacting a compound of the formula XIII prepared by process a) with a base and then reacting with a compound of the formula XIV to give a compound of the formula XV, or
• d) reacting a compound of formula XII with a compound of formula XIV to a compound of formula XVI wherein R¹, R², R³, R⁴, n and m are as defined in formula I, or
• e) converting a compound of the formula XV into a compound of the formula XVI, or
• f) a compound of the formula XV prepared by process b) or c) with the hydroxylamine of the formula XVII (XVII) H₂N-OR _y wherein R _{y is} hydrogen atom or an oxygen protecting group, to give the compound of the formula I, or
• g) reacting a compound of the formula XVI prepared by process d) or e) with the hydroxylamine of the formula XVII to give the compound of the formula I, or
• h) a compound of the formula I prepared by processes f) or g), which occurs in enantiomeric forms owing to its chemical structure, 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 the diastereomers thus obtained, and the chiral auxiliary group is split off into the pure enantiomers, or
• i) the compound of the formula I prepared by processes f), g) or h) is either isolated in free form or, if acidic or basic groups are present, converted into physiologically tolerable salts, if appropriate.

5. Medicaments containing an effective amount of at least one A compound according to claims 1, 2 or 3 or as obtained after Claim 4 and / or a physiologically acceptable salt of the compound of formula I and / or a stereoisomeric form of the compound of Formula I, in addition to physiologically acceptable auxiliaries and carriers, optionally other additives and / or other active ingredients. 6. Use of at least one compound of the formula I according to one or more of claims 1 to 4, for the manufacture of medicaments for the prophylaxis and therapy of diseases, the course of which a enhanced activity of matrix-degrading metalloproteinases involved is. 7. Use according to claim 6, for the treatment of diseases of the Connective tissue such as collagenosis, periodontal diseases, wound healing disorders or chronic movement disorders apparatus such as flammable, immunological or metabolic acute and chronic arthritis, arthropathy, myalgia and Bone metabolism or degenerative joint disorders diseases such as osteoarthritis, spondylosis, cartilage loss Articular trauma or prolonged immobilization after meniscus or Patella injuries or torn ligaments or treatment of ulceration, Atherosclerosis and stenosis or inhibition of tumor necrosis factor Release or treatment of inflammation, cancer, Tumor metastasis, cachexia, anorexia and septic shock.   8. A method for producing a medicament according to claim 5, characterized in that at least one compound of Formula I and / or at least one physiologically acceptable salt of Compound of formula I and / or an optionally stereoisomeric Form of the compound of formula I and / or one according to the method Compound obtained according to claim 4 with physiologically acceptable Auxiliaries and carriers and optionally other additives and / or other active ingredients in a suitable dosage form.