CA2158517A1 - Aminomethylphosphonic and aminomethylphosponic acid derivates and their use for treating degenerative joint disorders - Google Patents

Aminomethylphosphonic and aminomethylphosponic acid derivates and their use for treating degenerative joint disorders

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Publication number
CA2158517A1
CA2158517A1 CA002158517A CA2158517A CA2158517A1 CA 2158517 A1 CA2158517 A1 CA 2158517A1 CA 002158517 A CA002158517 A CA 002158517A CA 2158517 A CA2158517 A CA 2158517A CA 2158517 A1 CA2158517 A1 CA 2158517A1
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another
alkyl
independently
substituted
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Erhard Wolf
Erhard Rossmanith
Werner Thorwart
Ruth Raiss
Klaus Ulrich Weithmann
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Hoechst AG
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Hoechst AG
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/32—Esters thereof
    • C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/3241—Esters of arylalkanephosphinic acids
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    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3882—Arylalkanephosphonic acids
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/48—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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    • C07F9/58—Pyridine rings
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems

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Abstract

Compounds of the formula I

Description

HOECHST ARTIENGESELLSCHAFT HOE 94/F 282 Dr. TH/Pl Description Aminomethylphosphonic and ~;no~thylphosphonic acid derivatives and their use for treating degenerative joint disorders Osteoarthritis is a degenerative joint disorder with inflammatory episodes and progressive cartilage destruc-tion which may lead to impairment of function or even complete ankylosis. Although to date the concomitant inflammations and states of pain associated with this disorder can be treated, there are no available pharma-ceuticals which have been proven to be able to stop or cure the progressive cartilage breakdown. Examples of known therapeutic agents for osteoarthritis are mixtures of sulfated glucosaminoglycans (Current Therapeutic Research, 40,6 (1986) 1034) or non-steroidal antiinflamm-atory drugs, but these are unable to stop the 1088 of cartilage.

Although the pathogenesis of osteoarthritis is still not known in detail, it i8 regarded as certain that the chondrocytes (cartilage cells) are crucially involved in the increased 1088 of matrix, and that, of the main constituents of this matrix, in particular the proteo-glycans (PG) are the first to undergo enzymatic break-down.

Accordingly, promising approaches to the therapy of osteoarthritis would be provided by those drugs which, because of their profile of action, stimulate proteo-glycan synthesis in chon~rocytes and, furthermore, counteract a pathologically increased rate of cartilage breakdown. Moreover, the breakdown of proteoglycans can be reduced either by inhibiting relevant matrix metallo-proteinases or else by inactivating reactive oxygen free radicals.

It has now been found that the aminomethylphosphonic and ~1S8517 -phosphinic acid derivatives according to the invention ~timulate proteoglycan synthesis in cartilage, inhibit cartilage breakdown and effectively reduce the cartilage breakdown induced by oxygen free radicals.

Because of their pharmacological properties, the compounds according to the invention are outstAn~ingly suitable for the treatment and prophylaxis of degenerative joint disorders, as well as of disorders of the rheumatic type in which cartilage breakdown is to be found, such as for rheumatoid arthritis, joint trauma and chondrolysis after lengthy immobilization of the joint.

Some of the compounds which can be used according to the invention have already been described, but nothing is known about their use for degenerative joint disorders (DE 2 751 943; H. Oswiecimska et al., J. Prakt. Chem. 318 (1976) pages 403-408; H. Gross et al., J. Prakt. Chem.
317 (1975) pages 890-896; M.G. Pavlichenko et al., Zh Obshch Khim 56 (1986) pages 2000-2004; R.R. Ismagilov et al., Zh Obshch Rhim 61 (1991) pages 387-391).

The invention relates to a pharmaceutical containing a compound of the formula I
C(CH~)5 ( C H 3 ), C~ ~

/\ I
Rl R2 ( ) and/or a physiologically tolerated salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, where 5 Rl and R2 are identical or different and are, indepen-dently of one another, 215~517 a) a hydrogen atom, b) (C1-Cl2)-alkyl, c) (C1-C12)-alkyl, substituted one or more times independently of one another by 1) phenyl, 2) phenyl, substituted once to three times independently of one another by 2.1. fluorine, chlorine, bromine or iodine atom, 2.2. (C1-C3)-alkyl, 2.3. (C1-C3)-alkoxy, 2.4. methylenedioxy, 2.5. nitro, 2.6. amino, 2.7. amidino, 2.8. guanidino, 2.9. hydroxyl, 2.10. (C1-C6)-alkoxycarbonyl or 2.11. cyano, 3) a monocyclic 5- or 6-membered saturated heterocyclic ring, 4) amino, unsubstituted or substituted once or twice by (C1-C3)-alkyl, or 5) -C(O)-O-(C1-C3)-alkyl d) tetralin, e) phenyl, f) phenyl, substituted once to three times indepen-dently of one another by 1) (Cl-C4)-alkyl, 2) (C1-C4)-alkyl, substituted one or more times by fluorine, chlorine, bromine or iodine atom, 3) fluorine, chlorine, bromine or iodine atom 4) nitro, 5) aminosulfonyl, 6) amidino, 7) guanidino, 8) (C1-C3)-alkyloxy, 9) methylenedioxy, 21~8517 10) hydroxyl, 11) carboxyl, 12) cyano, 13) (C1-C3)-alkoxycarbonyl, 14) -CH=CH-COOH, o 15) -CH ~ CH-C-O-~C1-C3)-AIkyl, 16) amino or 17) amino, sub~tituted by the radical of the formula II, ~ OH

- CH
\~X (1l) o in which X and Y are, independently of one another, 17.1. hydrogen atom, 17.2. (C1-C6)-alkyl, 17.3. (C1-C6)-alkoxy, 17.4. (C3-C6)-alkenyloxy, 17.5. phenoxy or 17.6. hydroxyl, g) naphthyl, h) naphthyl, substituted one or more time~ as defined under f)l) to f)17), i) heteroaryl, 21~i8517 k) heteroaryl, substituted one or more times by phenyl, benzyl or as defined under f)l) to f)17), or l) Rl and R2 form, together with the nitrogen atom to which they are bonded, a 4- to 7-membered ring, m) Rl and R2 form, together with the nitrogen atom to which they are bonded, a 5- to 7-membered ring in which one carbon atom in the ring is replaced by an oxygen atom or a nitrogen atom, or n) Rl and R2 form, together with the nitrogen atom to which they are bonded, a 5- to 7-membered ring in which one carbon atom in the ring is replaced by a nitrogen atom and this nitrogen atom is substituted by 1) phenyl or 2) the radical of the formula II in which X and Y ha~e, independently of one another, the ~n;ng gpecified under f)l7.1. to f)l7.6.
and, X and Y are identical or different and have, indepen-dently of one another, the meaning specified under f)l7.1. to f)l7.6.;
and a physiologically tolerated ~ehicle.

A preferred pharmaceutical contains at least one compound of the formula I and/or a physiologically tolerated salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, where Rl and R2 are identical or different and are, indepen-dently of one another, a) hydrogen atom, b) (Cl-Cl2)-alkyl, c) (Cl-Cl2)-alkyl, substituted one or more times independently of one another by 1) phenyl, 2) phenyl, substituted once to three times ~1~8~17 independently of one another by 2.1. fluorine, chlorine, bromine or iodine atom, 2.2. (C1-C3)-alkyl, 2.3. (Cl-C3)-alkoxy, 2.4. methylenedioxy, 2.5. nitro, 2.6. amino, 2.7. amidino, 2.8. guanidino, 2.9. hydroxyl, 2.10. (C1-C 6 ) - alkoxycarbonyl or 2.11. cyano, 3) piperazinyl or, 4) morpholinyl, d) phenyl, e) phenyl, substituted once to three times indepen-dently of one another by 1 ) ( Cl - C4 ) - alkyl, 2) (Cl-C4)-alkyl, substituted one or more times by fluorine, chlorine, bromine or iodine atom, 3) fluorine, chlorine, bromine or iodine atom 4) nitro, 5) aminosulfonyl, 6) amidino, 7) guanidino, 8) (C1-C3)-alkyloxy, 9) methylenedioxy, 10) hydroxyl, 11) carboxyl, 12) cyano, 13) (C1- C3 ) - alkoxycarbonyl, 14) -CH=CH-COOH, -CH = CH-C O-(C1-C3l-AIkYI, 15) 21~8517 16) amino or 17) amino, substituted by the radical of the formula II in which X and Y are, indepen-dently of one another, 17.1. hydrogen atom, 17.2. (C1-C6)-alkyl, 17.3. (Cl-C6)-alkoxy, 17.4. (C3-C6)-alkenyloxy, 17.5. phenoyy or 17.6. hydroxyl, f) (Cs~ C7) -cyc loalkyl, g) (C5-C7)-cycloalkyl, substituted one or more times independently of one another by the radi-cals mentioned under c)1) to c)4), h) adamantyl, i) (Cl-Cl2)-alkyl substituted by amino, unsubsti-tuted or substituted once or twice by (Cl-C3)-alkyl, j) (Cl-Cl2)-alkyl substituted by -C(O)-O-(Cl-C3)-alkyl, k) naphthyl, l) tetralin, m) pyridyl, n) pyridyl, substituted one or more times indepen-dently of one another as defined under e)1) to e)l7), o) pyrimidyl p) pyrimidyl, substituted one or more times independently of one another as defined under e)1) to e)17), q) piperidyl radical, unsubstituted or substituted once to four times by 1) (Cl-C4)-alkyl, 2) phenyl or 3) benzyl, or r) Rl and R2 form, together with the nitrogen atom to which they are bonded, a piperidino radical, 8) Rl and R2 form, together with the nitrogen atom to which they are bonded, a piperazino or 21~8517 morpholino radical, or t) Rl and R2 form, together with the nitrogen atom to which they are bonded, a piperazino radical which is substituted on the nitrogen atom by 1) phenyl or 2) the radical of the formula II in which X and Y have, independently of one another, the meAn; ng gpecified under e)17.1. to e)17.6.
and, X and Y are identical or different and have, indepen-dently of one another, the me~n;ng specified under e)17.1. to e)17.6.;
and a physiologically tolerated vehicle.

A particularly preferred pharmaceutical contains at least one compound of the formula I and/or a physiologically tolerated salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, where Rl and R2 are identical or different and are, indepen-dently of one another, a) hydrogen atom, b) (Cl-C5)-alkyl, c) (Cl-C5)-alkyl, substituted one or more times independently of one another by 1) phenyl, 2) phenyl, substituted once to three times independently of one another by 2.1. fluorine or chlorine atom, 2.2. methyl, ethyl or propyl, 2.3. methoxy, 2.4. methylenedioxy, 2.5. nitro, 2.6. amino, 2.7. amidino, 2.8. guanidino, 2.9. hydroxyl, 2.10. methoxycarbonyl or 2.11. cyano, or g 3) morpholinyl, d) (C5-C7)-cycloalkyl, e) (C5-C7)-cycloalkyl, substituted once to three times independently of one another as defined under c)l) to c)3), f) adamantyl, g) naphthyl, h) phenyl, i) phenyl, substituted once to three times indepen-dently of one another by 1) (Cl-C2)-alkyl, 2) trifluoromethyl, 3) fluorine or chlorine atom, 4) nitro, 5) aminosulfonyl, 6) amidino, 7) guanidino, 8) methoxy, 9) methylenedioxy, 10) hydroxyl, 11) carboxyl, 12) cyano, 13) methoxycarbonyl, 14) -CH=CH-COOH, Il 15) - CH=CH-C-O-CH3, 16) amino or 17) amino, substituted by the radical of the formula II in which X and Y are, indepen-dently of one another, 17.1. hydrogen atom, 17.2. methoxy, ethoxy, propoxy or butyloxy, 17.3. allyl, 17.4. phenoYy or, 17.5. hydroxyl, k) pyridyl, l) pyrimidyl, or m) Rl and R2 form, together with the nitrogen atom to which they are bonded, a piperidino radical, n) R1 and R2 form, together with the nitrogen atom to which they are bonded, a piperazino or morpholino radical, or o) Rl and R2 form, together with the nitrogen atom to which they are bonded, a piperazino radical which i8 subgtituted on the nitrogen atom by 1) phenyl or 2) the radical of the formula II in which X and Y have, independently of one another, the me~n;ng specified under i)17.1. to i)17.5.
and, X and Y are identical or different and have, indepen-dently of one another, the meaning specified under i)17.1. to i)l7.6.;
and a physiologically tolerated vehicle.

A further preferred pharmaceutical contains at least one compound of the formula I and/or a physiologically tolerated salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, where R1 and R2 are identical or different and are, indepen-dently of one another, a) hydrogen atom, b) phenyl, c) phenyl, substituted once to three times indepen-dently of one another by 1) fluorine or chlorine atom, 2) methylenedioxy or 3) (Cl-C3)-alkoxy, and X and Y are, independently of one another, 1) hydrogen atom, 2) (C1-C3)-alkoxy, or 3) hydroxyl;
and a physiologically tolerated vehicle.

The term alkyl or alkoxy mean~ radicals whose carbon chain can be straight-chain, branched or cyclic. Examples 21~ 8 ~1~

of cyclic alkyl radicals are 5- to 7-memhered monocycles such as cyclopentyl, cyclohexyl or cycloheptyl. The cyclic alkyl radicals also include polycycles such as adamantane, twistane or diamantane radicals.

The term "monocyclic 5- or 6-membered saturated, heterocyclic ring" includes, for example, radicals derived from pyrrolidine, piperidine, pyrazolidine, imidazolidine, piperazine, isoxazolidine, morpholine, isothiazolidine or thiomorpholine.

The term "R1 and R2 form, together with the nitrogen atom to which they are bonded, a 4- to 7-membered ring"
includes, for example, radicals derived from azetidine, pyrrolidine, piperidine or azepine.

The term "R1 and R2 form, together with the nitrogen atom to which they are bonded, a 5- to 7-membered ring in which one carbon atom in the ring is replaced by an oxygen atom or nitrogen atom" includes, for example, radicals derived from isoxazolidine, morpholine, imidazolidine or piperazine.

The term "heteroaryl" represents aromatic ring systems which, apart from carbon atoms, also contain hetero atoms as ring members, for example nitrogen, oxygen or sulfur.
5- or 6-membered monocyclic radicals are preferred, such as pyrrole, pyridine, furan, thiophene, pyrazole, imidazole, pyridazine, pyrimidine, pyrazine, oxazole, isoxazole, thiazole or isothiazole. Also preferred are 9-to l0-m~hered bicyclic rings such as indole, quinoline, isoquinoline, indazole, benzimidazole, phthalazine, quinazoline, ~l;nox~line, purine or pteridine.

Examples of degenerative joint disorders are osteoarthritis, rheumatic disorders with cartilage breakdown, rheumatoid arthritis, cho~rolysis after joint trauma such as after meniscus or patella injuries or ruptured ligaments, or cho~olysis after immobilization ~1~8~ ~

of joints.

The invention furthermore relates to novel compounds of the formula I and/or physiologically tolerated salts of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, where Rl and R2 are identical or different and are, independently of one another, a) a hydrogen atom, b) (Cl-Cl2)-alkyl, substituted one or more times independently of one another by 1) phenyl, substituted once to three times independently of one another by 1.1. fluorine, chlorine, bromine or iodine atom, 1.2. (Cl-C3)-alkyl, 1.3. (Cl-C3)-alkoxy, 1.4. methylenedioxy, 1.5. nitro, 1.6. amino, 1.7. amidino, 1.8. guanidino, 1.9. hydroxyl, 1.10. (Cl-C6)-alkoxycarbonyl or 1.11. cyano, 2) a monocyclic 5- or 6-m~hered saturated heterocyclic ring, 3) amino, unsubstituted or substituted once or twice by (Cl-C3)-alkyl, or 4) -C(0)-0-(Cl-C3)-alkyl c) tetralin, d) phenyl, substituted once to three times indepen-dently of one another by 1) (Cl-C4)-alkyl, 2) (Cl-C4)-alkyl, substituted one or more times by fluorine, chlorine, bromine or iodine atom, 3) nitro, 4) aminosulfonyl, 21~17 S) amidino, 6) guanidino, 7) (C1-C3)-alkyloxy, 8) methylenedioxy, 9) hydroxyl, 10) carboxyl, 11) cyano, 12) (Cl-C3)-alkoxycarbonyl, 13) -CH=CH-COOH, Il 14) -CH=CH-C-O-(C1-C3)-alkyl, 15) amino or 16) amino, substituted by the radical of the formula II, in which X and Y are, indepen-dently of one another, 16.1. hydrogen atom, 16.2. (C1-C6)-alkyl, 16.3. (C1-C6)-alkoxy, 14.4. (C3-C6)-alkenyloxy, 16.5. phenoxy or 16.6. hydroxyl, e) naphthyl, substituted one or more times as defined under d)1) to d)16), f) heteroaryl, g) heteroaryl, substituted one or more times by phenyl, benzyl or as defined under d)1) to d)16), or h) Rl and R2 form, together with the nitrogen atom to which they are bonded, a 5- to 7-membered ring in which one carbon atom in the ring i6 replaced by an oxygen atom or a nitrogen atom, or i) R1 and R2 form, together with the nitrogen atom to which they are bonded, a 5- to 7-membered ring in which one carbon atom in the ring is replaced by a nitrogen atom and thi~ nitrogen atom is substituted by 1) phenyl or 21~8517 2) the radical of the formula II in which X and Y have, independently of one another, the me~n;ng specified under d)16.1. to d)16.6.
and, X and Y are identical or different and have, indepen-dently of one another, the me~n;ng Qpecified under d)16.1. to d)16.6.; or where R1 is phenyl or phenyl substituted once to three time~
by fluorine, chlorine, bromine or iodine atom, R2 is hydrogen atom and X and Y are, independently of one another, 1) hydrogen atom, 2) (Cl-C6)-alkyl, 3) (C3-C6)-alkenyloxy, 4) phenoxy or 5) hydroxyl.

Preferred novel compounds of the formula I are those where R1 and R2 are identical or different and are, independently of one another, a) hydrogen atom, b) (C1-C12)-alkyl, ~ub~tituted one or more times independently of one another by 1) phenyl, substituted once to three times independently of one another by 1.1. fluorine, chlorine, bromine or iodine atom, 1.2. methylenedioxy or 1.3. cyano, 2) amino, unsub~tituted or substituted once or twice by (Cl-C3)-alkyl, or 3) -C(O)-O-(Cl-C3)-alkyl c) phenyl, substituted once to three times indepen-dently of one another by 1) (Cl-C4)-alkyl, substituted one or more times by fluorine, chlorine, bromine or iodine atom, 2) (Cl-C3)-alkyloxy, 3) methylenedioxy, 21~;8~17 4) cyano, or 5) amino, substituted by the radical of the formula II, in which X and Y are, indepen-dently of one another, 5.1. hydrogen atom, 5.2. (C1-C6)-alkyl, 5.3. (C1-C6)-alkoxy, 5.4. (C3-C6)-alkenyloxy, 5.5. phenoxy or 5.6. hydroxyl, d) pyridyl or e) pyrimidyl, and in which X and Y have, independently of one another, the meaning specified under c)5.1. to c)5.6.; or where 5 R1 is phenyl or phenyl substituted once to three times by fluorine or chlorine atom, R2 is hydrogen atom and X and Y are, independently of one another, 1) hydrogen atom, 2) (Cl-C2)-alkyl, or 3) hydroxyl.

The invention furthermore relates to processes for preparing the compound of the formula I, where one embodiment comprises 5 A) reacting a phosphorous diester or phosphorous mono-ester of the formula III
O
ll/x \~. (111) where X and Y are, independently of one another, a) hydrogen atom, b) (Cl-C6)-alkyl, c) (C1-C6)-alkoxy, d) (C3-C6)-alkenyloxy or e) phenoxy, with an azomethine of the formula IV

- 16 - 21~17 H O ~

~H
Il N ~
~ R , ( I V ) where Rl has the me~n;ng specified under formula I
for b) to k), to give a compound of the formula Ia ~ O

H~l ~P \r ~/ \R, (I~) where R1 has the meaning stated in formula IV, and X and Y have the ~e~n;ng stated in formula III, or B) reacting a compound of the formula NHRlR2, where Rl and R2 have, independently of one another, the meaning stated in formula I, in the preRence of 4-hydroxy-3,5-di-tert-butylbenzaldehyde and a com-pound of the formula III to give a compound of the formula I, or C) reacting an addition compound of the formula V
Rl NH ~ X ~2 R2 (V) where R1 and R2 have, independently of one another, the meaning stated in formula I, in the pre~ence of 4-hydroxy-3,5-di-tert-butylbenz-aldehyde to give a compound of the formula Ib 21~8~17 H0 ~

Rl R2 (l~) or D) hydrolyzing a compound of the formula I where X and Y are, independently of one another, a) (C1-C6)-alkyl, b) (C1-C6)-alkoxy, c) (C3-C6)-alkenyloxy or d) phenoxy, to give a compound of the formula I where X and Y
are, independently of one another, hydroxyl, or 0 E) fractionating a compound of the formula I which has been prepared by process A)-D) and which, by reason of its chemical structure, occurs in enantiomeric forms into the pure enantiomers by salt formation with enantiomerically pure acids or bases, chroma-tography on chiral stationary phases or derivatiza-tion using chiral enantiomerically pure compounds such as amino acids, separation of the diastereomers obtained in this way, and elimination of the chiral auxiliary group, or 0 F) either isolating in free form the compound of the formula I prepared by process A)-E) or, in the case where acidic or basic groups are present, where appropriate converting it into physiologically tolerated crystalline salts.
5 The procedure for process variant A) is, for example, to add the compound of the formula III on to the C=N double bond of the azomethine compound of the formula IV
(E.K. Fields, J. Am. Chem. Soc. 74 (1952) 1528;
K. Issleib et al., Z. Naturforsch. 36 b (1981) 1392).

2 ~ 17 Equimolar amounts of the compound of the formula III and formula IV are preferably used in the reaction. The reaction takes place in the presence of non-polar 801-ventg such as toluene, xylene, benzene, cyclohexane or high-boiling hydrocarbons or else in polar solvents such as alcohols, for example methanol, ethanol, propanol or butanol, or else in lower aliphatic carboxylic acids such as acetic acid, dimethylformamide and acetonitrile or mixtures of the said solvents. The reaction can also be carried out without addition of solvents, especially when phosphorous diester such as diethyl phosphite is used in equimolar amounts or in up to 10-fold excess as phos-phorus component.

The reaction is carried out in the range from room temperature to the boiling point of the solvent used in each case, preferably at 60 to 120C, with reaction times from 2 to 6 hours. A preferred variant of this proces6 comprises using a Lewis acid such as aluminum chloride, which is added in up to equimolar amounts, in which case the reaction preferably takes place in an inert solvent such as toluene, expediently at the boiling point of the solvent.
The azomethines of the formula IV needed for the process can be prepared by processes known to the skilled worker, for example by condensation of 4-hydroxy-3,5-di-tert-butylbenzaldehyde with the appropriate primary amines H2N-Rl in the presence of a catalyst, for example p-toluenesulfonic acid in a preferably non-polar solvent such as toluene or benzene, separating out the water which is liberated.

The procedure for process variant C) is, for example, to react the reactants - compound of the formula NHRlR2, 4-hydroxy-3,5-di-tert-butylbenzaldehyde and the compound of the formula III - in equimolar amounts. The reaction takes place in a solvent which is immiscible with water, such as toluene or benzene. To increase the rate of water elimination, it proves particularly advantageous to add 2~8~17 a Lewis acid such as AlCl3, ZnCl2 or sulfonic acids such as p-toluene sulfonic acid. The preferred reaction temperature is from about 50C to the boiling point of the solvent, in which case the reaction times are 2 to 6 hours.

The reaction conditions for process variant C) are the same as for process variants A) and B). The compound of the formula V is prepared by reacting equimolar amounts of amine and hypophosphorous acid in an inert solvent such as acetonitrile, an ether, for example diethyl ether or tert-butyl methyl ether, toluene or methylene chlor-ide. The reaction takes place at temperatures from 20 to 50C.

The hydrolysis in process ~ariant D) takes place by known processes. The hydrolysis preferably takes place by acidolytic cleavage with hydrobromic acid in glacial acetic acid, preferably at room temperature with reaction times of up to 8 hours.

The preparation of physiologically tolerated salts from compounds of the formula I which are capable of salt formation, including their stereoisomeric forms, takes place in a manner known per se. Thus, the carboxylic acids, phosphonic and phosphinic acids and the phosphonic monoesters form with basic reagents, such as hydroxides, carbonates, bicarbonates, alcoholates and ~mmo~; a or organic bases, for example trimethyl- or triethylamine, ethanolamine or else basic amino acids, for example lysine, ornithine or arginine, stable alkali metal, alkaline earth metal or optionally substituted ammonium salts. Where the compounds of the formula I have basic groups in the radical R1 or R2, it is also possible to prepare stable non-toxic acid addition salts with strong acids. Suitable for this purpose are both inorganic and organic acids such as hydrochloric, hydrobromic, sul-3S furic, phosphoric, methanesulfonic, benzene~ulfonic,p-toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylsulfamic, trifluoromethylsulfonic, acetic, oxalic, tartaric or trifluoroacetic acid.

Where the compounds of the formula I occur in diastereo-isomeric or enantiomeric forms, and mixtures thereof are produced in the chosen synthesis, it is possible to separate into the pure stereoisomers either by chromato-graphy on an optionally chiral support material or, where the racemic compounds of the formula I are able to form salts, by fractional crystallization of the diastereo-meric salts formed with an optically active base or acidas auxiliary. Examples of suitable chiral stationary phases for the separation of enantiomers by thin-layer or column chromatography are modified silica gel ~upports (so-called Pirkle phases) and high molecular weight carbohydrate~ such as triacetylcellulose. For analytical purposes, gas chromatography methods on chiral stationary phases can also be used after appropriate derivatization known to the skilled worker. To separate enantiomers of the racemic carboxylic acids, phosphonic acids and pho~phinic acids, an optically active base, which is usually commercially available, such as (-)-nicotine, (+)- and (-)-phenylethylamine, quinine bases, L-lysine or L- and D-arginine are used to form the diastereomeric salts which have different solubilities, and the less soluble component is isolated as solid, the more soluble diastereomer is precipitated from the mother liquor, and the pure enantiomers are obtained from the diastereomeric salts obtained in this way. The racemic compounds of the formula I which contain a basic group such as an amino group can be converted into the pure enantiomers in the same way in principle, using optically active acids such as (+)-camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L-lactic acid and (+)- and (-)-mandelic acid.
Chiral compounds which contain alcohol or amine func-tionalities can also be converted with appropriatelyactivated or optionally n-protected enantiomerically pure amino acids into the correspo~;ng ester~ or amides, or conversely chiral carboxylic acids can be converted with 21~8~17 carboxyl-protected enantiomerically pure amino acids into the amides or with enantiomerically pure hydroxy carboxylic acids such as lactic acid into the corres-pon~;ng chiral esters. The chirality of the amino acid or alcohol residue which has been introduced in enantio-merically pure form can then be utilized for separation of the isomers by carrying out a separation of the diastereomers which are now present by crystallization or chromatography on suitable stationary phases, and then the chiral moiety included in the molecule can be eliminated again by suitable methods.

The invention furthermore relates to the use of the compound of the formula I for the production for pharmaceuticals for the prophylaxis and therapy of degenerative joint disorders.

The invention also relates to a process for the produc-tion of a pharmaceutical, which comprises converting at least one compound of the formula I into a suitable administration form with a pharmaceutically suitable and physiologically tolerated vehicle and, where appropriate, other suitable active substances, additives or ancillary substances.

The pharmaceuticals according to the invention are administered orally, intramuscularly, periarticularly, intraarticularly, intravenously, intraperitoneally, subcutaneously or rectally.

Examples of suitable solid or liquid pharmaceutical formulations are granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, solutions, suspensions, emulsions, drops or injectable solutions, and products with protracted release of active substance, in whose production conventional auxiliaries such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavor-ings, sweeteners and solubilizers are used. Examples of ancillary substances which are frequently used are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactalbumin, gelatin, starch, cellulose and derivatives thereof, ~n;~l and vegetable oils such as fish liver oil, sunflower, arachis or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols, for example glycerol.

The pharmaceutical products are preferably produced and administered in dosage units, where each unit contains as active ingredient a particular dose of the compound of the formula I according to the invention. This dose can be up to about 1000 mg, but preferably about 50 to 300 mg, in solid dosage units such as tablets, capsules, coated tablets or suppositories, and up to about 300 mg, but preferably about 10 to 100 mg, in injection solutions in ampoule form.

The daily doses indicated for the treatment of an adult patient weighing about 70 kg are - depending on the activity of the compounds of the formula I, about 20 mg to 1000 mg of active substance, preferably about 100 mg to 500 mg. However, higher or lower daily doses may also be appropriate in certain circumstances. The daily dose may be administered either by a single ~; n; stration in the form of a single dosage unit or else several smaller dosage units and by multiple administration of divided doses at defined intervals.

Example 1 by process variant A) Diethyl 1-(4-chloroanilino)-1-(3,5-di-tert-butyl-4-hydroxyphenyl)methanephosphonate al) N-(3,5-di-tert-butyl-4-hydroxybenzylidene)-4-chloro-aniline 21~8~17 12.2 g (50 mmol) of 3,5-di-tert-butyl-4-hydroxybenz-aldehyde semihydrate and 6.4 g (50 mmol) of 4-chloro-aniline in 130 ml of toluene are heated under reflux together with 0.2 g of p-toluenesulfonic acid until the calculated amount of water of reaction has separated out azeotropically. After concentration of the reaction mixture under reduced pressure, the residue is recrystallized from ethanol.

Yield: 15.0 g (87% of theory) Melting point: 108-110C

a2) Diethyl 1-(4-chloroanilino)-1-(3,5-di-tert-butyl-4-hydroxyphenyl)methanephosphonate A solution of 15.0 g (44 mmol) of N-(3,5-di-tert-butyl-4-hydroxybenzylidene)-4-chloroaniline and 7.0 g (50 mmol) of diethyl phosphite in 100 ml of toluene is heated under reflux in the presence of 0.1 g of anhydrous AlCl3 while stirring with simultaneous azeotropic removal of water for 6 hours. The re~idue remaining after concentration of the reaction mixture is recrystallized from diisopropyl ether.

Yield: 19.5 g (92% of theory) Melting point: 130-131C
C2sH3sClN4P (MW = 482-0) Analysi~:
calculated: C 62.30% H 7.74% Cl 7.36% N 2.81% P 6.43%
found: C 61.98% H 7.73% Cl 7.47% N 2.97% P 6.70%

Example 2 by process variant B) Di-n-propyl 1-(3,4-methylenedioxybenzylamino)-1-(3,5-di-tert-butyl-4-hydroxyphenyl)methanephosphonate hydrochloride 2i~8~17 A solution of 12.2 g (50 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde semihydrate and 7.5 g (50 mmol) of 3,4-methylenedioxybenzylamine plu8 300 mg of p-toluene-sulfonic acid in 100 ml of toluene is heated to the reflux temperature and then 9.1 g (50 mmol) of dipropyl phosphite and 0.1 g of anhydrous aluminum(III) chloride are added while stirring. After heating under reflux with simultaneous azeotropic removal of the water of reaction for 6 hours, the mixture is filtered hot and, after cool-ing, methanolic hydrochloric acid is added. The substancewhich precipitates in the form of the hydrochloride is subsequently recrystallized from acetonitrile.

Yield: 18.1 g (63% of theory) Melting point: 162-163C
C29H45ClNO6P (MW = 570.11) Analysis:
calculated: C 61.10% H 7.96% N 2.46% P 5.43%
found: C 59.80% H 8.30% N 2.45% P 4.93%

Example 3 by process variant C) 1-(3,4-Methylenedioxybenzylamino)-1-(3,5-di-tert-butyl-4-hydroxyphenyl)methanephosphinic acid cl) 3,4-Methylenedioxyaniline hypophosphite 13.2 g (0.12 mol) of 60% strength hypophosphorous acid are slowly added dropwise to a solution of 13.8 g (0.1 mol) of 3,4-methylenedioxyaniline in 20 ml of acetonitrile while stirring at room temperature. The precipitate which forms after stirring for 2 hours and stAn~;ng overnight is filtered off, washed with acetonitrile and dried under reduced pressure.

Yield: 14.0 g (69% of theory) Melting point: 132-136C

215~S17 C7HloNO4P (MW = 203.14) c2) 1-(3,4-Methylenedioxybenzylamino)-1-(3,5-di-tert-butyl-4-hydroxyphenyl)methanephosphinic acid A mixture of 11.7 g (50 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 10.15 g (50 mmol) of 3,4-methy-lenedioxyaniline hypophosphite in 400 ml of acetonitrile i8 heated under reflux with stirring for 4 hours. After cooling, the precipitate is filtered off with suction and digested several times with hot acetone.

Yield: 19.0 g (91% of theory) Melting point: 196-197C
C22H30Nosp (MW = 419.46) Analysis:
calculated: C 63.00% H 7.21% N 3.34% P 7.38%
found: C 62.72% H 6.97% N 3.29% P 7.26%

Example 4 by process D) 1-(4-Choroanilino)-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-methanephosphonic acid 20 ml of 33% hydrobromic acid in glacial acetic acid are added to 2 g (4.4 mmol) of dimethyl 1-(4-chloroanilino)-1-(3,5-di-tert-butyl-4-hydroxyphenyl)methanephosphonate, and the mixture is then stirred at room temperature for 1.5 hours. Water is added to the mixture, which is then extracted with ethyl acetate, and the organic phase is washed with water and dried over Na2SO4. Concentration is followed by recrystallization from i-propanol/diisopropyl ether.

Yield: 1.45 g (78% of theory) Melting point: 162-165C
C21H29ClNO4P (MW = 425.9).

21~8~ 17 Table I: Compound~ of the formula I

E7~ample R1 R2 X Y Melting Process point ~3 H-OC~H5 -OC2H6130-131 a 2 o~ H-OC3H7 -OC3H7162-163 -Cl12~0 3 o~ H -H -OH 196-197 c ~o 4 ~_ H -OH -OH 162-165 d -nC4Hg H -OH -OH 183-185 d 6 -nC4Hg H-OC2H5 -OC2H5 93-96 7 {~ H-OCH3 -OCH3 143-145 a 8 {~ H-OC2H5 -OC2H5 104-106 {~ H-OC4Hg -OC4Hg 99-l10 a H-OC2H5 -OC2H5 148-149 a (HCI) 12 Adamantyl H -OH -OH Subl. from d 21~8~17 Rl R2 ~,~ yMelting Process Example point 13 Adam~n~l H -OC2H6 -OC2H6 132-133 14 -cH2-cH2-Nlc2Hsl2 H -H -OH 213-216 c /__~ H -OC2H6 -OC2Hs 244~245 -(Cl12)J~ o 16 ~ H -OC2H5-OC2H5112-113 n -Cll,-CH2-N O

17 ~ H -OC2H5-OC2H5144~145 a 18/~~~ H -OC2H5-OC2H5119-121 ~ 2 1 19C H 3 H -OC2H5 -OC2Hs110-111 b -C~-C02c~ ~HCI~
~ H -OC2H5-OC2H5 135-136 b -CH-C02CH~

21 -C3H7 -C3H~ -OC2H5 OC2H5 138-139 b 22 ~ -OC2H5 -OC2Hs 128129 b 23 /__~ -OC2H5 -OC2H5 107-109 b , - o 8~17 Example R1 R2 % Y Melting Process point 24 /~ h -OC2H5 -OC2H5 62-63 b \_J ~.2HCI~
~ ~ -OC2Hs -OC2H5 11 ~119 b \J .
26~0 - P (0 C 2 ~ -OC2H5 -OC2H5 213-214 b ~ -c~
\ ~
~-011 27 -C~2~ H H -OH 223 c 28 o' H H -OH 240-241 c 29 o~ H -OCH3 -OCH3 146-147 b -CH24~--o~ ` H -OC2H5 -OC2H5 125 b - C N 24~--o 21~8~17 Example Rl R2 X Y Melting Process point 31 o~ H-OC~,Hg -OC~H9162-163 b -CH~ ~HCI) 32 -CH~OCH~ H -OC2HS-OC2H6 87-88 b -CH2~C I H -OC2H5-OC2H5 10~107 b -C~ 3NHz H -OC2H5-OC2H5 77-78 b ~HCII

- C H z~3C N H -OC2H5-OC2H5 98 99 b (HCI) 36 ~3 H H OH189-190 c 37 ~3 H -OC2H5-OC2H5 125-127 b 38 ~3 H-OC2H5-OC2H5 98 b ~1~8~17 Example Rl R2 X Y MeltingProcess point 39 ~3 H-OC2Hs -OC2Hs 128-129 ~

~3_ H H -OH 215-217 c 41 ~3 H -CH3 -OH 166-168 8 42 ~c I H -CH3 -OC2H5 185 8 HOCH3 -OCH3 154-156 b ~ H-OC3H7 -OC3H7 120-121 b-~ H-OC4Hg -OC~,Hg 78-79 b 46 ~3 H-O-Allyl -O-Allyl 9496 21S8~17 Example R1 R2 X Y Melting Process point 47 ~3~ H -OPh -OPh 178 180 b 48 ~c I H -OC2H5 -OC2H5143-145 b 49 ~ H-OC,,Hg -OC"H9100-102 b ~ H H -OH 187 c .

C~.

~3 H -OC2H5 -OC2H5 154-155 52 ~ H -OC2Hs -C2Hs 121 a ~ ~
cr, 53 ~ -CH3 -OC2H5 -OC2H5 85-86 b , _/
54 ~3 -CH3 -OC2H5 -OC2H5 109-111 b Example Rt R2 X Y Melting Process polnt S5 ~30 H H OH 208-210 c 56 ~30CH, H H OH 231-233 c ~30CHI H-OC2H5 -OC2H5106-107 8 58 ~--OOH, H-OC2H5 -OC2H5117-118 a OCH, ~oJ -CH3 -C2Hs 230 8 H-OC2H5 -OC2H512~126 21~17 Example Rl R2 X Y Melting Process point 62 ~_ H-OC3H7 -OC3H~ 25~252 a ~< J (HCI) 63 ~_ H-OC4Hg -OC4H~ 241-242 ~< J (HCI) 64 0c~, H H -OH 16~161 c ~o~, OC~

~ H-OC2H5 -OC2H5 45-47 COOCH, 66 ~3cooc~1, H -OC2H5 -OC2H5 135136 a-67 ~ ."1 ",c", H -OC2H5 -OC2H5 184-185 68 {~ H -OC2H5 -0C2HS 223-225 a 2158~17 Example Rl R2 X Y Meltin~ Process point 69 ~3-02 H -OC2H5 -OC2H5192~193 ~3_ CH3-OC2H6 -OC2H5109-110 b ~HCI) 71 ~ N, H -0C2H6 OC2HS 197-199 ~HCI~
72 ~3--N, CH3-OC2H5 -0C2H6 68-69 b ~HCI~
73 ~N, "~1 N H -OC2Hs -OC2H5 139-141 b 74 o H -OC2H5 -OC2H5 156-158 ~=~ N ~ ( C2 N, J, ~ON

~ H -OC2H5 OC2H6 137-138 76 ~ . H -OC2H5 -OC2H5 128-130 21~517 ~ample Rl R2 X Y Melting Process point 77 ~ H-OC4Hg -OC~H9 135136 ~, ~.3 79 N H -OC2Hs -OC2Hs 12~126 ~ (HCI) N H -OC2Hs -OC2Hs 132-133 a ~/~
N--J

21~517 Pharmacological tests 1. Activity in stimulating synthesis of cartilage matrix, test in cho~rocyte culture Cells: The hyaline cartilage is removed from the foot joints of freshly slaughtered cattle, the natural matrix i8 enzymatically broken down with Pronase (Boehringer M~nnheim) and collagenase (Sigma), and the cho~ocytes are plated out in 1% low melting agarose in 24-well dishes at a cell density of 4 x 106 per well.

Medium: Complete medium contains HAM's F12 (Biochrom RG, Berlin) and 10% fetal calf serum (Boehringer M~nnheim), the test substance is dissolved in medium, normally added in a concentration of 10-5 M and added again at each change of medium.

Experimental procedure: Treatment takes place from the third to the tenth day of primary culture and, on day 9, 20 ~Ci/ml (7.4 x 105 Bq) Na235S04 are added to the medium for 24 h. Dissociative extraction of the proteoglycans from the agarose layer is carried out with 8M guanidinium hydrochloride and added proteinase inhibitors (Sigma) by shaking up at 4C for 24 h. The supernatant after centrifugation is separated into free and incorporated sulfate on a PD lO~Sephadex G 25 column, and the activity thereof is measured on aliquots in a ~ scintillation counter.

Evaluation: The parameter for matrix production by c~o~ocytes is the amount of proteoglycans synthesized, measured as sulfate incorporation in cpm. The mean is calculated from four wells for each group. This mean is divided by the mean for the untreated control and thus yields a stimulation factor which is greater than 1 on stimulation of matrix synthesis, is less than 1 on inhibition thereof by the effect of the substance, and is equal to 1 when matrix synthesis is unchanged.

21~17 Diacerein, which i u~ed a~ therapeutic agent for osteoarthritis under the proprietary name~ "Artodar" of Proter and Fi~iodar of Gentili in Italy (Drugs of the Future 11 (6), 1986) i~ used as ~t~n~rd.

2 1 ~ 7 Table II:
Stimulation of proteoglycan synthesis in agarose cell culture Compound of Proteoglycan synthesis Example stimulation factor 1 1.4 2 1.2 6 1.2 8 1.2 22 1.2 1.4 34 1.2 36 1.2 38 1.7 49 1.2 51 1.6 52 1.7 57 1.5 58 2.5 61 2.9 62 1.2 1.3 78 1.4 79 1.6 Diacerein 1.0 21~851~

2. Activity in cho~rocytic cho~rolysis, test in chon~rocyte culture Cells are obtained and plated as in Experiment 1. Medium:
5 ~/ml human rec. interleukin-1 alpha (IL-1, Sigma) are additionally added to the complete medium as in Test 1 from the start of treatment and is again added, like the test substance, at each change of medium.

Experimental procedure: Treatment takes place from day 5 to day 13 of primary culture and, on day 12, 20 ~Ci/ml Na235S04 are added to the medium for 24 h. Dissociative extraction of the proteoglycans and measurement of sulfate incorporation are carried out a~ in Test 1.

Evaluation: IL-1 leads to inhibition of synthesis and increase in degradation of the proteoglycans, which is reflected by a smaller content of labeled matrix mole-cules in the agarose layer. The stimulation factor is therefore related to the mean for the IL-1-treated control.

Results: The results are listed in Table III.

Table III:
Effect on IL-1 induced chon~rolysis in agarose cell culture Compound of Proteoglycan synthesis Example stimulation factor 1 1.5 2 4.3 3 1.3 6 1.4 7 1.5 1.5 2~58517 Compound of Proteoglycan synthesis Example stimulation factor 12 2.0 13 2.0 14 1.2 19 4.3 27 1.2 28 5.5 29 1.5 1.5 31 1.7 32 1.4 33 2.2 3.9 36 2.5 37 1.5 38 1.3 2.1 41 3.5 43 1.4 44 1.5 1.2 47 1.8 48 1.7 49 1.5 53 1.7 54 1.4 21~8~17 Compound of Proteoglycan synthesis Example stimulation factor 57 1.4 58 1.2 1.4 61 1.3 62 1.2 63 1.5 67 1.9 68 1.3 74 3.8 77 1.3 79 1.2 2.4 Diacerein 1.1 3. Inhibition of matrix metalloproteases (MMP) The compounds according to the invention showed distinct inhibitory effects on proteolytic enzymes, the so-called matrix metalloproteases. This is very important because these enzymes, which are known per se to the skilled worker, are crucially involved in the proteolytic break-down of the intact cartilage matrix.

Cell culture:

Rabbit synoviocytes (HIG-82; ATCC, Rockville, Maryland, USA) are cultivated in HAM's F12 nutrient medium (Sigma, Deisenhofen, Germany, Catalog No. N-6760) with 10% fetal bovine serum (Sigma, Deisenhofen, Germany, Catalog No.
F-2442), together with penicillin 100 U/ml and strepto-mycin 100 ~g/ml. After confluent cell growth, MMP

2~8517 expression is induced in serum-free HAM's F12 by adding 0.3 ~mol/l phorbol 12-myristate 13-acetate. After an incubation time of 20 h at 37C, the supernatant is removed.

Activation of MMP:

The supernatant is activated with trypsin (5 ~g/ml).
After 15 minutes (min) at 37C, the activation is stopped by adding 1 mmol/l phenylmethylsulfonyl fluoride (PMSF) and incubation is continued for a further 10 min. The total volume of the mixture is 210 ~1.

Measurement of MMP activity (Lit.: C.G. Rnight et al., FEBS Lett. 296, 263 (1992)):

20 ~1 of the abovementioned supernatant are diluted 1:10 and mixed with 240 ~1 of buffer (0.1 Tris/HCl pH 7.5; 0.1 M NaCl; 0.01 M CaCl2; 0.05% Brij). The test substance is added in the stated concentration (see Table). After an incubation time of 15 min, the reaction is started by adding 20 ~mol/l fluorescent substance ((7-methoxycoumarin-4-yl)acetyl-pro-Leu-Gly-Leu-[3-(2',4'-dinitrophenyl)-L-2,3-diaminopropionyl~-Ala-Arg-NH2;
Bachem, Heidelberg, Germany, Cat. No.: M-1895). The reaction is stopped after 30 min by adding 10 mmol/EDTA.
The total volume of the mixture is 320 ~1. The measured parameters are the fluorescence intensities at ~eX:
328 nm and AeX 393 nm. In order to take account of the possible intrinsic fluorescence of the test substances, the fluorescence intensities from parallel measurement6 without substrate are subtracted from the measurements with substrate. All operations take place at 20C. In the control experiment without inhibitor, the fluorescence is equivalent to 0% inhibition, whereas complete quenching of fluorescence means 100% inhibition.

21S8~;17 Inhibition of MMP

Example 3 83% Inhibition at100 ~M
20% 30 ~M
3% 10 ~M
Example 22 34% 100 ~M
12% 30 ~M
Example 53 25% 100 ~M
11% 30 ~M
Example 59 43% 30 ~M
19% 10 ~M
Example 62 83% 100 ~M
68% 30 ~M
23% 10 ~M
Example 63 60% 30 ~M
26% 10 ~M
Example 74 74% 50 ~M
47% 30 ~M
20% 10 ~M

4. Inhibition of microsomal lipid peroxidation Oxidative degradation processes are also involved to a considerable extent in the unwanted breakdown of cartilage matrix. The compounds according to the invention showed a strong inhibitory action on biological oxidation processes and are therefore particularly suitable for inhibition of oxidative cartilage breakdown.

Isolation of rat liver microsomes:

All steps are carried out at 0C. The liver from a rat is thoroughly rinsed with 0.9% NaCl solution to remove all hemoglobin. The coarsely comminuted liver is then treated in a Potter in 10 mM Tri~/HCl pH 7.4; 250 mM sucrose (10 ml of buffer/g of liver). Centrifugation is first 21~8517 carried out at 600xg for 5 minutes. The supernatant i8 then centrifuged at 12000xg for 10 min and adjusted to a concentration of 8 mM with solid CaCl2 (117.6 mg/100 ml). Centrifugation at 25000xg (15 min) results in a microsome pellet. This pellet is rehomogenized in the same volume of buffer (10 mM
Tris/HCl pH 7.4; 150 mM KCl) and again centrifuged at 25000xg for 15 min.

Peroxidation by rat liver microsomes:

A test mixture is composed of 20 ~1 of microsomes (100 mg/ml), see above, dissolved in buffer (250 mM
Tris/HCl pH 6.6, 750 mM gCl), 10 ~1 of 50 mM MgCl2, 10 ~1 of 200 mM isocitric acid, 10 ~1 of 4 mM NADP
(30.028 mg/ml of water), 10 ~1 of 25 mM niacinamide, 10 ~1 of isocitrate dehydrogenase (diluted 1:100) and 20 ~1 of water or test substance. The reaction is started with 10 ~1 of 0.25 mM FeSO4. Incubation takes place at 37C for 10 minutes. The reaction is stopped with 500 ~1 of ice-cold 20% strength trichloroacetic acid. The malonaldehyde which has been produced is converted by addition of 500 ~1 of 0.67% strength thiobarbituric acid and incubation at 90C for 30 minutes into a pink-colored compound which is measured at 532 nm. The extinction in the control mixture without test product is set at 0%
inhibition, while complete disappearance of the signal means 100% inhibition.

Results: Microsomal lipid peroxidation Example IC50 (~mol/l) 1 2.43 2 2.30 3 0.79 4 0.71 6 2.25 - 2158~17 Example IC50 (~mol/l) 7 2.40 8 0.73 9 2.10 9 . oo 12 2.70 13 0.83 17 3.18 18 2.03 2.10 21 6.35 22 2.45 23 2.45 2.45 29 0.69 31 2.18 34 0.70 39 2.40 0.49 43 0.79 44 1.05 6.15 46 0.86 48 2.95 49 ~ 10 53 2.03 21~3517 Example IC50 (~mol/l) 54 2.80 0.71 62 0.24 63 0.24 0.73 67 2.22 68 2.37 73 0.67 74 1.25 2.90 76 2.05 77 8.70 79 2.30 2.90 5. Release of interleukins (in particular IL-l~) from human mo~o~uclear cells The compounds according to the invention have a strong inhibitory effect on the release of interleukin~ from human cells. This is of great pharmacological importance because interleukins may induce unwanted degradation of cartilage matrix.

Isolation of mononuclear cells from human blood 10 ml of human blood stabilized with 1 ml of 3.8%
~trength sodium citrate solution are diluted with 10 ml of PM 16 (Serva, Heidelberg), and a layer of 15 ml of Lymphoprep (Dr. Molter GmbH, Heidelberg) is introduced 2158~17 underneath. The samples are centrifuged at 400xg (1600 rpm Minifuge 2, Heraeus, Osterode) for 40 minutes (room temperature). The ~o~uclear cells are visible as a white ring at the Lymphoprep/plasma boundary. This ring is carefully removed using a syringe, diluted with the same volume of PM16 and centrifuged at 400xg for 10 minutes. The precipitate i~ washed with ~ 10 ml of RPMI
1640 (+ 300 mg/l L-gluta_ine, Gibco, Eggenstein). After resuspension of the cells in ~ 1 ml of RPMI 1640 (+ 300 mg/l L-glutamine, + 25 mM HEPES, + 100 ~g/ml streptomycin, + 100 ~g/ml penicillin), the cell density is determined with a Coulter counter JT (Coulter Diagnostics) and adjusted to 5X106 ml. The cells are typically composed of 90% lymphocytes and 10% monocytes.

Stimulation of release of cytokines, in particular interleukin 1~

230 ~l of mo~o~uclear cells are incubated with 10 ~l of test substance (10 ~M in DMSO/water 1/10) and 10 ~l of lipopolysaccharides (500 ~g dissolved in 1 ml of dimethyl sulfoxide (DMSO) and diluted 1/10 with water before start of test, from Salmonella abortus equi, Sigma, Deisenhofen) at 37C, 5% CO2 for 20-22 hours. The samples are cooled to 0C in an ice bath and centrifuged in a Sigma centrifuge (2 minute~; 2000 rpm). Aliquots of the supernatant are determined using a commercially available ELISA (Biermann, Bad Nauheim).

Results:
Inhibition of interleukin release (all substances from the examples were tested at 10 ~mol/l) Example % Inhibition Interleukin 7 21 IL-lalpha 22 80 I-lalpha 21~8517 Example % Inhibition Interleukin 22 86 TNF-alpha 23 75 IL-lalpha 23 70 TNF-alpha IL-lalpha 36 TNF-alpha 31 32 IL-lbeta 22 IL-lalpha 53 53 IL-lbeta 24 TNF-alpha 61 24 IL-lbeta 62 46 IL-lbeta 63 31 IL-lbeta 67 26 IL-lbeta 21 TNF-alpha

Claims (17)

1. A pharmaceutical containing a compound of the formula I

(I) and/or a physiologically tolerated salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, where R1 and R2 are identical or different and are, inde-pendently of one another, a) a hydrogen atom, b) (C1-C12)-alkyl, c) (C1-C12)-alkyl, substituted one or more times independently of one another by 1) phenyl,
2) phenyl, substituted once to three times independently of one another by 2.1. fluorine, chlorine, bromine or iodine atom, 2.2. (C1-C3)-alkyl, 2.3. (C1-C3)-alkoxy, 2.4. methylenedioxy, 2.5. nitro, 2.6. amino, 2.7. amidino, 2.8. guanidino, 2.9. hydroxyl, 2.10. (C1-C6)-alkoxycarbonyl or 2.11. cyano,
3) a monocyclic 5- or 6-membered saturated heterocyclic ring,
4) amino, unsubstituted or substituted once or twice by (C1-C3)-alkyl, or
5) -C(O)-O-(C1-C3)-alkyl d) tetralin, e) phenyl, f) phenyl, substituted once to three times independently of one another by 1) (C1-C4)-alkyl, 2) (C1-C4)-alkyl, substituted one or more times by fluorine, chlorine, bromine or iodine atom, 3) fluorine, chlorine, bromine or iodine atom 4) nitro, 5) aminosulfonyl,
6) amidino,
7) guanidino,
8) (C1-C3)-alkyloxy,
9) methylenedioxy,
10) hydroxyl,
11) carboxyl,
12) cyano,
13) (C1-C3)-alkoxycarbonyl,
14) -CH=CH-COOH,
15) ,
16) amino or
17) amino, substituted by the radical of the formula II, (II) in which X and Y are, independently of one another, 17.1. hydrogen atom, 17.2. (C1-C6)-alkyl, 17.3. (C1-C6)-alkoxy, 17.4. (C3-C6)-alkenyloxy, 17.5. phenoxy or 17.6. hydroxyl, g) naphthyl, h) naphthyl, substituted one or more times as defined under f)1) to f)17), i) heteroaryl, k) heteroaryl, substituted one or more times by phenyl, benzyl or as defined under f)1) to f)17), or l) R1 and R2 form, together with the nitrogen atom to which they are bonded, a 4- to 7-membered ring, m) R1 and R2 form, together with the nitrogen atom to which they are bonded, a 5- to 7-membered ring in which one carbon atom in the ring is replaced by an oxygen atom or a nitrogen atom, or n) R1 and R2 form, together with the nitrogen atom to which they are bonded, a 5- to 7-membered ring in which one carbon atom in the ring is replaced by a nitrogen atom and this nitrogen atom is substituted by 1) phenyl or 2) the radical of the formula II in which X and Y have, independently of one another, the meaning specified under f)17.1. to f)17.6. and, X and Y are identical or different and have, independently of one another, the meaning specified under f)17.1. to f)17.6.;
and a physiologically tolerated vehicle.

2. A pharmaceutical as claimed in claim 1, wherein at least one compound of the formula I and/or a physiologically tolerated salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I is used, where R1 and R2 are identical or different and are, independently of one another, a) hydrogen atom, b) (C1-C12)-alkyl, c) (C1-C12)-alkyl, substituted one or more times independently of one another by 1) phenyl, 2) phenyl, substituted once to three times independently of one another by 2.1. fluorine, chlorine, bromine or iodine atom, 2.2. (C1-C3)-alkyl, 2.3. (C1-C3)-alkoxy, 2.4. methylenedioxy, 2.5. nitro, 2.6. amino, 2.7. amidino, 2.8. guanidino, 2.9. hydroxyl, 2.10. (C1-C6)-alkoxycarbonyl or 2.11. cyano, 3) piperazinyl or, 4) morpholinyl, d) phenyl, e) phenyl, substituted once to three times independently of one another by 1) (C1-C4)-alkyl, 2) (C1-C4)-alkyl, substituted one or more times by fluorine, chlorine, bromine or iodine atom, 3) fluorine, chlorine, bromine or iodine atom 4) nitro, 5) aminosulfonyl, 6) amidino, 7) guanidino, 8) (C1-C3)-alkyloxy, 9) methylenedioxy, 10) hydroxyl, 11) carboxyl, 12) cyano, 13) (C1-C3)-alkoxycarbonyl, 14) -CH=CH-COOH, 15) , 16) amino or 17) amino, substituted by the radical of the formula II in which X and Y are, independently of one another, 17.1. hydrogen atom, 17.2. (C1-C6)-alkyl, 17.3. (C1-C6)-alkoxy, 17.4. (C3-C6)-alkenyloxy, 17.5. phenoxy or 17.6. hydroxyl, f) (C5-C7)-cycloalkyl, g) (C5-C7)-cycloalkyl, substituted one or more times independently of one another by the radicals mentioned under c)1) to c)4), h) adamantyl, i) (C1-C12)-alkyl substituted by amino, unsubstituted or substituted once or twice by (C1-C3)-alkyl, j) (C1-C12)-alkyl substituted by -C(O)-O-(C1-C3)-alkyl, k) naphthyl, l) tetralin, m) pyridyl, n) pyridyl, substituted one or more times independently of one another as defined under e)1) to e)17), o) pyrimidyl p) pyrimidyl, substituted one or more times independently of one another as defined under e)1) to e)17), q) piperidyl radical, unsubstituted or substituted once to four times by 1) (C1-C4)-alkyl, 2) phenyl or 3) benzyl, or r) R1 and R2 form, together with the nitrogen atom to which they are bonded, a piperidino radical, s) R1 and R2 form, together with the nitrogen atom to which they are bonded, a piperazino or morpholino radical, or t) R1 and R2 form, together with the nitrogen atom to which they are bonded, a piperazino radical which is substituted on the nitrogen atom by 1) phenyl or 2) the radical of the formula II in which X and Y have, independently of one another, the meaning specified under e)17.1. to e)17.6. and, X and Y are identical or different and have, independently of one another, the meaning specified under e)17.1. to e)17.6.;

and a physiologically tolerated vehicle.

3. A pharmaceutical as claimed in claim 1 or 2, wherein at least one compound of the formula I and/or a physiologically tolerated salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I is used, where R1 and R2 are identical or different and are, independently of one another, a) hydrogen atom, b) (C1-C5)-alkyl, c) (C1-C5)-alkyl, substituted one or more times independently of one another by 1) phenyl, 2) phenyl, substituted once to three times independently of one another by 2.1. fluorine or chlorine atom, 2.2. methyl, ethyl or propyl, 2.3. methoxy, 2.4. methylenedioxy, 2.5. nitro, 2.6. amino, 2.7. amidino, 2.8. guanidino, 2.9. hydroxyl, 2.10. methoxycarbonyl or 2.11. cyano, or 3) morpholinyl, d) (C5-C7)-cycloalkyl, e) (C5-C7)-cycloalkyl, substituted once to three times independently of one another as defined under c)1) to c)3), f) adamantyl, g) naphthyl, h) phenyl, i) phenyl, substituted once to three times independently of one another by 1) (C1-C2)-alkyl, 2) trifluoromethyl, 3) fluorine or chlorine atom, 4) nitro, 5) aminosulfonyl, 6) amidino, 7) guanidino, 8) methoxy, 9) methylenedioxy, 10) hydroxyl, 11) carboxyl, 12) cyano, 13) methoxycarbonyl, 14) -CH=CH-COOH, 15) , 16) amino or 17) amino, substituted by the radical of the formula II in which X and Y are, independently of one another, 17.1. hydrogen atom, 17.2. methoxy, ethoxy, propoxy or butyloxy, 17.3. allyl, 17.4. phenoxy or, 17.5. hydroxyl, k) pyridyl, l) pyrimidyl, or m) R1 and R2 form, together with the nitrogen atom to which they are bonded, a piperidino radical, n) R1 and R2 form, together with the nitrogen atom to which they are bonded, a piperazino or morpholino radical, or o) R1 and R2 form, together with the nitrogen atom to which they are bonded, a piperazino radical which is substituted on the nitrogen atom by 1) phenyl or 2) the radical of the formula II in which X and Y have, independently of one another, the meaning specified under i)17.1. to i)17.5. and, X and Y are identical or different and have, independently of one another, the meaning specified under i)17.1. to i)17.6.;
and a physiologically tolerated vehicle.

4. A pharmaceutical as claimed in one or more of claims 1 to 3, wherein at least one compound of the formula I and/or a physiologically tolerated salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I is used, where R1 and R2 are identical or different and are, inde-pendently of one another, a) hydrogen atom, b) phenyl, c) phenyl, substituted once to three times independently of one another by 1) fluorine or chlorine atom, 2) methylenedioxy or 3) (C1-C3)-alkoxy, and X and Y are, independently of one another, 1) hydrogen atom, 2) (C1-C3)-alkoxy, or 3) hydroxyl;
and a physiologically tolerated vehicle.

5. A compound of the formula I as claimed in claim 1 and/or physiologically tolerated salts of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, where R1 and R2 are identical or different and are, independently of one another, a) a hydrogen atom, b) (C1-C12)-alkyl, substituted one or more times independently of one another by 1) phenyl, substituted once to three times independently of one another by 1.1. fluorine, chlorine, bromine or iodine atom, 1.2. (C1-C3)-alkyl, 1.3. (C1-C3)-alkoxy, 1.4. methylenedioxy, 1.5. nitro, 1.6. amino, 1.7. amidino, 1.8. guanidino, 1.9. hydroxyl, 1.10. (C1-C6)-alkoxycarbonyl or 1.11. cyano, 2) a monocyclic 5- or 6-membered saturated heterocyclic ring, 3) amino, unsubstituted or substituted once or twice by (C1-C3)-alkyl, or 4) -C(O)-O-(C1-C3)-alkyl c) tetralin, d) phenyl, substituted once to three times independently of one another by 1) (C1-C4)-alkyl, 2) (C1-C4)-alkyl, substituted one or more times by fluorine, chlorine, bromine or iodine atom, 3) nitro, 4) aminosulfonyl, 5) amidino, 6) guanidino, 7) (C1-C3)-alkyloxy, 8) methylenedioxy, 9) hydroxyl, 10) carboxyl, 11) cyano, 12) (C1-C3)-alkoxycarbonyl, 13) -CH=CH-COOH, 14) , 15) amino or 16) amino, substituted by the radical of the formula II, in which X and Y
are, independently of one another, 16.1. hydrogen atom, 16.2. (C1-C6)-alkyl, 16.3. (C1-C6)-alkoxy, 16.4. (C3-C6)-alkenyloxy, 16.5. phenoxy or 16.6. hydroxyl, e) naphthyl, substituted one or more times as defined under d)1) to d)16), f) heteroaryl, g) heteroaryl, substituted one or more times by phenyl, benzyl or as defined under d)1) to d)16), or h) R1 and R2 form, together with the nitrogen atom to which they are bonded, a 5- to 7-membered ring in which one carbon atom in the ring is replaced by an oxygen atom or a nitrogen atom, or i) R1 and R2 form, together with the nitrogen atom to which they are bonded, a 5- to 7-membered ring in which one carbon atom in the ring is replaced by a nitrogen atom and this nitrogen atom is substituted by 1) phenyl or 2) the radical of the formula II in which X and Y have, independently of one another, the meaning specified under d)16.1. to d)16.6. and, X and Y are identical or different and have, independently of one another, the meaning specified under d)16.1. to d)16.6.; or where R1 is phenyl or phenyl substituted once to three times by fluorine, chlorine, bromine or iodine atom, R2 is hydrogen atom and X and Y are, independently of one another, 1) hydrogen atom, 2) (C1-C6)-alkyl, 3) (C3-C6)-alkenyloxy, 4) phenoxy or 5) hydroxyl.

6. A compound of the formula I as claimed in claim 5, wherein R1 and R2 are identical or different and are, independently of one another, a) hydrogen atom, b) (C1-C12)-alkyl, substituted one or more times independently of one another by 1) phenyl, substituted once to three times independently of one another by 1.1. fluorine, chlorine, bromine or iodine atom, 1.2. methylenedioxy or 1.3. cyano, 2) amino, unsubstituted or substituted once or twice by (C1-C3)-alkyl, or 3) -C(O)-O-(C1-C3)-alkyl c) phenyl, substituted once to three times independently of one another by 1) (C1-C4)-alkyl, substituted one or more times by fluorine, chlorine, bromine or iodine atom, 2) (C1-C3)-alkyloxy, 3) methylenedioxy, 4) cyano, or 5) amino, substituted by the radical of the formula II, in which X and Y
are, independently of one another, 5.1. hydrogen atom, 5.2. (C1-C6)-alkyl, 5.3. (C1-C6)-alkoxy, 5.4. (C3-C6)-alkenyloxy, 5.5. phenoxy or 5.6. hydroxyl, d) pyridyl or e) pyrimidyl, and in which X and Y have, independently of one another, the meaning specified under c)5.1. to c)5.6.; or where R1 is phenyl or phenyl substituted once to three times by fluorine or chlorine atom, R2 is hydrogen atom and X and Y are, independently of one another, 1) hydrogen atom, 2) (C1-C2)-alkyl, or 3) hydroxyl.

7. A process for preparing the compound of the formula I, which comprises A) reacting a phosphorous diester or phosphorous monoester of the formula III

(III) where X and Y are, independently of one another, a) hydrogen atom, b) (C1-C6)-alkyl, c) (C1-C6)-alkoxy, d) (C3-C6)-alkenyloxy or e) phenoxy, with an azomethine of the formula IV

(IV) where R1 has the meaning specified under formula I for b) to k), to give a compound of the formula Ia (Ia) where R1 has the meaning stated in formula IV, and X and Y have the meaning stated in formula III, or B) reacting a compound of the formula NHR1R2, where R1 and R2 have, independently of one another, the meaning stated in formula I, in the presence of 4-hydroxy-3,5-di-tert-butylbenzaldehyde and a compound of the formula III to give a compound of the formula I, or C) reacting an addition compound of the formula V

(V) where R1 and R2 have, independently of one another, the meaning stated in formula I, in the presence of 4-hydroxy-3,5-di-tert-butylbenzaldehyde to give a compound of the formula Ib (Ib) or D) hydrolyzing a compound of the formula I where X
and Y are, independently of one another, a) (C1-C6)-alkyl, b) (C1-C6)-alkoxy, c) (C3-C6)-alkenyloxy or d) phenoxy, to give a compound of the formula I where X and Y are, independently of one another, hydroxyl, or E) fractionating a compound of the formula I which has been prepared by process A)-D) and which, by reason of its chemical structure, occurs in enantiomeric forms into the pure enantiomers 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 obtained in this way, and elimination of the chiral auxiliary group, or F) either isolating in free form the compound of the formula I prepared by process A)-E) or, in the case where acidic or basic groups are present, where appropriate converting it into physiologically tolerated crystalline salts.

8. The use of at least one compound of the formula I as claimed in one or more of claims 1 to 4 for the production of pharmaceuticals for the prophylaxis and therapy of degenerative joint disorders.

9. The use as claimed in claim 8, for the treatment of osteoarthritis, rheumatic disorders with cartilage breakdown, rheumatoid arthritis, chondrolysis after joint trauma or chondrolysis after lengthy immobilization of joints.

10. A process for the production of a pharmaceutical as claimed in claims 1 to 4, which comprises converting at least one compound of the formula I and/or at least one physiologically tolerated salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I and/or a compound obtained by the process as claimed in claim 7 into a suitable administration form with physiologically acceptable ancillary substances and excipients and, where appropriate, further additives and/or other active substances.
CA002158517A 1994-09-19 1995-09-18 Aminomethylphosphonic and aminomethylphosponic acid derivates and their use for treating degenerative joint disorders Abandoned CA2158517A1 (en)

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US6872711B2 (en) 2000-10-23 2005-03-29 Ilex Oncology Research S.A. β-substituted β-aminoethyl phosphonate derivatives
CN101717407B (en) * 2008-10-09 2014-12-03 中国人民解放军军事医学科学院毒物药物研究所 Highly substituted alpha-amino phosphonate derivative as well as preparation method and medical application thereof
CN102942590A (en) * 2012-11-01 2013-02-27 武汉三聚生物技术有限公司 Alpha-(adamantane)amino phosphonic acid, its preparation method and application
CN102942590B (en) * 2012-11-01 2015-12-16 武汉三聚生物技术有限公司 α-(diamantane) aminophosphonic acid and its production and use

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AU3068695A (en) 1996-04-04
IL115330A0 (en) 1995-12-31
JPH08104694A (en) 1996-04-23
ZA957674B (en) 1996-04-15
DE4433244A1 (en) 1996-03-28
KR960010670A (en) 1996-04-20
EP0703239A1 (en) 1996-03-27

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