CA1324383C - Process for the manufacture of novel substituted aminomethanediphosphonic acids - Google Patents
Process for the manufacture of novel substituted aminomethanediphosphonic acidsInfo
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- CA1324383C CA1324383C CA000552085A CA552085A CA1324383C CA 1324383 C CA1324383 C CA 1324383C CA 000552085 A CA000552085 A CA 000552085A CA 552085 A CA552085 A CA 552085A CA 1324383 C CA1324383 C CA 1324383C
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
- C07F9/6541—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- 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, i.e. RP(=X)(XH)2 (X = S, Se)
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- 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
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
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- C—CHEMISTRY; METALLURGY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- 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
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
- C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
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- C—CHEMISTRY; METALLURGY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- 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
- C07F9/653—Five-membered rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- 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
- C07F9/653—Five-membered rings
- C07F9/65324—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
- C07F9/65392—Five-membered rings containing two nitrogen atoms
- C07F9/65397—Five-membered rings containing two nitrogen atoms having the two nitrogen atoms in positions 1 and 3
Abstract
Process for the manufacture of novel substituted aminomethanediphosphonic acids Abstract Heteroarylaminomethanediphosphonic acids of the formula (I) in which R1 represents an optionally benzo- or cyclohexeno-fused 5-membered heteroaryl radical that contains, as hetero atom(s), either from 2 to 4 N-atoms or 1 or 2 N-atoms as well as 1 O-atom or S-atom and that is unsubstituted or is substituted by lower alkyl; by phenyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy and/or by halogen; by lower alkoxy;
by hydroxy; by di-lower alkylamino; by lower alkylthio and/or by halogen; and R2 represents hydrogen or lower alkyl, and their salts, have a regulatory action on the calcium metabolism and can be used as active ingredients in medicaments for the treatment of illnesses that can be attributed to disorders of the calcium metabolism.
They are manufactured, for example, as follows: in a compound of the formula
by hydroxy; by di-lower alkylamino; by lower alkylthio and/or by halogen; and R2 represents hydrogen or lower alkyl, and their salts, have a regulatory action on the calcium metabolism and can be used as active ingredients in medicaments for the treatment of illnesses that can be attributed to disorders of the calcium metabolism.
They are manufactured, for example, as follows: in a compound of the formula
Description
- 1 ~ 3 2 ~
4-l6l?9/-Process for the manufacture of novel substituted aminomethane-di~hosphonic acids ,~ _ The invention relates to a process for the manufacture of novel substituted aminomethanediphosphonic acids, especlally of heteroarylaminomethanediphosphonic acids of the formula ¦ Rl - N- CH (I) in which R1 represents an optionally benzo- or cyclohexeno-fused 5-membered heteroaryl radical that contains, as hetero atom(s), either from 2 to 4 N-atoms or 1 or 2 N-atoms as well as 1 O-atom or S-atom and that is unsubstitutad or is C-substituted by lower alkyl;
by phenyl that is unsubstituted or ~s substituted by lower alkyl, lower alkoxy and/or by halogen; by lower alkoxy; by hydroxy; by di-lower alkylamlno; by lower 2 1 3 2 ~ . ~
alkylthio and/or by halogen; and/or that is N-substi-tuted by lower alkyl; or by phenyl-lower alkyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy and/or by halogen; and R2 represents hydrogen or lower alkyl, with the proviso that R2 is other than hydrogen when R1 represents a pyrazol-3-yl or isoxazol-3-yl radical that is optionally substituted by alkyl and/or by halogen, and of their sal~s.
Optionally benzo- or cyclohexeno-fused S-membered heteroaryl radicals containing, as hetero atom(s), either fro~ 2 to 4 N-atoms or 1 or 2 N-atoms as well as 1 O-atom or S-atom are, for example, imidazolyl, for example imidazol-2-yl or -4-yl, thiazolyl, for example thiazol-2-yl, or also thiazol-5-yl or -4-yl, oxazolyl, for example oxazol-2-yl, or also oxazol-4 yl, triazolyl, for example 4H-1,2,4-triazol-3-yl or 2H-1,2,3-triazol-4-yl, tetrazolyl, for example tetrazol-5-yl, thiadia-zolyl, for example 1,2,5-thiadiazol-3-yl, oxadiazolyl, for example 1,3,4-oxadiazol-2-yl, benzimidazolyl, for example benzimidazol-2-yl, benzoxazolyl, for example benzoxazol-2-yl, or benzothiazolyl, for example benzothiazol-2-yl. The radicals mentioned may contain one or several identical or different, especially one or two identical or different, substituents from among those mentioned at the beginnin~. Radicals R1 having substitutable N-atoms are preferably N-substituted as indicated. Radicals R1 are, for example, 1-C1-C4-alkylimidazol-2-yl radicals, such as 1-methylimidazol-2-yl, 1-phenyl-C1-C4-alkylimidazol-2-yl radicals, such as 1-benzylimidazol-2-yl, oxazol-2-yl, thiazol-2-yl, 4- and 5-C1-C4-alkylthiazol-2-yl radicals, such as 4- or 5-methylthiazol-2-yl, 5-phenylthiazol-2-yl, 1,2,4-thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 1 3 2 ~ 3 ~ ~
1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, benzoxazol-2-yl and benzothiazol-2-yl.
Hereinbelow, there is to be understood by lower radicals and compounds, for example, those containing up to and including 7, especially up to and including 4, C-atoms. In addition, the general terms have, for example, the following meanings:
- -~ Lower alkyl is, for example, C1-C4-alkyl, such as methyl, ethyl, propyl or butyl, or also iso-, sec.- or tert.-butyl, but may also be a C5-C7-alkyl group, such as a pentyl, hexyl or heptyl group.
Phenyl-lower alkyl is, for example, phenyl-C1-C4-alkyl, espe~ially 1-phenyl-C1-C4-alkyl, such as benzyl.
Lower alkoxy is, for example, C1-C4-alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.~butoxy or tert.-butoxy.
Di-lower alkylamino is, for example, di-C1-C4-alkylamino, such as dimethylamino, diethylamino~
N-ethyl-N-methylamino, dipropylamino, N-methyl-N-propyl-amino or dibutylamino.
Lower alkylthio is, for example, C1-C4-alkylthio, such as methylthio, ethylthio, propylthio or butylthio, or also iso-, sec.- or tert.-butylthio.
Halogen is, for example, halogen having an atomic number of up to and including 35, such as fluorine, chlorine or bromine.
Salts of compounds of the formula I are especially the salts thereof with pharmaceutically acceptable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, IIa and IIb, for example alkali metal salts, especially sodium or potassium salts, alkaline earth metal salts, especially calcium or magnesium salts, copper salts~ aluminium salts or zinc salts, or ammonium salts with ammonia or organic amines or quaternary ammonium bases, such as optionally 'j 'J ~ ~!
C-hydroxylated aliphatic amines, especially mono-, di-or tri-lower alkylamines, for example methyl-, ethyl-, dimethyl- or diethyl-amine, mono-, di- or tri-(hydroxy-lower alkyl)-amines, such as ethanol-, diethanol- or triethanol-amine, tris(hydroxymethyl)amino-m~thane or 2-hydroxy-tert.-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-lower alkylamines or N-(polyhydroxy-lower alkyl)-N-lower alkylamines, such as 2-(dimethylamino)-ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, for example tetrabutylammonium hydroxide.
It should also be mentioned in this connection that the compounds of the formula I may be in the form of internal salts, for example of the formula H PO3H~3 R - ~ - CH (I').
,l The mentioned compounds can accordingly also be converted, by treatment with a strongly protonic acid, such as with a hydrohalic acid, sulphuric acid, sulphonic acid, for example methane- or p-toluene-sulphonic acid, or sulphamic acid, for example N-cyclohexylsulphamic acid, into the corresponding acid addition salts of the formula 11 ~ 2 ~
Rl - ~ - CH A~ (I"), ~2 P3H2 in which A~ represents the anion of the protonic acidO
The compounds of the formula I and their salts have valuable pharmacological propertiesO In particular, they exhibit a pronounced regulatory action on the calcium metabolism of warm-blooded animals. In particular, in rats, they bring about pronounced inhibition of bone resorption, which can be demonstrated both in the test procedure according to Acta Endocrinol.
78, 613-24 (1975) by reference to the PTH-induced increase in the serum calcium level after subcutaneous administration in doses of from approximately 0.01 to approximately 1.0 mg/kg, and in the TPTX tthyropara-thyroidectomised) rat model by reference to the experimental hypercalcaemia, induced by vitamin D3, after the administration of doses of approximately from 0.001 to 1.0 mg s.c.. The tumour hypercalcaemia induced by Walker-256-tumours is likewise inhibitsd after peroral administration of from approximately 1.0 to approximately 100 mg/kg. Further, in adjuvant arthritis in rats in the test procedure according to Newbould, Brit. J. Pharmacology 21, 127 (1963) and according to Kaibara et al., J. Exp. Med. 1~9, 1388-96 ~1984), they exhibit a marked inhibition of the progression of chronic arthrltic processes in doses of approximately from 0.01 to 1.0 mg/kg s.c.. They are therefore excellently suitable as active ingredients in medicaments for the treatment of illnesses that can be - 6 - 1 ~ 21~J~
attributed to calcium metabolism disorders, for example inflammatory processes in joints and degenerative processes in the arthrodial cartilage, of osteoporosis, periodontitis, hyperparathyroidism and of calcium deposits in blood vessels or on prosthetic implants.
favourable effect is produced both in illnesses in which an anomalous deposition of sparingly soluble calcium salts is to be observed, such as those from among the forms of arthritis, for example Morbus Bechterew, neuritis, bursitis, periodontitis and tendinitis, fibrodysplasia, osteoarthrosis and of artereosclerosis, and in those illnesses in which an anomalous degener-ation of hard body tissue is well to the fore, such as hereditary hypophosphatasis, degenerative processes in the arthrodial cartilage, osteoporoses of various origins, Morbus Paget and osteodystrophia fibros~, and also in tumour-induced osteolytic processes.
The invention relates especially to the manufacture of compounds of the formula I in which Rl represents an imidazolyl, benzimidazolyl, 2H-1,2,3- or 4H-1,2,4-tri-azolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzothiazolyl or thiadiazolyl radical that is C-unRubstituted or C-mono- or C-di-substituted by lower alkyl; by lower alkoxy; by phenyl that is unsubstituted or is mono- or di-subsl:ituted by lower alkyl, lower alkoxy and/or by halogen; by hydroxy; by di-lower alkylamino; by lower alkylthio and/or by halogen; and that is unsubstituted at a substitutable N-atom which may optionally be present or preferably N-mono- or N-di-substituted by lower alkyl or by phenyl-lower alkyl that is unsubstituted or is mono- or di-substituted by lower alkyl, lower alkoxy and/or by halogen; and R2 represents hydrogen or lower alkyl, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention relates especially, for example, to the manufacture of compounds of the formula I in which Rl represents an imidazolyl, benzimidazolyl, 2~ 1,2,3-or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzothiazolyl or thiadiazolyl radical that is unsubstituted or is mono- or di-substi-tuted by lower alkyl; by lower alkoxy; by phenyl that is unsubstituted or is mono- or di-substituted by lower .
alkyl, lower alkoxy and/or by halogen; by hydroxy; by di-lower alkylamino; by lower alkylthio and/or by halogen;
and R2 represents hydrogen or lower alkyl, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The inv~ntion rel~tes espeeially to the manufacture of compounds of the formula I in whieh Rl represents a thiazolyl, such as thiazol-2-yl, radical, a benzothiazol-2-yl radieal, a thiadiazolyl, sueh as 1,2,4-thiadiazol-5-yl or 1,3,4-thiadiazol-2-yl, radieal, an oxazolyl, sueh as oxazol-2-yl, radical or a benzoxazol-2-yl radieal eaeh of which is unsubstituted or is C-substituted by Cl-C4-alkyl, such as methyl, or by a phenyl radieal that is unsubstituted or is mono- or di-substituted by Cl-C4-.
alkyl, such as methyl, Cl-C4-alkoxy, such as methoxy, and/or by halogen, sueh as ehlorine; or represents an imidazolyl, such as imidazol-2-yl or imidazol-4-yl, radieal or a henzimidazol-2-yl radieal eaeh of whieh is unsubstituted or is C-substituted by C1-C4-alkyl, sueh as methyl, or by a phenyl radieal that is unsubstituted or is mono- or di-substituted by C1-C4-alkyl, such as methyl, C1-C4-alkoxy, sueh as methoxy, and/or by halogen, such as chlorine, and/or each of which is N-substituted by C1-C4-alkyl, sueh as methyl, sr by a phenyl-C1-C4-alkyl radical, such as a benzyl radical, that is unsubstituted or is mono- or di-substituted by C1~C4-alkyl, sueh as methyl, C1-C4-alkoxy, sueh as methoxy, and/or by halogen, such as chlorine; and ~2 represents hydrogen, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention relates more especially to the manufacture of compounds of the formula I in which R1 represents a thiazolyl, such as thiazol-2-yl or thiazol-4-yl, radical that is unsubstituted or is.substituted by Cl-C4-alkyl, suc~ as methyl, by Cl-C4-alkoxy, such as methoxy, by phenyl, by hydroxy, by di-Cl-C4-alkylamino, such as dimethylamino or diethylamino, by Cl-C4-alkylthio, such as methylthio, or by halogen having an atomic number of up to and including 35, such as chlorine, and R2 represents hydrogen, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention relates even more especially to the manufacture of compounds of the formula I in which Rl represents a thiazolyl, such as thiazol-2-yl, radical, a l-Cl-C4-alkyl-, such as 1-methyl-imidazol-2-yl or -4-yl, radical, or a phenyl-Cl-C4-alkyl-, such as benzyl-imidazol-2-yl or -4-yl, radical each of which is unsubstituted or is C-substituted by Cl-C4-alkyl, such as methyl, by Cl-C4-alkoxy, such as methoxy, by phenyl, by hydroxy, by di-Cl-C4-alkylamino, such as dimethylamino or diethylamino, by C1-C4-alkylthio, such as methylthio, or by halogen having an atomic number of up to and including 35, such as chlorine, and R2 represents hydrogen, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention relates most especially to the manufacture of compounds of the formula I in which Rl represents a thiazol-2-yl radical that is unsubstituted or is mono- or disubstituted, especially in the 4- and/or 5-position, by Cl-C4-alkyl, such as methyl, or by phenyl, o~ represents an imidazol-2-yl or benzimidazol-2-yl rad~cal that is unsubstituted or is mono-substituted in g the l-position by Cl-C4-alkyl, such as methyl, or by phenyl-Cl-C4-alkyl, such as benzyl, respectively, or represents an unsubstituted benzoxazol-2-yl or benzo-thiazol-2-yl radical, and R2 represents hydrogen, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention relates specifically to the manufacture of the compounds of the formula I mentioned in the Examples and of heir salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention process for the manufacture of compounds of the formula I and to their salts is based on methods that are known per se and is characterised in that a3 in a compound of the formula Rl - N - 1 - H (II) which is optionally intermediately protected at a substitutable N-atom of the radical R1 and in which X1 represents a functionally modified phosphono group X and X2 represents phosphono or similarly represents a functionally modified phosphono group X, the group(s) X
is(are) converted into free phosphono, or b) a compound of the formula 132~383 R~ CH=O . ( III ), which is optionally intermediately protected at a substitutable N-atom of the radical R1, is reacted first with phosphorus trioxide and then with water, and, if desired, in each case, a resulting compound is converted into a different compound of the formula I
and/or a resulting free compound is converted into a salt or a resulting sait is converted into the free compound or into a different salt.
Functionally modified phosphono groups X that are to be converted into free phosphono according to process variant a) are, for example, in the form of an ester, especially in the form of a diester of the formula -P(=O)(OR)2 (IIa) in which OR represents, for example, lower alkoxy, or a phenoxy group that is optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or by hydroxy.
The conversion of a functionally modified phosphono group into a free phosphono group is effected in customary manner by hydrolysis, for example in the presence of a mineral acid~ such as hydrochloric or hydrobromic acid or sulphuric acid, or by reaction with a tri-lower alkyl-halosilane, for example with trimethylchlorosilane or, especially, trimethyliodo-sllane or trimethylbromosilane, preferably while cooling, for example in a temperature range of from 132~383 approximately 0 to approximately 25C.
The starting materials of the formula II can be manufactured, for example, by condensing a compound of the formula R1-N(R2)-H (IIb; R2=H) with at least the equimolar amount of an orthoformic acid triester of the formula H-C(OR)3 (IIc~
in which OR represents, for example, lower alkoxy, or a phenoxy group that is optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or by hydroxy, there probably being formed initially a corresponding compound of the formula R1-NH-CH(OR)2 (IId1) or R1-N=CH-OR (IId2), and by further reactinq the condensation product with at least double the molar amount of a phosphorous acid diester, for example of the formula H-p(oR)2 ~IXe), and, if desired, lower alkylating the resulting compound (II, R2=~l) to form the corresponding compound (II; R2=
lower alkyl)~
In intermediates II in which the radical R1 is N-substituted by lower alkyl or by phenyl-lower alkyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy and/or by halogen, the N-substituent can be removed, lower al~yl being removed, for example, by treatment with a haloformic acid ester, such as a bromoformic or chloroformic acid lower alkyl ester, and subsequent hydrolysis of the resulting carbamate, and ~-phenyl-lower alkyl radicals being remo~ed, for example, by hydrogenolysis, for example by treatment with hydrogen in the presence of a hydrogenation catalyst, for example palladium-on-carbon and/or platinum oxide, or by reduction with a metal, for example by treatment with an alkali metal in ammoniaO
It is also possible, however, to reac~ the starting material IIb in a manner known Per se with the phosphorous acid diester IIe in the presence of an orthoformic acid triester IIc without isolating the intermediate stage. Thus, according to an especially preferred embodiment, the corresponding compound IIb is reacted at boiling heat in the presence of at least the equimolar amount of an orthoformic acid triester IIc with at least double the molar amount of the phosphorous acid diester IIe without isolating the intermediate stage, ~or example of the formula IId1 or IId2, and the primary product II is hydrolysed by treatment with aqueous hydrochloric acid at boiling heat.
The reaction of compounds III with phosphorus trioxide according to process variant b) is preferably effected with the latter bein~ formed in situ, for example by reacting phosphorus trichloride and phosphorous acid at elevated temperature, for example at approximately from 50 to 65C, adding the reactant III, heating further and working up the primary product, a 1:1 adduct of the aldehyde of the formula R1-~-CH=O (III) with phosphorus trioxide of hitherto-unknown structure, by hydrolysis, preferably by treatment with water.
In a modification o~ this 2referred embodiment of process variant b), orthophosphoric acid is reacted, at approximately from 50C to 70C, with an approximately 1.1- to approximately 2-fold, preferably approximately 1.5-fold, excess of phosphorus trichloride, the reactant III is added, the whole is heated for a prolonged period at approximately from 50C to 70C, diluted with 80%
phosphoric acid and worked up by hydrolysis.
- Starting materials III can be manufactured in customary manner, for example by reacting an amine of the formula 1-N(R2)-H (IIb; R=H) with formic acid or a functional carboxy derivative thereof, for example with a formic acid ester of the formula H-COOR (IIe) in which OR represents, for example, a phenoxy group that is optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or by hydroxy, or with formamide.
For the intermediate protection of a substitutable N-atom of the radical R1 the customary N-protecting groups and methods of introducing and removing them are suitable, for example 2,2,2-trihaloethoxycarbonyl radicals, such as 2,2,2-triiodo-, 2,2,2-tribromo- or 2,2,2-trichloro-ethoxycarbonyl radicals, which can be removed, for example, by treatment with zinc in acetic acid, a-phenyl-lower alkoxycarbonyl radicals, such as benzyloxycarbonyl, which can be removed, for example, by catalytic hydrogenation, and lower alkanesulphonyl groups, such as methanesulphonyl, which can be removed, for example, by treatment with bis(2-methoxyethoxy)_ sodium aluminium hydride, and also, however, ~-phenyl-- 14 - 132~383 alkyl or alkyl groups, the removal of which is dealt with hereinafter.
Cornpounds of the formula I obtained in accordance with the process of the invention or by another process that is known Per se can be converted into other compounds of the formula I in a manner known Per se.
For example, lower alkyl R2 can be introduced into compounds of the formula I in which R2 represents hydroqen by reaction with a reactive ester, such as a hydrohalic acid ester or an organic sulphonic acid ester, of a lower alkanol. It is also possible, however, to introduce an aliphatic radical, for example methyl, by reaction with an aliphatic aldehyde, for example with formaldehyde and formic acid.
It is also possible in compounds of the formula I
in which the radical R1 is N-substituted by lower alkyl or by phenyl-lower alkyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy and/or by halogen, to remove the N-substituent, lower alkyl being removed, for example, by treatment with a haloformic acid ester, such as a bromoformic or chloroformic acid lower alkyl ester, and subsequent hydrolysis of the resulting carbamate, and ~-phenyl-lower alkyl radicals being removed, for example, by hydrogenolysis, for example by treatment with hydrogen in the presence of a hydrogenation catalyst, for example palladium-on-carbon and/or platinum oxide~ or by reduction with a metal, for example by treatment with an alkali metal in ammonia.
Resulting free compounds of the formula I, including their internal salts of the formula I', can be converted into salts with bases by partial or complete neutralisation with one of the bases mentioned at the be~inning. Acid addition salts of the formula I" also can be converted in an analogous manner into the corresponding free compounds of the formula I or internal salts of the formula I'.
Conversely, resulting free compounds of the formula I can be converted into acid addition salts of the formula I" by treatment with one of the protonic acids mentioned at the beginning.
Resulting salts can be converted into the free compounds in a manner known ~ se, for example by treatment with an acid reagent~ such as a mineral acid, or, as the case may be, with a base, for example alkali liquor.
The compounds, including their salts, may also be obtained in the form of their hydrates or may include the solvent used for crystallisation.
Owing to the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter there is to be understood by the free compounds or their salts, where appropriate and expedient, optionally also the corresponding salts or free compounds, respectively.
The invention relates also to those embodiments of the process according to which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining steps are carried out or a starting material in the form of a salt and/or racemate or antipode is used or especLally is formed under the reaction conditions.
The starting materials that are used in the process of the present invention are preferably those which result in the compounds described at the beginning as being especially valuable. The invention relates also to novel starting materials and processes for the manufacture thereof~
The invention relates also to pharmaceutical compositions containing, as the active ingredient, a known compound of the formula I, wherein R2 represents a pyrazol-3-yl or isoxazol-3-yl radical that is unsubstituted or mono- or disubstituted by lower alkyl and/or halogen and R2 denotes hydrogen, specifically l-(isoxazol-3-ylamino)methane-1,1-diphosphonic acid, l-(4-methylisoxazol-3-ylamino)methane-1,1-diphosphonic acid, l-(5-methylisoxazol-3-ylamino)methane-1,1-diphosphonic acid, l-(pyrazol-3-ylamino)methane~ di-phosphonic acid, l-t4-methylpyrazol-3-ylamino)methane-1,1-diphosphonic acid or l-(5-methylpyrazol-3-ylamino)methane-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof, to the use of the active ingredient as a medicament and to a method of treatment of illnesses associated with calcium metabolism disorders.
The pharmaceutical preparations, which contain compounds of the formula I or pharmaceutically acceptable salts thereof, are for enteral, such as oral or rectal, and parenteral administration and contain the pharmacological active ingredient on its own or together with a pharmaceuti-cally acceptable carrier. The dosage of the active ingredient depends upon the species of warm-blooded animal, its age and individual condition and also on the mode of administration. In a normal case, the estimated approximate daily dose for a warm-blooded animal of approximately 75 kg body weight is approximately from 20 to 1000 mg, preferably approximately from 30 to 300 mg, ~n the case of oral administration and approximately from 1 to 25 mg, preferably approximately from 1 to 10 mg, in the case of intravenous administration, the dose advantageously being dlvided into several equal partial doses.
132~383 The pharmaceutical preparations contain, fGr example, from approximately 10~ to approximately 80%, preferably from approximately 20% to approximately 60%, active ingredient. Pharmaceutical preparations ~ccording to the invention for enteral and parenteral administration are, for example, those in dosage unit form, such as dragées, tablets, capsules or supposi-tories, and also ampoules. These are prepared in a manner known Per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical preparations ~or oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture and, if desired or necessary, processing the mixture or granulate, after the addition of suitable ad~uncts, into tablets or dragée cores.
Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes using, for example, corn, wheat, rlce or potato starch, . . ~ ., gelatine, tragacanth, methylcellulose and/or polyvlnyl-pyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Ad~uncts are especlally flow-regulating and lubricating agents, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or poly-ethylene ~lycol. Dragée cores are provided with suitable coatings which may be resistant to gastric juices, there being used, nter alia, concentrated sugar solutions which may conta~n gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures, or, for the preparation of coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetyl-cellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or dragée coatings, for example for iden~ifi-cation purposes or to indicate different doses of active ingredient.
Other orally administrable pharmaceutical preparations are dry-filled capsules consisting of gelatine, and also soft sealed capsules consisting of gelatine and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, if desired, stabilisers. In soft capsules, the active ingredient is preferably d~ssol~ed or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also to add stabilisers.
Suitable rectally administrable pharmaceutical preparations are, for example, suppositories that consist of a combination of the active ingredient with a suppository base material. Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatine rectal capsules that contain a combination of the active ingredient with a base material; suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
For parenteral administration there are suitable, especially, aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, or suspensions of the active ingredient, such as corresponding oily injection suspensions in which suitable lipophllic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, are used, or aqueous injection suspensions that contain vicosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran and, if desired, also stabilisers.
The present invention relates also to the use of the compounds of the formula I and their salts, preferably for the treatment of illnesses that can be attributed to calcium metabolism disorders, for example of the rheumatic type, and especially of osteoporoses.
Dosages under 0~01 mg/kg body weight have only a negligible effect on pathological calcification or the degeneration of hard tissue. At dosages above 100 mg/kg body weight, toxic side-effects may occur in long-term use. The compounds of the formula I and their salts can be adm~nistered both orally and, in the form of a hypertonic solution, subcutaneously, intramuscul-arly or intravenously. The preferred daily doses are in the range of approximately from 0.1 to 5 mg/kg in the case of oral administration, in the range of approxi-mately from 0.1 to 1 mg/kg in the case of subcutaneous and intramuscular administration and in the range of approximately from 0.01 to 2 mg/kg in the case of intravenous administration.
The dosage of the compounds used is, however, variable and depends on the particular conditions, such as nature and severity of the illness, duration of treatment and on the particular compound. Single doses contain, for example, from 0.01 to 10 mg, dosage unit forms for parenteral, such as intravenous, admini-stration contain, for example, from 0.01 to 0.1 mg, preferably C.02 to 0.08 mg, and oral dosage unit forms contain, for example, from 0.2 to 2.5 mg, preferably from ~.3 to 1.5 mg, per kg of body weight. The preferred individual dosage for oral administration is from 10 to 100 mg and for intravenous administration from 0.5 to 5 mg and can be administered in up to 4 single doses per day. The higher dosages in the case of oral administration are necessary owing to the limited resorption. In the case of long-term treatments, the initially higher dosage can normally be converted to low dosages while still maintaining the desired effect.
The following Examples illustrate the invention described above; they are not intended, however, to limit the scope thereof in any way. Temperatures are given in degrees Celsius.
- 21 - ~32 4383 Example 1: 6.57 g (17 mmol) of 1~(thiazol-2-ylamino)-methane-1,1-dipho~phonic acid tetraethyl ester are dissolved in 70 ml of N hydrochloric acid and heated under reflux for 6 hours. In the course of the reaction, the product separates out in the form of a fine white precipita.e. After cooling to room temper-ature, filtration is carried out and the product is washed with aqueous methanol. 4.33 g (93% of the theoretical yield) of 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 275 Idecomposition) are obtained.
The starting material can be prepared, for example, in the following manner:
A mixture consisting of 10.0 g (0.1 mol) of 2-aminothiazole, 20.0 ml (0.12 mol) of orthoformic acid triethyl ester and 26.6 ml (0.2 mol) of diethyl phosphite is heated under reflux for 1 hour. The ethanol liberated is distilled off, the internal temperature gradually increasing to approximately 150.
The residue is taken up in chloroform and filtered over silica gel. The crude product is purified by column chromatography (silica gel/ethyl acetate). 4.37 g (11%
of the theoretlcal yield) of 1-(thiazol-2-ylamino)-methane-1,1-diphosphonic acid tetraethyl ester of m.p.
1~3-104 are o~ained.
ExamPle 2: In a manner analogous to that described in Example 1 it is also possible to prepare 1-(oxazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 245 (decomposition) and 1-(benzoxazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 270 (decomposition).
Example 3: 4.36 g (10 mmol) of 1-~benzothiazol-2-ylamlno)methane-1,1-diphosphonic acid tetraethyl ester are heated in 40 ml of N hydrochloric acid at 110-120 for 6 hours. In the course of the reaction, the product - 22 - 132~383 separates out in the form of a white precipitate. After cooling to room temperature, filtration is carried out and the product is washed with aqueous methanol. 3.09 g ~95% of the theoretical yield) of 1-(benzothiazol-~-yl-amino1methane-1,1-diphosphonic acid of m.p. 290 (decomposition) are obtained.
The starting material can be prepared, for example, in the following manner:
A mixture consisting of 3.0 g (20 mmol) of 2-amino-benzothiazole, 4.0 ml (24 mmol) of orthoformic acid triethyl ester and 5.3 ml (40 mmol) of diethyl phosphite is heated at 120-125 for 5 hours~ The yellow precipi-tate which separates out at the beginning of the reaction gradually goes into solution again. The ethanol liberated is distilled off during the reaction.
The crude product, which solidifies on being left to stand, is purified by column chromatography (silica gel/ethyl acetate/methanol). 5.62 g (64% of the theoretical yield) of 1-(benzothiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester of m.p. 165-167 are obtained.
ExamPle 4: 1.30 g (3.2 mmol) of 1-(4-methylthia-zol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester are heated in 20 ml of 1N hydrochloric acid at 100 for 20 hours. After cooling, 20 ml of methanol are added. During subsequent stirring, the product separates out in the form of fine white crystals. The filtrate is subsequently washed with methanol and petroleum ether. Yield: 615 mg (67% of the theoretical yield) of 1-(4-methylthiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. ~94 (decomposition).
The starting material can be prepared, for example, in the following manner:
A mixture conslsting of 2.33 g (20 mmol) of 2-amino-4-methylthiazole, 4.0 ml (24 mmol) of - 23 - 13243~3 orthoformic acid triethyl ester and 5.3 ml (40 mmol) of diethyl phosphite is heated at 120-125 for 4 hours.
The ethanol liberated is distilled off. The residue is purified by column chromatography (silica gel/ethyl acetate/methanol). 1.32 g (17% of the theoretical yield) of 1-(4-methylthiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester are obtained in the form of a viscous oil.
Example 5: 1.97 g (4.9 mmol) of 1-(5-methylthiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester are heated under reflux in 20 ml of N hydrochloric acid for 6 hours. Upon cooling and leaving the reaction mixture to stand at room temperature, the product crystallises~ It is filtered and washed with acetone and petroleum ether. Yield: 0.64 g (45% of the theoretical yield) of 1-(5-methylthiazol-2-ylamino)-methane-1,1-diphosphonic acid of m.p. 208 IdecomPo-sition).
The starting material can be prepared, for example, in the following manner:
A mixture consisting of 1.14 g (10 mmol) of 2-amino-5-methylthiazole, 2.0 ml (12 mmol) of orthoformic acid triethyl ester and 2.65 ml (20 mmol) of diethyl phosphite is heated at 120-125 for 4~ hours.
The ethanol liberated is distilled off. The residue is purified by column chromatography ~silica gel/ethyl acetate/methanol). 1.97 g ~49% of the theoretical yield) of 1-(5-methylthiazol-2-ylamino~methane-1,1-diphosphonic acid tetraethyl ester are obtained in the form of a viscous oil.
ExamPle 6: 4.02 g (8.7 mmol) of 1-(5-phenylthiazol-2-ylamino)methane-1,1-diphosphonic acid are heated under reflux in 30 ml of N hydrochloric acid for 18 hours.
After cooling to room temperature, a small quantity of methanol is added and the whole is filtered. The filtrate is heated under reflux in methanol for 1 hour, filtered while hot and washed twice with hot methanol.
Yield: 2.90 g (95% of the theoretical yield) of 1-(5-phenylth~azol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 290 (decomposition).
The starting material can be prepared, for example, in the following manner:
A mixture consisting of 2.93 g (16.6 mmol) of 2-amino-5-phenylthiazole, 3.3 ml (l9.9 mmol) of orthoformic acid triethyl ester and 4.4 ml (33.5 mmol) of diethyl phosphite is heated first for 2 hours at 120 and then for 2 hours at 130. The ethanol liberated is distilled off in the course of the reaction. The product, which solidifies upon cooling, is purified by chromatography (silica gel/ethyl acetate/methanol).
4.12 g (54% of the theoretical yield) of 1-(5-phenyl-thiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester of m.p. 151-153 are obtained.
Example 7: 2.5 g (5.96 mmol) of 1-(1-benzimidazol-2-ylamino)methane~ diphosphonic acid tetraethyl ester are dissolved in 25 ml of 1N hydrochloric acid and heated at 100-110 for 26 hours~ In the course of the reaction, the product separates out in the form of a fine white precipitate. It is filtered while hot and washed with water and then with methanol. 0.23 g (13%
of the theoretical yield) of 1~ benzimidazol-2-yl-amino)methane-1,1-diphosphonic acid of m.p. 265 (decomposition) is obtained.
The starting material can be prepared, for example, in the following manner:
4-l6l?9/-Process for the manufacture of novel substituted aminomethane-di~hosphonic acids ,~ _ The invention relates to a process for the manufacture of novel substituted aminomethanediphosphonic acids, especlally of heteroarylaminomethanediphosphonic acids of the formula ¦ Rl - N- CH (I) in which R1 represents an optionally benzo- or cyclohexeno-fused 5-membered heteroaryl radical that contains, as hetero atom(s), either from 2 to 4 N-atoms or 1 or 2 N-atoms as well as 1 O-atom or S-atom and that is unsubstitutad or is C-substituted by lower alkyl;
by phenyl that is unsubstituted or ~s substituted by lower alkyl, lower alkoxy and/or by halogen; by lower alkoxy; by hydroxy; by di-lower alkylamlno; by lower 2 1 3 2 ~ . ~
alkylthio and/or by halogen; and/or that is N-substi-tuted by lower alkyl; or by phenyl-lower alkyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy and/or by halogen; and R2 represents hydrogen or lower alkyl, with the proviso that R2 is other than hydrogen when R1 represents a pyrazol-3-yl or isoxazol-3-yl radical that is optionally substituted by alkyl and/or by halogen, and of their sal~s.
Optionally benzo- or cyclohexeno-fused S-membered heteroaryl radicals containing, as hetero atom(s), either fro~ 2 to 4 N-atoms or 1 or 2 N-atoms as well as 1 O-atom or S-atom are, for example, imidazolyl, for example imidazol-2-yl or -4-yl, thiazolyl, for example thiazol-2-yl, or also thiazol-5-yl or -4-yl, oxazolyl, for example oxazol-2-yl, or also oxazol-4 yl, triazolyl, for example 4H-1,2,4-triazol-3-yl or 2H-1,2,3-triazol-4-yl, tetrazolyl, for example tetrazol-5-yl, thiadia-zolyl, for example 1,2,5-thiadiazol-3-yl, oxadiazolyl, for example 1,3,4-oxadiazol-2-yl, benzimidazolyl, for example benzimidazol-2-yl, benzoxazolyl, for example benzoxazol-2-yl, or benzothiazolyl, for example benzothiazol-2-yl. The radicals mentioned may contain one or several identical or different, especially one or two identical or different, substituents from among those mentioned at the beginnin~. Radicals R1 having substitutable N-atoms are preferably N-substituted as indicated. Radicals R1 are, for example, 1-C1-C4-alkylimidazol-2-yl radicals, such as 1-methylimidazol-2-yl, 1-phenyl-C1-C4-alkylimidazol-2-yl radicals, such as 1-benzylimidazol-2-yl, oxazol-2-yl, thiazol-2-yl, 4- and 5-C1-C4-alkylthiazol-2-yl radicals, such as 4- or 5-methylthiazol-2-yl, 5-phenylthiazol-2-yl, 1,2,4-thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 1 3 2 ~ 3 ~ ~
1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, benzoxazol-2-yl and benzothiazol-2-yl.
Hereinbelow, there is to be understood by lower radicals and compounds, for example, those containing up to and including 7, especially up to and including 4, C-atoms. In addition, the general terms have, for example, the following meanings:
- -~ Lower alkyl is, for example, C1-C4-alkyl, such as methyl, ethyl, propyl or butyl, or also iso-, sec.- or tert.-butyl, but may also be a C5-C7-alkyl group, such as a pentyl, hexyl or heptyl group.
Phenyl-lower alkyl is, for example, phenyl-C1-C4-alkyl, espe~ially 1-phenyl-C1-C4-alkyl, such as benzyl.
Lower alkoxy is, for example, C1-C4-alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.~butoxy or tert.-butoxy.
Di-lower alkylamino is, for example, di-C1-C4-alkylamino, such as dimethylamino, diethylamino~
N-ethyl-N-methylamino, dipropylamino, N-methyl-N-propyl-amino or dibutylamino.
Lower alkylthio is, for example, C1-C4-alkylthio, such as methylthio, ethylthio, propylthio or butylthio, or also iso-, sec.- or tert.-butylthio.
Halogen is, for example, halogen having an atomic number of up to and including 35, such as fluorine, chlorine or bromine.
Salts of compounds of the formula I are especially the salts thereof with pharmaceutically acceptable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, IIa and IIb, for example alkali metal salts, especially sodium or potassium salts, alkaline earth metal salts, especially calcium or magnesium salts, copper salts~ aluminium salts or zinc salts, or ammonium salts with ammonia or organic amines or quaternary ammonium bases, such as optionally 'j 'J ~ ~!
C-hydroxylated aliphatic amines, especially mono-, di-or tri-lower alkylamines, for example methyl-, ethyl-, dimethyl- or diethyl-amine, mono-, di- or tri-(hydroxy-lower alkyl)-amines, such as ethanol-, diethanol- or triethanol-amine, tris(hydroxymethyl)amino-m~thane or 2-hydroxy-tert.-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-lower alkylamines or N-(polyhydroxy-lower alkyl)-N-lower alkylamines, such as 2-(dimethylamino)-ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, for example tetrabutylammonium hydroxide.
It should also be mentioned in this connection that the compounds of the formula I may be in the form of internal salts, for example of the formula H PO3H~3 R - ~ - CH (I').
,l The mentioned compounds can accordingly also be converted, by treatment with a strongly protonic acid, such as with a hydrohalic acid, sulphuric acid, sulphonic acid, for example methane- or p-toluene-sulphonic acid, or sulphamic acid, for example N-cyclohexylsulphamic acid, into the corresponding acid addition salts of the formula 11 ~ 2 ~
Rl - ~ - CH A~ (I"), ~2 P3H2 in which A~ represents the anion of the protonic acidO
The compounds of the formula I and their salts have valuable pharmacological propertiesO In particular, they exhibit a pronounced regulatory action on the calcium metabolism of warm-blooded animals. In particular, in rats, they bring about pronounced inhibition of bone resorption, which can be demonstrated both in the test procedure according to Acta Endocrinol.
78, 613-24 (1975) by reference to the PTH-induced increase in the serum calcium level after subcutaneous administration in doses of from approximately 0.01 to approximately 1.0 mg/kg, and in the TPTX tthyropara-thyroidectomised) rat model by reference to the experimental hypercalcaemia, induced by vitamin D3, after the administration of doses of approximately from 0.001 to 1.0 mg s.c.. The tumour hypercalcaemia induced by Walker-256-tumours is likewise inhibitsd after peroral administration of from approximately 1.0 to approximately 100 mg/kg. Further, in adjuvant arthritis in rats in the test procedure according to Newbould, Brit. J. Pharmacology 21, 127 (1963) and according to Kaibara et al., J. Exp. Med. 1~9, 1388-96 ~1984), they exhibit a marked inhibition of the progression of chronic arthrltic processes in doses of approximately from 0.01 to 1.0 mg/kg s.c.. They are therefore excellently suitable as active ingredients in medicaments for the treatment of illnesses that can be - 6 - 1 ~ 21~J~
attributed to calcium metabolism disorders, for example inflammatory processes in joints and degenerative processes in the arthrodial cartilage, of osteoporosis, periodontitis, hyperparathyroidism and of calcium deposits in blood vessels or on prosthetic implants.
favourable effect is produced both in illnesses in which an anomalous deposition of sparingly soluble calcium salts is to be observed, such as those from among the forms of arthritis, for example Morbus Bechterew, neuritis, bursitis, periodontitis and tendinitis, fibrodysplasia, osteoarthrosis and of artereosclerosis, and in those illnesses in which an anomalous degener-ation of hard body tissue is well to the fore, such as hereditary hypophosphatasis, degenerative processes in the arthrodial cartilage, osteoporoses of various origins, Morbus Paget and osteodystrophia fibros~, and also in tumour-induced osteolytic processes.
The invention relates especially to the manufacture of compounds of the formula I in which Rl represents an imidazolyl, benzimidazolyl, 2H-1,2,3- or 4H-1,2,4-tri-azolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzothiazolyl or thiadiazolyl radical that is C-unRubstituted or C-mono- or C-di-substituted by lower alkyl; by lower alkoxy; by phenyl that is unsubstituted or is mono- or di-subsl:ituted by lower alkyl, lower alkoxy and/or by halogen; by hydroxy; by di-lower alkylamino; by lower alkylthio and/or by halogen; and that is unsubstituted at a substitutable N-atom which may optionally be present or preferably N-mono- or N-di-substituted by lower alkyl or by phenyl-lower alkyl that is unsubstituted or is mono- or di-substituted by lower alkyl, lower alkoxy and/or by halogen; and R2 represents hydrogen or lower alkyl, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention relates especially, for example, to the manufacture of compounds of the formula I in which Rl represents an imidazolyl, benzimidazolyl, 2~ 1,2,3-or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzothiazolyl or thiadiazolyl radical that is unsubstituted or is mono- or di-substi-tuted by lower alkyl; by lower alkoxy; by phenyl that is unsubstituted or is mono- or di-substituted by lower .
alkyl, lower alkoxy and/or by halogen; by hydroxy; by di-lower alkylamino; by lower alkylthio and/or by halogen;
and R2 represents hydrogen or lower alkyl, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The inv~ntion rel~tes espeeially to the manufacture of compounds of the formula I in whieh Rl represents a thiazolyl, such as thiazol-2-yl, radical, a benzothiazol-2-yl radieal, a thiadiazolyl, sueh as 1,2,4-thiadiazol-5-yl or 1,3,4-thiadiazol-2-yl, radieal, an oxazolyl, sueh as oxazol-2-yl, radical or a benzoxazol-2-yl radieal eaeh of which is unsubstituted or is C-substituted by Cl-C4-alkyl, such as methyl, or by a phenyl radieal that is unsubstituted or is mono- or di-substituted by Cl-C4-.
alkyl, such as methyl, Cl-C4-alkoxy, such as methoxy, and/or by halogen, sueh as ehlorine; or represents an imidazolyl, such as imidazol-2-yl or imidazol-4-yl, radieal or a henzimidazol-2-yl radieal eaeh of whieh is unsubstituted or is C-substituted by C1-C4-alkyl, sueh as methyl, or by a phenyl radieal that is unsubstituted or is mono- or di-substituted by C1-C4-alkyl, such as methyl, C1-C4-alkoxy, sueh as methoxy, and/or by halogen, such as chlorine, and/or each of which is N-substituted by C1-C4-alkyl, sueh as methyl, sr by a phenyl-C1-C4-alkyl radical, such as a benzyl radical, that is unsubstituted or is mono- or di-substituted by C1~C4-alkyl, sueh as methyl, C1-C4-alkoxy, sueh as methoxy, and/or by halogen, such as chlorine; and ~2 represents hydrogen, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention relates more especially to the manufacture of compounds of the formula I in which R1 represents a thiazolyl, such as thiazol-2-yl or thiazol-4-yl, radical that is unsubstituted or is.substituted by Cl-C4-alkyl, suc~ as methyl, by Cl-C4-alkoxy, such as methoxy, by phenyl, by hydroxy, by di-Cl-C4-alkylamino, such as dimethylamino or diethylamino, by Cl-C4-alkylthio, such as methylthio, or by halogen having an atomic number of up to and including 35, such as chlorine, and R2 represents hydrogen, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention relates even more especially to the manufacture of compounds of the formula I in which Rl represents a thiazolyl, such as thiazol-2-yl, radical, a l-Cl-C4-alkyl-, such as 1-methyl-imidazol-2-yl or -4-yl, radical, or a phenyl-Cl-C4-alkyl-, such as benzyl-imidazol-2-yl or -4-yl, radical each of which is unsubstituted or is C-substituted by Cl-C4-alkyl, such as methyl, by Cl-C4-alkoxy, such as methoxy, by phenyl, by hydroxy, by di-Cl-C4-alkylamino, such as dimethylamino or diethylamino, by C1-C4-alkylthio, such as methylthio, or by halogen having an atomic number of up to and including 35, such as chlorine, and R2 represents hydrogen, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention relates most especially to the manufacture of compounds of the formula I in which Rl represents a thiazol-2-yl radical that is unsubstituted or is mono- or disubstituted, especially in the 4- and/or 5-position, by Cl-C4-alkyl, such as methyl, or by phenyl, o~ represents an imidazol-2-yl or benzimidazol-2-yl rad~cal that is unsubstituted or is mono-substituted in g the l-position by Cl-C4-alkyl, such as methyl, or by phenyl-Cl-C4-alkyl, such as benzyl, respectively, or represents an unsubstituted benzoxazol-2-yl or benzo-thiazol-2-yl radical, and R2 represents hydrogen, and of their salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention relates specifically to the manufacture of the compounds of the formula I mentioned in the Examples and of heir salts, especially their internal salts and pharmaceutically acceptable salts with bases.
The invention process for the manufacture of compounds of the formula I and to their salts is based on methods that are known per se and is characterised in that a3 in a compound of the formula Rl - N - 1 - H (II) which is optionally intermediately protected at a substitutable N-atom of the radical R1 and in which X1 represents a functionally modified phosphono group X and X2 represents phosphono or similarly represents a functionally modified phosphono group X, the group(s) X
is(are) converted into free phosphono, or b) a compound of the formula 132~383 R~ CH=O . ( III ), which is optionally intermediately protected at a substitutable N-atom of the radical R1, is reacted first with phosphorus trioxide and then with water, and, if desired, in each case, a resulting compound is converted into a different compound of the formula I
and/or a resulting free compound is converted into a salt or a resulting sait is converted into the free compound or into a different salt.
Functionally modified phosphono groups X that are to be converted into free phosphono according to process variant a) are, for example, in the form of an ester, especially in the form of a diester of the formula -P(=O)(OR)2 (IIa) in which OR represents, for example, lower alkoxy, or a phenoxy group that is optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or by hydroxy.
The conversion of a functionally modified phosphono group into a free phosphono group is effected in customary manner by hydrolysis, for example in the presence of a mineral acid~ such as hydrochloric or hydrobromic acid or sulphuric acid, or by reaction with a tri-lower alkyl-halosilane, for example with trimethylchlorosilane or, especially, trimethyliodo-sllane or trimethylbromosilane, preferably while cooling, for example in a temperature range of from 132~383 approximately 0 to approximately 25C.
The starting materials of the formula II can be manufactured, for example, by condensing a compound of the formula R1-N(R2)-H (IIb; R2=H) with at least the equimolar amount of an orthoformic acid triester of the formula H-C(OR)3 (IIc~
in which OR represents, for example, lower alkoxy, or a phenoxy group that is optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or by hydroxy, there probably being formed initially a corresponding compound of the formula R1-NH-CH(OR)2 (IId1) or R1-N=CH-OR (IId2), and by further reactinq the condensation product with at least double the molar amount of a phosphorous acid diester, for example of the formula H-p(oR)2 ~IXe), and, if desired, lower alkylating the resulting compound (II, R2=~l) to form the corresponding compound (II; R2=
lower alkyl)~
In intermediates II in which the radical R1 is N-substituted by lower alkyl or by phenyl-lower alkyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy and/or by halogen, the N-substituent can be removed, lower al~yl being removed, for example, by treatment with a haloformic acid ester, such as a bromoformic or chloroformic acid lower alkyl ester, and subsequent hydrolysis of the resulting carbamate, and ~-phenyl-lower alkyl radicals being remo~ed, for example, by hydrogenolysis, for example by treatment with hydrogen in the presence of a hydrogenation catalyst, for example palladium-on-carbon and/or platinum oxide, or by reduction with a metal, for example by treatment with an alkali metal in ammoniaO
It is also possible, however, to reac~ the starting material IIb in a manner known Per se with the phosphorous acid diester IIe in the presence of an orthoformic acid triester IIc without isolating the intermediate stage. Thus, according to an especially preferred embodiment, the corresponding compound IIb is reacted at boiling heat in the presence of at least the equimolar amount of an orthoformic acid triester IIc with at least double the molar amount of the phosphorous acid diester IIe without isolating the intermediate stage, ~or example of the formula IId1 or IId2, and the primary product II is hydrolysed by treatment with aqueous hydrochloric acid at boiling heat.
The reaction of compounds III with phosphorus trioxide according to process variant b) is preferably effected with the latter bein~ formed in situ, for example by reacting phosphorus trichloride and phosphorous acid at elevated temperature, for example at approximately from 50 to 65C, adding the reactant III, heating further and working up the primary product, a 1:1 adduct of the aldehyde of the formula R1-~-CH=O (III) with phosphorus trioxide of hitherto-unknown structure, by hydrolysis, preferably by treatment with water.
In a modification o~ this 2referred embodiment of process variant b), orthophosphoric acid is reacted, at approximately from 50C to 70C, with an approximately 1.1- to approximately 2-fold, preferably approximately 1.5-fold, excess of phosphorus trichloride, the reactant III is added, the whole is heated for a prolonged period at approximately from 50C to 70C, diluted with 80%
phosphoric acid and worked up by hydrolysis.
- Starting materials III can be manufactured in customary manner, for example by reacting an amine of the formula 1-N(R2)-H (IIb; R=H) with formic acid or a functional carboxy derivative thereof, for example with a formic acid ester of the formula H-COOR (IIe) in which OR represents, for example, a phenoxy group that is optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or by hydroxy, or with formamide.
For the intermediate protection of a substitutable N-atom of the radical R1 the customary N-protecting groups and methods of introducing and removing them are suitable, for example 2,2,2-trihaloethoxycarbonyl radicals, such as 2,2,2-triiodo-, 2,2,2-tribromo- or 2,2,2-trichloro-ethoxycarbonyl radicals, which can be removed, for example, by treatment with zinc in acetic acid, a-phenyl-lower alkoxycarbonyl radicals, such as benzyloxycarbonyl, which can be removed, for example, by catalytic hydrogenation, and lower alkanesulphonyl groups, such as methanesulphonyl, which can be removed, for example, by treatment with bis(2-methoxyethoxy)_ sodium aluminium hydride, and also, however, ~-phenyl-- 14 - 132~383 alkyl or alkyl groups, the removal of which is dealt with hereinafter.
Cornpounds of the formula I obtained in accordance with the process of the invention or by another process that is known Per se can be converted into other compounds of the formula I in a manner known Per se.
For example, lower alkyl R2 can be introduced into compounds of the formula I in which R2 represents hydroqen by reaction with a reactive ester, such as a hydrohalic acid ester or an organic sulphonic acid ester, of a lower alkanol. It is also possible, however, to introduce an aliphatic radical, for example methyl, by reaction with an aliphatic aldehyde, for example with formaldehyde and formic acid.
It is also possible in compounds of the formula I
in which the radical R1 is N-substituted by lower alkyl or by phenyl-lower alkyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy and/or by halogen, to remove the N-substituent, lower alkyl being removed, for example, by treatment with a haloformic acid ester, such as a bromoformic or chloroformic acid lower alkyl ester, and subsequent hydrolysis of the resulting carbamate, and ~-phenyl-lower alkyl radicals being removed, for example, by hydrogenolysis, for example by treatment with hydrogen in the presence of a hydrogenation catalyst, for example palladium-on-carbon and/or platinum oxide~ or by reduction with a metal, for example by treatment with an alkali metal in ammonia.
Resulting free compounds of the formula I, including their internal salts of the formula I', can be converted into salts with bases by partial or complete neutralisation with one of the bases mentioned at the be~inning. Acid addition salts of the formula I" also can be converted in an analogous manner into the corresponding free compounds of the formula I or internal salts of the formula I'.
Conversely, resulting free compounds of the formula I can be converted into acid addition salts of the formula I" by treatment with one of the protonic acids mentioned at the beginning.
Resulting salts can be converted into the free compounds in a manner known ~ se, for example by treatment with an acid reagent~ such as a mineral acid, or, as the case may be, with a base, for example alkali liquor.
The compounds, including their salts, may also be obtained in the form of their hydrates or may include the solvent used for crystallisation.
Owing to the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter there is to be understood by the free compounds or their salts, where appropriate and expedient, optionally also the corresponding salts or free compounds, respectively.
The invention relates also to those embodiments of the process according to which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining steps are carried out or a starting material in the form of a salt and/or racemate or antipode is used or especLally is formed under the reaction conditions.
The starting materials that are used in the process of the present invention are preferably those which result in the compounds described at the beginning as being especially valuable. The invention relates also to novel starting materials and processes for the manufacture thereof~
The invention relates also to pharmaceutical compositions containing, as the active ingredient, a known compound of the formula I, wherein R2 represents a pyrazol-3-yl or isoxazol-3-yl radical that is unsubstituted or mono- or disubstituted by lower alkyl and/or halogen and R2 denotes hydrogen, specifically l-(isoxazol-3-ylamino)methane-1,1-diphosphonic acid, l-(4-methylisoxazol-3-ylamino)methane-1,1-diphosphonic acid, l-(5-methylisoxazol-3-ylamino)methane-1,1-diphosphonic acid, l-(pyrazol-3-ylamino)methane~ di-phosphonic acid, l-t4-methylpyrazol-3-ylamino)methane-1,1-diphosphonic acid or l-(5-methylpyrazol-3-ylamino)methane-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof, to the use of the active ingredient as a medicament and to a method of treatment of illnesses associated with calcium metabolism disorders.
The pharmaceutical preparations, which contain compounds of the formula I or pharmaceutically acceptable salts thereof, are for enteral, such as oral or rectal, and parenteral administration and contain the pharmacological active ingredient on its own or together with a pharmaceuti-cally acceptable carrier. The dosage of the active ingredient depends upon the species of warm-blooded animal, its age and individual condition and also on the mode of administration. In a normal case, the estimated approximate daily dose for a warm-blooded animal of approximately 75 kg body weight is approximately from 20 to 1000 mg, preferably approximately from 30 to 300 mg, ~n the case of oral administration and approximately from 1 to 25 mg, preferably approximately from 1 to 10 mg, in the case of intravenous administration, the dose advantageously being dlvided into several equal partial doses.
132~383 The pharmaceutical preparations contain, fGr example, from approximately 10~ to approximately 80%, preferably from approximately 20% to approximately 60%, active ingredient. Pharmaceutical preparations ~ccording to the invention for enteral and parenteral administration are, for example, those in dosage unit form, such as dragées, tablets, capsules or supposi-tories, and also ampoules. These are prepared in a manner known Per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical preparations ~or oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture and, if desired or necessary, processing the mixture or granulate, after the addition of suitable ad~uncts, into tablets or dragée cores.
Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes using, for example, corn, wheat, rlce or potato starch, . . ~ ., gelatine, tragacanth, methylcellulose and/or polyvlnyl-pyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Ad~uncts are especlally flow-regulating and lubricating agents, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or poly-ethylene ~lycol. Dragée cores are provided with suitable coatings which may be resistant to gastric juices, there being used, nter alia, concentrated sugar solutions which may conta~n gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures, or, for the preparation of coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetyl-cellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or dragée coatings, for example for iden~ifi-cation purposes or to indicate different doses of active ingredient.
Other orally administrable pharmaceutical preparations are dry-filled capsules consisting of gelatine, and also soft sealed capsules consisting of gelatine and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, if desired, stabilisers. In soft capsules, the active ingredient is preferably d~ssol~ed or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also to add stabilisers.
Suitable rectally administrable pharmaceutical preparations are, for example, suppositories that consist of a combination of the active ingredient with a suppository base material. Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatine rectal capsules that contain a combination of the active ingredient with a base material; suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
For parenteral administration there are suitable, especially, aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, or suspensions of the active ingredient, such as corresponding oily injection suspensions in which suitable lipophllic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, are used, or aqueous injection suspensions that contain vicosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran and, if desired, also stabilisers.
The present invention relates also to the use of the compounds of the formula I and their salts, preferably for the treatment of illnesses that can be attributed to calcium metabolism disorders, for example of the rheumatic type, and especially of osteoporoses.
Dosages under 0~01 mg/kg body weight have only a negligible effect on pathological calcification or the degeneration of hard tissue. At dosages above 100 mg/kg body weight, toxic side-effects may occur in long-term use. The compounds of the formula I and their salts can be adm~nistered both orally and, in the form of a hypertonic solution, subcutaneously, intramuscul-arly or intravenously. The preferred daily doses are in the range of approximately from 0.1 to 5 mg/kg in the case of oral administration, in the range of approxi-mately from 0.1 to 1 mg/kg in the case of subcutaneous and intramuscular administration and in the range of approximately from 0.01 to 2 mg/kg in the case of intravenous administration.
The dosage of the compounds used is, however, variable and depends on the particular conditions, such as nature and severity of the illness, duration of treatment and on the particular compound. Single doses contain, for example, from 0.01 to 10 mg, dosage unit forms for parenteral, such as intravenous, admini-stration contain, for example, from 0.01 to 0.1 mg, preferably C.02 to 0.08 mg, and oral dosage unit forms contain, for example, from 0.2 to 2.5 mg, preferably from ~.3 to 1.5 mg, per kg of body weight. The preferred individual dosage for oral administration is from 10 to 100 mg and for intravenous administration from 0.5 to 5 mg and can be administered in up to 4 single doses per day. The higher dosages in the case of oral administration are necessary owing to the limited resorption. In the case of long-term treatments, the initially higher dosage can normally be converted to low dosages while still maintaining the desired effect.
The following Examples illustrate the invention described above; they are not intended, however, to limit the scope thereof in any way. Temperatures are given in degrees Celsius.
- 21 - ~32 4383 Example 1: 6.57 g (17 mmol) of 1~(thiazol-2-ylamino)-methane-1,1-dipho~phonic acid tetraethyl ester are dissolved in 70 ml of N hydrochloric acid and heated under reflux for 6 hours. In the course of the reaction, the product separates out in the form of a fine white precipita.e. After cooling to room temper-ature, filtration is carried out and the product is washed with aqueous methanol. 4.33 g (93% of the theoretical yield) of 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 275 Idecomposition) are obtained.
The starting material can be prepared, for example, in the following manner:
A mixture consisting of 10.0 g (0.1 mol) of 2-aminothiazole, 20.0 ml (0.12 mol) of orthoformic acid triethyl ester and 26.6 ml (0.2 mol) of diethyl phosphite is heated under reflux for 1 hour. The ethanol liberated is distilled off, the internal temperature gradually increasing to approximately 150.
The residue is taken up in chloroform and filtered over silica gel. The crude product is purified by column chromatography (silica gel/ethyl acetate). 4.37 g (11%
of the theoretlcal yield) of 1-(thiazol-2-ylamino)-methane-1,1-diphosphonic acid tetraethyl ester of m.p.
1~3-104 are o~ained.
ExamPle 2: In a manner analogous to that described in Example 1 it is also possible to prepare 1-(oxazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 245 (decomposition) and 1-(benzoxazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 270 (decomposition).
Example 3: 4.36 g (10 mmol) of 1-~benzothiazol-2-ylamlno)methane-1,1-diphosphonic acid tetraethyl ester are heated in 40 ml of N hydrochloric acid at 110-120 for 6 hours. In the course of the reaction, the product - 22 - 132~383 separates out in the form of a white precipitate. After cooling to room temperature, filtration is carried out and the product is washed with aqueous methanol. 3.09 g ~95% of the theoretical yield) of 1-(benzothiazol-~-yl-amino1methane-1,1-diphosphonic acid of m.p. 290 (decomposition) are obtained.
The starting material can be prepared, for example, in the following manner:
A mixture consisting of 3.0 g (20 mmol) of 2-amino-benzothiazole, 4.0 ml (24 mmol) of orthoformic acid triethyl ester and 5.3 ml (40 mmol) of diethyl phosphite is heated at 120-125 for 5 hours~ The yellow precipi-tate which separates out at the beginning of the reaction gradually goes into solution again. The ethanol liberated is distilled off during the reaction.
The crude product, which solidifies on being left to stand, is purified by column chromatography (silica gel/ethyl acetate/methanol). 5.62 g (64% of the theoretical yield) of 1-(benzothiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester of m.p. 165-167 are obtained.
ExamPle 4: 1.30 g (3.2 mmol) of 1-(4-methylthia-zol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester are heated in 20 ml of 1N hydrochloric acid at 100 for 20 hours. After cooling, 20 ml of methanol are added. During subsequent stirring, the product separates out in the form of fine white crystals. The filtrate is subsequently washed with methanol and petroleum ether. Yield: 615 mg (67% of the theoretical yield) of 1-(4-methylthiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. ~94 (decomposition).
The starting material can be prepared, for example, in the following manner:
A mixture conslsting of 2.33 g (20 mmol) of 2-amino-4-methylthiazole, 4.0 ml (24 mmol) of - 23 - 13243~3 orthoformic acid triethyl ester and 5.3 ml (40 mmol) of diethyl phosphite is heated at 120-125 for 4 hours.
The ethanol liberated is distilled off. The residue is purified by column chromatography (silica gel/ethyl acetate/methanol). 1.32 g (17% of the theoretical yield) of 1-(4-methylthiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester are obtained in the form of a viscous oil.
Example 5: 1.97 g (4.9 mmol) of 1-(5-methylthiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester are heated under reflux in 20 ml of N hydrochloric acid for 6 hours. Upon cooling and leaving the reaction mixture to stand at room temperature, the product crystallises~ It is filtered and washed with acetone and petroleum ether. Yield: 0.64 g (45% of the theoretical yield) of 1-(5-methylthiazol-2-ylamino)-methane-1,1-diphosphonic acid of m.p. 208 IdecomPo-sition).
The starting material can be prepared, for example, in the following manner:
A mixture consisting of 1.14 g (10 mmol) of 2-amino-5-methylthiazole, 2.0 ml (12 mmol) of orthoformic acid triethyl ester and 2.65 ml (20 mmol) of diethyl phosphite is heated at 120-125 for 4~ hours.
The ethanol liberated is distilled off. The residue is purified by column chromatography ~silica gel/ethyl acetate/methanol). 1.97 g ~49% of the theoretical yield) of 1-(5-methylthiazol-2-ylamino~methane-1,1-diphosphonic acid tetraethyl ester are obtained in the form of a viscous oil.
ExamPle 6: 4.02 g (8.7 mmol) of 1-(5-phenylthiazol-2-ylamino)methane-1,1-diphosphonic acid are heated under reflux in 30 ml of N hydrochloric acid for 18 hours.
After cooling to room temperature, a small quantity of methanol is added and the whole is filtered. The filtrate is heated under reflux in methanol for 1 hour, filtered while hot and washed twice with hot methanol.
Yield: 2.90 g (95% of the theoretical yield) of 1-(5-phenylth~azol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 290 (decomposition).
The starting material can be prepared, for example, in the following manner:
A mixture consisting of 2.93 g (16.6 mmol) of 2-amino-5-phenylthiazole, 3.3 ml (l9.9 mmol) of orthoformic acid triethyl ester and 4.4 ml (33.5 mmol) of diethyl phosphite is heated first for 2 hours at 120 and then for 2 hours at 130. The ethanol liberated is distilled off in the course of the reaction. The product, which solidifies upon cooling, is purified by chromatography (silica gel/ethyl acetate/methanol).
4.12 g (54% of the theoretical yield) of 1-(5-phenyl-thiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester of m.p. 151-153 are obtained.
Example 7: 2.5 g (5.96 mmol) of 1-(1-benzimidazol-2-ylamino)methane~ diphosphonic acid tetraethyl ester are dissolved in 25 ml of 1N hydrochloric acid and heated at 100-110 for 26 hours~ In the course of the reaction, the product separates out in the form of a fine white precipitate. It is filtered while hot and washed with water and then with methanol. 0.23 g (13%
of the theoretical yield) of 1~ benzimidazol-2-yl-amino)methane-1,1-diphosphonic acid of m.p. 265 (decomposition) is obtained.
The starting material can be prepared, for example, in the following manner:
6.66 g (50 mmol) of 2-aminobenzimidazole, 10.0 ml (60 mmol) of orthoformic acid triethyl ester and 13.3 ml (101 mmol) of diethyl phosphite are mixed together and then stirred for 2 hours at 125-130~ until no more - 25 - 132~383 ethanol is distilled off. The residue is purified by column chromatography (silica gel/ethyl acetate/-methanol, 9:1). 2.89 g (14% of the theoretical yield) of 1~ benzimidazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester of m.p~ 169-170 are obtained.
Example 8: 7 g of phosphorus trichloride are mixed with 4.0 g of phosphorous acid and the mixture is heated, while stirring, at 60 for 1 hour. 6.12 g of N-(thiazol-2-yl)formamide are added thereto and the mixture is heated for a further 6 hours at approximately 60. The mixture is then stirred with 30 ml of water, filtered with suction, subsequently washed with aqueous methanol and dried u~der reduced pressure. 2.0 g of 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 275 (decomposition) are obtained.
ExamPle 9: 2.0 g (20.4 mmol) of crystalline orthophosphoric acid are stirred with 3.5 g (25.5 mmol) of phosphorus trichloride for 1 hour at 55-60~. 4.08 g ~20.0 mmol) of N-(4-phenylthiazol-2-yl)formamide are then added thereto. The reaction mixture is left to stand for approximately 24 hours at 60. For dilution, 10 ml of 80% phosphoric acid are added thereto and the whole is left to stand overnight at room temperature.
It is then heated again to 60-70 and a further 1.37 g (10 mmol) of phosphorus trichloride are added thereto, the whole is further stirred for 2 hours at 60-70, 30 ml of water and 20 ml of acetone are added and the whole is stirred for 2 hours at 60 to complete the reaction. The reaction mixture is allowed to cool to room temperature, and the fine, pale yellow precipitate is filtered off and washed with water/acetone 3:2~ The residue is purified by being boiled once with water/-acetone 1:1 and twice with methanol. 18Q mg (2.6% of the theoretical yield) of 1-(4-phenylthiazol-2-yl-_ 26 - 13243~3 amino)methane~ diphosphonic acid of m.p. 238 tdecomposition) are obtained.
The starting material can be prepared, for example, in the following manner:
13.22 g (75 mmol) of 2-amino 4-phenylthiazole are heated at 110 for 5 hours with 40 ml sf formic acid.
The reaction mixture is cooled to room temperature and poured onto ice. The white precipitate which separates out is filtered and washed with ice-water. The product is purified by means of petroleum ether. 7.01 g (45.8%
of the theoretical yield) of 4-(phenylthiazol-2-yl-aminc3formamide of m.p. 161-164 are obtained.
.
Example 10: In a manner known Per se, for example as described in Examples 1 to 7, it is also possible to prepare the following:
1-(imidazol-2-ylamino)methane-1,1-diphosphonic acid, 1-(imidazol-4-ylamino)methane-1,1-diphosphonic acid, 1-(1-methylimidazol-2-ylamino)methane-1,1-diphosphonic acid, 1-(tetrazol-5-ylamino)methane-1,1-diphosphonic acid, 1-(oxazol-2-ylamino)methane-1,1-diphosphonic acid, 1-(1,3,4-thiadiazol-2-ylamino)methane-1,1-diphosphonic acid, 1-(5-methyl-1,3,4-thiadiazol-2-ylamino)methane-1,1-diphosphonic acid, m.p. 260 (decomposition), 1-(3-phenyl-1,2,4-thiadiaæol-5-ylamino)methane~
diphosphonic acid, m.p. 198.
ExamPle 11. Tablets, each containing 50 mg of active ingredient, for example 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof, can be prepared in the following manner:
Constituents (for 1000 tablets) active ingredient 50.0 g lactose 50.7 g wheat starch 7.5 g polyethylene glycol 6000 5.0 g talc 5 0 g magnesium stearate 1.8 g demineralised water q.s.
Preparation: ~ll the solid ingredients are first forced through a sieve of 0.6 mm mesh width. Then the active ingredient, the lactose, the talc, the magnesium stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water. The resulting paste is added to the pulverulent substances and the mixture is granulated, if necessary with the addition of water. The granulate is dried overnight at 35, forced through a sieve of l.2 mm mesh width and com-pressed to form tablets of approximately 6 mm diameter which are concave on both sides.
ExamPle 12: Tablets, each containing 100 mg of active ingredient, for example 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof, can be prepared in the following manner:
Constituents (for 1000 tablets) active ingredient 100.0 g lactose 100.0 g wheat starch 47.0 g magnesium stearate 3.0 g Preparation: All the solid ingredients are first forced through a sieve of 0.6 mm mesh width~ Then the active ingredient, the lactose, the magnesium . , 13243~3 stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and t~is suspension is added to 100 ml of boiling water.
The resulting paste is added to the pulverulent sub-stances and the mixture is granulated, if necessary with the addition of water. The granulate is dried overnight at 35~ forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.
Example 13: In a manner analogous to that described in Examples 11 and 12, it is also possible to prepare tablets each containing 100 mg or 50 mg of another of the compounds of the formula I mentioned in Examples 1 to 10, which compounds may also be in the form of salts with bases, for example in the form of the disodium salt.
Example 14: Tablets for chewing, each containing 75 mg of active ingredient, for example 1-(thiazol-2-ylamino)me~hane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof, can be prepared, for example, in the following manner:
Com~osition: (for 1000 tablets) active ingredient 75.0 g mannitol 230~0 g lactose 150.0 g talc 21.0 g glycine 12.5 g stearic acid 10.0 g saccharin 1.5 g 5% gelatine solution q.s.
Preparation: All the solid ingredients are first forced through a sieve of 0.25 mm mesh width. The mannitol and the lactose a e mixed, granulated with the . , ~32~ 83 addition of gelatine solution, forced thxough a sieve of 2 mm mesh width, dried at 50 and again forced through a sieve of 1.7 mm mesh width. The active ingredient, the glycine and the saccharin are carefully mixed, the mannitol, the lactose granulate, the stearic acid and the talc are added and the whole is mixed thoroughly and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking groove on the upper side.
In an analogous manner, it is also possible to prepare tablets each containing 75 mg of another of the compounds of the formula I mentioned in Examples 1 to 9, which compounds may also be in the form of salts with bases, for example in the form of the disodium salt.
Example 15: Tablets, each containing 10 mg of active ingredient, for example 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof, can be prepared in the following manner:
Composition (for 1000 tablets) active ingredient 10.0 g lactose 328.5 g corn starch 17.5 g polyethylene glycol 6000 S.0 g talc 25.0 g magnesium stearate 4.0 g demineralised water q.s.
Preparation: The solid ingredients are first forced through a sieve of 0.6 mm mesh widtho Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are intimately mixed. The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting - 30 ~ ~32~383 paste is added to the pulverulent substances, and the whole is mixed and granulated, if necessary with ~he addition of water. The granulate is dried overnight at 35, forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking notch on the upper side.
In an analogous manner, it is also possible to prepare tablets each containing 10 mg of another compound of the formula I according to Examples 1 to 9, which compound may also be in the form of a salt with a base, for example in the form of the disodium salt.
Example 16: Gelatine dry-filled capsules, each containing 100 mg of active ingredient, for example 1-(thiazol-2-ylamino~methane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof, can be prepared in the following manner:
Composition (for 1000 capsules) active ingredient 350.0 g microcrystalline cellulose 30.0 g sodium lauryl sulphate 2.0 g magnesium stearate 8.0 g The sodium lauryl sulphate is sieved into the active ingredient (lyophilised) through a sieve of 0.2 mm mesh width and the two components are intimately mixed for 10 minutes. The microcrystalline cellulose is then added through a sieve of 0.9 mm mesh width and the whole is again intimately mixed for 10 minutes.
Finally, the magnesium stearate is added through a sieve of 0.8 mm mesh width and, after mixing for a further 3 minutes, the mixture is introduced in portions of 390 mg each into slze 0 (elongated) gelatine dry-fill capsules.
~ 31 - 1324383 In an analogous manner, it is also possible to prepare capsules each containing 100 mg of another compound of the formula I according to Examples 1 to 9, which compound may also be in the form of a salt with a base, for example in the form of the disodium salt.
Example_17: A 0.2% injection or infusion solution can be prepared, for example, in the following manner:
active ingredient, for example 1-(thiazol-2-ylamino)-methane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof 5.0 g sodium chloride 22.5 g phosphate buffer pH 7.4 300.0 g demineralised water to 2500.0 ml The active ingredient is dissolved in 1000 ml of water and filtered through a microfilter. The buffer solution is added and the whole is made up to 2500 ml with water. To prepare dosage unit forms, portions of 1.0 or 2.5 ml each are introduced into glass ampoules (each containing respectively 2.0 or 5.0 mg of active ingredient).
Example 8: 7 g of phosphorus trichloride are mixed with 4.0 g of phosphorous acid and the mixture is heated, while stirring, at 60 for 1 hour. 6.12 g of N-(thiazol-2-yl)formamide are added thereto and the mixture is heated for a further 6 hours at approximately 60. The mixture is then stirred with 30 ml of water, filtered with suction, subsequently washed with aqueous methanol and dried u~der reduced pressure. 2.0 g of 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 275 (decomposition) are obtained.
ExamPle 9: 2.0 g (20.4 mmol) of crystalline orthophosphoric acid are stirred with 3.5 g (25.5 mmol) of phosphorus trichloride for 1 hour at 55-60~. 4.08 g ~20.0 mmol) of N-(4-phenylthiazol-2-yl)formamide are then added thereto. The reaction mixture is left to stand for approximately 24 hours at 60. For dilution, 10 ml of 80% phosphoric acid are added thereto and the whole is left to stand overnight at room temperature.
It is then heated again to 60-70 and a further 1.37 g (10 mmol) of phosphorus trichloride are added thereto, the whole is further stirred for 2 hours at 60-70, 30 ml of water and 20 ml of acetone are added and the whole is stirred for 2 hours at 60 to complete the reaction. The reaction mixture is allowed to cool to room temperature, and the fine, pale yellow precipitate is filtered off and washed with water/acetone 3:2~ The residue is purified by being boiled once with water/-acetone 1:1 and twice with methanol. 18Q mg (2.6% of the theoretical yield) of 1-(4-phenylthiazol-2-yl-_ 26 - 13243~3 amino)methane~ diphosphonic acid of m.p. 238 tdecomposition) are obtained.
The starting material can be prepared, for example, in the following manner:
13.22 g (75 mmol) of 2-amino 4-phenylthiazole are heated at 110 for 5 hours with 40 ml sf formic acid.
The reaction mixture is cooled to room temperature and poured onto ice. The white precipitate which separates out is filtered and washed with ice-water. The product is purified by means of petroleum ether. 7.01 g (45.8%
of the theoretical yield) of 4-(phenylthiazol-2-yl-aminc3formamide of m.p. 161-164 are obtained.
.
Example 10: In a manner known Per se, for example as described in Examples 1 to 7, it is also possible to prepare the following:
1-(imidazol-2-ylamino)methane-1,1-diphosphonic acid, 1-(imidazol-4-ylamino)methane-1,1-diphosphonic acid, 1-(1-methylimidazol-2-ylamino)methane-1,1-diphosphonic acid, 1-(tetrazol-5-ylamino)methane-1,1-diphosphonic acid, 1-(oxazol-2-ylamino)methane-1,1-diphosphonic acid, 1-(1,3,4-thiadiazol-2-ylamino)methane-1,1-diphosphonic acid, 1-(5-methyl-1,3,4-thiadiazol-2-ylamino)methane-1,1-diphosphonic acid, m.p. 260 (decomposition), 1-(3-phenyl-1,2,4-thiadiaæol-5-ylamino)methane~
diphosphonic acid, m.p. 198.
ExamPle 11. Tablets, each containing 50 mg of active ingredient, for example 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof, can be prepared in the following manner:
Constituents (for 1000 tablets) active ingredient 50.0 g lactose 50.7 g wheat starch 7.5 g polyethylene glycol 6000 5.0 g talc 5 0 g magnesium stearate 1.8 g demineralised water q.s.
Preparation: ~ll the solid ingredients are first forced through a sieve of 0.6 mm mesh width. Then the active ingredient, the lactose, the talc, the magnesium stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water. The resulting paste is added to the pulverulent substances and the mixture is granulated, if necessary with the addition of water. The granulate is dried overnight at 35, forced through a sieve of l.2 mm mesh width and com-pressed to form tablets of approximately 6 mm diameter which are concave on both sides.
ExamPle 12: Tablets, each containing 100 mg of active ingredient, for example 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof, can be prepared in the following manner:
Constituents (for 1000 tablets) active ingredient 100.0 g lactose 100.0 g wheat starch 47.0 g magnesium stearate 3.0 g Preparation: All the solid ingredients are first forced through a sieve of 0.6 mm mesh width~ Then the active ingredient, the lactose, the magnesium . , 13243~3 stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and t~is suspension is added to 100 ml of boiling water.
The resulting paste is added to the pulverulent sub-stances and the mixture is granulated, if necessary with the addition of water. The granulate is dried overnight at 35~ forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 6 mm diameter which are concave on both sides.
Example 13: In a manner analogous to that described in Examples 11 and 12, it is also possible to prepare tablets each containing 100 mg or 50 mg of another of the compounds of the formula I mentioned in Examples 1 to 10, which compounds may also be in the form of salts with bases, for example in the form of the disodium salt.
Example 14: Tablets for chewing, each containing 75 mg of active ingredient, for example 1-(thiazol-2-ylamino)me~hane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof, can be prepared, for example, in the following manner:
Com~osition: (for 1000 tablets) active ingredient 75.0 g mannitol 230~0 g lactose 150.0 g talc 21.0 g glycine 12.5 g stearic acid 10.0 g saccharin 1.5 g 5% gelatine solution q.s.
Preparation: All the solid ingredients are first forced through a sieve of 0.25 mm mesh width. The mannitol and the lactose a e mixed, granulated with the . , ~32~ 83 addition of gelatine solution, forced thxough a sieve of 2 mm mesh width, dried at 50 and again forced through a sieve of 1.7 mm mesh width. The active ingredient, the glycine and the saccharin are carefully mixed, the mannitol, the lactose granulate, the stearic acid and the talc are added and the whole is mixed thoroughly and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking groove on the upper side.
In an analogous manner, it is also possible to prepare tablets each containing 75 mg of another of the compounds of the formula I mentioned in Examples 1 to 9, which compounds may also be in the form of salts with bases, for example in the form of the disodium salt.
Example 15: Tablets, each containing 10 mg of active ingredient, for example 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof, can be prepared in the following manner:
Composition (for 1000 tablets) active ingredient 10.0 g lactose 328.5 g corn starch 17.5 g polyethylene glycol 6000 S.0 g talc 25.0 g magnesium stearate 4.0 g demineralised water q.s.
Preparation: The solid ingredients are first forced through a sieve of 0.6 mm mesh widtho Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are intimately mixed. The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting - 30 ~ ~32~383 paste is added to the pulverulent substances, and the whole is mixed and granulated, if necessary with ~he addition of water. The granulate is dried overnight at 35, forced through a sieve of 1.2 mm mesh width and compressed to form tablets of approximately 10 mm diameter which are concave on both sides and have a breaking notch on the upper side.
In an analogous manner, it is also possible to prepare tablets each containing 10 mg of another compound of the formula I according to Examples 1 to 9, which compound may also be in the form of a salt with a base, for example in the form of the disodium salt.
Example 16: Gelatine dry-filled capsules, each containing 100 mg of active ingredient, for example 1-(thiazol-2-ylamino~methane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof, can be prepared in the following manner:
Composition (for 1000 capsules) active ingredient 350.0 g microcrystalline cellulose 30.0 g sodium lauryl sulphate 2.0 g magnesium stearate 8.0 g The sodium lauryl sulphate is sieved into the active ingredient (lyophilised) through a sieve of 0.2 mm mesh width and the two components are intimately mixed for 10 minutes. The microcrystalline cellulose is then added through a sieve of 0.9 mm mesh width and the whole is again intimately mixed for 10 minutes.
Finally, the magnesium stearate is added through a sieve of 0.8 mm mesh width and, after mixing for a further 3 minutes, the mixture is introduced in portions of 390 mg each into slze 0 (elongated) gelatine dry-fill capsules.
~ 31 - 1324383 In an analogous manner, it is also possible to prepare capsules each containing 100 mg of another compound of the formula I according to Examples 1 to 9, which compound may also be in the form of a salt with a base, for example in the form of the disodium salt.
Example_17: A 0.2% injection or infusion solution can be prepared, for example, in the following manner:
active ingredient, for example 1-(thiazol-2-ylamino)-methane-1,1-diphosphonic acid or a salt, for example the sodium salt, thereof 5.0 g sodium chloride 22.5 g phosphate buffer pH 7.4 300.0 g demineralised water to 2500.0 ml The active ingredient is dissolved in 1000 ml of water and filtered through a microfilter. The buffer solution is added and the whole is made up to 2500 ml with water. To prepare dosage unit forms, portions of 1.0 or 2.5 ml each are introduced into glass ampoules (each containing respectively 2.0 or 5.0 mg of active ingredient).
Claims (14)
1. A process for the manufacture of a heteroarylamino-methanediphosphonic acid of the formula (I) in which R1 represents an optionally benzo- or cyclohexeno-fused 5-membered heteroaryl radical that contains, as hetero atom(s), either from 2 to 4 N-atoms or 1 or 2 N-atoms as well as 1 O-atom or S-atom and that is unsubstituted or is C-substituted by lower alkyl; by phenyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy or by halogen; by lower alkoxy; by hydroxy; by di-lower alkylamino; by lower alkylthio or by halogen; or that is N-substituted by lower alkyl; or by phenyl-lower alkyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy or by halogen; and R2 represents hydrogen or lower alkyl, with the proviso that R2 is other than hydrogen when R1 represents a pyrazol-3-yl or isoxazol-3-yl radical that is optionally substituted by alkyl or by halogen, and salts or a pharmaceutically acceptable salt thereof which process comprises a) in a compound of the formula (II) which is optionally intermediately protected at a substitutable N-atom of the radical R1 and in which X1 represents a functionally modified phosphono group X and X2 represents phosphono or similarly represents a functionally modified phosphono group X, the group(s) X is(are) converted into free phosphono, or b) a compound of the formula (III), which is optionally intermediately protected at a substitutable N-atom of the radical R1, is reacted first with phosphorus trioxide and then with water, and, if required, in each case, a resulting compound is converted into a different compound of the formula I or a resulting free compound is converted into a salt or a resulting salt is converted into the free compound or into a different salt.
2. A process according to claim 1, characterised in that a compound of the formula II, wherein X1 and X2 denote groups of the formula -P(=O)(OR)2 (IIa) in which R represents lower alkoxy, is hydrolysed in the presence of a mineral acid.
3. A process according to claim 1, characterised in that a compound of the formula III is reacted with phosphorous trioxide formed in situ by reaction of a phosphorous trihalide and phosphorous or phosphoric acid, and subsequently treated with water.
4. A heteroarylaminomethanediphosphonic acid of the formula (I) in which R1 represents an optionally benzo- or cyclohexeno-fused
5-membered heteroaryl radical that contains, as hetero atom(s), either from 2 to 4 N-atoms or 1 or 2 N-atoms as well as 1 O-atom or S-atom and that is unsubstituted or is C-substituted by lower alkyl; by phenyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy or by halogen; by lower alkoxy; by hydroxy; by di-lower alkylamino; by lower alkylthio or by halogen; or that is N-substituted by lower alkyl; or by phenyl-lower alkyl that is unsubstituted or is substituted by lower alkyl, lower alkoxy or by halogen; and R2 represents hydrogen or lower alkyl, with the proviso that R2 is other than hydrogen when R1 represents a pyrazol-3-yl or isoxazol-3-yl radical that is optionally substituted by alkyl or by halogen or a pharmaceutically acceptable salt thereof.
5. A compound of the formula I according to claim 4, in which R1 represents an imidazolyl, benzimidazolyl, 2H-1,2,3- or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzothiazolyl or thiadiazolyl radical that is C-unsubstituted or C-mono or C-di-substituted by lower alkyl; by lower alkoxy; by phenyl that is unsubstituted or is mono- or di-substituted by lower alkyl, lower alkoxy or by halogen; by hydroxy; by di-lower alkylamino; by lower alkylthio or by halogen; and that is unsubstituted at a substitutable N-atom which may optionally be present or preferably N-mono-substituted by lower alkyl or by phenyl-lower alkyl that is unsubstituted or is mono or di-substituted by lower alkyl, lower alkoxy or by halogen; and R2 represents hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof.
5. A compound of the formula I according to claim 4, in which R1 represents an imidazolyl, benzimidazolyl, 2H-1,2,3- or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, thiazolyl, benzothiazolyl or thiadiazolyl radical that is C-unsubstituted or C-mono or C-di-substituted by lower alkyl; by lower alkoxy; by phenyl that is unsubstituted or is mono- or di-substituted by lower alkyl, lower alkoxy or by halogen; by hydroxy; by di-lower alkylamino; by lower alkylthio or by halogen; and that is unsubstituted at a substitutable N-atom which may optionally be present or preferably N-mono-substituted by lower alkyl or by phenyl-lower alkyl that is unsubstituted or is mono or di-substituted by lower alkyl, lower alkoxy or by halogen; and R2 represents hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof.
6. A compound of the formula I according to claim 4, in which R1 represents a thiazolyl radical, benzothiazol-2-yl radical, thiadiazolyl radical, oxazolyl radical or benzoxazol-2-yl radical each of which is unsubstituted or is C-substituted by C1-C4-alkyl or by a phenyl radical that is unsubstituted or is mono- or di-substituted by C1-C4-alkyl, C1-C4-alkoxy or by halogen; or represents an imidazol-2-yl radical or benzimidazol-2-yl radical each of which is unsubstituted or is C-substituted by C1-C4-alkyl or by a phenyl radical that is unsubstituted or is mono- or di-substituted by C1-C4-alkyl, C1-C4-alkoxy or by halogen, or each of which is N-substituted by C1-C4-alkyl or by a phenyl-C1-C4-alkyl radical that is unsubstituted or is mono- or di-substituted by C1-C4-alkyl, C1-C4-alkoxy or by halogen; and R2 represents hydrogen, or a pharmaceutically acceptable salt thereof.
7. A compound of the formula I according to claim 4, in which R1 represents a thiazolyl radical, a 1-C1-C4-alkyl-imidazol-2-yl or -4-yl radical or a phenyl-C1-C4-alkyl-imidazol-2-yl or -4-yl radical each of which is unsubstituted or is C-substituted by C1-C4-alkyl, by C1-C4-alkoxy, by phenyl, by hydroxy, by di-C1-C4-alkylamino, by C1-C4-alkylthio or by halogen having an atomic number of up to and including 35, and R2 represents hydrogen, or a pharmaceutically acceptable salt thereof.
8. A compound of the formula I according to claim 4, in which R1 represents a thiazol-2-yl radical that is unsubstituted or is mono- or di-substituted by C1-C4-alkyl or by phenyl, or represents an imidazol-2-yl or benzimidazol-2-yl radical that is unsubstituted or is mono-substituted in the 1-position by C1-C4-alkyl or by phenyl-C1-C4-alkyl, respectively, or represents an unsubstituted benzoxazol-2-yl or benzothiazol-2-yl radical, and R2 represents hydrogen, or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 4 being 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof.
10. A compound according to claim 4 selected from 1-(5-methyl-1,3,4-thiadiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof, 1-(1,3,4-thiadiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof, 1-(1-methylimidazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof, 1-(oxazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof, 1-(3-phenyl-1,2,4-thiadiazol-5-ylamino)methane-1,1-diphosphonic acid or a salt thereof, 1-(benzimidazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof, 1-(benzothiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof, 1-(benzoxazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof, 1-(4-methylthiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof, 1-(5-methylthiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof, 1(5-phenylthiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof, and 1-(4-phenylthiazol-2-ylamino)methane-1,1-diphosphonic acid or a salt thereof.
11. A pharmaceutical composition containing a compound of formula I according to any one of claims 4 to 10 or a pharmaceutically acceptable salt thereof, in admixture with a conventional carrier or auxiliary.
12. A pharmaceutical composition containing a heteroarylmethanediphosphoric acid of the formula (I) in which R1 represents a pyrazol-3-yl or isoxazol-3-yl radical that is optionally substituted by C1-C7 alkyl or by halogen, and R2 denotes hydrogen, or a pharmaceutically acceptable salt thereof in admixture with a conventional carrier or auxiliary.
13. Use of a compound according to any one of claims 4 to 1 to treat an illness associated with a calcium metabolism disorder in a warm-blooded animal.
14. A commercial package comprising a pharmaceutically effective amount of a compound according to any one of claims 4 to 10 together with instructions for use thereof to treat an illness associated with a calcium metabolism disorder in a warm-blooded animal.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH4665/86-9 | 1986-11-21 | ||
| CH466586 | 1986-11-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1324383C true CA1324383C (en) | 1993-11-16 |
Family
ID=4280333
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000552085A Expired - Fee Related CA1324383C (en) | 1986-11-21 | 1987-11-18 | Process for the manufacture of novel substituted aminomethanediphosphonic acids |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0274346B1 (en) |
| JP (1) | JPS63150290A (en) |
| KR (1) | KR880006217A (en) |
| AT (1) | ATE61371T1 (en) |
| AU (1) | AU605203B2 (en) |
| CA (1) | CA1324383C (en) |
| DD (1) | DD265900A5 (en) |
| DE (1) | DE3768463D1 (en) |
| DK (1) | DK168869B1 (en) |
| ES (1) | ES2038693T3 (en) |
| FI (1) | FI87653C (en) |
| GR (1) | GR3001611T3 (en) |
| HU (1) | HU201087B (en) |
| IE (1) | IE60148B1 (en) |
| IL (1) | IL84494A (en) |
| MY (1) | MY103191A (en) |
| NO (1) | NO170283C (en) |
| NZ (1) | NZ222608A (en) |
| PH (1) | PH23959A (en) |
| PT (1) | PT86166B (en) |
| ZA (1) | ZA878656B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0282309A3 (en) * | 1987-03-11 | 1990-03-14 | Yamanouchi Pharmaceutical Co. Ltd. | Azole-aminomethylene bisphosphonic acid derivatives |
| US5270365A (en) * | 1991-12-17 | 1993-12-14 | Merck & Co., Inc. | Prevention and treatment of periodontal disease with alendronate |
| TW237386B (en) * | 1992-04-15 | 1995-01-01 | Ciba Geigy | |
| EP0600834A1 (en) * | 1992-11-30 | 1994-06-08 | Ciba-Geigy Ag | Use of methanebisphosphonic acid derivatives for the manufacture of a medicament for fracture healing |
| US5880111A (en) * | 1995-06-07 | 1999-03-09 | Farcasiu; Dan | Therapeutic derivations of diphosphonates |
| AU7213196A (en) * | 1995-09-29 | 1997-04-28 | Ciba-Geigy Ag | Method of treating the navicular disease in horses |
| DE10226420A1 (en) * | 2002-06-13 | 2004-01-15 | Eucro European Contract Research Gmbh & Co Kg | Procedure for the treatment of atherosclerosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS54135724A (en) * | 1978-04-11 | 1979-10-22 | Nissan Chem Ind Ltd | Preparation of amino-methylenedisulfonic acid derivative |
| IL77243A (en) * | 1984-12-21 | 1996-11-14 | Procter & Gamble | Pharmaceutical compositions containing geminal diphosphonic acid compounds and certain such novel compounds |
-
1987
- 1987-11-16 DE DE8787810665T patent/DE3768463D1/en not_active Expired - Lifetime
- 1987-11-16 IL IL84494A patent/IL84494A/en not_active IP Right Cessation
- 1987-11-16 ES ES198787810665T patent/ES2038693T3/en not_active Expired - Lifetime
- 1987-11-16 EP EP87810665A patent/EP0274346B1/en not_active Expired - Lifetime
- 1987-11-16 AT AT87810665T patent/ATE61371T1/en not_active IP Right Cessation
- 1987-11-18 CA CA000552085A patent/CA1324383C/en not_active Expired - Fee Related
- 1987-11-18 PH PH36078A patent/PH23959A/en unknown
- 1987-11-18 FI FI875095A patent/FI87653C/en not_active IP Right Cessation
- 1987-11-19 PT PT86166A patent/PT86166B/en not_active IP Right Cessation
- 1987-11-19 DD DD87309213A patent/DD265900A5/en not_active IP Right Cessation
- 1987-11-19 ZA ZA878656A patent/ZA878656B/en unknown
- 1987-11-19 NZ NZ222608A patent/NZ222608A/en unknown
- 1987-11-20 AU AU81452/87A patent/AU605203B2/en not_active Ceased
- 1987-11-20 MY MYPI87003074A patent/MY103191A/en unknown
- 1987-11-20 KR KR1019870013062A patent/KR880006217A/en not_active Application Discontinuation
- 1987-11-20 JP JP62292196A patent/JPS63150290A/en active Pending
- 1987-11-20 HU HU875159A patent/HU201087B/en not_active IP Right Cessation
- 1987-11-20 IE IE314787A patent/IE60148B1/en not_active IP Right Cessation
- 1987-11-20 DK DK609387A patent/DK168869B1/en not_active IP Right Cessation
- 1987-11-20 NO NO874855A patent/NO170283C/en unknown
-
1991
- 1991-03-15 GR GR90401110T patent/GR3001611T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0274346B1 (en) | 1991-03-06 |
| FI87653B (en) | 1992-10-30 |
| NO170283C (en) | 1992-09-30 |
| PT86166A (en) | 1987-12-01 |
| MY103191A (en) | 1993-05-29 |
| DK168869B1 (en) | 1994-06-27 |
| ES2038693T3 (en) | 1993-08-01 |
| IE60148B1 (en) | 1994-06-01 |
| ZA878656B (en) | 1988-08-31 |
| NO874855D0 (en) | 1987-11-20 |
| ATE61371T1 (en) | 1991-03-15 |
| JPS63150290A (en) | 1988-06-22 |
| HUT46329A (en) | 1988-10-28 |
| EP0274346A1 (en) | 1988-07-13 |
| IL84494A0 (en) | 1988-04-29 |
| HU201087B (en) | 1990-09-28 |
| PT86166B (en) | 1990-11-20 |
| AU8145287A (en) | 1988-05-26 |
| NO170283B (en) | 1992-06-22 |
| GR3001611T3 (en) | 1992-11-23 |
| DK609387A (en) | 1988-05-22 |
| IE873147L (en) | 1988-05-21 |
| NO874855L (en) | 1988-05-24 |
| FI875095A0 (en) | 1987-11-18 |
| DD265900A5 (en) | 1989-03-15 |
| DK609387D0 (en) | 1987-11-20 |
| NZ222608A (en) | 1990-09-26 |
| FI87653C (en) | 1993-02-10 |
| KR880006217A (en) | 1988-07-22 |
| PH23959A (en) | 1990-01-23 |
| IL84494A (en) | 1992-08-18 |
| AU605203B2 (en) | 1991-01-10 |
| DE3768463D1 (en) | 1991-04-11 |
| FI875095A (en) | 1988-05-22 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |