FI86638B - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT EFFEKTIVA OMAETTADE FOSFONSYROR. - Google Patents

Abstract

Compounds of the formula I <IMAGE> in which one or both of the acidic hydroxyl groups of the phosphonic acid part can be etherified, m is one or zero, R<1> denotes carboxyl, esterified carboxyl or amidated carboxyl, the heterocyclic five- or six-membered ring can additionally be substituted on the carbon and/or nitrogen, can have a carbon-carbon double bond or can be condensed with a carbocyclic 6-membered ring, starting from adjacent carbon atoms, A represents lower alkenylene; and salts thereof. These compounds are suitable as antagonists of the N-methyl-D-aspartate- sensitive amino acid stimulant receptor in mammals.

Description

86638

A process for the preparation of therapeutically effective unsaturated phosphonic acids

The present invention relates to a process of formula I.

HM "V \

Ah | x (I)! I-R

Y

in which one or both of the acidic hydroxy groups of the phosphonic acid moiety may be etherified with lower alkyl, benzyl, in the phenyl moiety with halo, lower alkyl or lower alkoxyalkyl-substituted alkoxyalkyl-allyl-alkyloxy 1 or O, R 1 denotes carboxy, carboxy esterified with lower alkyl or lower alkanoyloxymethyl or unsubstituted or N-lower alkylated carbamoyl, the heterocyclic 5- or 6-membered ring may be further substituted on carbon by lower alkyl or lower alkyl, lower alkyl, lower alkyl and / or types , or with lower alkoxycarbonyl, it may contain a carbon-carbon double bond or it may be fused to a carbocyclic 6-membered ring starting side by side of the carbon atoms, A represents lower alkenylene. These compounds are suitable as mammalian N-methyl-D-aspartate-sensitive amino acid stimulant receptor antagonists.

The compounds of the invention are effective and can be used in mammals as selective antagonists of N-methyl-D-aspartate-sensitive (NMDA) amino acid stimulus receptors. The compounds according to the invention are therefore also suitable, alone or in combination, for the treatment of diseases which respond to NMDA receptor blockade, for example for the treatment of cerebral ischemia, muscle spasms (spasticity), convulsive diseases (epilepsy) and conditions of fear. The compounds of the invention are also considered effective in the treatment of Huntington's disease (Chorea hereditiva).

Condensation starting from adjacent carbon atoms having a carbocyclic 6-membered ring is condensation with, for example, cyclohexyl or phenyl, such that the fused heterocyclic ring of formula I represents a bicyclic ring system having 9 or 10 ring-forming atoms depending on the value of m in formula I.

The heterocyclic ring system of the compounds of formula I as defined above together with the substituent R 1 denotes, for example, optionally substituted 2-carboxy-pyrrolidinyl, 2-carboxy-2,5-dihydropyrrolyl, 2-carboxy-1,2,3,6-tetrahydropyridinyl, 2-carboxy- 1,2,5,6-tetrahydropyridinyl, 2-carboxypiperidinyl, 2-carboxy-tetrahydroquinolinyl, 2-carboxyperhydroquinolinyl, 2-carboxy-2,3-dihydroindolyl or 2-carboxyperhydroindolyl, in which the carboxy may be esterified or amidated.

Etherified hydroxy is, for example, lower alkoxy, benzyloxy, benzyloxy substituted in the phenyl moiety by halogen, lower alkyl or lower alkoxy, lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted in the oxymethyl moiety by lower alkyl or cycloalkyl.

A preferred embodiment of the invention relates to phosphonic acid derivatives of the formula I and their derivatives, 3 8 6 6 53

wherein the heterocyclic ring represents optionally substituted 2-carboxypiperidinyl, 2-carboxy-1,2,3,6-tetrahydropyridinyl or 2-carboxy-1,2,5,6-tetrahydropyridinyl, in particular of formula II

RJ— + \ ÖR (II) • «'

Compounds of formula Yv and compounds of formula II having a double bond between the C-3 and C-4 or C-4 and C-5 atoms of the piperidinyl ring and salts of these compounds wherein the phosphonone-containing chain is attached to the piperidinyl or tetrahydropyridinyl ring In the 3-, 4- or 5-position and in which R and R 'independently of one another denote hydrogen, lower alkyl, benzyl or benzyl substituted in the phenyl part by halogen, lower alkyl or lower alkoxy, lower alkanoyloxymethyl or lower alkanoyloxymethyl, which is lower alkyl or cycloalkyl, R 1 represents carboxy or pharmaceutically acceptable esterified or amidated carboxy, R 2 represents hydrogen, lower alkyl, aryl-lower alkyl or acyl, R 3 represents hydrogen, lower alkyl or aryl-lower alkyl and A represents lower.

Preferred are compounds of formula II and pharmaceutically acceptable salts thereof, wherein R and R 'are independently hydrogen, lower alkyl, benzyl, lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted in the oxymethyl moiety with carbalkyl or carbocyclohexyl, cyclohexyl or cyclohexyl. 4 suitable esterified carboxy as defined herein, R 2 and R 3 represent hydrogen or lower alkyl and A represents alkenylene having 2 to 4 carbon atoms.

B 6 6 5 8

Further preferred are compounds of formula II and pharmaceutically acceptable salts thereof, wherein R and R 'independently represent hydrogen, Lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted in the oxymethyl moiety with lower alkyl, lower alkyloxy-lower alkaryloxy, carbamoyl or lower; of the chains di-lower alkylamino-C2-C4-alkoxycarbonyl or pyridylmethoxycarbonyl, R2 and R3 denote hydrogen and A is in the 4-position and denotes alkenylene having 3 or 4 carbon atoms and the double bond is adjacent to the phosphono group.

Particularly preferred are those of formula III

A one-OH

ÖH (III) • ·

I I

Compounds of formula Y '*' and pharmaceutically acceptable salts thereof, wherein A represents 1,3-propenylene, wherein the double bond is preferably adjacent to a phosphono group, and R 3 · represents carboxy or pharmaceutically acceptable esterified carboxy, as defined herein.

A preferred embodiment relates to compounds of formula III wherein the 2- and 4-substituents are in the cis position relative to each other.

5 S ή 6 ό B

The invention further relates to phosphonic acid derivatives of the formula I and to the abovementioned derivatives in which the heterocyclic ring represents an optionally substituted 2-carboxy-1,2,3,4-tetrahydro- or perhydroquinolinyl, the phosphonone-containing chain being tetrahydro- or in the 3- or 4-position of the perhydroquinolinyl ring, i.e. of formula IV

A-F-OR '

, / Y <iT

Compounds or perhydro derivatives of the formula R'-4H-HI (IV) νγν and their salts, in which R and R 'independently of one another denote hydrogen, lower alkyl, benzyl or benzyl substituted in the phenyl part by halogen, lower alkyl or lower alkoxy, lower alkoxy , lower alkanoyloxymethyl substituted in the oxymethyl moiety with lower alkyl or cycloalkyl, R 1 represents carboxy or pharmaceutically acceptable esterified or amidated carboxy, R 2 represents hydrogen, lower alkyl, haloalkyl and aryl-lower alkyl or acyl, R 4 represents hydrogen; A denotes lower alkylene.

Preferred are formula V

6 b <5 6 b 3

A P-OH

AA

Compounds of formula (I) I (V) νγν or perhydroquinoline derivatives thereof, wherein A represents 1,3-propenyl and the double bond is adjacent to a phosphono group and R 1 represents carboxy or a pharmaceutically acceptable esterified carboxy as defined herein, and a salt-forming functional group thereof pharmaceutically acceptable salts of the compounds containing.

Particularly preferred are compounds of formula V wherein the 2- and 4-substituents are in the cis position relative to each other.

The invention further relates to phosphonic acid derivatives of the formula I and to the derivatives mentioned above, in which the heterocyclic ring represents an optionally substituted 2-carboxypyrrolidinyl, i. of formula VI

Compounds of formula RJ-f 4 AP —- OR '(VI) γν r and those compounds of formula VI having a double bond between the C-3 and C-4 atoms of the pyrrolidinyl ring, in which the phosphonone-containing chain is in particular 2- or 4 of the pyrrolidine ring and wherein R and R 'are independently hydrogen, lower alkyl, benzyl or benzyl substituted in the phenyl moiety by halogen, lower alkyl or lower-coke, lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted in allyl or oxymethyl represents carboxy or pharmaceutically acceptable esterified or amidated carboxy, R2 represents hydrogen, lower alkyl or acyl, R3 represents hydrogen, lower alkyl or aryl-lower alkyl and A represents lower alkenylene, and salts of these compounds.

Preference is given to those compounds of the formula VI and their pharmaceutically acceptable salts in which the phosphonone-containing group is in the 3-position, R and R1 denote hydrogen, R1 denotes carboxy or a pharmaceutically acceptable esterified carboxy, for example lower alkoxycarbonyl, Lower alkanoyloxymethoxyacetyl -C 2 -C 4 alkoxycarbonyl or pyridylmethoxycarbonyl, R 2 and R 3 denote hydrogen and A denotes 1,3-propenylene and the double bond is adjacent to the phosphono group.

The general definitions used herein have the following meanings within the scope of the invention: The term "lower" as used above and below in connection with organic groups, radicals or compounds means those having up to 7 carbon atoms, in particular up to 4 carbon atoms and preferably 1, 2 or 3 carbon atoms.

Lower alkyl preferably contains 1 to 4 carbon atoms and is, for example, ethyl, propyl, butyl or preferably methyl.

Lower alkenylene A preferably contains 2 to 4 carbon atoms and denotes e.g. ethenylene, 1,3-propenylene, 1,4-

B o 6 6 B

o but-1-enylene or 1,4-but-2-enylene, where the double bond is preferably adjacent to the phosphono group.

Lower alkoxy preferably contains 1 to 4 carbon atoms and denotes, for example, ethoxy, propoxy or, preferably, methoxy.

Lower alkanoyl preferably contains 2 to 7 carbon atoms and preferably represents acetyl, propionyl, n-butyryl, isobutyryl or pivaloyl, but may also be formyl.

Lower alkanoyloxy preferably means acetoxy, propionyloxy, n- or i-butyryloxy or pivaloyloxy.

Cycloalkyl preferably contains 3 to 8 carbon atoms and means, for example, cyclohexyl or cyclopentyl.

Halogen is especially fluorine or chlorine, but it can also be bromine or iodine.

Aroyl denotes arylcarbonyl, in particular benzoyl or benzoyl substituted by 1 to 3 substituents selected from lower alkyl, lower alkoxy, trifluoromethyl and halogen, or pyridylcarbonyl, in particular nicotinoyl.

Aroxyloxy means benzoyloxy, benzoyloxy substituted on the phenyl ring by lower alkyl, halogen or lower alkoxy, e.g. methyl, chloro or nitroxy, or nicotinoyloxy.

Aryl denotes in particular optionally substituted phenyl, e.g. phenyl or phenyl substituted by 1 to 6 substituents selected from lower alkyl, lower alkoxy, trifluoromethyl and halogen, or pyridyl, in particular 3-pyridyl.

Aryl-lower alkyl means in particular aryl-C1-C4-alkyl, where aryl has the meanings given above, preferably benzyl or 2-phenylethyl.

Acyl means carboxy-derived acyl, especially lower alkanoyl, aryl-lower alkanoyl, aroyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl, alpha-amino-lower alkanoyl or alpha-amino-aryl-lower alkanoyl.

Aryl-lower alkanoyl means in particular aryl-C 1 -C 4 -alkanoyl, preferably phenylacetyl or 3-phenylpropionyl.

Lower alkoxycarbonyl contains in particular 1 to 4 carbon atoms in the alkoxy moiety and denotes, for example, methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or, preferably, ethoxycarbonyl.

Aryl-lower alkoxycarbonyl means in particular benzyloxycarbonyl.

Alpha-amino-lower alkanoyl and alpha-aminoaryl-lower alkanoyl denote acyl groups of alpha-amino acids, e.g. alanyl, glycyl, leucyl, isoleucyl and phenylalanyl.

The N-mono-lower alkylcarbamoyl group contains in particular 1 to 4 carbon atoms in the alkyl moiety and is, for example, N-methylcarbamoyl, N-propylcarbamoyl or preferably N-ethylcarbamoyl.

The β, Ν-di-lower alkylcarbamoyl group contains in particular 1 to 4 carbon atoms in each lower alkyl moiety and denotes, for example, Ν, yy-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and preferably Ν, Ν-diethylcarbamoyl.

Di-lower alkylamino-N-lower alkylcarbamoyl is in particular di-C1-C4-alkylamino-N-C2-C4-alkylcarbamoyl, the two nitrogen atoms being separated by 2-4 carbon atoms, and denoting e.g. N- (2-diethylaminoethyl) carbamoyl or N - (3-diethylaminopropyl) carbamoyl.

Mono-lower alkylamino contains in particular 1 to 4 carbon atoms and denotes, for example, methylamino, ethylamino, n- or i-propylamino or butylamino.

The di-lower alkylamino contains in particular 1 to 4 carbon atoms in each lower alkyl group and denotes, for example, dimethylamino, diethylamino, di- (n-propyl) amino and di- (n-butyl) amino.

Di-lower alkylamino-lower alkoxycarbonyl contains in particular 2 to 4 carbon atoms in the alkoxy moiety, the oxygen and nitrogen atoms are then separated by 2 to 4 carbon atoms, and denotes, for example, Ν, Ν-diethylaminoethoxycarbonyl or N, N-diethylaminopropoxycarbonyl.

For the purposes of this invention, a pharmaceutically acceptable esterified carboxy means an esterified carboxy group R1, in particular a carboxylic acid prodrug ester which can be converted to free carboxy under physiological conditions.

Pharmaceutically acceptable esterified carboxy is, in particular, e.g. lower alkoxycarbonyl, (amino-, mono- or di-Lower-alkylalkylamino) -substituted straight-chain C2-C5-lower alkoxycarbonyl, carboxy-substituted lower alkoxycarbyl 8, 3 6 and 3 carbonyl, e.g. α-carboxy-substituted lower alkoxycarbonyl, lower alkoxycarbonyl-substituted lower alkoxycarbonyl, e.g. α-lower alkoxycarbonyl-substituted lower alkoxycarbonyl, aryl-substituted lower alkoxycarbonyloxy-substituted-alkyloxycarboxyl, e.g. unsubstituted or substituted B-unsubstituted or substituted methoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl, (lower alkanoyloxy or lower alkoxy) -substituted lower alkoxymethoxycarbonyl, bicyclo [2.2.1] heptyloxycarbonyl-haloalcarbonyloxampinyloxycarbonyl, allylcarbonyloxycarbonyl, allyl ) -substituted 3-phthalodioxycarbonyl, Alem-pialko xicarbonyloxy-lower alkoxycarbonyl, e.g. 1- (methoxy or ethoxycarbonyloxy) -ethoxycarbonyl.

The best prodrug esters are e.g. straight chain C 1 -C 4 alkyl esters, e.g. ethyl, lower alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, di-lower alkylamino straight chain C 2 -C 4 alkyl esters, e.g. 2-diethylamino , pyridylmethyl esters, e.g. 3-pyridylmethyl.

Within the scope of the invention, a pharmaceutically acceptable amidated carboxy denotes an amidated carboxy group R1, in particular a carboxylic acid amide which can be converted into free carboxy under physiological conditions.

Suitable amidated carboxy is e.g. carbamoyl, N-mono-lower alkylcarbamoyl, e.g. N-ethylcarbamoyl, N, N-di-lower alkylcarbamoyl, e.g. N, N-diethylcarbamoyl, or di-lower alkylamino-N-lower alkylcarbamoyl N- (2-diethylaminoethyl) carbamoyl or N- (3-diethylaminopropyl) carbamoyl.

i2 86 6 33

Salts of the compounds according to the invention are in particular pharmaceutically acceptable salts, on the other hand metal or ammonium salts of the compounds according to the invention containing a free phosphonium or carboxy group, in particular alkali or alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, or preferably crystallize ammonium salts derived from ammonia or organic amines such as methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris- (hydroxymethyl) aminomethane or benzyltrimethylammonium hydroxide. On the other hand, the compounds according to the invention which are basic amines form acid addition salts, in particular with pharmaceutically acceptable inorganic or organic acids, such as strong mineral acids, such as hydrohalic acids, e.g. hydrochloric acid or hydrobromic acid, sulfuric, phosphoric or nitric acid, carboxylic or sulfonic acids, e.g., acetic acid, propionic acid, we, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, ascorbic acid, Monday acid, fumaric acid, pyruvic acid, pamoahapon, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic , with p-toluenesulfonic or naphthalenesulfonic acid.

Salts which are not suitable for pharmaceutical use can be used for isolation or purification. Only pharmaceutically acceptable salts are used for therapeutic use, which are therefore preferred.

The compounds of the invention have valuable pharmacological properties, e.g., selective blockade of N-methyl-D-aspartate-sensitive amino acid stimulus receptors in mammals. The compounds can thus be used for the treatment of diseases which respond to amino acid stimulus blockade in mammals, i.e. for example for the treatment of diseases of the nervous system, in particular seizure disorders (epilepsy) and conditions of fear.

These properties can be demonstrated in in vitro or in vivo animal experiments, preferably using mammals or their tissue or enzyme preparations, e.g., mice, rats, or monkeys. These compounds can be administered enterally or parenterally, preferably orally or transdermally, but also subcutaneously, intravenously or intraperitoneally, for example in gelatin capsules or in the form of aqueous suspensions or solutions. The in vivo dose administered is about 0.01 to 100 mg / kg, especially about 0.05 to 50 mg / kg, and preferably about 0.1 to 10 mg / kg. These compounds can be administered in vitro, for example, in the form of aqueous solutions at a dose of about 10-4 to 10-8 molar concentrations.

The inhibitory effect on NMDA-type amino acid stimulator receptors is determined in vitro by measuring the inhibition of NMDA-triggered 3H-acetylcholine (3H-ACh) release from rat corpus striatum tissue according to J. Lehmann and B. Scatton, Brain Research 252, 77-89. (1982) and Nature 297, 422-424 (1982).

NMDA-type amino acid stimulant receptor antagonists act competitively against NMDA-triggered 3H-acetylcholine (3H-ACh) release from Corpus striatum tissue in the brain.

The inhibition of NMDA-triggered N-acetylcholine (3H-ACh) release from rat striatum tissue plates by a compound of the invention is expressed as the percentage of 3H-ACh release in response to a stimulus produced with 50 M NMDA. , compared to the control experiment. The experiments are in two parts, where n is at least 4 in each group. IC50 values represent the concentration of test compound required to inhibit 50% NMDA-induced 3H-ACh release.

The inhibitory effect of NMDA-type amino acid stimulus receptors can be demonstrated in mice by inhibiting NMDA-triggered seizures.

The compounds of the invention inhibit NMDA-triggered seizures in mice at i.p. doses of up to about 1.2 mg / kg.

Another indication of anticonvulsant activity is that the compounds of the invention effectively inhibit audiogenically triggered seizures in DBA / 2 mice [Chapman et al., Arzneim.-Forsch. 34, 1261 (1984)].

The effect is determined as follows: 45 minutes after administration of the compound or vehicle, the mice are individually placed in a soundproof chamber. After an adaptation time of 30 seconds, the mice are given a sound stimulus (110 dB) for 1 minute, or until a tonic-clonic seizure occurs. Control seizures consist of the initial stage of endless running. Inhibition of endless running is an indication of an anticonvulsant effect.

The test compounds are administered orally or intraperitoneally either as solutions in distilled water or as a suspension in 3% colloidal corn starch with 5% by weight of polyethylene glycol 400 and 0.34% of Tween 80 at a dose of 10 ml / kg of body weight.

is B 6 6 6 3

One indication of anxiolytic activity is the fact that the compounds of the invention are effective in a Cook / Davidson conflict model [Psychopharmacologia 3 ^, 159-168 (1969)].

Serially anti-ischemic activity, i. the effect of the compounds of the invention on preventing or reducing mammalian brain damage as a result of transient cerebral ischemia (such as stroke) can be determined using a Mongolian model of Gerbil ischemia, e.g., the model presented by T. Kirino in Brain Research 239, 57-69 (1982).

The inhibitory effect on the observed hyperactivity and neuronal degeneration in the area of cerebral edema after 5 minutes of ischemia is measured. The test compound is administered i.p. 15 minutes before ischemia or 2, 4 or 6 hours after ischemia.

The compounds of the invention administered before or after the ischemic period at 10 mg / kg i.p. inhibit Gerbil tissue ischemia-induced hyperactivity and reduce cerebral neuronal degeneration, as can be measured in the edema region.

Due to the above-mentioned advantageous properties, the compounds of the invention can be used as antagonists of the N-methyl-D-aspartate-sensitive amino acid stimulus receptor in mammals and for the treatment of such conditions as, for example, conditions of fear and convulsions.

The compounds of the invention, i.e. the above-mentioned compounds can be prepared by conventional methods, e.g., so that 16 s x'6 '3

(a) formula VII

i V · ’. (VII) 1 1 — Rl

Y

an aldehyde or ketone according to the formula wherein the symbols m and R1 and the heterocyclic ring have the meaning given in connection with formula I, however, R1 and the amino groups are in protected form, and A 'represents lower alkyl substituted by oxo and having one carbon atom less than the alkenylene group A, is condensed with a tetraester derivative of methylenediphosphonic acid, in particular a tetra-lower alkyl ester of methylenediphosphonic acid, under basic conditions and, if necessary, the protecting groups are cleaved to give a compound of formula I in which the double bond of group A is directly adjacent to T!) · (Vn)! : - &

'Y

wherein the symbols A, m and R 1 and the heterocyclic ring have the meaning given in connection with formula I and X represents reactive esterified hydroxy, is condensed with a compound capable of attaching to a phosphonic acid moiety of formula IX or X

17 8 ιλ 7 o H P --- OR ”(IX) P (R" ') j (X) 0R "where R" represents lower alkyl and R "' represents halogen or lower alkoxy, and, if necessary, the phosphonic acid derivative formed is converted into phosphonic acid or one of its as a second ester derivative, or c) in the corresponding compounds of formula XI, loTV \! Xi (xi)

B

the cyano group or optionally lower alkylated amidino group is hydrolytically modified, wherein in the formula one or both of the acidic hydroxy groups of the phosphonic acid moiety may be esterified as shown and the heterocyclic 5- or 6-membered ring may be substituted as indicated and A is as defined above and Xj is as defined above R1 above, and if desired in the obtained compound of formula I in which one or both acidic hydroxy groups of the phosphonic acid moiety are etherified as shown, the phosphonic acid group is liberated, in the obtained compound of formula I wherein R1 is esterified or amidated carboxy as shown, the carboxy group is liberated or In the obtained compound of formula I wherein R 1 represents carboxy, the carboxy group 18 h15 6 23 is esterified as shown, in the obtained compound of formula I wherein R 1 is free or esterified as carboxy, it is optionally amidated with a lower alk. from the compound of formula I obtained in which the nitrogen is substituted as shown, the N-substituent is cleaved off the heterocyclic ring of the compound which is otherwise identical to the compound of the invention; these methods are also carried out, if necessary, by temporarily protecting all interfering reactive groups and then releasing the compound of the invention formed, and / or if desired converting the formed free compound to a salt or salt formed and / or separating the resulting isomer mixture or racemate into individual isomers or racemates and / or separating the racemate into optical antipodes.

The reactive esterified hydroxy in each of the methods disclosed herein, e.g. X in a compound of formula VIII, is esterified with a strong acid, especially hydrohalic acid, e.g. , e.g. methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid. Said reactive esterified hydroxy is in particular halogen, e.g. chlorine, bromine or iodine, or aliphatically or aromatically substituted sulfonyloxy, e.g. methanesulfonyloxy, phenylsulfonyloxy or 4-methylphenylsulfonyloxy (tosyloxy).

The starting compounds and intermediates which are converted to the compounds of the invention as described herein are therefore protected from the functional groups present.

i9 8 6 6 ό 8 such as carboxy, amino (including ring NH) and hydroxy groups, if desired with conventional protecting groups conventionally used in preparative organic chemistry. Protected carboxy, amino and hydroxy groups are those that can be converted to free carboxy, amino and hydroxy groups under mild conditions without breaking the backbone of the molecule or causing undesired reactions.

The purpose of the addition of protecting groups is to protect the functional groups from undesired reactions with the reaction components and under the conditions under which the desired chemical conversion is performed. The need for protecting groups and their selection for a particular reaction is known to those skilled in the art and depends on the properties of the functional groups to be protected (carboxy group, amino group, etc.), further the structure and stability of the molecule of which the substituent is a part and reaction conditions.

Commonly known protecting groups corresponding to these conditions, as well as their attachment and removal, are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York, 1981 and also "The Peptides", Part I, Schroeder and Luebke, Academic Press, London, New York 1965 and Houben-Weyl, "Methoden der Organischen Chemie", Part 15/1, Georg Thieme Verlag, Stuttgart, 1974.

The preparation of compounds of the invention in which the double bond is adjacent to a phosphono group according to variant (a), in which an aldehyde or ketone is condensed with, for example, a lower alkyl ester of methylenediphosphonic acid, is carried out according to condensation reactions known to those skilled in the art. in an inert polar solvent, e.g. tetrahydrofuran, especially under reflux. The starting aldehydes or ketones of the formula VII can be prepared, e.g., by oxidation of the corresponding alcohols, for example with pyridinium chlorochromate, or according to another method, e.g. as described in the examples.

The alcohols in question can in turn be prepared in a manner known per se, e.g. by reducing the corresponding aromatic alcohols using methods known for the reduction of pyrrole, pyridine, indole and quinoline compounds. For example, the reduction of a pyridine or quinoline ring is carried out in particular with an organometallic reducing agent or by catalytic hydrogenation, e.g. in the presence of platinum oxide or an acidic solvent such as acetic acid, to give the corresponding tetrahydropyridines of the invention, e.g. , 2,3,4-tetrahydroquinolines or perhydroquinolines and their derivatives. Quaternary quinolinium and pyridinium compounds, e.g.

O

those in which R represents lower alkyl or aryl-lower alkyl can be reduced accordingly.

The alcohols, aldehydes or ketones thus prepared can also be converted to aldehydes or ketones of greater chain length, using conventional methods, e.g. by performing Wittig condensation of the aldehyde with methoxymethyltriphenylphosphonium chloride to give a homologous aldehyde, or by any other method known per se. which are shown, for example, in the examples.

The above-mentioned aromatic 2-carboxy-heterocyclyl-substituted lower alkanols, for example 2-carboxy-pyr- [f 'r' Ί 21 0 0 Λ ridinyl- or 2-carboxy-quinolinyl-substituted Lower alkanols or their derivatives can in turn be is prepared by treating 2-unsubstituted pyridinyl- or 2-unsubstituted quinolinyl-substituted lower alkanols in a suitably protected form with, for example, a peracid such as m-chloroperbenzoic acid to give the corresponding pyridine N-oxides or quinoline N-oxides. Condensation with a reactive cyanide, e.g. trialkylsilyl cyanide, such as trimethylsilyl cyanide, especially under basic conditions, e.g. in the presence of triethylamine, affords the corresponding 2-cyanopyridine or 2-cyanoquinoline derivatives, which are then converted to carboxy in the same manner (2-R carboxy) -substituted pyridine or quinoline derivatives.

The condensation according to process (b) is preferably used for the preparation of compounds of formula I in which the double bond of the alkenylene group A is not immediately adjacent to the phosphono group.

The target sensation of a compound of formula VII according to process b) with a compound of formula X, e.g. triethyl phosphite, is carried out, for example, by heating in an inert solvent and under conditions known for the Michaelis-Arbuzov reaction from Angew. Chem. Int. Ed. _16, 477 (1977) and Chem. Rev. 81, 415 (1981). In a similar manner, condensation with e.g. phosphorus trichloride and subsequent hydrolysis then gives a compound of formula I.

The condensation of a compound of formula VIII according to process b) with a compound of formula IX, e.g. diethylphosphonate (diethylphosphite), takes place, for example, in a strongly basic medium, e.g. alkali metal, alkali metal alkali metal hydride, e.g. sodium hydride, alkali metal , such as in the presence of potassium t-butoxide in an inert solvent such as toluene or dimethylformamide.

The starting compounds of the formula VII and their reactive derivatives can be prepared in a manner known per se, starting from intermediates of the formula VII in which A 'denotes oxo-substituted lower alkyl and the preparation of which is described above.

For example, a starting material of formula VIII wherein A represents propenylene is prepared by condensing an aldehyde of formula VII wherein group A 'represents formyl (CH = O) with a suitable Wittig reagent, e.g. formylmethylene triphenylphosphorane. The resulting unsaturated aldehyde (in which the chain is extended by 2 carbon atoms) is reduced to an alcohol, e.g. with sodium borohydride, and the resulting unsaturated alcohol is converted to a reactive derivative, e.g., bromide with triphenylphosphine / N-bromo-succinimide.

The transformations according to method c) are carried out according to generally known methods.

Groups which can be converted to R1 include, for example, carboxy groups in the form of anhydrides or acid halides, cyano, amidino groups, also cyclic amidino groups, such as 5-tetrazolyl, iminoether groups, also cyclic iminoether groups, for example dihydro-2 -oxazolinyl or dihydro-2-oxazolinyl groups substituted by lower alkyl and also hydroxymethyl, etherified hydroxymethyl, lower alkanoyloxymethyl, trialkoxymethyl, acetyl, trihaloacetyl, halomethyl, carboxycarbonyl (COCOOH), formyl (CHO), formyl (CHO) ) -alkoxymethyl, alkylenedioxymethyl or vinyl.

23 8 66 6 8

Some of the terms used in the methods have the following meanings:

Oxy-substituted lower alkyl means in particular formyl, formylmethyl, formylethyl or 2-oxopropyl.

Trialkoxymethyl means in particular tri- (lower alkoxy) methyl, in particular triethoxy or trimethoxymethyl.

Etherified hydroxymethyl means in particular lower alkoxymethyl, lower alkoxyalkoxymethyl, e.g. methoxymethoxymethyl or 2-oxa or 2-thiacycloalkoxymethyl, in particular 2-tetrahydropyranyloxymethyl.

Halomethyl is especially chloromethyl, but it can also be bromomethyl or iodomethyl.

Alkali metal means especially lithium, but it can also be potassium or sodium.

Groups that can be converted to a carboxy group R1 include esterified and amidated carboxy and are not limited to esterified or amidated carboxy, as defined herein for R1. The conversion to carboxy is usually carried out by solvolysis with an acid or a base.

Benzyloxycarbonyl or nitrobenzyloxycarbonyl can also be converted to carboxy by catalytic hydrogenation, the latter group also by means of a chemical reducing agent, e.g. sodium dithionite or zinc and a carboxylic acid. In addition, tert-butyloxycarbonyl can also be cleaved with trifluoroacetic acid.

Acetyl can be converted to carboxy by oxidation by first converting it to trihaloacetyl, e.g. tribromoacetyl or triiodoacetyl, treating e.g. with sodium hypobromite and then cleaving with e.g. an aqueous base such as sodium hydroxide.

Formyl, di- (lower) alkoxymethyl or alkylenedioxymethyl (formyl, protected in the form of an acetal), e.g. as dimethylacetal, is oxidized to carboxy with, for example, silver anitrate, pyridinium dichromate or ozone.

Vinyl can be converted to carboxy by ozonolysis to formyl, which in turn is oxidized to carboxy.

The hydrolysis of trialkoxymethyl to carboxy preferably takes place with inorganic acids, e.g. hydrogen halide or sulfuric acid. Hydrolysis of etherified hydroxymethyl to hydroxymethyl is best accomplished with solutions of inorganic acids, e.g., hydrohalic acid. Hydroxymethyl is in turn oxidized to carboxy with an oxidizing agent, e.g. pyridinium dichromate.

Halomethyl can also be converted to the corresponding carboxaldehydes, e.g. with dimethyl sulfoxide in the presence of triethylamine and silver tetrafluoroborate or with chromium trioxide and pyridine in dichloromethane.

The conversion of cyano to lower alkoxycarbonyl is preferably carried out by first treating with lower alkanol, e.g. anhydrous ethanol, in the presence of a strong acid, e.g. hydrochloric acid, preferably at reflux temperature and then hydrolysing with water.

In addition, the conversion of cyano to carbamoyl is carried out in particular by treatment with an alkali metal hydroxide, e.g. dilute sodium hydroxide and hydrogen peroxide, especially at room temperature.

25 86638

Esterified carboxy, such as lower alkoxycarbonyl, can be amidated unsubstituted, mono- or di (lower) alkylcarbamoyl with ammonia, mono- or di (lower) alkylamines, such as methylamine, dimethylamine, in an inert solvent, e.g., lower alkanol, such as lower alkanol.

Thus, the compounds of the invention can be converted into other compounds of the invention, for example by converting functional groups in a generally known manner.

Thus, for example, the conversion of carboxylic acid esters and amides into carboxylic acids is preferably carried out by hydrolysis with inorganic acids, such as hydrohalic or sulfuric acid, or aqueous alkalis, in particular alkali metal hydroxides, such as lithium or sodium hydroxide.

The free carboxylic acids can be esterified with lower alkanols, such as ethanol, in the presence of a strong acid, for example sulfuric acid, or diazo (lower) alkanes, e.g. diazomethane, in a solvent such as ethyl ether, especially at room temperature, to give the corresponding lower alkyl esters.

In addition, free carboxylic acids can be converted to compounds in which R 1 represents unsubstituted, mono- or di- (lower) alkylcarbamoyl by treating a reactive derivative thereof, e.g. an acyl halide such as an acid chloride or a mixed anhydride, e.g. , ammonia, mono- or di (lower) alkylamines, in an inert solvent such as dichloromethane, especially in the presence of a basic catalyst such as pyridine.

26 80633

Phosphonic acid esters are converted to the corresponding phosphonic acids by treatment with an acid such as aqueous hydrochloric acid or hydrobromic acid in glacial acetic acid or bromotrimethylsilane as described in J. Chem. Soc. Chem. Comm. 1979, 739. Benzyl esters can also be converted to acids by hydrogenation.

Phosphonic acids are converted to esters, e.g. optionally substituted lower alkyl esters, for example by condensation with an optionally substituted lower alkyl halide, especially in a basic anhydrous medium such as triethylamine.

In a preferred embodiment of the invention, a compound of formula II, IV and VI wherein R and R 'are Lower alkyl, benzyl or benzyl substituted on the phenyl moiety by halogen, lower alkyl or Lower alkoxy, lower alkanoyloxymethyl or lower alkanoyl onyloxymethyl substituted with lower alkyl or cycloalkyl, especially lower alkyl, R 1 represents a pharmaceutically acceptable esterified or amidated carboxy, especially lower alkoxycarbonyl, and R 2 represents an acyl, especially lower alcohol aliphatic acid, or , especially with lithium or sodium hydroxide, especially at elevated temperature, to a compound of formula II, IV or VI, wherein R and R 'represent hydrogen, R1 represents carboxy and R2 represents hydrogen.

The above reactions are carried out by standard methods, in the presence of diluents, in particular in the presence of solvents which are inert to the reaction components and their solvents, further in the presence or absence of catalysts, condensation or other substances mentioned, and / or in an inert atmosphere. temperatures, room temperature or elevated temperatures, especially at the boiling point of the solvent used and at atmospheric or superatmospheric pressure. Preferred solvents, catalysts and reaction conditions are set forth in the following illustrative examples.

The invention further relates to all variations of these processes in which an intermediate obtained at an arbitrary stage of the process is used as starting material and the missing steps are carried out, or in which the process is terminated at an arbitrary stage or in which the starting materials are formed under reaction conditions or in the form of their salts or pure antipodes.

In the main reactions mentioned, starting materials should be used which give the compounds described above as very preferred.

The invention also relates to all new starting materials and methods for their preparation.

Depending on the choice of starting materials and methods, the new compounds may exist in the form of a possible isomer or as a mixture of isomers, for example depending on the number of asymmetric carbon atoms as pure optical isomers such as antipodes or mixtures of optical isomers such as racemates or diastereoisomers or geometric isomers. Said possible isomers and mixtures thereof are also within the scope of this invention. Various specific isomers are preferred, as already mentioned above.

28 86638

Mixtures of diastereoisomers or mixtures of racemates can be separated into pure isomers, diastereoisomers, racemates or geometric isomers in a manner known from the physicochemical differences of the components, for example by chromatography and / or fractional crystallization.

The racemates formed can be separated into optical antipodes by known methods, for example by reacting the acidic end product with an optically active base which forms salts with the racemic acid and separating the salts thus obtained, for example by fractional crystallization to give diastereoisomeric acid salts. after making. The basic racemic products can likewise be separated into the optical antipodes, e.g. by separating their diastereoisomeric salts with an optically active acid and liberating the optically active basic compound by treatment with a standard base. The racemic products according to the invention can thus be separated into their optical antipodes, e.g. by fractional crystallization of d- or 1-tartrates, mandelates, camphorsulfonates or d- or 1- (α-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroin , brucine or strychnine) salts. The acidic compounds of the invention can be separated by separating diastereomeric ester or amide derivatives prepared from an optically active alcohol or amine and liberating the separated optically active compound. Preferably, the more active antipode is separated.

Finally, the compounds of the invention are obtained either in free form or as salts. Each base formed may be converted into the corresponding acid addition salt, in particular by the use of a therapeutically useful acid or anion exchange preparation, or the corresponding salts may be converted into the corresponding free bases, for example by using a stronger base such as a metal or ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchange preparation or an alkylene oxide, such as propylene oxide. Thus, a compound of the invention containing a free carboxylic or phosphonic acid group can be converted to the corresponding metal or ammonium salts. These or other salts, for example picrates, can also be used to purify the resulting bases. The bases can be converted to salts, the salts separated and the bases released from the salts.

Due to the close relationship between the free compounds and the compounds in the form of their salts, it is meant, if the compound is mentioned in this context, also the corresponding salt, provided that this is possible or appropriate in the circumstances in question.

The compounds as well as their salts can also be obtained in the form of their hydrates or contain other solvents used for their crystallization.

The pharmaceutical preparations containing the compounds of this invention are intended for administration to mammals, including humans, enterally, i.e. for example orally or rectally, transdermally and parenterally, to block the N-methyl-Daspartate-sensitive amino acid stimulator receptor and to treat diseases which react with N-methyl -sensitive amino acid stimulus receptor blockade, i.e., for the treatment of, for example, cerebral ischemia, convulsive diseases, and fear conditions, and contain an effective amount of a pharmacologically active compound of this invention

30 B 6 6 6 B

alone or in combination with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds according to the invention are suitable for the preparation of pharmaceutical preparations containing an effective amount of the active compound and carriers suitable for enteral or parenteral use. Preference is given to tablets and gelatin capsules which contain the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, b) lubricants, e.g. silica, talc, stearic acid, its with magnesium or calcium salts and / or polyethylene glycol. The tablets may likewise contain c) binders, e.g. magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired d) disintegrants, e.g. starch, agar or agar, algin, agar, algin, ) adsorbents, colorants, flavors and sweeteners. Formulations for injection are preferably isotonic aqueous solutions or suspensions, and suppositories are preferably prepared from fat emulsions or suspensions. These preparations may be sterilized and / or may contain adjuvants, e.g. preservatives, stabilizers, wetting and / or emulsifying agents, solubilizing agents, salts for regulating the osmotic pressure and / or buffers. In addition to this, they may also contain other therapeutically valuable substances. These preparations are prepared by conventional mixing, granulating and coating methods and contain from about 0.1 to 75%, in particular from about 1 to 50%, of active ingredient.

Formulations suitable for transdermal use contain an effective amount of a compound of formula I with the carrier 3ΐ 0όβο8. Preferred carriers are absorbent pharmacologically acceptable solvents that support the passage of the host through the skin. Typically, transdermal systems are in the form of a patch with a protective layer, a layer of active agent and possible carriers, possibly a flow rate control device that delivers the active agent to the skin of the host in a controlled and predetermined amount over a long period of time, and excipients.

The compounds of the invention may be used in a method of blocking the N-methyl-D-aspartate-sensitive amino acid stimulus receptor in mammals and blocking mammalian diseases, e.g. , wherein an effective amount of a compound of the invention is used as a pharmacologically active substance, in particular in the form of the above-mentioned pharmaceutical preparations.

Particularly preferred is a method of treating cerebral ischemia and preventing brain damage resulting from cerebral ischemia (paralysis) in a mammal, which method is characterized by administering to the mammal an effective amount of a N-methyl-D-aspartate blocking compound of the invention or a pharmaceutical composition containing such a compound.

The dosage of the active compound depends on the species, weight, age, individual condition and route of administration of the warm-blooded (mammalian).

A unit dose for a mammal weighing about 50 to 70 kg may contain about 5 to 100 mg of active ingredient.

32 Bo 063

The following examples illustrate the invention without, however, limiting it in any way. Temperatures are shown in degrees Celsius. Unless otherwise indicated, all evaporations are carried out under reduced pressure, especially at about 2-13 kPa.

Example 1: 4- [1- (3-Diethylphosphonoprop-2-enyl)] - 1-tert-butoxycarbonylpiperidine-2-carboxylic acid ethyl ester is hydrolyzed with 6N hydrochloric acid. There is thus obtained 4- [1- (3-phosphonoprop-2-enyl)] - piperidine-2-carboxylic acid.

The starting material is prepared as follows: 4- (2-hydroxyethyl) pyridine is oxidized to 4- (2-hydroxyethyl) pyridine N-oxide, which in turn is treated with trimethylsilyl cyanide to give 4- (2-hydroxyethyl) -2-cyanopyridine. This is converted to 4- (2-hydroxyethyl) -2-pyridinecarboxylic acid ethyl ester and then hydrogenated to 4- (2-hydroxyethyl) -piperidine-2-carboxylic acid ethyl ester.

A solution of 2.01 g of 4- (2-hydroxyethyl) -piperidine-2-carboxylic acid ethyl ester in 5 ml of dichloromethane is added to a solution of 2.20 g of di-tert-butyl dicarbonate in 10 ml of dichloromethane. Allow to stand for 10 minutes, then remove the solvent and flash the residue with a 1: 1 mixture of hexane and ethyl acetate.

There is thus obtained 4- (2-hydroxyethyl) -1-tert-butoxycarbonyl-lipiperidine-2-carboxylic acid ethyl ester.

To a solution of 1.56 g of dimethyl sulfoxide in 10 ml of dichloromethane is added 2.2 g of oxalyl chloride at -78 °. After 20 minutes, 2.4 g of 4- (2-hydroxyethyl) -1-tert-butoxycarbonylpiperidine-2-carboxylic acid-3'-acid-ethyl ester in 5 ml of dichloromethane are added. The batch is stirred for one hour and 2.2 g of triethylamine are added. The ice bath is removed, the solvent is removed and the residue is flash chromatographed with hexane / ethyl acetate (7: 3). There is thus obtained 1-tert-butoxycarbonylpiperidine-2-ethoxycarbonyl-4-acetaldehyde.

At -78 °, 2.73 ml of m-butyllithium are added to 2.02 g of bis (diethylphosphono) methane in 20 ml of anhydrous tetrahydrofuran. After 5 minutes, 2.08 g of 1-tert-butoxycarbonylpiperidine-2-ethoxycarbonyl-4-acetaldehyde in 5 ml of tetrahydrofuran are added. The mixture is then heated to reflux for 16 hours. The cooled batch is evaporated and flash chromatographed (95: 5 dichloromethane / methanol). There is thus obtained 4- [1- (3-diethylphosphonoprop-2-enyl)] - 1-tert-butoxycarbonylpiperidine-2-carboxylic acid ethyl ester.

Example 2: The following compounds can be prepared according to the methods set forth in the above example in general form: (a) trans-3- [1- (4-phosphonobut-3-enyl)] - pyrrolidine-2-carboxylic acid, (b) trans-3- [1- (4-phosphonobut-2-enyl)] - pyrrolidine-2-carboxylic acid.

The starting material of compound (a) can be prepared as follows:

Trans-N-ethoxycarbonyl-pyrrolidine-2-ethoxycarbonyl-3-acetaldehyde is condensed with (CgH5) 3P = CHOCH3 under Wit-tig reaction conditions to give trans-N-ethoxycarbonyl-pyrrolidine-2-ethoxycarbonyl-3 -propionial-aldehyde. Condensation with bis (diethylphosphono) methane under the above conditions (cf. e.g. 1) affords trans-3- [1- (4-diethylphosphonobut-3-enyl)] pyrrolidine-2-carboxylic acid ethyl ester.

34 8 6 6 53

The starting material of compound (b) can be prepared as follows:

The alcohol trans-N-ethoxycarbonyl-3- (2-hydroxyethyl) -pyrrolidine-2-carboxylic acid ethyl ester is oxidized to the aldehyde trans-N-ethoxycarbonylpyrrolidine-2-ethoxycarbonyl-3-acetaldehyde condensed with triphenylphosphoraldehyde . The resulting α, β-unsaturated C4 aldehyde is reduced to the corresponding alcohol, which is converted to the bromide. Condensation with triethyl phosphite yields 3- [1- (4-diethylphosphonobut-2-enyl)] pyrrolidine-2-carboxylic acid ethyl ester.

Example 3: 4- [1- (3-Phosphonoprop-1-enyl)] piperidine-2-carboxylic acid can be prepared in a similar manner using 4-hydroxymethyl-N-ethoxycarbonylpiperidine-2-carboxylic acid ethyl ester as an intermediate.

Example 4: At -78e, 20.3 ml of butyllithium (1.64 M) are added to 8.5 ml of tetraethylmethylene diphosphonate [bis (diethylphosphono) methane] in 100 ml of anhydrous tetrahydrofuran. After 5 minutes, 9.26 g of 1- (tert-butoxycarbonyl) -2-ethoxycarbonylpiperidine-4-acetaldehyde in 125 ml of anhydrous tetrahydrofuran are added. The mixture is heated at reflux for 18 hours, cooled, evaporated and purified by flash chromatography using ethyl acetate / hexane (75:25 -9: 1). There is thus obtained 4- [1- (3-diethylphosphonoprop-2-enyl)] - 1- (tert-butoxycarbonyl) -piperidine-2-carboxylic acid ethyl ester.

The starting material is prepared as follows:

A solution of 4-pyridylacetic acid in 500 ml of anhydrous ethanol and containing 75 ml of concentrated sulfuric acid is heated to reflux for 18 hours. The solution is cooled to 0 ° and neutralized by the addition of sodium hydroxide solution and saturated aqueous sodium bicarbonate solution. Extract with ethyl acetate and evaporate in vacuo to give 4-pyridylacetic acid ethyl ester.

A solution of 23.8 g of 4-pyridylacetic acid ethyl ester in 100 ml of anhydrous tetrahydrofuran is added dropwise under a nitrogen atmosphere to 5.5 g of lithium aluminum hydride in 150 ml of anhydrous tetrahydrofuran. The mixture is heated to 50 ° (bath temperature) within 40 minutes, then cooled in an ice bath. Excess lithium aluminum hydride is decomposed by adding 6.6 ml of water and then 6.6 ml of 15% aqueous sodium hydroxide and 20 ml of water. The solid is filtered off and the filtrate is evaporated in vacuo to give 4-pyridylethanol.

A solution of 16.3 g of 4-pyridylethanol, 21.8 g of chloro-tert-butyldimethylslanane and 10.9 g of imidazole in 150 ml of dimethylformamide is stirred for 1 hour at room temperature. The product is isolated by extraction with ethyl acetate / hexane (1: 1) and washed 4 times with 400 ml of water. The extract is filtered through silica gel and evaporated in vacuo. This gives 4- (tert-butyl-dimethylsilyloxy-ethyl) -pyridine.

To a stirred solution of 28.8 g of 4- (tert-butyl-dimethylsilyloxyethyl) -pyridine in 300 ml of dichloromethane is added 24 g of m-chloroperbenzoic acid. After 4 hours, the solution is washed with aqueous sodium carbonate solution, then with water. The solution is dried over sodium sulfate, filtered and evaporated in vacuo. There is thus obtained 4- (tert-butyl-dimethylsilyloxyethyl) -pyridine N-oxide.

36 86638

A solution of 28.6 g of 4- (tert-butyl-dimethylsilyloxyethyl) -pyridine N-oxide, 60.3 ml of trimethylsilylcyanide and 31.5 ml of triethylamine is heated and stirred under nitrogen for 3 hours under reflux. . The dark solution is cooled in an ice bath, 30 ml of ethanol are added, then 400 ml of ethyl acetate and 200 ml of hexane. The solution is washed twice with 150 ml of water, dried over sodium sulfate, filtered, evaporated in vacuo and purified by flash chromatography using ethyl acetate / hexane (1:10). This gives 4- (tert-butyl-dimethylsilyloxyethyl) -2-cyanopyridine.

A solution of 22.2 g of 4- (tert-butyl-dimethylsilyloxyethyl) -2-cyanopyridine in 220 ml of anhydrous ethanol and 0.19 g of sodium is stirred for 24 hours at room temperature. The solution is then cooled to 0e and 22 ml of 6N hydrochloric acid are added. The solution is stirred for 16 hours at room temperature, cooled to 0e, 7.5 ml of 6N sodium hydroxide are added, then 75 ml of saturated aqueous sodium bicarbonate. Extract with dichloromethane and flash chromatograph using ethyl acetate / hexane to give 4- (2-hydroxyethyl) -pyridine-2-carboxylic acid ethyl ester.

A mixture of 8.37 g of 4- (2-hydroxyethyl) pyridine-2-carboxylic acid ethyl ester in 130 ml of acetic acid and 4 g of platinum oxide is hydrogenated at 345 kPa. Filter, evaporate in vacuo, neutralize with potassium carbonate and extract with dichloromethane to give an oil which is purified by flash chromatography using dichloromethane / methanol saturated with ammonia (20: 1). There is thus obtained 4- (2-hydroxyethyl) -piperidine-2-carboxylic acid ethyl ester.

A solution of 7.9 g of 4- (2-hydroxyethyl) -piperidine-2-carboxylic acid ethyl ester and 9.0 g of di-tert-butyl dicarbonate in 80 ml of dichloromethane is stirred for 2 hours at room temperature and then evaporated in vacuo. There is thus obtained 1- (tert-butoxycarbonyl) -4- (2-hydroxyethyl) -piperidine-2-carboxylic acid ethyl ester.

A solution of 11.8 g of 1- (tert-butoxycarbonyl) -4- (2-hydroxyethyl) -piperidine-2-carboxylic acid ethyl ester and 12.6 g of pyridinium chlorochromate in 175 ml of dichloromethane is stirred under a nitrogen atmosphere at room temperature for 80 minutes. . The mixture is filtered and purified by flash chromatography using ethyl acetate / hexane (25:75). There is thus obtained 1- (tert-butoxycarbonyl) -2-ethoxycarbonylpiperidine-4-acetaldehyde.

Example 5: A mixture of 4.67 g of 4- [1- (3-diethylphosphonoprop-2-enyl) -1-1- (tert-butoxycarbonyl) -piperidine-2-carboxylic acid ethyl ester and 75 ml of 6N hydrochloric acid, heated at reflux for 12 hours. The residue is taken up in 50 ml of ethanol and 3.8 ml of propylene oxide are added. The separating solid is filtered off and dried in vacuo. There is thus obtained cis-4- [1- (3-phosphono-prop-2-enyl)] - piperidine-2-carboxylic acid, m.p. 163-165 °.

Example 6: At -78 °, 6.9 ml of butyllithium (1.6 M) are added to 2.9 ml of tetraethyl methylene diphosphonate in 30 ml of anhydrous tetrahydrofuran. After 5 minutes, 2.47 g of trans-1-acetylpiperidine-2-ethoxycarbonyl-4-acetaldehyde in 55 ml of anhydrous tetrahydrofuran are added. The mixture is heated at reflux for 18 hours, cooled, evaporated and purified by flash chromatography using dichloromethane / ethanol (100: 3).

There is thus obtained trans-4- [1- (3-diethylphosphonoprop-2-enyl)] - 1-acetyl-piperidine-2-carboxylic acid ethyl ester.

The starting material is prepared as follows: At 38 ° C, 9.4 ml of acetic anhydride are added to a stirred solution of 13.5 g of 4- (2-hydroxyethyl) -piperidine-2-carboxylic acid ethyl ester in 75 ml of pyridine. Stir at room temperature for 30 minutes and then evaporate the solution in vacuo and add ethyl acetate (300 ml). The solution is washed twice with 2N hydrochloric acid, once with water and once with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is taken up in 100 ml of ethanol, 5 g of powdered potassium carbonate are added and the mixture is stirred for 1 hour at room temperature. The solution is filtered, evaporated in vacuo and purified by flash chromatography using dichloromethane / methanol (95: 5). There is thus obtained trans-1-acetyl-4- (2-hydroxyethyl) -piperidine-2-carboxylic acid ethyl ester.

A mixture of 3.7 g of trans-1-acetyl-4- (2-hydroxyethyl) -piperidine-2-carboxylic acid ethyl ester and 5.4 g of pyridinium chlorochromate in 75 ml of dichloromethane is stirred under a nitrogen atmosphere for 2 hours. The mixture is filtered and purified by flash chromatography using ethyl acetate / hexane (7: 3 to 8: 2). This gives trans-1-acetylpiperidine-2-ethoxycarbonyl-4-acetaldehyde.

Example 7: A mixture of 2.5 g of 4- [1- (3-diethylphosphonoprop-2-enyl)] - 1-acetylpiperidine-2-carboxylic acid ethyl ester and 40 ml of 6N hydrochloric acid is heated under reflux for 12 hours. The solution is evaporated to dryness in vacuo. The residue is taken up in 20 ml of ethanol and then 2.3 ml of propylene oxide are added. The separating solid is filtered off and dried in vacuo. There is thus obtained trans-4- [1- (3-phosphonoprop-2-enyl)] piperidine-2-carboxylic acid, m.p. 132-140 °.

39 86 638

Example 8: A solution of 0.334 g of trans-4- [1- (3-bromo-miprop-1-enyl)] - 1- (tert-butoxycarbonyl) -piperidine-2-carboxylic acid ethyl ester and 3.5 ml of triethylphosphite , is heated under nitrogen for 70 minutes at reflux. The cooled solution is evaporated in vacuo and purified by flash chromatography using dichloromethane / methanol (100: 3). There is thus obtained trans-4- [1- (3-diethylphosphonoprop-1-enyl)] - 1- (tert-butoxycarbonyl) -piperidine-2-carboxylic acid ethyl ester.

The starting material is prepared as follows:

A solution of 20 g of 4-pyridylcarbinol, 28.9 g of chloro-tert-butyldimethylsilane and 14.4 g of imidazole in 200 ml of dimethylformamide is stirred for 3 hours at room temperature. The product is isolated by extraction with ethyl acetate / hexane (1: 1) and the extract is washed 4 times with 400 ml of water. The solution is filtered through silica gel and evaporated in vacuo. This gives 4- (tert-butyl-dimethylsilyloxymethyl) pyridine.

A solution of 40.6 g of 4- (tert-butyl-dimethylsilyloxymethyl) pyridine and 40 g of m-chloroperbenzoic acid in 500 ml of dichloromethane is stirred for 16 hours at room temperature. The solution is washed with 2N sodium hydroxide and water, dried over sodium sulfate, filtered and evaporated in vacuo. This gives 4- (tert-butyldimethylsilyloxymethyl) pyridine N-oxide.

A solution of 37.9 g of 4- (tert-butyldimethylsilyloxymethyl) pyridine N-oxide, 84 ml of trimethylsilyl cyanide and 44 ml of triethylamine is heated and stirred under nitrogen for 2 1/2 hours under reflux. The dark solution is cooled in an ice bath, then 40 ml of ethanol are added, followed by 500 ml of ethyl acetate. The solution is washed twice with water, dried over sodium sulfate, filtered, evaporated in vacuo and purified by flash chromatography using ethyl acetate / hexane (1:10). There is thus obtained 4- (tert-butyl-dimethylsilyloxymethyl) -2-cyanopyridine.

A solution of 21.7 g of 4- (tert-butyl-dimethylsilyloxymethyl) -2-cyanopyridine in 220 ml of anhydrous ethanol and 0.2 g of sodium is stirred at room temperature for 18 hours, cooled to 0e, then 22 ml of 6N hydrochloric acid. The solution is stirred at room temperature for 18 hours, cooled to 0 °, 7.5 ml of 6N sodium hydroxide are added, then 20 ml of saturated aqueous sodium carbonate solution. Extract with dichloromethane, dry, filter and evaporate the extract to give an oil which crystallizes from ether. There is thus obtained 4- (hydroxymethyl) pyridine-2-carboxylic acid ethyl ester.

A mixture of 13.9 g of 4- (hydroxymethyl) pyridine-2-carboxylic acid ethyl ester and 5 g of platinum oxide in 250 ml of acetic acid is hydrogenated at 344 kPa. Filter, evaporate in vacuo and neutralize with potassium carbonate in dichloromethane to give an oil which is purified using ammonia saturated dichloromethane / methanol (20: 1). There is thus obtained 4- (hydroxymethyl) piperidine-2-carboxylic acid ethyl ester.

A solution of 5.16 g of 4- (hydroxymethyl) piperidine-2-carboxylic acid ethyl ester and 6.33 g of di-tert-butyl carbonate in 100 ml of dichloromethane is stirred at room temperature for 18 hours. The solution is evaporated in vacuo to give 1- (tert-butoxycarbonyl) -4- (hydroxymethyl) -piperidine-2-carboxylic acid ethyl ester.

A solution of 7.9 g of 1- (tert-butoxycarbonyl) -4- (hydroxymethyl) -piperidine-2-carboxylic acid ethyl ester 41 80638 and 9.9 g of pyridinium chlorochromate in 175 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is filtered and purified by flash chromatography using ethyl acetate / hexane (25:75). There is thus obtained 1- (tert-butoxycarbonyl) -2-ethoxycarbonylpiperidine-2-carboxaldehyde.

A solution of 1 g of 1- (tert-butoxycarbonyl) -2-ethoxycarbonylpiperidine-4-carboxaldehyde and 2 g of formylmethylene triphenylphosphorane in 16 ml of toluene is heated to 100 ° (bath temperature) over 2 hours. The solution is cooled and purified by flash chromatography using ethyl acetate / hexane (25:75). There is thus obtained 1- (tert-butoxycarbonyl) -2-ethoxycarbonylpiperidine-4-acrylicaldehyde.

A solution of 0.83 g of 1- (tert-butoxycarbonyl) -2-ethoxycarbonylpiperidine-4-acryaldehyde and 0.11 g of sodium borohydride in 8 ml of ethanol is stirred at 0 ° for 30 minutes. 0.2 ml of ethyl acetate are added, then ice-cold water and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate, filtered and evaporated in vacuo. Purify by flash chromatography using ethyl acetate / hexane (25:75) to give trans-1- (tert-butoxycarbonyl) -4- [1- (3-hydroxy-prop-1-enyl)] -piperidine-2-carboxylic acid ethyl ester.

A solution of 0.367 g of trans-1- (tert-butoxycarbonyl) -4- [1- (3-hydroxyprop-1-enyl)] piperidine-2-carboxylic acid ethyl ester, 0.35 g of triphenylphosphine and 0.23 g bromosuccinimide in 8 ml of dichloromethane, stirred first at 0e and then at room temperature for 40 minutes. Purify by flash chromatography using ethyl acetate / hexane (1: 9) to give trans-42 86638 4- [1- (3-bromoprop-1-enyl)] - 1- (tert-butoxycarbonyl) -piperidine-2- carboxylic acid ethyl ester.

Example 9: A solution of 0.39 g of trans-4- [1- (3-diethylphosphonoprop-1-enyl)] - 1- (tert-butoxycarbonyl) -piperidine-2-carboxylic acid ethyl ester and 2.3 ml of tri -fluoroacetic acid in 8 ml of dichloromethane, stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution is added and the mixture is extracted with dichloromethane. Purify by flash chromatography using ammonia saturated dichloromethane / methanol (20: 1) to give trans-4- [1- (3-diethyl-phosphonoprop-1-enyl)] - piperidine-2-carboxylic acid ethyl ester.

Example 10: A solution of 0.265 g of trans-4- [1- (3-diethylphosphonoprop-1-enyl)] piperidine-2-carboxylic acid ethyl ester in 5 ml of anhydrous ethanol and 0.074 ml of butyllithium (1.6 ml). M), heated to 80® (bath temperature) within 72 hours. After cooling, 0.025 ml of acetic acid are added, followed by additional saturated sodium bicarbonate solution and the mixture is extracted with dichloromethane. Evaporate the dichloromethane extract in vacuo to give an oil. It is purified by flash chromatography using ammonia-saturated dichloromethane / isopropanol (20: 1) to give cis-4- [1- (3-diethyl-phosphonoprop-1-enyl)] - piperidine-2-carboxylic acid ethyl ester.

Example 11: a) A mixture of 0.142 g of cis-4- [1- (3-diethylphosphono-prop-1-enyl)] - piperidine-2-carboxylic acid ethyl ester and 2.5 ml of 6N hydrochloric acid is heated for 12 hours. reflux. The solution is evaporated to dryness in vacuo. The residue is taken up in 2 ml of ethanol and then 0.15 43 8 o 6 33 ml of propylene oxide are added. The separating solid is filtered off and dried in vacuo. There is thus obtained cis-4- [1- (3-phosphono-prop-1-enyl)] - piperidine-2-carboxylic acid, m.p. 175 ° (dec.).

b) In a similar manner, hydrolysis of the trans ester of Example 9 gives the corresponding trans acid, m.p. 130-135 °.

c) A solution of cis-4- [1- (3-phosphonoprop-1-enyl)] - piperidine-2-carboxylic acid in ethanol saturated with hydrogen chloride is heated at reflux overnight. The solvent is removed in vacuo. A solution of the residue in ethanol is treated with propylene oxide and evaporated to dryness. There is thus obtained cis-4- [1- (3-phosphonoprop-1-enyl)] piperidine-2-carboxylic acid ethyl ester.

Example 12: To a solution of 0.234 g of trans-1-ethoxycarbonyl-2-ethoxycarbonyl-pyrrolidine-3-propionaldehyde in 5 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere cooled to -78 ° is slowly added a solution of 0.23 ml of tetraethyl methylene diphosphonate and 0.57 ml of butyllithium (1.6 M) in 5 ml of anhydrous tetrahydrofuran, also at -78 °. The solution is heated at reflux for 14 hours, cooled and treated with 0.15 ml of acetic acid. The batch is evaporated, diluted with water and extracted with dichloromethane. The extract is dried over sodium sulfate, filtered and evaporated. Purify by flash chromatography using ethyl acetate to give trans-1-ethoxycarbonyl-3- [1- (4-diethylphosphonobut-3-enyl)] pyrrolidine-2-carboxylic acid ethyl ester.

The starting material is prepared as follows: 44 8 6 638

A mixture of 50 g of N- (2-cyanoethyl) glycine in 300 ml of ethanol saturated with hydrogen chloride gas is stirred for 1 hour at room temperature, then heated under reflux for 1 hour. After cooling, the solid is filtered off and the filtrate is neutralized with sodium bicarbonate, filtered again and evaporated. This gives N- (ethoxycarbonylmethyl) -alanine ethyl ester.

To a mixture of 49 g of N- (ethoxycarbonylmethyl) -alanine ethyl ester and 30 ml of water cooled to -10e is added dropwise 27.6 ml of ethyl chloroformate, followed by a solution of 12.7 g of sodium carbonate. in ml of water. The mixture is warmed to room temperature, then heated to 55 ° over 50 minutes. The mixture is cooled, extracted with toluene and the extract is washed with 2N hydrochloric acid and water. The extract is dried over sodium sulfate, filtered, evaporated and distilled in vacuo. There is thus obtained N- (ethoxycarbonylmethyl) -N- (ethoxycarbonyl) -alanine ethyl ester.

A solution of 53.9 g of N- (ethoxycarbonylmethyl) -N- (ethoxycarbonyl) -alanine ethyl ester in 200 ml of toluene is added dropwise to a stirred solution of potassium hexamethyldisilazide (429 ml, 0.653 M) in 125 ml of toluene under a nitrogen atmosphere. and cooled to 0 °. Hold for 45 min. At 0 ° and then 21.6 ml of acetic acid and then a solution of 100 g of sodium phosphate (monobasic) in 1 l of water are added. The phases are separated, the organic phase is washed with buffer (pH = 7), dried over sodium sulfate, filtered, evaporated and purified by flash chromatography using ethyl acetate / hexane (3: 7). There is thus obtained 1-ethoxycarbonyl-3-oxopyrrolidine-2-carboxylic acid ethyl ester.

45 80638

To a stirred suspension of 24 g of benzyloxycarbonylmethyltriphenylphosphonium bromide in 225 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere and cooled to 0 ° is added 73 ml of potassium hexamethyldisilazide (0.625 M). After 10 minutes, a solution of 11 g of 1-ethoxycarbonyl-3-oxo-pyrrolidine-2-carboxylic acid ethyl ester in 50 ml of tetrahydrofuran is added and the mixture is heated under reflux for 2 1/2 hours. After cooling, the mixture is filtered and evaporated in vacuo. The residue is taken up in ethyl acetate, washed with water, dried over sodium sulfate, filtered, evaporated and purified by flash chromatography using ethyl acetate / hexane (1: 4). This gives an oil which is hydrogenated in 200 ml of ethanol with 5 g of 10% palladium on carbon. Thus, after filtration and evaporation of the filtrate, 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetic acid is obtained.

A solution of 10 g of 1-ethoxycarbonyl-2-ethoxycarbonyl-lipyrrolidine-3-acetic acid in 50 ml of tetrahydrofuran is cooled to 0 ° and then 55 ml of borane / tetrahydrofuran (1 M) are added dropwise. Stir for 2 hours at 0 ° and then add 20 ml of water, extract the mixture with ethyl acetate, wash twice with water and dry over sodium sulfate. The solution is filtered, evaporated and purified by flash chromatography using ethyl acetate / hexane (1: 1 to 7: 3). There is thus obtained cis-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol.

A solution of 6 g of cis-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol in 75 ml of dichloromethane and 7.3 ml of diisopropylethylamine to which 5.1 ml of 85% benzyloxymethyl chloride has been added is stirred. 3 1/2 hours at room temperature. The solution is washed with water and saturated aqueous sodium bicarbonate solution. The solution is then dried over sodium sulfate, filtered, evaporated and purified by flash chromatography using ethyl acetate / hexane (1: 4). There is thus obtained cis-1-ethoxycarbonyl-3- [2- (benzyloxymethoxy) ethyl] pyrrolidine-2-carboxylic acid ethyl ester.

A solution of 6.2 g of cis-1-ethoxycarbonyl-3- [2- (benzyloxymethoxy) ethyl] pyrrolidine-2-carboxylic acid ethyl ester in 75 ml of anhydrous ethanol and 1 ml of butyllithium (1.6 M ) is heated under reflux under nitrogen for 6 days. After cooling, 1.7 ml of 1N hydrochloric acid are added, the solution is evaporated in vacuo, cold water is added and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, evaporated and purified by high pressure liquid chromatography using ethyl acetate / hexane (15:85). There is thus obtained trans-1-ethoxycarbonyl-3- [2- (benzyloxymethoxy) -ethyl] -pyrrolidine-2-carboxylic acid ethyl ester.

A mixture of 1.64 g of trans-1-ethoxycarbonyl-3- [2- (Benzyloxymethoxy) -ethyl] -pyrrolidine-2-carboxylic acid ethyl ester and 2 g of 10% palladium on carbon in 35 ml acetic acid, hydrogenated at 310 kPa. The mixture is filtered, evaporated in vacuo and purified by flash chromatography using ethyl acetate / hexane (6: 4 to 7: 3). There is thus obtained trans-1-ethoxycarbonyl-2-ethoxycarbonyl-pyrrolidine-3-ethanol.

A solution of 0.991 g of trans-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol and 1.24 g of pyridinium chlorochromate in 20 ml of dichloromethane is stirred under a nitrogen atmosphere for 4 hours. The mixture is filtered and purified by flash chromatography using ethyl acetate / hexane (1: 1). There is thus obtained trans-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde.

47 b 6 6 3 8 To 0.4 g of trans-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde in 5 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere, cooled to -78 °, is added dropwise a solution of 1.17 g of methoxymethyl-triphenylphosphonium chloride in 15 ml of anhydrous tetrahydrofuran and 1.55 ml of potassium tert-butoxide / tetrahydrofuran (1.6 M). The solution is stirred at room temperature for 4 hours. 11 ml of 2N hydrochloric acid are added and the mixture is stirred for 45 minutes. The solution is evaporated and then extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, evaporated and the residue is purified by flash chromatography using ethyl acetate / hexane (1: 5 to 3: 7). There is thus obtained trans-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-propionaldehyde.

Example 13: A mixture of 0.193 g of trans-1-ethoxycarbonyl-3- [1- (4-diethylphosphonobut-3-enyl)] pyrrolidine-2-carboxylic acid ethyl ester and 4 ml of concentrated hydrochloric acid is heated for 16 hours. reflux. The solution is cooled and evaporated to dryness in vacuo. The separating solid is filtered off and dried in vacuo. There is thus obtained trans-3- [1- (4-phosphonobut-3-enyl)] pyrrolidine-2-carboxylic acid, m.p. 110-115 ° (dec.).

Example 14: To a solution of 0.426 g of cis-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-propionaldehyde under a nitrogen atmosphere and cooled to -78 ° is slowly added a solution of 0.45 ml of tetraethyl methylene phosphide. 1.06 ml of butyllithium (1.6 M) in 10 ml of anhydrous tetrahydrofuran, also at -78 °. The solution is heated to reflux for 14 hours, cooled and 0.3 ml of acetic acid are added. The batch is evaporated, water is added and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, evaporated and purified by flash chromatography using ethyl acetate. There is thus obtained cis-1-ethoxycarbonyl-3- [1- (4-diethylphosphonobut-3-enyl}] pyrrolidine-2-carboxylic acid ethyl ester.

The starting material is prepared as follows:

A solution of 0.908 g of cis-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol and 1.14 g of pyridinium chlorochromate in 20 ml of dichloromethane is stirred for 4 hours under a nitrogen atmosphere. The mixture is filtered and purified by flash chromatography using ethyl acetate / hexane (1: 1). There is thus obtained cis-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde.

To 0.663 g of cis-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde in 10 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere, cooled to -78 °, is added dropwise a solution of 2.21 g of methoxymethyltriphenylphosphonium chloride in ml of anhydrous tetrahydrofuran and 2.6 ml of potassium tert-butoxide / tetrahydrofuran (1.6 M). The solution is stirred for 4 hours at room temperature. 15 ml of 2N hydrochloric acid are added and the mixture is stirred for 45 minutes. The solution is evaporated and then extracted with dichloromethane. The extract is dried over sodium sulfate, filtered and evaporated. Purify by flash chromatography using ethyl acetate / hexane (1: 5 to 3: 7). There is thus obtained cis-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-propionaldehyde.

Example 15: A mixture of 0.176 g of cis-1-ethoxycarbonyl-3- [1- (4-diethylphosphonobut-3-enyl)] pyrrolidine-2-carboxylic acid ethyl ester and 3.5 ml of concentrated hydrochloric acid is heated for 18 hours. reflux. The solution is evaporated to dryness in vacuo, the residue is taken up in 1.5 ml of isopropanol / methanol (5: 1) and 0.2 ml of 49 8 6 6 o 8 propylene oxide are added. The separating solid is filtered off and dried in vacuo. There is thus obtained cis-3- [1- (4-phosphonobut-3-enyl)] pyrrolidine-2-carboxylic acid, m.p. 132-140 °.

Example 16: A solution of 0.0665 g of trans-1-ethoxycarbonyl-3- [1- (4-bromobut-2-enyl)] pyrrolidine-2-carboxylic acid ethyl ester in 0.75 ml of triethyl phosphite, heated to reflux for 20 minutes. The solution is evaporated in vacuo and the residue is purified by flash chromatography using dichloromethane / ethanol (30: 1). There is thus obtained trans-1-ethoxycarbonyl-3- [1- (4-diethylphosphonobut-2-enyl)] pyrrolidine-2-carboxylic acid ethyl ester.

The starting material is prepared as follows:

A solution of 0.225 g of trans-1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde and 0.4 g of (formylmethylene) triphenylphosphorane in 2 ml of dichloromethane is heated under reflux for 44 hours.

The solution is evaporated and the residue is purified by flash chromatography using ethyl acetate / hexane (2: 3). There is thus obtained trans-1-ethoxycarbonyl-3- [1- (4-oxobut-2-enyl)] pyrrolidine-2-carboxylic acid ethyl ester.

To a stirred solution of 0.102 g of trans-1-ethoxycarbonyl-3- [1- (4-oxobuten-2-enyl)] pyrrolidine-2-carboxylic acid ethyl ester in 2 ml of ethanol, cooled to 0 °, is added 0.035 g of sodium borohydride. . After 30 minutes at 0 ° and 30 minutes at room temperature, 0.05 ml of acetic acid are added, the solution is evaporated, water is added and the mixture is extracted with dichloromethane. The solution is dried over sodium sulfate, filtered and evaporated in vacuo. There are thus obtained 50 86 633 trans-1-ethoxycarbonyl-3- [1- (4-hydroxybut-2-enyl)] pyrrolidine-2-carboxylic acid ethyl ester.

To a stirred solution of 0.0937 g of trans-i-ethoxycarbonyl-3- [1- (4-hydroxybut-2-enyl)] pyrrolidine-2-carboxylic acid ethyl ester and 0.1 g of triphenylphosphine in 2 roles of dichloromethane, 0.067 g of N-bromosuccinimide are added at 0e. Maintain at room temperature for 30 minutes and then purify the mixture by flash chromatography using ethyl acetate / hexane (1: 3). There is thus obtained trans-1-ethoxycarbonyl-3- [1- (4-bromobut-2-enyl)] pyrrolidine-2-carboxylic acid ethyl ester.

Example 17: A mixture of 0.053 g of trans-1-ethoxycarbonyl-3- [1- (4-diethylphosphonobut-2-enyl)] pyrrolidine-2-carboxylic acid ethyl ester and 1.5 ml of concentrated hydrochloric acid is heated to 16 ml. for one hour at reflux. The solution is evaporated to dryness in vacuo, the residue is taken up in 1 ml of methanol, 0.2 ml of propylene oxide are added and the solution is evaporated. The residue is purified by ion exchange chromatography, eluting with 0.1N ammonium hydroxide solution. There is thus obtained trans-3- [1- (4-phosphonobut-2-enyl)] pyrrolidine-2-carboxylic acid, m.p. 138-145 °.

Example 18: An injectable preparation containing 10 mg of active compound / 5 ml of solution is prepared as follows:

Composition cis-4- [1- (3-phosphonoprop-1-enyl)] - piperidine-2-carboxylic acid 10.0 g propyl paraben 0.5 g water ad 5000 ml si 866.58

The active substance and preservatives are dissolved in 3500 ml of water and the solution is diluted to 5000 ml. The solution is filtered through a sterile filter and filled under sterile conditions into ampoules, with 1 ampoule containing 5 ml of solution.

Example 19: a) Preparation of 10,000 tablets containing 10 mg of active substance:

Ingredients cis-4- [1- (3-phosphonoprop-1-enyl)] - piperidine-2-carboxylic acid 100.00 g lactose 2535.00 g corn starch 125.00 g polyethylene glycol 6000 150.00 g magnesium stearate 40 .00 g of water (sterile) qs

The powdered substances are sieved through a sieve with a mesh size of 0.6 mm. The active ingredient, lactose, magnesium stearate and half of the starch are then mixed together in a blender. The rest of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 260 ml of water. The paste formed is added to the powder mixture, which is optionally granulated by adding more water. The granulate is dried overnight at 35 °, then sieved through a sieve with a mesh size of 1.2 mm and compressed into concave tablets with a broken groove.

Similarly, tablets containing about 1 to 50 mg of any of the other compounds described above are prepared.

52 86638 (b) Preparation of 1000 capsules containing 5 mg of active substance:

Ingredients cis-4- [1- (3-phosphonoprop-1-enyl)] - piperidine-2-carboxylic acid 5.00 g lactose 212.00 g starch 80.00 g magnesium stearate 3.00 g

All powdered ingredients are sieved through a sieve with a mesh size of 0.6 mm. The active ingredient, magnesium stearate and then lactose and starch are then mixed together in a mixer until a homogeneous mass is obtained. Hard gelatin capsules, No. 2, are each filled with 300 mg of the prepared mixture.

Similarly, capsules containing 1 to 50 mg of any of the other compounds described above may be prepared.

Claims (9)

53 86638 A process for the preparation of therapeutically effective unsaturated phosphonic acids of the formula I and their salts, in which one or both of the acidic hydroxy groups of the phosphonic acid moiety may be etherified with lower alkyl, benzyl, in the phenyl moiety with halo, lower alkyl, lower alkyl lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted on the oxymethyl moiety by lower alkyl or cycloalkyl, m is 1 or 0, R 1 denotes carboxy, carboxy substituted by lower alkyl or lower alkanoyloxymethyl is additionally esterified or unsubstituted or unsubstituted or N-lower alkyl on carbon with lower alkyl or phenyl-lower alkyl and / or on nitrogen with lower alkyl, phenyl-lower alkyl, lower alkanoyl or lower alkoxycarbonyl, it may contain a carbon-carbon double bond or it may be oi is condensed with a carbocyclic 6-membered ring starting from adjacent carbon atoms, and A represents lower alkylene, characterized in that a) the formula VII 54 B0638 Y fab) (»n)! Aldehyde or ketone according to U "Y, in which the symbols m and R1 and the heterocyclic ring have the meaning given in connection with formula I, however, R1 and the amino groups are in protected form, and A 'denotes lower alkyl substituted by oxo and having one carbon atom less than alkenylene group A, is condensed with a tetraester derivative of methylenediphosphonic acid under basic conditions and, if necessary, the protecting groups are cleaved from the resulting product to give a compound of formula I wherein the group A double bond is immediately adjacent to the phosphono group, or b) A compound of formula r * in which the symbols A, m and R 1 and the heterocyclic ring have the meaning given in connection with formula I and X represents reactive esterified hydroxy is condensed with a compound capable of attaching to a phosphonic acid moiety of formula IX or x 55 8663B f H OR "( ιχ) P (R "') i (X) OR" joi wherein R "represents lower alkyl and R '" represents halogen or lower alkoxy, and if necessary the resulting phosphonic acid derivative is converted into a phosphonic acid or another ester derivative thereof, or c) in the corresponding compounds of formula XI s H01 V \ Hi i (Xl) γ-cyano or optionally lower the amidino group Xj is hydrolytically modified, wherein in the formula one or both of the acidic hydroxy groups of the phosphonic acid moiety may be esterified as shown and the heterocyclic 5- or 6-membered ring may be substituted as given and A is as defined above and X 1 is as defined for R 1 above, and if desired, in the obtained compound of formula I in which one or both of the acidic hydroxy groups of the phosphonic acid moiety are etherified as shown, the phosphonic acid group is liberated in the resulting compound of formula I wherein R 1 represents an esterified or amidated carboxy as shown is released or in a compound of formula I wherein R1 is carboxy, the carboxy group is esterified as shown, in a compound of formula I where R1 is free or esterified as carboxy, it is optionally amidated to the lower alkylated 56 80638 carboxy from a compound of formula I wherein nitrogen is substituted as shown, the N-substituent is cleaved from the heterocyclic ring of a compound otherwise identical to a compound of the invention; these methods are also carried out, if necessary, by temporarily protecting all interfering reactive groups and then releasing the compound of the invention formed, and / or, if desired, converting the formed free compound to a salt or salt formed and / or separating the resulting isomer mixture or racemate into individual isomers or racemates and / or, if desired, separating the racemate into optical antipodes. Process according to Claim 1, characterized in that the heterocyclic ring system together with the substituent R 1 denotes optionally substituted 2-carboxypyrrolidinyl, 2-carboxy-2,5-dihydropyrrolyl, 2-carboxy-1,2,3 , 6-tetrahydropyridinyl, 2-carboxy-1,2,5,6-tetrahydropyridinyl, 2-carboxypiperidinyl, 2-carboxy-tetrahydroquinolinyl, 2-carboxy-perhydroquinolinyl, 2-carboxy-2,3-dihydroindolyl or 2-carboxyperhydroindolyl in which the carboxy may be esterified or amidated. A process according to claim 1 for the preparation of compounds of formula II A-P-OR '/ X L R 3 -f Y Yv and compounds of formula II having a double bond of the piperidinyl ring C-3- 57 B6 6 between 6'S and C-4- or C-4- and C-5 atoms, and for the preparation of salts of these compounds, in which the phosphonone-containing chain is bonded to the 3-, 4- or 5-position of the piperidinyl or tetrahydropyridinyl ring and wherein R and R 'are independently hydrogen or lower alkyl, R1 is carboxy, lower alkoxycarbonyl or carbamoyl, R2 is hydrogen, lower alkyl, lower alkanoyl or lower alkoxycarbonyl, R3 is hydrogen or lower alkyl and A3 is hydrogen or lower alkyl. A process according to claim 1 for 4- [1- (3-phosphonoprop-2-enyl)] piperidine-2-carboxylic acid, 4- [1- (3-phosphonoprop-1-enyl)] piperidine-2- for the preparation of a carboxylic acid and their pharmaceutically acceptable salts. A process for the preparation of compounds of the formula IV f A— -OR 'y' \ / * x L R1 * - + ni ° R (iv) νϊν or their perhydro derivatives and their salts according to claim 1, wherein R and R 'are independently of hydrogen or lower alkyl, R 1 represents carboxy, lower alkoxycarbonyl or carbamoyl, R 2 represents hydrogen, lower alkyl, lower alkanoyl or lower alkoxycarbonyl, R 4 represents hydrogen or lower alkyl and A represents lower alkenylene. A process according to claim 1 for the preparation of compounds of formula VI 86638 58 r3-4 4-A-I-OR '(VI) T "· and compounds of formula VI having a double bond between the C-3 and C-4 atoms of the pyrrolidinyl ring. and to prepare these salts, wherein R and R 'are independently hydrogen or lower alkyl, R1 is carboxy, lower alkoxycarbonyl or carbamoyl, R2 is hydrogen, lower alkanoyl or lower alkoxycarbonyl, R3 is hydrogen and A is lower or lower alkyl. A process according to claim 1 for trans-3- [1- (4-phosphonobut-3-enyl) N-pyrrolidine-2-carboxylic acid, trans-3- [1- (4-phosphonobut-2-enyl)] pyrrolidine- For the preparation of 2-carboxylic acid and their pharmaceutically acceptable salts. A process according to claim 1 for the preparation of the following compounds: cis-4- [1- (3-phosphonoprop-2-enyl)] piperidine-2-carboxylic acid, trans-4- [1- (3-phosphonopropyl) 2-enyl)] - piperidine-2-carboxylic acid, cis-4- [1- (3-phosphonoprop-1-enyl)] - piperidine-2-carboxylic acid, trans-4- [1- (3-phosphonopropyl- 1-enyl)] - piperidine-2-carboxylic acid and cis-3- [1- (4-phosphonobut-3-enyl)] - pyrrolidine-2-carboxylic acid and their pharmaceutically acceptable salts. Process according to Claim 1, characterized in that the compound of the formula II, IV or VI in which R and R 'denote lower alkyl and R 1 and R 2 denote lower alkoxycarbonyl is converted by treatment with an inorganic acid or aqueous alkali of formula II , IV or VI, wherein R and R 'are hydrogen, R1 is carboxy and R2 is hydrogen. 60 80638