Cyclic and heterocyclic N-substituted .alpha.-iminohydroxamic and carboxyclic acids

Compounds of the formula I ##STR1## are suitable for preparing pharmaceuticals for the treatment of disorders in the course of which is involved an increased activity of matrix-degrading metalloproteinases.

This application is filed under 35 U.S.C. .sctn. 371 from Application No.
 PCT/EP96/04776, filed Nov. 4, 1996.
 The invention relates to cyclic and heterocyclic N-substituted
 .alpha.-imino-hydroxamic and -carboxylic acids, to processes for their
 preparation and to their use as pharmaceuticals.
 EP 0 606 046 discloses some arylsulfonamidohydroxamic acid derivatives and
 their action as matrix metalloproteinase inhibitors.
 In the effort to find further efficacious compounds for the treatment of
 connective tissue disorders, it has now been found that the
 imino-hydroxamic acid derivatives according to the invention are
 inhibitors of metalloproteinases.
 The invention relates to a compound of the formula I
 ##STR2##
 and/or an optionally stereoisomeric form of the compound of the formula I
 and/or a physiologically tolerable salt of the compound of the formula I,
 where in the case i)
 R.sup.1 is
 a) a radical of the formula II
 ##STR3##
 b) a radical of the formula III
 ##STR4##
 c) a radical of the formula IV
 ##STR5##
 where Z is a radical of a heterocycle or a substituted heterocycle such as
 1) pyrrole,
 2) thiazole,
 3) pyrazole,
 4) pyridine,
 5) imidazole,
 6) pyrrolidine,
 7) piperidine,
 8) thiophene,
 9) oxazole,
 10) isoxazole,
 11) morpholine or
 12) piperazine,
 d) naphthyl,
 e) naphthyl, mono- or trisubstituted by R.sup.2, or
 f) a radical of the formula V
 ##STR6##
 where o is the number 1 or 2 and one of the carbon atoms in the ring may be
 replaced by --O-- or --S--, and
 Q as part of the structural formula I
 ##STR7##
 1) is the structural moiety VI
 ##STR8##
 2) the structural moiety VII
 ##STR9##
 3) is the structural moiety VIII
 ##STR10##
 4) the structural moiety IX
 ##STR11##
 5) is the structural moiety X
 ##STR12##
 R.sup.2 is
 1) phenyl or
 2) phenyl which is mono- to trisubstituted by
 2.1 hydroxyl,
 2.2 --O--R.sup.10, where R.sup.10
 1) is (C.sub.1 -C.sub.6)-alkyl,
 2) is (C.sub.3 -C.sub.6)-cycloalkyl,
 3) is benzyl or
 4) is phenyl,
 2.3 --COOH,
 2.4 (C.sub.1 -C.sub.6)-alkyl,
 2.5 (C.sub.3 -C.sub.6)-cycloalkyl-O-(C.sub.1 -C.sub.4)-alkyl,
 2.6 halogen,
 2.7 --CN,
 2.8 --NO.sub.2,
 2.9 --CF.sub.3,
 2.10 --O--C(O)--R.sup.10 and R.sup.10 is as defined above,
 2.11 --O--C(O)-phenyl, mono- or disubstituted by R.sup.3,
 2.12 --C(O)--O--R.sup.10 and R.sup.10 is as defined above,
 2.13 methylenedioxo,
 2.14 --C(O)--NR.sup.11 R.sup.12, where
 R.sup.11 and R.sup.12 may be identical or different and each is
 1) a hydrogen atom,
 2) (C.sub.1 -C.sub.4)-alkyl or
 3) benzyl or
 4) R.sup.11 and R.sup.12 together with the linking nitrogen atom form a
 pyrrolidine, piperidine, morpholine or piperazine radical, or
 2.15 --NR.sup.13 R.sup.14, where
 R.sup.13 is a hydrogen atom or (C.sub.1 -C.sub.4)-alkyl and R.sup.14
 1) is a hydrogen atom,
 2) is (C.sub.1 -C.sub.4)-alkyl,
 3) is benzyl,
 4) is --C(O)--R.sup.10 or
 5) is --C(O)--O--R.sup.10,
 R.sup.3 and R.sup.4 are identical or different and each is
 1) a hydrogen atom,
 2) (C.sub.1 -C.sub.5)-alkyl,
 3) (C.sub.1 -C.sub.5)-alkoxy,
 4) halogen,
 5) hydroxyl,
 6) --O--C(O)--R.sup.10 and R.sup.10 is as defined above, or
 7) R.sup.3 and R .sup.4 together form the radical --O--CH.sub.2 --O--,
 R.sup.5 is
 a) a hydrogen atom,
 b) (C.sub.1 -C.sub.5)-alkyl or
 c) benzyl, and
 R.sup.6, R.sup.7 and R.sup.8 are identical or different and each is
 a) a hydrogen atom, or
 b) has, in the case of i), the meaning of R.sup.2 under items 2.1 to 2.14,
 and
 n is zero, 1 or 2,
 m is zero, 1 or 2, the sum of n and m being 1, 2 or 3, or
 where in the case ii)
 R.sup.1 is
 1) phenyl or
 2) phenyl, mono- to trisubstituted by R.sup.2 where R.sup.2 is as defined
 for the case i) under items 2.1 to 2.15,
 Q is the structural moiety X and
 R.sup.6, R.sup.7 and R.sup.8 are identical or different and each is defined
 as above,
 n is 1 and
 m is 1, or
 where in the case iii)
 R.sup.1, Q, R.sup.6, R.sup.7 and R.sup.8 are identical or different and
 each has the meaning mentioned for the case ii),
 m and n are zero, 1 or 2 and where the meanings of n and m are not
 identical, and
 X is
 a) a covalent bond,
 b) --O--,
 c) --S--,
 d) --S(O)--,
 e) --S(O).sub.2 --,
 f) --C(O)-- or
 g) --C(OH)--, and
 Y is
 a) --O-- or
 b) --S--, and
 A is HO--NH-- C(O)-- or HO--C(O)-- and
 B is
 a) --(CH.sub.2).sub.q --, where q is zero, 1, 2, 3 or 4, or
 b) is --CH.dbd.CH--.
 Preference is given to a compound of the formula I and/or a physiologically
 tolerable salt of the compound of the formula I and/or an optionally
 stereoisomeric form of the compound of the formula I, where
 R.sup.1 in the case i) is a radical of the formula II or III and Q is the
 structural moiety VI, VII, VIII or X,
 R.sup.1 in the case ii) is phenyl or phenyl, mono- to trisubstituted by
 methoxy, and Q is the structural moiety X, or
 R.sup.1 in the case iii) is phenyl, Q is the structural moiety X, n is zero
 and m is 2, and
 A is HO--NH--C(O)-- or HO--C(O)--,
 B is a covalent bond,
 X is an oxygen atom or a covalent bond, and
 R.sup.2 is phenyl or phenyl substituted by
 a) hydroxyl,
 b) --O--R.sup.10, where R.sup.10 is (C.sub.1 -C.sub.3)-alkyl or benzyl,
 c) (C.sub.1 -C.sub.2)-alkyl,
 d) fluorine or chlorine,
 e) --CN,
 f) --CF.sub.3 or
 g) NR.sup.13 R.sup.14, where R.sup.13 and R.sup.14 are each (C.sub.1
 -C.sub.3)-alkyl,
 R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are identical or
 different and each is
 a) a hydrogen atom,
 b) methoxy,
 c) methylenedioxo,
 d) amino or
 e) hydroxyl.
 Particular preference is given to the compounds
 R-2-(biphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,
 R-2-(4-chlorobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic
 acid,
 R-2-(4-chlorobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
 acid,
 R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic
 acid,
 R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
 acid,
 R-2-(4-(4-dimethylaminophenoxy)benzenesulfonyl)-1,2,3,4-tetrahydroisoquinol
 ine-3-hydroxamic acid,
 R-2-(4-dimethylaminobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carb
 oxylic acid,
 R-2-(4-benzoylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic
 acid,
 R-2-(4-methoxybenzenesulfonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-h
 ydroxamic acid,
 R-2-(4-methoxybenzenesulfonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline-3-hyd
 roxamic acid,
 2-(4-methoxybenzenesulfonyl)-6,7-propylene-1,2,3,4-tetrahydroisoquinoline-1
 -hydroxamic acid,
 R-5-(4-methoxybenzenesulfonyl)4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridin
 e-6-hydroxamic acid,
 R-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-c)-indole-
 3-hydroxamic acid,
 R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-c)-indole-
 3-hydroxamic acid.
 Furthermore, particular emphasis is given to those compounds of the formula
 I where the central carbon atom between amino and acid group is present as
 R enantiomer.
 The term halogen is understood as meaning fluorine, chlorine, bromine or
 iodine. The term alkyl or alkoxy is understood as meaning radicals whose
 carbon chain may be straight-chain, branched or cyclic. Cyclic alkyl
 radicals are, for example, 3- to 6-membered monocycles such as
 cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
 The "heterocycles of the formula V" include, for example, thiomorpholine,
 piperidine, morpholine or piperazine.
 Suitable physiologically tolerable salts of the compound of the formula I
 are, for example, alkali metal, alkaline earth metal and ammonium salts
 including those of organic ammonium bases or basic amino acids.
 The invention also provides a process for preparing the compound of the
 formula I and/or a physiologically tolerable salt of the compound of the
 formula I and/or an optionally stereoisomeric form of the compound of the
 formula I which comprises
 a) reacting an imino acid of the formula XI
 ##STR13##
 where the radical Q and n and m are as defined in the formula I with a
 (C.sub.1 -C.sub.4)-alcohol or a benzyl alcohol to give the compound of the
 formula XII
 ##STR14##
 where R.sub.x is (C.sub.1 -C.sub.4)-alkyl or benzyl, or
 b) reacting a compound of the formula XII prepared according to process a)
 with the compound of the formula XIII
 ##STR15##
 where R.sup.1 is as defined in formula I and R.sub.Z is a chlorine atom,
 imidazolyl or --OH, in the presence of a base or, if appropriate, a
 dehydrating agent to give a compound of the formula XIV
 ##STR16##
 where Q, R.sup.1, n and m are as defined in formula I and R.sub.x is as
 defined in formula XII, or
 c) reacting a compound of the formula XII prepared according to process a)
 with a base and subsequently with a compound of the formula XIII to give a
 compound of the formula XIV, or
 d) reacting a compound of the formula XI with a compound of the formula
 XIII to give a compound of the formula XV
 ##STR17##
 where Q, R.sup.1, n and m are as defined in formula I, or
 e) reacting a compound of the formula XIV to give a compound of the formula
 XV, or
 f) reacting a compound of the formula XIV prepared according to process b)
 or c) with the hydroxylamine of the formula XVI
EQU H.sub.2 N--OR.sub.y (XVI)
 where R.sub.y is a hydrogen atom or a protective group for oxygen, to give
 the compound of the formula I and, if appropriate, removing the protective
 group for oxygen, or
 g) reacting a compound of the formula XV prepared according to process d)
 or e) with the hydroxylamine of the formula XVI to give the compound of
 the formula I, or
 h) separating into the pure enantiomers a compound of the formula I
 prepared according to process f) or g) which, owing to its chemical
 structure, exists in enantiomeric forms, by forming salts with
 enantiomerically pure acids or bases, chromatography using 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, or
 i) isolating the compound of the formula I prepared according to processes
 f), g) or h) either in free form or, if acidic or basic groups are
 present, converting it, if appropriate, into physiologically tolerable
 salts.
 In the case of the (C.sub.1 -C.sub.4)-alcohols, the reaction according to
 process step a) is carried out under customary reaction conditions in the
 presence of HCl gas or thionyl chloride. The preparation of the
 corresponding benzyl esters of the formula XII is carried out in benzene
 or toluene using the appropriate alcohol and an acid such as
 p-toluenesulfonic acid. Tert-butyl esters can be prepared, for example, by
 known processes using isobutene and sulfuric acid.
 The reaction according to 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 even
 in the presence of water. Preference is given to using the sulfonyl
 chlorides of the formula XIII in the presence of NMM in THF.
 The reaction according to 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) is carried out in an aqueous
 organic solvent system, preferably in THF and water in the presence of a
 base such as sodium carbonate and the compound of the formula XIII.
 Furthermore, the reaction can be carried out in the absence of solvent
 with or without base under reduced pressure, as obtained by use of an oil
 pump.
 The hydrolysis of the compound of the formula XIV to give the compound of
 the formula XV (process step e) is carried out, for example, basic,
 preferably acidic or, in the case of the benzyl derivatives, by
 hydrogenolysis. In the case of basic hydrolysis, it is necessary to free
 the carboxylic acid from the carboxylic acid salt by treatment with
 another acid, for example dilute hydrochloric acid.
 The reaction according to process step f) is carried out under the
 conditions which are customary for the formation of carboxamides, in a
 suitable solvent, for example an alcohol or dimethylformamide.
 For the reaction according to process step g), the carboxylic acids of the
 formula XV are activated. Activated carboxylic acids are, for example,
 acyl halides, acyl azides, mixed anhydrides and carbonates. Preference is
 given to acyl chlorides or fluorides, mixed anhydrides and carbonates of
 pivaloyl chloride, ethyl, isopropyl or isobutyl chloroformate; active
 esters such as cyanoethyl, o- or p-nitrophenyl, succinimido or
 phthalimido, and to the activated carboxylic acids which are obtainable
 using coupling reagents such as diisopropylcarbodiimide (DIC),
 carbonyldiimidazole (CDI), dicyclohexylcarbodimide (DCC) or
 benzotriazolyltetramethyluronium tetrafluoroborate (TBTU), if appropriate
 with addition of hydroxybenzotriazole (HObt) or oxohydroxybenzotriazine
 (HOObt), preferred solvents being aprotic solvents.
 The starting materials and reagents employed can either be prepared by
 known processes, or they are commercially available.
 Suitable imino acids of the formula XI where n and m are 1 its, for
 example, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
 1,2,3,4-tetrahydro-9H-pyrido(3,4-b)-indole-3-carboxylic acid or optionally
 1- or 3-substituted
 4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridine-6-carboxylic acids. They
 are preferably prepared by cyclizing the corresponding amino acids with
 formaldehyde in the presence of an acid such as hydrochloric acid or
 sulfuric acid using the method of Pictet-Spengler (see W. M. Whaley,
 Organic Reactions 6 (1951) 151.
 In the case that in the imino acid of the formula XI n is zero and m is 2,
 it is possible to use, for example,
 1,2,3,4-tetrahydro-9H-pyrido(3,4-b)indol-1-carboxylic acid and
 6,7-propylene-1,2,3,4-tetraisoquinoline-1-carboxylic acid as starting
 material. To prepare the latter compound, indane is Friedel-Crafts
 alkylated with phenylsulfonylarziridine. The cyclization of the resulting
 4-(2-benzenesulfonamidoethyl)indane is carried out using glyoxylic acid in
 HBr/glacial acetic acid; the subsequent cleavage of the benzenesulfonyl
 radical is carried out using iodine/red phosphorus in HBr/glacial acetic
 acid.
 An example of the case where in the compound XI n is 1 and m is zero is
 indoline-2-carboxylic acid. It is prepared, for example, by catalytic
 hydrogenation of indol-2-carboxylic acid. Furthermore, mention may be made
 of the cyclization of 2-chlorophenylalanine or
 2-hydroxy-3-(2-chlorophenyl)-propionic acid to give imino acids of the
 formula XI.
 If compounds of the formula I permit diastereomeric or enantiomeric forms
 and are obtained as mixtures thereof in the synthesis chosen, separation
 into the pure stereoisomers is possible either by chromatography over an
 optionally chiral carrier material or, if the racemic compound of the
 formula I or a compound of the formula XI is capable of forming salts, by
 fractional crystallization of the diastereomeric salts formed with an
 optically active base or acid as auxiliary. Suitable chiral stationary
 phases for thin-layer- or column-chromatographic separation of enantiomers
 are, for example, modified silica carriers (Pirkle phases) and
 high-molecular-weight carbohydrates such as triacetylcellulose. For
 analytical purposes, gas-chromatographic methods using chiral stationary
 phases may also be used, after appropriate derivatization known to the
 person skilled in the art. The enantiomers of racemic carboxylic acids are
 separated using an optically active, usually commercially available base
 such as (-)-nicotine, (+)- and (-)-phenylethylamine, quinine bases,
 L-lysine or L- and D-arginine to form the diastereomeric salts, which
 differ in solubility. The less soluble component is isolated as a solid,
 the more soluble diastereomer is recovered from the mother liquor, and the
 pure enantiomers are obtained from the resulting diastereomeric salts. In
 basically the same manner, the racemic compounds of the formula I which
 contain a basic group such as an amino group can be converted into the
 pure enantiomers using optically active acids such as
 (+)-camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L-lactic acid
 and (+) and (-)-mandelic acid. It is also possible to convert chiral
 compounds containing alcohol or amine functions into the corresponding
 esters or amides using appropriately activated or optionally n-protected
 enantiomerically pure amino acids, or, conversely, to convert chiral
 carboxylic acids into the amides using carboxyl-protected enantiomerically
 pure amino acids, or into the corresponding chiral esters using
 enantiomerically pure hydroxycarboxylic acids such as lactic acid. The
 chirality of the enantiomerically pure amino acid or alcohol radical can
 then be employed to separate the isomers by resolving the diastereomers
 that are now present using crystallization or chromatography over suitable
 stationary phases and then removing the chiral moiety which has been
 carried along by means of suitable methods.
 Acidic or basic products of the compound of the formula I may be present in
 the form of their salts or in free form. Preference is given to
 pharmacologically tolerable salts, for example alkali metal or alkaline
 earth metal salts or hydrochlorides, hydrobromides, sulfates,
 hemisulfates, all possible phosphates and salts of the amino acids,
 natural bases or carboxylic acids.
 Hydroxylamine can be employed in free form, obtainable from hydroxylamine
 salts and a suitable base in solution or in O-protected form, or in each
 case also in the form of its salts. The preparation of free hydroxylamine
 is known from the literature and can be carried out, for example, in
 alcoholic solution. Preference is given to using the hydrochloride
 together with alkoxides such as Na methoxide, potassium hydroxide or
 potassium t-butoxide.
 O-protected hydroxylamine derivatives preferably contain protective groups
 which can be removed under mild conditions. Particular preference is given
 here to protective groups of the silyl, benzyl and acetal types.
 Particularly suitable for this purpose are the O-trimethylsilyl,
 O-tert-butyldimethylsilyl, O-benzyl, O-tert-butyl and the
 O-tetrahydropyranyl derivative.
 Starting materials and intermediates which are employed for preparing the
 compound of the formula I may, if they contain functional groups such as
 hydroxyl, thiole, amino or carboxyl, for example in the radicals R.sup.1,
 R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8, be
 employed in suitably protected form.
 The introduction of protective groups is required in all those cases where,
 in a desired chemical reaction, undesirable side-reactions are to be
 expected at other locations than reaction centers (T. W. Greene,
 Protective Groups in Organic Synthesis, Wiley, New York, 1991).
 The protective groups employed can be removed before or after the
 conversion of the compound of the formula XII into the compound of the
 formula I.
 Particularly suitable for use as auxiliaries and bases are: HObt, HOObt,
 N-hydroxysuccinamide (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.degree. C. and +90.degree. C.,
 depending on the boiling point and the nature of the solvent used.
 Particular preference is given to the temperature range from -20 to
 +30.degree. C.
 The preparation of physiologically tolerable salts from compounds of the
 formula I which are capable of forming salts, including their
 stereoisomeric forms, is carried out in a manner known per se. The
 carboxylic acids and hydroxamic acids form stable alkali metal, alkaline
 earth metal or optionally substituted ammonium salts with basic reagents
 such as hydroxides, carbonates, bicarbonates, alkoxides and ammonia or
 organic bases, for example trimethyl- or triethylamine, ethanolamine or
 triethanolamine or else basic amino acids, for example lysine, ornithine
 or arginine. If the compounds of the formula I have basic groups, it is
 also possible to prepare stable acid addition salts by using strong acids.
 Suitable for this purpose are both inorganic and organic acids, such as
 hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic,
 benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfonic,
 cyclohexylamidosulfonic, trifluoromethylsulfonic, acetic, oxalic,
 tartaric, succinic or trifluoroacetic acid.
 The invention also relates to pharmaceuticals which contain an effective
 amount of at least one compound of the formula I and/or of a
 physiologically tolerable salt of the compound of the formula I and/or an
 optionally stereoisomeric form of the compound of the formula I, together
 with a pharmaceutically suitable and physiologically tolerable excipient,
 additive and/or other active compounds and auxiliaries.
 On account of the pharmacological properties, the compounds according to
 the invention are suitable for the prophylaxis and therapy of all those
 disorders in the course of which is involved an increased activity of
 matrix-degrading metalloproteinases. These include degenerative joint
 disorders such as osteoarthroses, spondyloses, chondrolysis after joint
 traumas or relatively long immobilization of the joint after meniscus or
 patella injuries or tears of the ligaments. Furthermore, these also
 include disorders of the connective tissue such as collagenoses,
 periodontal disorders, wound healing disorders and chronic disorders of
 the locomotory apparatus such as inflammatory, immunologically or
 metabolically related acute and chronic arthritides, arthropathies,
 myalgias and disorders of the bone metabolism. The compounds of the
 formula I are also suitable for the treatment of ulceration,
 atherosclerosis and stenoses. The compounds of the formula I furthermore
 suppress the release of the cellular tumor necrosis factor (TNF.alpha.) to
 a considerable extent and are therefore suitable for the treatment of
 inflammations, carcinomatous disorders, formation of tumor metastases,
 cachexia, anorexia and septic shock.
 The pharmaceuticals according to the invention are in general administered
 orally or parenterally. Rectal or transdermal administration is also
 possible.
 The invention also relates to a process for the production of a
 pharmaceutical, which comprises bringing at least one compound of the
 formula I into a suitable administration form using a pharmaceutically
 suitable and physiologically tolerable excipient and, if appropriate,
 other suitable active compounds, additives or auxiliaries.
 Suitable solid pharmaceutical preparation forms are, for example, granules,
 powders, coated tablets, tablets, (micro)capsules, suppositories, syrups,
 juices, suspensions, emulsions, drops or injectable solutions and also
 preparations with protracted release of active compound, in whose
 preparation customary auxiliaries, such as excipients, disintegrants,
 binders, coating agents, swelling agents, glidants or lubricants,
 flavorings, sweeteners and solubilizers are used. Frequently used
 auxiliaries which may be mentioned are magnesium carbonate, titanium
 dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin,
 starch, cellulose and its derivatives, animal and vegetable oils such as
 fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol
 and solvents such as, for example, sterile water and mono- or polyhydric
 alcohols such as glycerol.
 The pharmaceutical preparations are preferably prepared and administered in
 dose units, each unit as active constituent containing a specific dose of
 the compound of the formula I according to the invention. In solid dose
 units such as tablets, capsules, coated tablets or suppositories, this
 dose can be up to approximately 1000 mg, but preferably approximately 50
 to 300 mg, and in injection solutions in ampoule form up to approximately
 300 mg, preferably approximately 10 to 100 mg.
 For the treatment of an adult patient weighing approximately 70
 kg--depending on the efficacy of the compounds according to formula I,
 daily doses of approximately 20 mg to 1000 mg of active compound,
 preferably approximately 100 mg to 500 mg, are indicated. Under certain
 circumstances, however, higher or lower daily doses may be appropriate.
 The daily dose can be administered both by single administration in the
 form of an individual dose unit or else of several smaller dose units and
 by multiple administration of subdivided doses at specific intervals.
 .sup.1 H-NMR spectra have been recorded on a 200 MHz apparatus from Varian,
 in general using tetramethylsilane (TMS) as an internal standard and at
 room temperature (RT). The solvents used are indicated in each case.
 Generally, final products are determined by mass spectroscopic methods
 (FAB-, ESI-MS). Temperature data in degrees Celsius, RT means room
 temperature (22.degree. C.-26.degree. C.). Abbreviations used are either
 explained or correspond to the customary conventions.

PREATION EXAMPLES
 The preparation of the compounds 1-12, 14-23, 27, 30 and 33 in Table 1 was
 carried out similarly to the procedures given in Examples 13, 24-26, 28,
 29, 31 and 32.
 In Examples 4 to 9, a sulfonation was initially carried out, using p-(Ex.
 4, 6, 9) or m-(Ex. 5,7,8) nitrobenzenesulfonyl chloride as described under
 "Tic-sulfonation" (see Example 13). Subsequently, the hydrogenation of the
 nitro group was carried out under standard conditions known to the person
 skilled in the art, using hydrogen under atmospheric pressure and 10% Pd
 on activated carbon in methanol to give the amine. In all cases, it is
 also possible to employ the Tic benzyl ester described under Example 13
 for the sulfonation. In the subsequent hydrogenation, cleavage of the
 benzyl ester and reduction to give the amine occur simultaneously. The
 identical products which are obtained in both cases, p- or
 m-aminobenzenesulfonyl Tic are subsequently reacted further as follows:
 Example 4
 Initially, acetylation under standard conditions (triethylamine/DMAP/acetic
 anhydride) is carried out; the N-acetyl compound, which is obtained in
 good yield, is subsequently reacted further to give the hydroxamic acid,
 as described in Example 25.
 Examples 5 and 6
 To prepare the hydroxamic acid, the p-aminobenzenesulfonyl-Tic is activated
 in the same manner as described in Example 13, except that double the
 amount of ethyl chloroformate and N-methylmorpholine is employed.
 Irreversible N-ethoxycarbonylation takes place in one step, together with
 the activation of the carboxylic acid.
 Examples 7, 8 and 9
 The p- or m-aminobenzenesulfonyl-Tic described above is acylated under the
 Schotten-Baumann conditions known to the person skilled in the art. For
 this purpose, use is made of: Ex. 7: salicyloyl chloride, Example 8:
 p-methoxybenzoyl chloride, Example 9: benzyl chloroformate. The further
 reaction to give the hydroxamic acid is carried out as described in
 Example 25.
 Example 13
 R-2-(4-phenoxybenzenesulfonyl )-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic
 acid
 General Procedure:
 Tic Benzyl Ester p-toluenesulfonate
 1 mol of Tic (free amino acid), 10 moles 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 using a water separator. After the
 reaction has ended, the solvent is evaporated and the solid crystalline
 residue is repeatedly taken up in diethyl ether and filtered off with
 suction and subsequently dried using oil pump vacuum. Yield: quantitative.
 .sup.1 H NMR: (200 MHz, .delta. in ppm, DMSO-d.sub.6) 9.7 (s, brd., 2 H,
 prot.NH), 7.5-7.25 (2m, 7H, arom.), 7.1 (d, 2H, arom. p-TsOH), 5.3 (s, 2H,
 CH.sub.2 benzyl); 4.7 (dd, 1H, CH.alpha.); 4.4 "d", 2H, CH.sub.2); 3.4-3.1
 (m, 2H, CH.sub.2); 2.3 (s, 1H, CH.sub.3 p-TsOH).
 Tic Sulfonation
 At 0.degree. C., 0.1 mol of Tic solution (free amino acid 17.7 g) in 50 ml
 of 2 N aqueous NaOH is admixed with finely powdered sulfonyl chloride (105
 mmol), followed by 14.2 g (110 mmol) of diisopropylethylamine and 50 ml of
 acetone or THF. The ice bath is removed after 10 min and the more or less
 homogeneous solution is stirred at RT for a further 6 h. The reaction
 mixture is subsequently concentrated, admixed with 300 ml of ethyl acetate
 and acidified with 4 N HCl. The organic phase is separated off and the
 aqueous phase is extracted two more times with in each case 50 ml of ethyl
 acetate. The combined organic phases are extracted with saturated NaCl
 solution and dried over sodium sulfate. The solvent is distilled off and
 the sulfonated tetrahydroisoquinolinecarboxylic acid remains as an oily or
 solid residue which in some cases may be purified by recrystallization
 from ethyl acetate/petroleum ether, but which frequently is sufficiently
 pure for further reaction.
 13a Methyl
 R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylat
 e
 A solution of 1.92 g (0.01 mol) of methyl
 R-1,2,3,4-tetrahydroisoquinoline-3-carboxylate and 2.7 g (0.01 mol) of
 4-phenoxybenzenesulfonyl chloride in 50 ml of absolute THF are heated
 under reflux in the presence of 1.7 ml (0.01 mol) of N-ethylmorpholine for
 8 h. The solvent is removed, the residue is taken up in dichloromethane
 and the solution is extracted successively with 5% citric acid, 5% sodium
 bicarbonate solution and 2.times. with water. The organic phase is dried
 over sodium sulfate and concentrated to give the ester which is subjected
 to further reactions without purification.
 Yield: 4.0 g (95% of theory) of 13a.
 13b
 R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
 acid
 At room temperature, a solution of 4.0 g (9.5 mmol) of the ester (13a) in
 50 ml of isopropanol is stirred after addition of 9.5 ml of 1 N aqueous
 sodium hydroxide solution for 24 h. The mixture is then acidified with 1 N
 hydrochloric acid and evaporated to dryness under reduced pressure. The
 residue is taken up in toluene, the solution is extracted with 5% citric
 acid and the organic phase is dried over sodium sulfate and concentrated
 under reduced pressure.
 Yield: 3.4 g of carboxylic acid 13b (83% of theory); Melting point:
 147.degree. C.
 13c
 R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic
 acid
 3.4 g (8.3 mmol) of the carboxylic acid 13b are dissolved in 30 ml of DMF
 and, at -20.degree. C., admixed successively with 1.4 g (12 mmol) of
 N-ethyl-morpholine and 1.13 g (8.3 mmol) of isobutyl chloroformate. After
 an activation time of 30 min, the mixture is admixed with 4.37 g (41.5
 mmol) of O-trimethylsilylhydroxylamine and stirred at room temperature for
 a further 4 h. 250 ml of ethyl acetate and 500 ml of water are added to
 the mixture which is then acidified with citric acid. The organic phase is
 separated off and the aqueous phase is extracted 4.times., and the
 combined organic phases are dried over sodium sulfate and concentrated
 under reduced pressure. Recrystallization from toluene/ethyl acetate (1:1)
 affords the title compound 13.
 Yield: 2.9 g (82% of theory) Melting point: 170.degree. C. (decomposition).
 Example 17
 Trans-beta-styrenesulfonyl chloride is employed for the sulfonation of the
 Tic benzyl ester under standard conditions (see Example 13). In the
 subsequent hydrogenation (H2, Pd/C), debenzylation and hydrogenation of
 the double bond are effected in one step. Subsequently formation of the
 hydroxamic acid by the method of Example 25.
 Examples 20, 21 and 22
 The starting material is commercially available 7-hydroxy-Tic. This is
 sulfonated under standard conditions according to process variant d). This
 gives, after customary work-up, a mixture of 2- and 7-disulfonated and
 exclusively 2-sulfonated 7-hydroxy-Tic. However, at this stage it is not
 necessary to separate the two compounds. Direct further conversion to give
 the hydroxamic acid is carried out under standard conditions. As expected,
 partial ethoxycarbonylation of the 7-hydroxyl group takes place during the
 activation. The hydroxamic acid product mixture therefore contains all
 three products which can be separated by chromatography over silica gel
 60, preparative thin-layer chromatography or HPLC.
 Example 23
 The starting material for the preparation of 7-nitro-Tic is
 enantiomerically pure commercial (R)-Tic-OH or (S)-Tic-OH. The 7-nitro-Tic
 is prepared according to E. D. Bergann, J. Am. Chem. Soc. 74, 4947 (1952)
 or according to E. Erlenmever, A. Lipp, Liebigs Ann. Chem. 219, 218 (1983)
 by nitration with nitrating acid. A mixture of the 6- and 7-nitro isomers
 is formed, and the reaction mixture additionally contains unnitrated
 starting materials. Prior to the separation, the mixture is initially
 sulfonated under standard conditions. The resulting mixture of the three
 sulfonamides can then be chromatographed over silica gel 60. Successively,
 mixed fractions containing educt/6-nitro- and
 6-nitro-/7-nitro-(4-methoxybenzenesulfonyl)-Tic are obtained; finally,
 fractions of pure 7-nitro compound are eluted. This can be further
 converted into the hydroxamic acid, in a customary manner similar to
 Example 25
 Example 24
 2-(4-Methoxybenzenesulfonyl)-6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquino
 line-3-hydroxamic acid
 The preparation of the corresponding benzyl carboxylate from the carboxylic
 acid corresponds to the general procedure (see Example 13). Sulfonation or
 benzyl ester cleavage is carried out similarly to Example 25a. The
 reaction of the free sulfonated carboxylic acid is carried out as
 described under 25b.
 After treatment with diethyl ether, the product is obtained in crystalline
 form. Yield: 140 mg, 57% of theory; melting point 166.degree. C.
 Example 25
 2-(4-Methoxybenzenesulfonyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydro-isoquinoli
 ne-3-hydroxamic acid
 25a
 2-(4-Methoxybenzenesulfonyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoli
 ne-3-carboxylic acid
 The preparation of the benzyl ester is carried out according to the general
 procedure (see Example 13). For the sulfonation, 1.2 g (3.05 mmol) of the
 benzyl ester are employed. This is dissolved in 20 ml of THF and, at
 0.degree. C., admixed with 0.63 g (3.05 mmol) of 4-methoxybenzenesulfonyl
 chloride. 0.32 ml of N-methylmorpholine are added and the reaction mixture
 is stirred at 0.degree. C. to room temperature overnight. The mixture is
 subsequently admixed with 20 ml of ethyl acetate and extracted with 10%
 strength sodium carbonate solution and saturated NaCl solution. The
 organic phase is dried over sodium sulfate, filtered and concentrated
 under reduced pressure. The residue that remains is subjected to
 chromatography under pressure over silica gel 60 using ethyl
 acetate/petroleum ester/glacial acetic acid 20/10/1. Pure product
 fractions (600 mg) are combined and, after concentration, directly
 hydrogenated using 100 mg of 10% Pd/C in 50 ml of ethanol. After the
 reaction has ended, the catalyst is separated off and the remaining
 solution is concentrated under reduced pressure. This gives 330 mg (66% of
 theory).
 25b
 2-(4-Methoxybenzenesulfonyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoli
 ne-3-hydroxamic acid
 330 mg (0.75 mmol) of the carboxylic acid from Example 25a are dissolved in
 15 ml of THF and, at -20.degree. C., admixed successively with 0.07 ml
 (0.75 mmol) of ethyl chloroformate and 0.15 ml (1.5 mmol) of
 N-methylmorpholine (NMM). After 30 min at this temperature, the mixture is
 mixed with 0.474 ml of O-trimethylsilylhydroxylamine (3.75 mmol). After 6
 h at RT, 30 ml of ethyl acetate are added to the mixture which is then
 extracted with 20% strength aqueous citric acid and saturated NaCl
 solution. The organic phase is dried over sodium sulfate and concentrated
 under reduced pressure, leaving 290 mg of a clear viscous oil which
 crystallizes on treatment with diethyl ether.
 Example 26
 2-(Morpholinosulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid
 26a Methyl
 2-(morpholinosulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
 With stirring, 4.2 g (0.025 mol) of morpholine-N-sulfonyl chloride in 20 ml
 of THF are added dropwise to a solution of 4.8 g (0.025 mol) of methyl
 1,2,3,4-tetrahydroisoquinoline-3-carboxylate and 2.9 g (0.025 mol) of
 N-ethylmorpholine. The mixture is stirred at RT for 2 h and then heated
 under reflux for another 2 h so that the reaction goes to completion.
 CHCl.sub.3 is added to the reaction solution, which is then treated with
 5% strength citric acid, 5% strength NaHCO.sub.3 solution and water. The
 organic phase is dried over Na.sub.2 SO.sub.4 and evaporated to dryness.
 Yield of ester (26a): 7.5 g (92% of theory)
 26b 2-(Morpholinosulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
 Reaction of 7.5 g (0.023 mol) of 26a by the method of 13b.
 Yield of carboxylic acid 26b: 6.7 g (93% of theory)
 26c 2-(Morpholinosulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid
 2.3 g (7.5 mmol) of the carboxylic acid 26b are dissolved in 40 ml of
 absolute THF and, at -20.degree. C., admixed successively with 1.2 g (12
 mmol) of N-methylmorpholine and 1.1 g (7.5 mmol) of isobutyl
 chloroformate. After 30 min, the mixture is admixed with 3.9 g (37.5 mmol)
 of O-trimethylsilylhydroxylamine and stirred at RT for a further 5 h. 200
 ml of water are added and the mixture is acidified with dilute HCl and
 extracted repeatedly with dichloromethane. The pooled organic phases are
 dried over Na.sub.2 SO.sub.4 and concentrated under reduced pressure. The
 resulting oil is chromatographed under pressure over silica gel 60 using
 ethyl acetate/dichloromethane (1:1) as mobile phase. Recrystallization of
 the product fractions from ethyl acetate gave crystalline hydroxamic acid
 26c.
 Yield: 1.4 g (55% of theory) Melting point: 164-165.degree. C.
 (decomposition)
 Example 28
 1-(4-Methoxybenzenesulfonyl)indoline-2-hydroxamic acid
 28a 1-(4-Methoxybenzenesulfonyl)indoline-2-carboxylic acid
 At 50.degree. C. and 0.02 mbar, 1 g (6.1 mmol) of indoline-2-carboxylic
 acid and 2.5 g (12.2 mmol) of 4-methoxybenzenesulfonyl chloride are kept
 for 4 hours (h) in a kugelrohr which is rotated slowly and continuously.
 The brown crystalline product is subsequently taken up in sodium carbonate
 solution and extracted twice with diethyl ether. The aqueous phase is
 acidified using 6 N HCl and extracted four times with ethyl acetate. The
 combined organic phases are extracted with saturated NaCl solution, dried
 over sodium sulfate and concentrated under reduced pressure. Residual
 solvent is removed using oil pump vacuum.
 Yield: 1.34 g, (65% of theory); .sup.1 H-NMR: (DMSO-d.sub.6) 7.8; 7.1 (2d,
 4H, arom. p-TsOH); 7.4-7.0 (m, 4H, arom.); 4.9 (dd, 1H, CH.alpha.); 3.8
 (2, 3H, OMe); 3.4-2.9 (2 dd, 2H, CH.sub.2).
 28b 1-(4-Methoxybenzenesulfonyl)indoline-2-hydroxamic acid
 1.3 g (3.9 mmol) of the 1-(4-methoxybenzenesulfonyl)indoline-2-carboxylic
 acid of Example 28a are dissolved in 10 ml of N,N-dimethylacetamide (DMA)
 and, at -20.degree. C., admixed successively with 0.37 ml (1 equivalent)
 of ethyl chloroformate and 0.81 ml of N-methylmorpholine. After an
 activation time of 30 minutes (min), the mixture is admixed with 3.8 ml
 (19.5 mmol) of O-trimethylsilylhydroxylamine and stirred at RT for a
 further 4 h. The mixture is diluted with ethyl acetate, acidified with
 citric acid and, after removal of the aqueous phase, washed with saturated
 NaCl solution. The organic phase is dried over sodium sulfate, filtered
 off and concentrated under reduced pressure. The resulting oil is
 subjected to chromatography under pressure over silica gel 60 using
 dichloromethane/ethyl acetate/acetic acid 5.5/3.5/1 as mobile phase.
 Product fractions (showing positive iron(III) chloride-reaction) are
 pooled and concentrated. The crystalline product is subsequently admixed
 with diethyl ether and freed of residual solvent under reduced pressure.
 Yield: 400 mg (33% of theory) Melting point: 142.degree. C.
 Example 29
 R-5-(4-methoxybenzenesulfonyl)4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridin
 e-6-hydroxamic acid hydrochloride
 29a:
 R-3,5-di(4-methoxybenzenesulfonyl)-4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-p
 yridine-6-carboxylic acid
 With ice-cooling, 15 ml of 2 N NaOH and 4.5 g (42 mmol) of sodium carbonate
 are added successively to a solution of 6.1 g (30 mmol) of
 4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridine-6-carboxylic acid
 hydrochloride in 50 ml of water. With stirring, 13.7 g (67 mmol) of
 4-methoxybenzenesulfonyl chloride in 40 ml of ether are added. The
 reaction mixture is stirred at RT for a further 24 hours and then with
 ice-cooling adjusted to pH 3-4 using 5 N HCl and extracted with ethyl
 acetate. The organic phase is dried over sodium sulfate, filtered and
 concentrated to dryness to give 11.9 g (78% of theory) of the desired
 product in the form of an oil.
 29b:
 R-5-(4-methoxybenzenesulfonyl)-4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyrid
 ine-6-carboxylic acid hydrochloride
 With ice-cooling and stirring, 23.5 ml each of a 1 N NaOH solution are
 added dropwise in intervals of 1 hour to a solution of 11.0 g (24 mmol) of
 disulfonated intermediate in 300 ml of methanol. After 6 hours, a final 15
 ml of 1 NaOH are added and the mixture is stirred at RT overnight. The
 methanol is removed under reduced pressure and the mixture is then
 adjusted to pH 5 using 5 N HCl. The precipitated crystals are filtered off
 with suction and dried under reduced pressure over P205.
 Yield: 5.2 g (60% of theory) of 29b; Melting point: 264-265.degree. C.
 (decomp.).
 29c:
 R-5-(4-methoxybenzenesulfonyl)-4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyrid
 ine-6-hydroxamic acid hydrochloride
 8.0 g (24 mmol) of compound 29b in 60 ml of DMF are admixed with 4.27 g (24
 mmol) of tetramethylammonium hydroxide and then, at 0.degree. C., with 2.7
 g (24 mmol) of N-ethylmorpholine and, a little at a time, with 5.2 g (24
 mmol) of di-tert-butyl dicarbonate. The reaction mixture is stirred
 overnight, poured onto ice-water, adjusted to pH 5 using dilute HCl and
 extracted repeatedly with ethyl acetate. After removal of the solvent, the
 combined dried organic phase affords 10.5 g of BOC-protected 29b which is
 used directly for preparing the hydroxamic acid.
 To this end, 10.5 g (23 mmol) of the above compound are dissolved in 150 ml
 of absolute THF and, at -20.degree. C., admixed with 4.4 g (38 mmol) of
 N-ethylmorpholine and 3.4 g (25 mmol) of isobutyl chloroformate. The
 mixture is stirred for 1 hour, after which 10.9 g (0.1 mol) of
 O-trimethylsilylhydroxylamine are added, the temperature being kept at
 -20.degree. C. for 1 hour. After a further 4 hours of stirring at RT, the
 reaction mixture is adjusted to pH=1 using 1N HCl, admixed with 300 ml of
 water and extracted repeatedly with dichloromethane. The combined organic
 phases are dried over sodium sulfate and concentrated to dryness under
 reduced pressure.
 To cleave the BOC protective group, 8.1 g of the remaining oil are taken up
 in 50 ml of dichloromethane and 25 ml of trifluoroacetic acid are added
 dropwise at 0.degree. C. The reaction mixture is stirred at RT for 4 hours
 and then concentrated under reduced pressure. The residue is digested with
 dichloromethane and then dissolved in 0.1 N HCl, filtered and
 freeze-dried.
 Yield of hydroxamic acid 29: 5.2 g (56% of theory); Melting point:
 110.degree. C.
 Example 31
 R-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-b)-indole-
 3-hydroxamic acid
 31a
 R-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-b)-indole
 -3-carboxylic acid
 A solution of 2.16 g (10 mmol) of
 1,2,3,4-tetrahydro-9H-pyrido-(3,4-b)-indole-3-carboxylic acid in a mixture
 of 10 ml of acetone and 10 ml of water is, after addition of 10.5 ml of 2
 N NaOH, admixed with stirring with 2.06 g (10 mmol) of
 4-methoxybenzenesulfonyl chloride. The solution is stirred at room
 temperature for 18 hours, the acetone is removed and the pH is adjusted to
 1 using concentrated HCl. The resulting precipitate is filtered off,
 washed with water and dried.
 Yield: 2.7 g of carboxylic acid 31a (85% of theory); Melting point:
 232-234.degree. C.
 31b
 R-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)-indole-
 3-hydroxamic acid
 2.5 g (7.4 mmol) of the carboxylic acid 31a are dissolved in 40 ml of
 absolute DMF and, at -20.degree. C., admixed successively with 1.4 ml (12
 mmol) of N-ethylmorpholine and 0.97 ml (7.4 mmol) of isobutyl
 chloroformate. After an activation time of 30 min, 4.53 ml (37 mmol) of
 O-trimethylsilylhydroxylamine are added and the mixture is subsequently
 stirred at room temperature for 19 hours. The mixture is adjusted to
 pH=3.5 using citric acid and then extracted repeatedly with ethyl acetate.
 The combined organic phases are dried over sodium sulfate, concentrated
 under reduced pressure and purified by silica gel chromatography using
 methylene chloride/methanol (95:5).
 Yield: 2.4 g of hydroxamic acid (91.5% of theory); Melting point:
 87.degree. C.
 Example 32
 R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)-indole-3
 -hydroxamic acid
 Preparation by the Method of Example 31
 Melting point: 110-111.degree. C.
 Example 33
 R-2-(4-morpholinobenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)-indol
 e-3-hydroxamic acid
 Preparation by the Method of Example 31
 Melting point: 125.degree. C. (decomposition).
 Example 42
 R-2-[4-(4-chlorophenoxy)benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline-3-c
 arboxylic acid
 8.2 g (46.4 mmol) of R-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are
 admixed with 46.4 ml of 1N NaOH and 50 ml of acetone and dissolved in
 water. At -5.degree. C. and with stirring, 14.1 g (46.4 mmol) of
 4-(4-chlorophenyloxy)benzenesulfonyl chloride in 50 ml of THF are added
 dropwise and, after half has been added, the reaction mixture is admixed
 with 0.6 g (46.4 mmol) of diisopropylethylamine. The mixture is stirred
 overnight, the precipitate is filtered off and the filtrate is adjusted to
 pH=3 using 2 N HCl and extracted repeatedly with dichloromethane. The
 combined organic phases are dried over sodium sulfate, filtered and
 evaporated to dryness under reduced pressure. Recrystallization from
 toluene and drying under reduced pressure gives the title compound.
 Yield: 16.1 g (78% of theory) Melting point: 168-169.degree. C.
 TABLE 1
 Hydroxamic acids of the formula I
 Exam- mp.
 ple No. Structure
 (.degree. C.) Solvent .sup.1 H NMR
 1
 ##STR18##
 DMSO-d6 2.7-3.1(m, 2H)
 4-4.7(2m, 2H) 7-7.8(3m, 9H) 9.5; 10.6(2s, br, 2H)
 2
 ##STR19##
 94 Decomp. CDCL3 2.65-2.8(m, 1H);
 3.1-3.25(m, 1H); 4.35-4.75(m, 3H); 6.9-7.2 m, 4H); 7.3-7.65(m, 7H); 7.8(d,
 2H)
 3
 ##STR20##
 DMSO-d6 2.9(m, 2H); 4.5(t,
 1H); 4.6(m, 2H); 7.0-7.9(m 12H); 9.9(s 1H); 10.8 (s, 1H)
 4
 ##STR21##
 DMSO-d6 2.1(s, 3H)2.8-3.5
 (2m; 2H), 4.3-4.6 (m, 3H)7.1; 7.7(2m, 8H)8.65; 8.85; 10.3; 10.8(4s, 2h)
 5
 ##STR22##
 DMSO-d6 1.2(t, 3H)2.85 (m,
 brd, 2H)4.15 (q, 2H)4.4-4.7(m, 3H)7.1(m, brd, 4H) 7.4(m, 2H)7.6 (m, 2H)8;
 9.9; 10.7(3s, 3H)
 6
 ##STR23##
 DMSO-d6 1.2(t, 3H)2.8(m,
 brd, 2H)4.15(q, 2H) 4.3-4.6(m, 3H) 7.1(m, brd, 4H) 7.55; 7.7(2d, 4H) 8.7;
 9.5(2s, 3H)
 7
 ##STR24##
 DMSO-d6 2(s, 3H)2.9(m, 2H)
 4.4-4.6(2m, 3H) 7.1; 7.5; 7.9; 8.3(4m, 14H)
 8
 ##STR25##
 DMSO-d6 2.85(m, 2H)3.85 (s,
 3H)4.4-4.7(2m, 3H)7.1; 7.4; 7.6; 8(4m, 13H) 8.9; 10.8(2s, 2H)
 9
 ##STR26##
 DMSO-d6 3(m, 2H)4.4-4.8 (m,
 3H)5.2(s, 3H 7.1-7.5(2m, 9H) 7.55; 7.8(2d, 4H) 8.8; 10.7(2s, 2H)
 10
 ##STR27##
 175 Decomp. DMSO-d6 2.7-3.0(m, 2H);
 3.25(m, 4H); 3.75(m, 4H); 4.45(t, 1H); 4.5(M, 2H); 6.9-7.65(m, 8H)
 11
 ##STR28##
 DMSO-d6 2.7-3.1(m, 2H)
 4.5-4.8(m, 3H) 6.8-7.2(m, 4H) 7.7(m, 3H) 7.9-8.2(m, 3H) 8.5(s, 1H)
 12
 ##STR29##
 DMSO-d6 2.8(s, 6H)2.95 (d,
 brd, 2H)4.4-4.8 m, 3H)7.1(m, 4H) 7.25(d, 1H)7.6 (dd, 2H)8.2("t", 2H)
 8.5(d, 1H)8.9; 10.7(2s, 2H)
 13c
 ##STR30##
 170 Decomp. DMSO-d6 2.9(d, 2H);
 4.4(m, 2H); 4.55(d, 1H); 6.9-7.85(m, 13H); 8.9(s, 1H); 10.75(s, 1H);
 14
 ##STR31##
 DMSO-d6 2.9(m, 2H); 3.64(s
 6H); 4.38(t, 1H); 4.5(m, 2H); 6.75-7.75(m, 12H);
 15
 ##STR32##
 DMSO-d6 2.85(m, 2H);
 4.45(t, 1H); 4.63(m, 2H); 6.9-8.7(m, 11H); 9.9(s, 1H); 10.8(s, 1H);
 16
 ##STR33##
 DMSO-d6 2.9-3.1(m, 2H)
 3.9-4.6(2m, 5H) 7.15(m, 4H)7.3 (m, 5H)8.85; 10.6 (2s, 2H)
 17
 ##STR34##
 DMSO-d6 2.8-3.6(m, 6H)
 4.5-4.7(m, 3H) 7.1-7.4(m, 9H) 8.7; 8.9; 9.5; 10.7 (4s, 2H)
 18
 ##STR35##
 DMSO-d6 2.95(m, 2H); 4.5(t,
 1H); 4.62(m 2H); 7.0-8.05(m, 13H);
 19
 ##STR36##
 DMSO-d6 2.85(m, 2H); 4.4(M,
 1H); 4.53(m, 2H); 6.95-7.8(M; 13H);
 20
 ##STR37##
 DMSO-d6 2.8(m, 2H)3.8(s,
 3H)4.35-4.6(m, 3H) 6.9-7.2; 7.6-7.8 (2m; 7H)8.9; 10.8(2s, 2H)
 21
 ##STR38##
 DMSO-d6 1.3(t, 3H)2.85 (m,
 2H)3.8(s, 3H) 4.0-4.6(m, 5H) 6.9-7.1; 7.6-7.8(2m, 7H)8.8; 10.8(2s, 2H)
 22
 ##STR39##
 DMSO-d6 2.8(m, 2H)3.8(s,
 3H)3.9(s, 3H) 4.35-4.6(m, 3H) 6.9-7.2; 7.6-7.8(2m, 11H)8.9; 10.9 (2s, 2H)
 23
 ##STR40##
 DMSO-d6 3.0(m, 2H)3.8(s,
 3H)4.4-4.8(m, 3H) 6.95; 7.7(2d, 4H) 7.4(d, 1H)7.95 (dd, 1H)8.05(d, 1H)
 8.95; 10.8(2s, 2H)
 24
 ##STR41##
 166 DMSO-d6 2.7(m, 2H)3.8(s,
 3H)4.2-4.5(m, 3H) 5.9; 6.7; 7.0; 7.7(4d, 6H)8.85; 10.7(2s, 2H)
 25
 ##STR42##
 DMSO-d6 2.8(m, 2H)
 3.65-3.85(4s, 12H) 4.3-4.5(mn, 3H) 6.5(s, 1H)7.0; 7.7(2d, 4H)8.8; 10.7(2s,
 2H)
 26
 ##STR43##
 165 DMSO-d6 2.9-3.35(m, 6H);
 3.45-3.65(m, 4H); 4.38(m, 1H); 4.5; 4.65(AB, 2H); 7.2 (s, 4H); 8.9(s, 1H);
 10.65(s, 1H)
 27
 ##STR44##
 DMSO-d6 1.95(m, 2H); 2.5-
 2.95m, 7H); 3.4 (m, 1H); 3.8(s, 3H); 3.8-4.1(m, 1H); 6.9-7.1(m, 4H); 7.7
 (d, 2H); 9.0-11.1 (s, 2H);
 28
 ##STR45##
 142 DMSO-d6 2.8-3.2(m, 2H)
 3.8(s, 3H)4.6 (dd 1H)7.0-7.8(3m, 8H)9.1; 10.9(2s 2H)
 NOT TO BE TAKEN INTO CONSIDERATION FOR THE PURPOSES OF INTERNATIONAL
 PROCESSING
 TABLE 2
 Carboxylic acids of the formula I
 mp.
 Ex. Structure
 (.degree. C.) .sup.1 H NMR
 34
 ##STR46##
 205 (in CDCl3): 3.0-3.25
 (m, 2H); 4.48(d, 1H); 4.65(d, 1H); 4.9-5.0 (m, 1H); 6.97-7.18 (m, 4H);
 7.38-7.7(m, 7H); 7.85(d, 2H)
 35
 ##STR47##
 207-209 (in DMSO-d6):
 3.05-3.15(m, 2H); 4.45-4.7(d, d, 2H); 4.9(m, 1H); 7.1-8.0 (m, 12H);
 12.8(s, 1H);
 36
 ##STR48##
 3.1(m, 2H); 4.6(m, 2H);
 4.90(d, 1H); 7.0-8.0(2m, 12H)
 37
 ##STR49##
 3.0-3.2(m, 2H); 4.55
 (dd, 2H); 4.90(d, 1H); 7.05-7.25(m, 4H); 7.1-8.0(3m, 12H)
 38
 ##STR50##
 3.0-3.2(m, 2H); 4.55
 (dd, 2H); 4.90(d, 1H); 7.05-7.25(m, 4H); 7.1-8.0(3m, 12H)
 39
 ##STR51##
 122-135 amorphous (in MeOH-d4):
 3.02- 3.36(m, 2H u. s, 6H); 4.57(d, 1H); 4.72(d, 1H); 4.85-5.01(m, 1H);
 7.03-7.19(m, 4H); 7.54(d, 2H); 7.7-7.98 (m, 6H)
 40
 ##STR52##
 2.9-3.2(m, 2H); 3.8 (s,
 3H); 4.3-4.6(dd, 2H); 4.8(m, 1H); 7.1 (m, 6H); 7.8(d, 2H)
 41 13b
 ##STR53##
 147 (in DMSO-d6):
 3.0-3.15(m, 2H); 4.4- 4.65(d, d, 2H); 4.8-4.9 (m, 1H); 7.0-7.9 (m, 13H);
 12.9(s, 1H);
 42
 ##STR54##
 167-168 (in DMSO-d6):
 3.0-3.15(m 2H); 4.4- 4.65(m, 2H); 4.85 (m, 1H); 7.0-7.9 (m, 12H); 12.9(s,
 1H);
 43
 ##STR55##
 oil (in DMSO-d6): 2.4-2.7
 (m, 6H)2.8-3.0(m, 2H); 3.3-3.5(m, 6H); 4.4- 4.6(m, 2H); 4.7(m, 1H);
 7.0-7.9(m, 13H)
 44
 ##STR56##
 in DMSO-d6): 2.9-3.2
 (m, 2H); 4.4-4.65(d, d, 2H); 4.85(m, 1H); 5.15 (s, 2H); 7.0-7.9(m, 12H);
 12.9(s, 1H);
 45
 ##STR57##
 oil (in DMSO-d6): 3.0-3.2
 (m, 2H); 4.4-4.75(d, d, 2H); 4.9(m, 1H); 7.1-8.1(m, 13H); 12.9(s, 1H);
 46
 ##STR58##
 218-219 (in DMSO-d6):
 3.0-3.1(m, 2H); 4.45-4.8(d, d, 2H); 4.9-5.0(m, 1H); 7.0-8.8(m, 1H);
 12.8(s, 1H);
 47
 ##STR59##
 211-213 amorphous 3.0-3.2(m, 2H);
 4.5 (d, 1H); 4.72(d, 1H); 4.9-5.05(m, 1H); 7.05-7.25(m, 4H); 7.6-7.75(m,
 3H); 7.85-8.05(m, 2H); 8.2-8.4(m, 3H); 12.9 (sb, 1H)
 48
 ##STR60##
 3.0; 3.2(2m, 4H);
 3.3-3.6(m, 2H); 4.5-4.75(dd, 2H); 4.8 ("t", 1H); 7.1-7.4 (m, 9H)
 49
 ##STR61##
 3.0-3.3(m, 2H); 3.8 (s,
 3H); 4.45-4.85 (dd, 2H); 4.85(m, 1H); 7.0; 7.4; 7.8(3d, 5H); 8.0(dd, 1H);
 8.1(d, 1H)
 50
 ##STR62##
 3.3(m, 2H); 4.5-4.85
 (dd, 2H); 5.05(m, 1H); 7.2-8.1(mm, 11H)
 51
 ##STR63##
 3.3(m, 2H); 4.5-4.8
 (dd, 2H); 5.05(dd, 1H); 7.2-8.0(4m, 11H)
 52
 ##STR64##
 3.1-3.4(m, 2H);
 4.5-5.0(dd, 2H); 4.95 (m, 1H); 7.2-8.1(2m, 11H)
 53
 ##STR65##
 3.1-3.4(m, 2H);
 4.5-4.9(dd, 2H); 4.95 (m, 1H); 7.2-8.15 (2m, 11H)
 54
 ##STR66##
 226-228 (in DMSO-d6): 2.8-
 3.1(m, 2H); 4.3-4.5 (d, d, 2H); 4.75(m, 1H); 5.95(s, 2H); 6.7-7.9 (m,
 11H); 12.9(s, 1H);
 55
 ##STR67##
 2.9-3.1(m, 2H); 3.8 (s,
 6H); 4.35-4.6(dd, 2H); 4.90(d, 1H); 6.7; 6.8(2s, 2H); 7.55; 7.80(2d, 4H);
 7.9(m, 4H)
 56
 ##STR68##
 2.8-3.1(m, 2H);
 4.3-4.6(dd, 2H); 4.85 (m, 1H); 6.5(m, 2H); 6.95(d, 1H); 7.5-8.0 (m, 8H);
 8.5; 8.8(2s, 1H)
 57
 ##STR69##
 115 (in DMSO-d6): 3.3-
 3.45(m, 2H); 4.4-4.65 (m, 2H); 5.8-5.9(m, 1H); 6.85-7.9(m, 13H); 10.7(s,
 1H);
 58
 ##STR70##
 3.1; 3.4(2m, 2H);
 5.05(m, 1H); 7.0-8.0 (m, 12H)
 59
 ##STR71##
 2.8-3.0(m, 2H);
 3.5-3.8(m, 2H); 4.3 (s, 1H); 7.1-8.0 (mm, 12H)
 60
 ##STR72##
 2.7-2.9(m, 2H);
 3.4-3.8(m, 2H); 3.8 (2s, 6H); 5.4(s, 1H); 6.7; 6.9(2s, 2H); 7.55; 7.80(2d,
 4H); 7.9(s, 4H)
 Pharmacological Examples
 Preparation and determination of the enzymatic activity of the catalytic
 domains of human stomelysine and of neutrophil collagenase.
 The two enzymes were prepared according to Ye et al., (Biochemistry 31
 (1992) 11231-5). To measure the enzyme activity or enzyme inhibitor
 action, 70 .mu.l of buffer solution and 10 .mu.l of enzyme solution are
 incubated for 15 minutes with 10 .mu.l of a 10% strength (v/v) aqueous
 dimethyl sulfoxide solution, which optionally contains the enzyme
 inhibitor. After addition of 10 .mu.l of a 10% strength (v/v) aqueous
 dimethyl sulfoxide solution which contains 1 mmol/l of the substrate, the
 enzyme reaction is monitored by fluorescence spectroscopy (328 nm (ex)/393
 nm(em)). The enzyme activity is shown as extinction increase/minute. The
 IC50 values listed in Table 3 were determined as the inhibitor
 concentration which leads to a 50% inhibition of the enzyme. The buffer
 solution contains 0.05% of Brij (Sigma, Deisenhofen, Germany) and also 0.1
 mol/l of tris/HCl, 0.1 mol/l of NaCl, 0.01 mol/l of CaCl.sub.2 (pH=7.5)
 for the determination of the hydroxamic acids up to and including Example
 33, or, for the determination of the carboxylic acids from Example 34, 0.1
 mol/l of piperazine-N,N'bis[2-ethanesulfonic acid] pH=6.5.
 The enzyme solution contains 5 .mu.g/ml of one of the enzyme domains
 prepared according to Ye et al. The substrate solution contains 1 mmol/l
 of the fluorogenic substrate
 (7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-3-(2',4'-dinitrophenyl)-L-2
 ,3-diaminopropionyl-Ala-Arg-NH.sub.2 (Bachem, Heidelberg, Germany).
 TABLE 3
 Stromelysine Neutrophil collagenase
 Example No. IC 50 [M] IC 50 [M]
 1 3*10.sup.-7 2*10.sup.-8
 2 2*10.sup.-8 2*10.sup.-10
 3 3*10.sup.-8 2*10.sup.-9
 4 7*10.sup.-7 1*10.sup.-7
 5 6*10.sup.-6 3*10.sup.-7
 6 5*10.sup.-7 3*10.sup.-8
 8 3*10.sup.-6 2*10.sup.-7
 9 4*10.sup.-7 8*10.sup.-7
 10 3*10.sup.-7 1*10.sup.-7
 11 4*10.sup.-7 7*10.sup.-8
 12 4*10.sup.-7 2*10.sup.-7
 13c 2*10.sup.-8 2*10.sup.-9
 14 3*10.sup.-8 2*10.sup.-9
 15 1*10.sup.-7 1*10.sup.-8
 17 1*10.sup.-7 2*10.sup.-8
 18 3*10.sup.-8 3*10.sup.-9
 19 2*10.sup.-6 3*10.sup.-7
 20 1*10.sup.-8 1*10.sup.-9
 21 2*10.sup.-8 2*10.sup.-9
 22 3*10.sup.-8 8*10.sup.-9
 23 8*10.sup.-8 8*10.sup.-9
 24 6*10.sup.-8 2*10.sup.-8
 25 4*10.sup.-7 3*10.sup.-7
 26 6*10.sup.-6 3*10.sup.-7
 27 3*10.sup.-8 4*10.sup.-9
 28 2*10.sup.-6 7*10.sup.-7
 29 2*10.sup.-8 4*10.sup.-9
 31 2*10.sup.-8 3*10.sup.-9
 32 6*10.sup.-8 7*10.sup.-9
 33 3*10.sup.-7 7*10.sup.-8
 34 5*10.sup.-7 1*10.sup.-8
 35 1*10.sup.-7 5*10.sup.-9
 36 3*10.sup.-6
 39 1*10.sup.-7 1*10.sup.-9
 41 (13b) 2*10.sup.-7 9*10.sup.-9
 42 5*10.sup.-7 2*10.sup.-8
 43 2*10.sup.-6 2*10.sup.-7
 44 2*10.sup.-7 3*10.sup.-8
 45 3*10.sup.-6 3*10.sup.-7
 46 3*10.sup.-6 3*10.sup.-7
 50 6*10.sup.-7 3*10.sup.-8
 51 5*10.sup.-7 2*10.sup.-8
 52 1*10.sup.-6 4*10.sup.-8
 53 5*10.sup.-7 2*10.sup.-8
 57 2*10.sup.-6 1*10.sup.-7
 2. Proteoglycan Degradation Assay
 Principle of the Assay:
 In the proteoglycan degradation assay, the extent of the degradation of
 ggrecan, the most important proteoglycan of the cartilage, is released
 proteoglycan fragments are determined using the tibody 5-D4 which
 recognizes the keratan sulfate side-chains which are located at the
 carboxy terminal of the G2 domain of aggrecan. Thus, the assay detects
 primarily pathologically important degradations which take place in the
 interglobular domain of aggrecan.
 After addition of compounds of the formula I and the enzyme in the form of
 the catalyic domain of stromelysine-1, the amount of hyaluronic acid-bound
 aggrecan which remains after degradation is measured. The more aggrecan is
 detected, the lower the residual activity of the enzyme. The
 concentrations of compounds of the formula I at which the initial enzyme
 activity (=100% residual activity) is reduced by half (=50% residual
 activity) is indicated by the IC50 values in Table 3.
 Description of the Test Protocol:
 Wells of 96 well microtiter plates (Nunc, Maxisorp) each containing 100
 .mu.l of hyaluronic acid solution (25 .mu.g/ml of hyaluronic acid (Sigma)
 in PBS) are incubated at room temperature (RT) for 12 h. The hyaluronic
 acid solution is removed by suction and the remaining free protein binding
 sites of the wells are saturated with in each case 100 ml of a 5% strength
 solution of bovine serum albumin (BSA), 0.05% of Tween20 in PBS at RT for
 1 h. The wells are subsequently covered with proteoglycane by incubating
 the wells with 100 .mu.l each of a solution of bovine nasal proteoglycane
 (ICI) (200 .mu.g/ml in 1.times.PBS, 5 mg/ml of BSA, 0.05% of Tween20) at
 RT for 1 h. The wells are washed twice with 1.times.PBS, 0.1% Tween20 to
 remove the free proteoglycanes. Subsequently, for the actual assay, 60 ng
 of purified catalytic domain of Stromelysine-1 (for the recombinant
 expression and purification, see Ye et al. (1992)) plus corresponding
 concentrations of the inhibitor to be tested in 100 .mu.l of degradation
 buffer (100 mM MES pH 6.0, 100 mM NaCl, 10 mM CaCl.sub.2, 0.05 % of Brij)
 are pipetted into the wells and incubated at RT for 3 h. The wells are
 washed twice with 1.times.PBS, 0.1% of Tween20 and then incubated with 100
 .mu.l of a solution of the detection antibody (monoclonal antibody clone
 5-D-4 (ICI), immunoreactive with the keratan sulfate side-chains of the
 proteoglycane, dilution 1:1000 in 1.times.PBS, 5 mg/ml BSA, 0.05%
 Tween20). The wells are washed twice with 1.times.PBS, 0.1% of Tween20,
 after which the immune reaction of the bound detection antibodies is
 carried out using 100 .mu.l per well of an antibody solution for detection
 (goat anti Maus IgG, labeled with peroxidase (Dianova), diluted 1:1000 in
 1.times.PBS, 5 mg/ml of BSA, 0.05% of Tween20) at RT for 1 h. The wells
 are again washed twice (as above), and the color reaction is then
 initiated using 100 .mu.l each of 2 mg/ml of ABTS, activated with H.sub.2
 O.sub.2. The reaction products are measured in an ELISA reader at a
 wavelength of 405 mm. The results are shown in Table 4.
 TABLE 4
 Proteoglycane degradation
 Example No. IC50 [M]
 2 8.5*10.sup.-8
 9 1.6*10.sup.-6
 13c 5.1*10.sup.-8
 14 6.7*10.sup.-9
 18 4.1*10.sup.-8
 20 1.3*10.sup.-7
 21 6.5*10.sup.-8
 29 2.5*10.sup.-8