FI58328C - PROCEDURE FOR FRAMSTATION OF AV 4-HYDROXY-1- (PHENETHYL-OCH 4-OXO-4-PHENYLBUTYL) PIPERID DERIVATIVES - Google Patents

Description

E5Sr * l M «dADFORMATION PUBLICATION ft

A 11 '; UTLÄGGN INGSSKRIFT O ö O L · O

SSft C Patent aySnnbtty 1C Cl 1081% SgSI <4S> Patent neddelat ^ ^ (S1) K ».ik? / Ir» t.a.3 0 07 D 211/44

FINLAND — FINLAND (21) FWttlhukumu * - Red lwln * 1811 / 7U

(22) HakrnnltpUvt - Anueknlngadif 13.06.7U

(23) Alkupllvt — GlMghutsdig 13.06.7U

(41) Tullut {ulkteulal - Bltvit offmtllg 23.12.7U

r> Mttl · rakliMrilnllltu · («) nmu *. »From here ·» r ».-

Patent · och rafletaratjrraltan 'AmMcm uttagtf och utUkrtftun publkarad 30.09.80 (32) (33) (31) Pyr> «nr Utuelkuui —Buglni prtorltut 22.06.73 28.06.73, 29.06.73, 02.07.73 Swiss

Schveiz (CH) 9177/73, 9UlU / 73, 9509/73, 9598/73 (71) Sandoz AG, Basel, Switzerland-Switzerland (CH) (72) Erwin Rissi, Basel, Anton Ebnöther, Arlesheim, Switzerland-Switzerland ( CH) (7U) Oy Kolster Ab (5U) Process for the preparation of therapeutically useful U-hydroxy-1- (phenethyl and U-oxo-U-phenylbutyl) piperidine derivatives - For the preparation of U-hydroxy-1- (phenethyl- and U-oxo-U-phenylbutyl) piperidine for therapeutic purposes

The invention relates to a process for the preparation of therapeutically useful U-hydroxyx-1- (phenethyl and 4-oxo-U-phenylbutyl) piperidine derivatives of the formula R0 R 1

HO C-C0-R

or 58328 wherein R is a phenethyl group, a phenethyl group monosubstituted by fluorine, chlorine, bromine, methyl or nitro, a butyrophenone group or a butyrophenone group monosubstituted by fluorine, and FL is an OR group in which R 5 is lower alkyl, allyl or phenyl, or R is a group of formula 6 wherein R 9 and R 6 are each hydrogen, lower alkyl XR 7 or cycloalkyl of 5 to 6 carbon atoms, phenyl, benzyl or cycloalkylmethyl of 5 to 6 carbon atoms, or R 8 and R 6 together with the nitrogen atom to which they are attached attached, a saturated 5-6 ring membered heterocycle, which may optionally contain oxygen as a second heteroatom, or a methyl-substituted nitrogen, and R 1 is lower alkyl or cycloalkyl of 5 to 6 carbon atoms, cycloalkylmethyl of 5 to 6 carbon atoms, phenyl, or chlorine, fluorine, phenyl monosubstituted with methyl or nitro, and R 1 is hydrogen or methyl, or R 1 and R 2 together with a carbon atom form a j, oho they are attached to a cycloalkyl ring having 3 to 6 carbon atoms and their acid addition salts.

According to the invention, novel compounds of the formula I and their acid addition salts are obtained by a) administering the compounds of the formula II, R-R,

3 \ / U

HO. .C-C0R2

II

^ n /

B

wherein R 1, R 2 and R 2 are as defined above, react with compounds of formula III,

X-R1 III

wherein R 1 is as defined above and X is an acid residue of a reactive ester, such as a halide ion, or 35328 b) for the preparation of compounds of formula Ia,

Rk / ^ i

SC

^ N '

ΡΛ IS

“8 wherein R and R 1 are as defined above, and R 1 is an OR group wherein R is 3. . 2 5 t> the same as above, or is a group of formula 6 wherein R 1 is lower

RT

alkyl or cycloalkylalkyl, cycloalkyl, phenyl or lower phenylalkyl, R 1 is if R 9 and / or are optionally substituted phenyl, hydrogen, or is lower alkyl or cycloalkyl of 5 to 6 carbon atoms, phenyl, benzyl or cycloalkylmethyl of 5 to 6 carbon atoms, if Rg is lower alkyl, or cycloalkyl or cycloalkylmethyl having 5 to 6 carbon atoms, or is hydrogen and Rg is phenyl, or

R 9 and R 6 together with the nitrogen atom to which they are attached form a saturated heterocycle containing 5-6 ring members, which may optionally contain oxygen as a second heteroatom, or a nitrogen substituted by lower alkyl, and R 8 is fluorine, chlorine, bromine, lower alkyl or lower alkoxy , is given for the compounds of formula IV, 0 A *.

\ N '

(CHJ5 IV

Λ I - R8 4 58328 in which formula

Rg is as defined above, to react with compounds of formula V, R3 h

H-C-CO-R 2 V

wherein R, R 1 and R 8 are as defined above, or c) for the preparation of compounds of formula Ib, X 1 - HO 2 - C-CO-R 8 (CH) 3 CO 2 - [4-¾ wherein R 8, R 2, and Rg are as defined above, the protecting group is cleaved from the compounds of formula VI,

R3 \ / RU

HO J C-CO-R

^ j8 (ch2) 3-a — V y VI

wherein R 9, R 2, R 2 and R 8 are as defined above and A is a ketally bonded carbonyl group, or d) for the preparation of compounds of formula Ie, 58328 r „R 1 X 14 HO x ^ ^ ^ C-CONH 2 Λ \ t in which formula, R 1 and R 2 are as defined above, are hydrolysed in compounds of formula VII,

R

HO C-CN

X

VII

X

wherein R 1, R 2 and R 2 are as defined above, a CN group to form an NH 9 -CO group or e) for the preparation of compounds of formula Id, R 3 / R, HO X-CO-N b X Xbt

Id f R 1 in the formula R 1, R 2> R 2 »R 8 and R y have the same meaning as above, are given for the compounds of the formula Ie, '-1 /' 58328 E3 Λ s' Ί HO C-COORi:> <

Ie

J

R 1 wherein R 1, and are as defined above and R 1 is phenyl or phenyl monosubstituted by fluorine, chlorine, bromine, lower alkyl, or lower alkoxy, to react with compounds of formula VIII,

ΗΝΓ VIII

R7 wherein R8 and are as defined above, and the compounds of formula I obtained are optionally converted into their acid addition salts.

In the compounds of formula I, R is preferably a W group.

VR7

The substituents R 9 and R 6 are preferably lower alkyl groups or cycloalkyl groups.

If Rg and R are lower alkyl groups, they preferably contain 1-1, in particular 1-2 carbon atoms. If Rg or R ^. contain cycloalkyl groups, these groups preferably having U-6 carbon atoms. Preferably R 9 is lower alkyl, especially methyl, and R 8 is preferably cycloalkyl, especially cyclohexyl. If Rg and R together with the nitrogen atom form a heterocycle, then this may preferably be a morpholine or N-methylpiperazine or piperidine ring.

If R0 in the compounds of formula I is an OR4 group, then R1. preferably represents lower alkyl or alkenyl. If R 1 represents lower alkyl, then this preferably contains 1-U carbon atoms and is especially methyl or ethyl. If R 1 represents lower alkenyl, then this preferably contains 3-5 carbon atoms and is in particular an allyl group. of

. . . . . / 6 1_ ·· "D

If R 1 in the compounds of formula I represents an N-D group, K is

c ^ / • • du 1 I i i mahdol I i i substitu tuui butyrophenone group. If R0 is an OR1 group, τ 58328 R1 is preferably an optionally substituted phenethyl group. If R 1 is a butyrophenone group, then this is preferably substituted or unsubstituted by fluorine, which is preferably in the p-position.

If there is a phenethyl group, this is preferably substituted or unsubstituted by chlorine, which is preferably in the o-position. If the phenethyl group is substituted by lower alkyl or lower alkoxy, then these groups preferably contain 1 to 3 carbon atoms and represent in particular a methyl or motoxy group.

Preferably, the substituent R 1 is lower alkyl, and the substituent is hydrogen.

If R 1 is lower alkyl, then this preferably contains 1 to 1 carbon atoms and represents in particular methyl or ethyl. If R 1 contains a cycloalkyl group, then there are preferably 1 to 6 carbon atoms.

Preferred are, for example, compounds in which R 1 is a butyrophenone group optionally substituted in the p-position by fluorine, R 2 is R 2 / R 6.

wherein Rg is lower alkyl or cycloalkyl and R1. is lower alkyl or R 1 is hydrogen or R 1 is an O-lower alkyl or O-allyl group and R 1 is lower alkyl and R 1 is hydrogen or methyl. Of these butyrophenone-containing compounds, highly preferred are those in which R 1 is preferably a disubstituted amine residue, in particular dimethylamine or N-cyclohexyl-N-methylamine residue.

Also preferred are those compounds wherein R is an phenethyl group optionally substituted in the o-position by chlorine, R 1 is an OR 1 group in which R is lower alkyl, preferably methyl or ethyl or allyl, or R 1 is a group in which R 8 is lower alkyl or cycloalkyl and R 1 is lower alkyl

RT

or R 1 is hydrogen and R 1 is lower alkyl and R 2 is methyl or hydrogen. Of these phenethyl-containing compounds, those in which R 1 is an O-alkyl or O-alkenyl group, especially a methoxy, ethoxy or allyloxy group, are highly preferred.

The reaction of the compounds of the formula II with the compounds of the formula III according to process a) is preferably carried out in inert organic 3 trusts, optionally by adding an acid-binding agent or by using an excess of the compound of the formula II. As inert solvents, aromatic hydrocarbons, such as benzene, toluene or xylene, chlorinated hydrocarbons, such as chloroform or carbon tetrachloride, or a lower alcohol, such as ethanol, or dimethylformamide can also be used.

8 58328

As the acid-binding agent, for example, alkali metal carbonates such as potassium carbonate or sodium carbonate, or tertiary amines such as triethylamine or pyridine can be used. Preferably, compounds of formula III are used in which X is chlorine, bromine, iodine or an organic sulphonic acid residue such as, for example, an alkylsulfonyloxy or arylsulfonyloxy residue. The reaction is preferably carried out at a temperature between room temperature and about 100 ° C.

The coupling of esters or amides of the formula V to the 1-piperidone derivatives of the formula IV according to process variant b) can take place, for example, in the presence of a strong basic condensing agent in an inert anhydrous solvent. Saturated hydrocarbons, such as hexane, ethers, such as diethyl ether, or tetrahydrofuran, or aromatic hydrocarbons, such as benzene or toluene, can be used as inert solvents. Hexane / tetrahydrofuran proves to be very advantageous.

If the CO-R 1 group in the compounds of formula V is an ester group or a tertiary amide group, suitable metal condensing agents are time metal amides such as lithium or sodium amides, in which case organic lithium amides, such as in particular diisopropyllithium amide, cyclohexylmethylcyclohexylmethyl-lithium amide, can be preferably used. the reaction can be carried out at lower temperatures, preferably between -75 and -20 °. Optionally, catalytic amounts of organic peroxides or dimethyl sulfoxide may be added to accelerate the reaction when lithium or sodium amide is used. If the CO-R 1 group is an optionally substituted secondary phenylamide group, the coupling can be performed in the presence of a very strong basic condensing agent capable of forming a dianion of formula Va, wherein R 1, R 2 and R 8 are as defined above, of the formula Vt> of amides wherein R, R and Rft are as defined above. For example, lower alkyl alkali metal compounds are suitable, preferably lower alkyllithium compounds, such as in particular n-butyllithium or methyllithium, or also phenyllithium or organic Grignard compounds, such as, for example, alkylmagnesium halides. The reaction temperature may be about 0-50 °.

The cleavage of the protecting groups from the ketals of the formula VI according to process variant c) can be carried out in a manner known per se. Mixed ketals of lower alcohols which are optionally suitable for protecting the carbonyl group. Preferred are cyclic ketals having 5 to 6 ring members, especially dioxolane. The ketal group can be cleaved by hydrolysis of the ketals of formula VI 9 58328 with acids, e.g., dilute mineral acids such as about 2N hydrochloric acid, preferably at a temperature of about 0-25 °. If the CO-R 2 group in the compounds of formula VI is an ester group, the reaction conditions in the ketal cleavage must be chosen so mild that concomitant ester cleavage is avoided.

The preparation of the compounds of formula Ie according to process variant d) can be carried out according to conventional methods used in the hydrolysis of cyanides. The compounds of formula VII may be reacted, e.g. with water, optionally with the further addition of an inert, preferably water-miscible, organic solvent, e.g. a lower alcohol, acetone or dioxane, preferably in the presence of a basic catalyst. Preferably, the hydrolysis is performed in the presence of bases such as dilute sodium hydroxide. According to a preferred embodiment of the process, the compounds of formula VII are converted into the amides of formula Ie in the presence of a lower alcohol and dilute 1N-5N sodium hydroxide with hydrogen peroxide at a temperature of about 20-50 °. In this case, the N-oxides which may form as a by-product can be reduced to the compounds of the formula Ie by treating the crude reaction product with a solution of sodium disulphite in aqueous solution at low temperatures, preferably at a temperature of about 0-20 °.

The formation of amides of formula Id from phenyl esters of formula Ie can take place in a manner known per se by reacting an ester of formula Ie, preferably in the presence of an excess of amine of formula VIII, preferably at a temperature of about 50-150 °. When low boiling amines are used, the reaction can preferably be carried out in an autoclave under pressure. Optionally, inert organic solvents may be added to the reaction mixture. Suitable solvents are, for example, aromatic hydrocarbons, such as benzene or xylene, cyclic ethers, such as dioxane or tetrahydrofuran, dimethylformamide or dimethylacetamide.

The compounds of the formula I can be isolated from the reaction mixture in a manner known per se and purified. The compounds can be converted into their acid addition salts in a manner known per se, and vice versa.

The starting compounds can be obtained as follows: a ') The compounds of the formula II can be obtained by debenzylating the compounds of the formula IX in which R1, <and i4 have the same meaning as above, in a manner known per se. In this case, any double bonds of the R 1 and R 2 residues are also hydrogenated.

b ') Compounds of formula II having an O-allyl group can be obtained preferably by esterifying the corresponding alkyl esters (R 1 = O-allyl group) with an alkenol in a manner known per se.

10 5 832 8 c ') Amides of the formula IIa in which Rg, ^ 5 and have the same meaning as above can also be obtained by reacting the corresponding phenyl esters of the formula II (Rg = O-phenyl) with the compounds of the formula VIII , e.g. under the reaction conditions described in method e).

d ') Compounds of formula VI may be obtained by reacting compounds of formula II with compounds of formula X wherein R 8, A and X are as defined above. The reaction can take place under the reaction conditions described in process a), e ') Formula VIIb, wherein R 1, R 8 and R 2 have the same meaning as in the above-mentioned compounds, can be obtained by administering compounds of formula XI wherein R 1 and R 2 have the same meaning. as above, react with compounds of formula III or compounds of formula X, e.g. under the reaction conditions described in process a) and cleavage any ketal protecting groups.

f ') Compounds of formula VIIa in which Rg, R1 and R8 are as defined above can be obtained, e.g., by reacting compounds of formula IV with compounds of formula XII in which R8 and R2 are as defined above, e.g. under the reaction conditions described in method b).

gJ) Compounds of formula IXa in which R *, R 9 and R 6 are as defined above can be obtained by reacting N-benzylpiperidone with compounds of formula V, e.g. under the reaction conditions described in process b).

h ') Compounds of formula IXb wherein R 9, R 2, R 8 and R 2. mean the same as above, can also be obtained by reacting the corresponding phenyl esters of formula IXa (R * = O-phenyl) with compounds of formula VIII, e.g. under the reaction conditions described in process e).

i) Compounds of formula IXb wherein R 9 and R 2 are. are hydrogen, can be obtained, for example, also by hydrolysis of nitriles of the formula XIII, in which R8 and R2 are as defined above, e.g. under the reaction conditions described in process d).

jJ) Compounds of formula XI can be obtained e.g. by reacting N-benzyl-U-piperidone with compounds of formula XII, e.g. under the reaction conditions described in process b) and finally debenzylating the resulting compounds of formula XIII, e.g. by catalytic hydrogenation as described in method a '),

The compounds of formula I and their pharmacologically acceptable acid addition salts have interesting pharmacodynamic properties and can therefore be used as medicaments. In particular, they have the analgesic property "58328. This is manifested, for example, in the" Tail-Flick test "performed in mice at a dosage of about J-30 mg / kg body weight when administered subcutaneously (s, e.) And by preventing phenylbenzoquinone syndrome. in mice at a dose of about 1.5 ~ 30 mg / kg orally,!

Due to their analgesic effect, the substances can be used in a variety of ways! for the treatment of pain conditions. Doses will, of course, vary with the nature of the substance, the mode of administration; and according to the patient's condition. In general, however, satisfactory i i are obtained in experimental animals

results at a dose of about 1-30 mg / kg body weight. This dose J

can be administered in 2-h part or also in retard form, if necessary. Larger mammals have a daily dose of about 50-500 mg. Thus, for oral administration: sub-doses contain about 12-250 mg of the compounds of formula I in admixture with solid or liquid excipients. j

In addition, the new compounds have an anti-serotonin effect, which has been observed, for example, in serotonin toxicity tests in guinea pigs, at a dose of 0.001-1.0 mg / kg body weight. Thus, the novel compounds can be used as migraine-relieving agents. The compounds mentioned in German application 2,033,852 were considered to be more suitable reference points because they also have a phenethyl or butyrophenone group in the 1-position and an OH or COO group in the U-position of the piperidine ring,

The analgesic effect was studied by the "Tail-Flick test" by measuring the time taken for a mouse to pull its tail out of a burning beam of light. A test substance has an analgesic effect if this time is valid for more than 75% ED <-0 is the dose of drug that is effective in 50% of experimental animals.

Phenylbenzoquinone at doses of 2 mg / kg in experimental animals causes e.g. abdominal muscle contractions prevented by analgesic agents. The test substance was administered to the animals orally, followed after 20 minutes by phenylbenzoquinone. Six minutes later, the number of contractions over four minutes was determined.

Serotonin antagonism was studied by subcutaneous administration of the test substance to the guinea pigs, followed by serotonin administration three hours later. ED, .q is the dose of drug that was able to inhibit the lethal effect of serotonin in 50 # of the experimental animals.

The results of the pharmacological tests are summarized in the following table: 5 8 3 2 8

·! ! S

: e a 0): £ 2 en 2 2 di cd

i ο. Λ o -P

: M · η OJ o no q en i cd en o r- o e 3; -p -¾ o o o cd -p i G O * r »Λ 2 I cd 4-! O O O q a

1 'd' d -H

ö C Tao cd; -n -h S>: * H * H> 3 'C C di O · Η

ι O O>, CM CU

: -P d d!

0 O O

? H e H

1) il) en

CO en <U

Pf

I MO CM

JOY *"

| o CM CM CM O O pr pL

j a ft CM ro u> C— MO

di bo o di • H 'x. -. 1 ......... - - - -. ___

H tlO CM

h E! ·> I I ro

I Ή O · CM V LO CM

-P-HLOO e— CM OJ _ ta LO

(l · (d Q · * · r «* ** cO

'rd E- <W en · - O ro *' o oo on o: 2 7 on ro! 3 --- A__ ro i w S ---———- o 1 · Η cd

I s E CM

! e o e i * H O CU - · cd

: S e a C Vä. -P

- O td tn <u - m e cd -p d; p>>, dd ω m 01 en · Η d d! · Η en · η h a S cd, · η C cd en di o cm O is ro Odi

a O tn -H O LO CO LO LO MO LO t — I

a e -P ft +3 p. ai -h cd e en T3: <ua> en <u en tafl O p H en ----- g cd -p id: CC di: <i OJ cd IS dd I -H di cd IH> 3 -P cO LO cd

Sdi Mu «« a S O a <u o co e— o o e— en C a "a q T- (0 <- aa i <u en taD-H en

i pd-! dj S cd ______—--- · H

: I II I I Si cd

j · Η I · Η I * H * H * H * H (—I

w 2 ι ω a en iHien ι q cd 1 di I I> 3 di I di I I> 3 S-H M> 3 0 tn! o-o o S o-h o-h o S Se o Se di en en a h h h h en a · η q o ei P> cd m

Td> 3 di · η ή d>) a S a -ha <u · η Td -—- tue en> 3 S oee> 3> 3> 3 S oe · η a ft> 3 a ee dden ι <u < uaaa en icuöio a to oe cu

Idi -i Pii I e Idi p4 ft 3 pj- e i —- <a ι e! p4 <UI -h en pt <u 4 mi -h CI ft 4 II r- '· η ia · η ft <u I ft led -eftooro I cm T- a cd • HO HI · Η · Η O -HO rH I · Η LO · Η '-HI I CO p

! '—I <—I S'P' 1 — I '—I 1 — I' —I 1 — I> 3-4 ft a Η ιΗ Ο · H —- H

> 3 di Si> 3 S · ^ S di SiooS S e mi · η IS> 3-ne-H> 3Sl> 3-HS> 3 a -he ι SS a diCM cd I dud «π-p dod dea cucnft pj -, aa >> O l -p! eu ι -h ft a <u cu ι -h <u ι iPdi-H ^ -H-Heue! e ^ e! eu cas-HOo easqa · η ο η ι eeq · η a · η <ue <ui3eeft <ui3 <ui eeS ^ oeutua> 3 h> ί · η b — i - ao ό ft ft ^ c ft ^ oa S ι ft a ft ^ s <C · H * HO e> 3 3 · Η · Η Ο · Η * H e> 3 -P Ή -h cn -Η Ή IS Si e rH · η r — ί aaeh * he tH * h satu cofttu e · —i p4 ao ^ fttHi-HoSftoSa sisai -hoS · η OSOlPfCOSOO SH 1 4 Ή 04 ho S s <ί e: nae ft ί o nae nag a ι ae ι> 3 ha co <u! a ή ft ί --- -nahp <a ή 3 i —- ia - S a · η · η i ft> ί e ή p4 · η ft ί e -π ί ee pt ή a> 3 · η aiec ο - h OOH— ΗΟΟΦΗΟΦΟ'— H-aHtuotuoeft ί ft hi S e ί ft> 3 ί ft-π ί>, ai S ο i ft eai * HS Γ "SP (·“ * hS r ”* Hfti'— Mj | iPJ - S ft · * H Cd> 3-i -— · ft ί-) vta o--, ^ ft, a ft oa γό -ha ft —- ft eai ί ί ο i P · η> ί ί <u ί ί e ί q · η 'ip cd ι ι ρ · η ή

r, | .. t ii CM, Ο H CM Pt g CM -4 ft CM a H CM a a CO pf ft OH

As compounds, the compounds of the formula X or their physiologically acceptable acid addition salts can be used as such or in admixture with pharmacologically inert excipients.

The pharmaceutical preparations can be used as tablets, granules, powders, granules, capsules, syrups and elixirs for oral administration, suppositories for rectal administration and as solutions, suspensions, dispersions and emulsions for parenteral administration. The pharmaceutical preparations may contain the above-mentioned active ingredients alone or in combination with customary excipients and carriers such as, for example, solvents such as ethanol, glycerin, water, solid carriers such as talc, lactose, starch, polyvinylpyrrolidone, magnesium stearate, natural or hardened oils, with wax, etc. In addition, the preparations may also contain suitable preservatives, stabilizers or wetting agents, solvent intermediates, flavoring agents, coloring agents, flavoring agents, fluxing agents, and the like.

If the preparation of the starting compounds is not described, the compounds are known or analogs of known compounds or can be prepared according to methods or analogous methods known per se.

In the following examples, which further illustrate the invention, the temperature values are expressed in degrees Celsius,

Example 1: 2-N, N-hydroxy-1- (U-oxo-U-phenylbutyl) -U-piperidyl-7-propionic acid ethyl ester

To a solution of 18.9 g of crude 2- (1+ -hydroxy-1 + -piperidyl) -propionic acid ethyl ester in 250 ml of Ν, Ν-dimethylformamide is added dropwise at 60 ° with stirring a solution containing 8.6 g of 1 + -chlorobutyrophenone in 30 ml of Ν, Ν-dimethylformamide. The reaction is allowed to proceed at 60 ° for 7.5 hours, the solvent is evaporated under reduced pressure, and the residue is dissolved in chloroform. The chloroform solution is extracted twice with water, dried over magnesium sulphate and evaporated to dryness. The residue is dissolved in ethanol, the ethanol / hydrochloric acid mixture is added, followed by ether until the solution becomes cloudy, and the crude crystals formed are purified by recrystallization from ethanol / ether. The hydrochloride of the title compound with a melting point of 130-132 ° is obtained. The ethyl 2- (1-hydroxy-k-piperidyl) propionate used as starting material is prepared as follows: a) To a solution containing N, N-diisopropyllithium amide (prepared 50, 7 rN of N, N-diisopropyl Li.imine in 300 ml of anhydrous betrahydrofuran 5 S 3 2 8 11+ and ΐβθ of 20 20 n-butyllithium in hexane -75 ° at -75 °, a solution of 23 ml of propionic acid ethyl ester in 100 ml of anhydrous tetrahydrofuran is added dropwise. Stir for 1 hour at the same temperature, then a solution of 37.8 g of 1-benzene is added dropwise. silyl-k-piperidone in 100 ml of anhydrous tetrahydrofuran, also at -75 °.

After continuing the reaction for 1 hour at the same temperature, the reaction mixture is allowed to warm to about -10 ° and the mixture is quenched with 200 ml of 20 R potassium carbonate solution. The mixture is extracted twice with ether, the extracts are dried over magnesium sulphate and evaporated to dryness. The resulting 2- (1-benzyl-1 + -hydroxy-1 + -piperidyl) -propionic acid ethyl ester is further processed as a crude product.

b) A solution of 57.1 g of 2- (1-benzyl-U-hydroxy-U-piperidyl) -propionic acid ethyl ester in 580 ml of glacial acetic acid is hydrogenated with 5 * 7 g of 10 Game palladium on carbon at 70 ° C. At a pressure of 20 at in a 1 liter autoclave. After the required amount of hydrogen has been introduced into the reaction mixture, the reaction mixture is filtered and evaporated to dryness. The residue is dissolved in 600 ml of chloroform, and a paste containing 216 g of potassium carbonate and 100 ml of water is added to the solution in an ice bath with stirring. The chloroform solution is decanted, the porridge product remaining in the reaction vessel is washed with chloroform, and the chloroform phases dried over magnesium sulfate are evaporated. The resulting 2- (1 + -hydroxy-1-piperidyl) -propionic acid ethyl ester is further processed as a crude product.

Example 2: 2- [1- (N-p-Fluorophenyl-U-oxobutyl) -N-hydroxy-U-piperidyl] -propionic acid ethyl ester 20.5 g of crude 2- (1- [+ + (2,2-ethylenedioxy)) t- (p-Fluorophenyl) -butyl] -4-hydroxy-1H-piperidyl) -propionic acid ethyl ester is dissolved in 750 ml of chloroform, 300 ml of 2N hydrochloric acid are added to the solution, and stirred for 11 hours at room temperature. The chloroform phase is separated, dried over magnesium sulphate and evaporated. The free base is recrystallized from ethanol by the addition of ether and converted into the hydrochloride. Its melting point is 183-185 °.

The starting material can be obtained as follows: a) To a solution of 9.7 g of crude 2- (1 + -hydroxy-1-piperidyl) -propionic acid ethyl ester in 100 ml of dimethylformamide is added 10.2 g of sodium carbonate and heated to 100 °. 13.0 g of 2- (3-chloropropyl) -2- (p-fluorophenyl) -1,3-dioxolane dissolved in 25 ml of dimethylformamide are added dropwise over 15 minutes and the mixture is stirred for 5 hours at 100 °: in. The dimethylformamide is evaporated under reduced pressure and the compound in the residue is worked up as such.

According to Example 1 or 2, the following compounds can also be prepared by reacting the corresponding (U-hydroxy-h-piperidyl) carboxylic acid esters prepared according to Example 1a and b with the corresponding N-chlorobutyrophenone derivatives or cleaving the corresponding 2-phenyl-2- 3- (t-hydroxypiperidyl) propyl] -1,3-dioxolane derivatives.

''> 58328

- ^ "g I

--- --- g ι G p ο ι p G CÖ · Η O P · H m · Η p o o-p p p c m Η · η p — I -p-p

h en \ cn d d · η · η O CO OP

K -Η -Η · Η j) ρ G ι — I α ο g ο o G H H G C O O O d P G ^ 0)

> 00 OO0 PGP OP -H

G G p <G o d ο mo G -h

P d d o H -h cn p -— d - O G

O p P ω G d oö <u —- -PO

en o o G m p - · -— o O OOP

• h-— - -— '* h co Olo MO cn o H -G G O O oo vd "oocflm

G O O Ol-P MO - <- 0Π h- - -— G

d J- p 1Λ 1Λ (Il LO 00 I r-LO I ----

Ji 1Λ 4 OO '- • H -— -— LO I t— LO O

• h -— -— T- * - h II - i on o o en ι ι ilo -ltonvo oo o -— o cm

CM CM 00 · Η G LO C— 00 »-LO> - CO

CM LO-ci cO G G -— -— -— -— --I I

«- <- · Η -P · · ON O

«-H <U ...... ... 1¾ ON CO

-p. . · I — I -—- · · Ph * UI

O Ph Ph Ph G Ph Ph Ph en Ph ....

ui ui tn ui PO m ui ui ui G · · K <H-H LO G .H Ph Ph (3 G G 0 (0-1 GG G -H G -pm m

4-3 * H »H * H G O'N * H * H 'H 4-3 * H OT

G -G -O Ό 00 -G -G --.- 0 --- G -G G G G

CÖ »H -H: CÖ -H G OJ · Η · Η G -H sd CÖ -H: G G · Η · Η

S G 0 P G · Η I G G P 0 P G 0 P -HP -P

o o O UI Oi — ICO O O UI O UI CÖ O UI O G G

G i — I G Ή i — I G 00 i — li — I -H G -H 0 G -H rH G G

K K K G Λ ci CVI · ^ M ΛΙ G P h G K G 5 ö O ö "3" OOP OG G O O O O O Vh O O 0 · Η: d -H: d

GG-P G -P ·· -P GG-PG-P> 3 G P 5, O P O P

g -g p -G G · en -O -G o G p p G p -p i — im · —im> 3> 3 O> 3 01 Ρη · Ρ> 3. >> LP> 3 O o> 3 0 11 G -H G · Η KKO K K m i — I K K G K O> K o> s g s g

•B

G

O I

-P I I -H I I I I I

CO »P -H i — I · Η · Η f——. · Η · Η

«Ui — I G ί = όι G G Ή * I — I I — I I

• h ^ jOp-j d G i — i> 3!> J I · η

-H> 3 · η p G G> 3> 3> 3 O O I

> 3 en Ph O -P UI> 3 P ui Ph ί> · Η

?> 3 K O O GKtÖPKPhOO

P O G Ph 00-H00dcn>

OK Ph Ph Ph K G Ph K K, · Η O

O O Γ-3 G O O O O O -H t'-. m

Phi — I · Η- K i — I i — I Ph * —I rH G · ι-Λ Ή pH K H · Η K K -H K K O H Γ "-.

G> i> 3 O> »> 3 Ph> 3> 3 -H Sh 'K en> 3> m cn ι en cn p,> jg • HIGOII -ϋ IIOG> 3 O CM · Η ω" -II OOOOG- H> 3

> I G-H I I - I I Ph G -G

r--. o-, o K, t—. r ^ -. ή Γ--, r-, rS ο · η

* γ-0 · Η pH "Η1 · Η · Η ί — I · ι-Α · Η \ · γ-0 Ph G

ί — I ί — I · Η ί — I ί — I ί — I> 3 ί — I ί — I ί — I · Η O

G G -K G G G G G G G -G -4 Ph

»H -H I -H · Η Ή Κ · Η · Η · Η I I

GG-HG GG-HGGG-HPt οιιωο ooHiiiioim ι ΡηΡιΚ Ph PhPh-oPhPhPhK-h • Η · Η Ο · γΗ * Η * Ρ κ-3 * Ρ Ή · Ρ O U1

PhPhGPh PhPhGPhPhPhGK

it -g ι ι ι ai ι ι ι -o o

pfpi S> jPi Pt -G "<i-H Pt pf i> aG

^ j- ί I ^ K -0 ^

• Η · Η Pf Ή · Η · Η I · Η · Η Ή -G- K

ι — I r ~ I I r — I HHOHHi— ^ 1 I

pp ι — I -P PP OPPPH - ^ · OGO to G GGI GGG> 3 · Η GKK S> jK ΚΚΚ-ΚΚΚ • Η * H · γ-Ι P · Η -Η · Η --- · Η * H · Η P r * 3 <1 ι — I ι — IG fH ι — I ι — II ι — l rH ι — IG!> 3

££ o £ ^^ T ^^^ OG

G G ui G GG-HGGGmK

oiiK ο ο · ηο m o o ok o

Ch <hh O G-i GhGIh K Gh Gh G-t O U1

II I I IOI Ol I I IK

pi Pi pf Pi Pippi g ρΤ · ηρτ · ηρτ Pi O

Il I I I m I · Η -O I G I G I I I

OO-H-H O OOOG Ι> ϊ · Η O 11 O 1) Ο -H Pi cntnGH m tn.HwoKGmpcDpco iH i KKiiS K Κι — I KP 111 Km Km K> 3 · η

0 Op> 3 O 0i> 30miPip01l01l0> 3 H

ι ι ui g ι ι> j ι o m ι ή ι ή ι · η g> 3 piPillll Pi Pippi-H laiPiHPiHPiGll> 3 · η

—- · Η G-h.H'— '- O'— H CM-H -> 3 --- i> 3'— O Gh-H GG

1 I Η · Η G I ΙΟ I> 3 I H I ί> 3 I i> 3 I p · Η G OO

- -> 3 GO - - ~ Ρπ - ί> 3 · Η ^ 3— P - P - CO GO G-iP

I ll> JOPI IPhIPHSIOIOIOOP-HM

• H -H P G CO · Η -H G · Η O> 3 P -Η Ο -Η Ο · Η · Η G m GO

ui en o ι — I O ui en K 1/1 O P> jO ei Ph eniK coi — 1 1 — ΙΟ O ή

KKOGh-gK K-gKPhPOKPhKOhKSG4-h GH

0 OQh I. — I O O H O Ph G Ph O G OG θ! >> IPH> 3 G G Ph Ph I> 3 G G> 3 G G OPhGK GK GP Ph> jP> 3

Ö Ö G Ι> 3-0 -GS-h-GK PhG-G-htG-H-GG l> 3 IP

> 3 K 4 p> 3> 3 en> 3-h ok r ^ 3 G l> 3 G> 3 K Pi p Pi O

K KG -— 0 K -H KK KG HG KO KO KI —- O -— 0 1 IKIOIG ΙΟΙΟΚΚΙ · ΗΙ · ΗΙ · ΙΟΙΟ yK, Pi, KH— Ph V-4 O PP PK>, MP Ph P Pi y4 P o Pi, - Ph

Gj Μ · η G-l Ph p ~ -4 G G m -H ^ -1 O ^ 4 O "Pi G ^ Ph V - l Ph ι ι p ι G ι co id id lp IGIG 10 id id

CM CM O CM K CM O - ~ K - ~ K OJ 41 CMPhCMPhCMP OI K CM K

16 5 832 8

Example 3: 2- (U-Hydroxy-1-piperidyl-1-phenethyl-1-piperidyl) propionic acid ethyl ester

To a suspension of 18.9 g of crude 2- (α-hydroxy-1 * -piperidyl) -propionic acid ethyl ester and 11.5 g of potassium carbonate in 150 ml of dimethylformamide is added dropwise at 60 ° with stirring a solution containing 12 .0 g of phenethyl bromide in 50 ml of dimethylformamide. Stirring is continued for 1 1/2 hours at 60 °, then the reaction mixture is poured into ice-cold 10% potassium carbonate solution and the mixture is extracted with ether. The ether extracts are dried over magnesium sulphate and the solvent is evaporated to give the title compound which is dissolved in acetone, the required amount of maleic acid is added to the solution and the precipitated crude hydrogen maleate is recrystallised several times from acetone. The hydrogen maleate of the title compound has a melting point of 138-139 °.

According to Example 3, the following compounds can also be prepared by reacting the corresponding (1-hydroxy-U-piperidyl) carboxylic acid esters prepared according to Examples 1a and b with the corresponding β-halophenethyl derivatives: 17 58328 cd ^ cd tn cd ^ cd

A -h -p ^ cd A

CO i — I CO ^ - * rt A CO

H O * rt * rt * rt G CO * H

rH G G A G O Ή G

O O Cd OO 00 + 0 CO

cm +0 +3 C NO A O 0 + 0

A cd NO CD O cd ON O CO + o (D

O + ot- -— en a ico cd (Dco • h (Dl ajo m cd en cd A o -— - ON - cd cd nO AO -— 'S> O · - f- OO —'O CO oa to \ cm amao oj + om ·· I m cr \ c oj 1— on o (θ'— · LfN '-' - O'— I On · -

CO I Pc »'ll + o I t I I

Ή CM CO CM OO * - + o OJ A NOO

A oo t— m lo ooJ'-ono

Cd ^ -C r- T- ^ <D ^ - cd · Η '·· Ή ·· "A · A ccd · .... rH · · · · • rt · Cd A · ·· O pH Ph PhPh

COPnCdCOpHpHpH C CO CO CO CO., LTD

> 1 CO C -rt CO COCO +0

lp cd C OCCCC

CE CD C CC Ph 'rt Ή -rt -rt «-rt 3 +0 -rt -rt · Η \ A +0 + 0 + 0 aa P a -p aa -rt cd cd cd cd O cd o cd cd e3 - C cd · - <cd ^ cd cd

co cdCO cd cd cd: cd o G: cd G: cd G G

AC -Ή CCCA 40 -rt +0 -rt +0 -rt -rt 3 cd (—I · ρ cd cdcdco + 00CQOC000 A e cd 1—1 E SS * po 1—1 a * —1 a 1—1 1 —1 G 3cdO 3 3 3c o cd C cd C cd cd

cd P c c P P P O —- E p S ^ S S

E r ^ s + ocd i> 9 ^ S -P A ^ A

O +0 C +0 + J +3 P + · +0 +3 +3 4O +3 +3

c OOO O OOO Ph O (D OO O O

ffi> 3 - *>>> O M> O> O>>

• H

• H J-i

• Hl CO

e -rt O +0 -H

0 I H +0 -rt CO C

+0 cd> i 1 co e o o CO A k O O O · Η +0

01 A PhI Ph-H-PHCO

rt O -rt O · Ph A CO ϊ >> <D

H Ph -P C -P Cd £ >> O >> - rt

> ϊ Ph O Ph C Ä P9 · Η M H

ί> ΐ cd * rt O O cd C A A> 9 A A A co +0 Ai O> 9 cd S

ocd> 9 A I AP i> 9 I A

O AI i = -i O O -rt O +0 O H

ft AI CO Ph Ph +0 pnCD ft cd

Ph -rt A! P <Ph CD Ph O PhO

cd + o o cd cd ή cd Ph cd P

A CD A A -G A A Ph A Ph

• rt * rt O ‘rt * rt I> 9 * rt rö * rt G

e rH (H e e S> 9 g A e a O >> A O O G O -H O -rt

• rt> 9 A Ή CD A O * rt O

Ph e »(0 Ph Ph Ch p i» Ph>

OA I OO I OOOO

CO CM C C OJ e CO CCO

Ph A I Ph Ph ^ vH Jft, · γΗ

• H rH · Η * H «H‘ H »H * Η · Η * H

I — 1 ^ I — I rH rH rH rH rH 1—! '-I

Td I TdTdTdTdTdTdTdTd • rt OJ · rt · rt * rt * rt · rt ‘rt * rt’ rt

Cl e e e e e e cc 0 - · o o o o o o 00 Ρη · Η Ph Ph Ph Ph Ph Ph Ph ft

• rt 1 — I * rt * rt 'rt' rt * rt * rt * rt * H

Ph S Ph Ph Ph Ph Ph P P PP

1!> S I I I I I I II

A · Td A A A A A A A AA

I -rt I I I I I I II

• H C * rt * rt ’rt * rt * rt * rt · γΗ * rt O en O co co co co to co coco

GAP Ai A A A A A AA

rt O Ή o o o o o o 00

<CP e e e e e H PP

Ai o) Td Td Td Td Td tJ Td A- 1 * 9!> 9 t * 9 r * 9 1 * 9 t * 9 r * 9 r | 9

AI AAAAAAAA

I -rt I I I I I I II

A 1 — I A A A A A A AA

t> »I I I I I I II

• rt i >> »rt 'rt' rt * rt · rt * rt * rt -rt

AA A Ή P h — 1 h — I A AA

£ c £: & ££££££

AO A A A A A +0 AA

OP O -rt O O O O O OO

G I CPG G G G G G GG

O’— OOO O CD O O OO

p I p a P P P P P PP

• rt »rt * rt CO * rt’ rt * rt * rt * rt * rt * rt * rt

C CO * rt C O C C C C · rt C C CC

O A C O A o oooco O OO

0 O O O A O O A O O O O OO

1-! C A A t * 9 A h — ICOi— (AA h — I Ai — I

A Td co A> 3 A X Cl ϋ o M A AA

1>, O I A I I -rt ΙΟ I I II

OAAOOOAOAO-rtO O O O

I I A I O I C I S I A I I I I

· - A> 9 H— Ph H— OH—,,? 9 - H—> 1 - H— * - H—. · - J> ^ · Ph - "A '---' 1A * - * P9 · - * * ^ - * * - "

I IA I G I CO I G I A I I I

OJOJOOJAOJOOJAOJOOJ OJOJOJ

ie 5 832 8

Example h: 2-Zfr-hydroxy-1- (h-oxo-h-phenylbutyl) -N-piperidyl-7-N, N-dimethylpropionamide

To a solution of 39.6 g of 2- (L-hydroxy-L-piperidyl) -propionic acid Ν, Ν-dimethylamide in 150 ml of Ν, Ν-dimethylformamide is added dropwise at 60 ° with stirring a solution containing 18, 1 g of L-chlorobutyrophenone in 30 ml of Ν, Ν-dimethylformamide. The reaction is allowed to proceed for 6 hours at 60 °, the solvent is evaporated off under reduced pressure, and the residue is dissolved in chloroform. The chloroform solution is extracted twice with water, dried over magnesium sulphate and evaporated to dryness. The residue is dissolved in ethanol, the required amount of fumaric acid and ether are added to the solution until the solution becomes cloudy. The crude hydrogen fumarate is purified by recrystallization from ethanol / ether. Hydrogen fumarate of the title substance with a melting point of 155-157 ° is obtained.

The starting material can be obtained as follows: a) To a solution of N, N-diisopropyllithium amide (prepared from 35 g of diisopropylamine in 200 ml of anhydrous tetrahydrofuran and 100 ml of a $ 20 solution of n-butyllithium in hexane at -75 °: At -75 ° C, a solution of 20.2 g of propionic acid N, N-dimethylamide in 75 ml of anhydrous tetrahydrofuran is added dropwise. After stirring for 1 hour at the same temperature, a solution of 37> 8 g of 1-benzyl-L-piperidone in 150 ml of tetrahydrofuran is added over 20 minutes and the reaction is allowed to proceed for 2 hours at about ~ 70 °. The reaction temperature is raised to about -10 ° and the reaction mixture is decomposed with 300 ml of 20 Arista potassium carbonate solution. The mixture is extracted twice with ether and the crude product is isolated by evaporation of the ether extracts dried over magnesium sulphate. The crude 2- (1-benzyl-U-hydroxy-L-piperidyl) propionic acid N, N-dimethylamide formed is further treated as such.

b) 57.7 g of 2- (1-benzyl-h-hydroxy-1H-piperidyl) propionic acid N, N-dimethylamide dissolved in 1 000 ml of glacial acetic acid are hydrogenated to 5.8 g of 10 ml. of palladium / carbon as a catalyst at 70 ° at a pressure of 20 at. After the required amount of hydrogen has been introduced into the reaction mixture, the reaction mixture is filtered and evaporated to dryness. The residue is dissolved in 600 ml of chloroform, and a paste containing 216 g of potassium carbonate and 100 ml of water is added to the solution in an ice bath with stirring. The chloroform solution is decanted, the porridge product remaining in the reaction vessel is washed with chloroform and the chloroform phases dried over magnesium sulphate are evaporated. The resulting 2- (L-hydroxy-L-piperidyl) propionic acid N, N-dimethylamide is further processed as a crude product.

Example 5: 2-β- (Up-fluorophenyl-h-oxobutyl) -N-hydroxy-h-piperidyl-7-N-phenylpropionamide 21.5 g of crude 2- (1- [N- (2,2-ethylenedioxy) -1 + β-Fluorophenylbutyl (1 * -hydroxy-U-piperidyl) -N-phenylpropionamide is dissolved in 750 ml of chloroform, and the solution is stirred for 10 hours at 25 ° while adding 100 ml of 2N hydrochloric acid. The organic phase is separated and evaporated under reduced pressure and the residue is dissolved in 2N hydrochloric acid. The acidic aqueous solution is extracted twice with ether, basified with 2N sodium hydroxide in an ice bath and the precipitated title compound is extracted with ether. To the crude product obtained is added an equivalent amount of maleic acid dissolved in acetone and crystallized by adding ether as maleinate. The melting point of the maleate of the title compound is 111-113 °.

The starting material can be obtained as follows: a) To a solution of 9 g of N-phenylpropionamide in 90 ml of anhydrous tetrahydrofuran, 18 ml of n-butyllithium dissolved in hexane are added dropwise at 0 ° with stirring under a nitrogen atmosphere. Stirring is continued for 2 1/2 hours at 15-18 °, and a solution of 7.9 g of N-benzyl-1-piperidone in 25 ml of anhydrous tetrahydrofuran is added dropwise over 50 minutes. The heating (oil bath) is removed and the reaction mixture is stirred slowly with cooling for 1 hour. The reaction solution is then decomposed with stirring in an ice bath with 10 ml of 20% potassium carbonate solution, diluted with ether, the organic phase decanted, dried over magnesium sulphate and evaporated under reduced pressure. The resulting crude 2- (1-benzyl-1-hydroxy-1-piperidyl) -N-phenylpropionamide is purified on silica gel (eluent 3% methanol in chloroform), the solution is concentrated by evaporation, and ethanol and an equivalent amount of fumaric acid are added, and the compound is crystallized as a fumar. . 228-239 °.

b) A solution of 16.0 g of 2- (1-benzyl-1-hydroxy-1-piperidyl) -N-phenylpropionamide in 160 ml of glacial acetic acid is hydrogenated with 1.6 g of $ 10 palladium / carbon acting as a catalyst at 50 ° C and 30 ° C for 15 hours. The reaction mixture is further treated in the same manner as in Example Ib, and the resulting 2- (U-hydroxy-1-piperidyl) -N-phenylpropionamide is further treated as a crude product.

c) To a solution of 11.0 g of crude 2- (1-hydroxy-1-piperidyl) -N-phenylpropionamide in 150 ml of dimethylacetamide is added 11.0 g of potassium carbonate and the mixture is heated to 100 ° C with stirring. A solution of 13.1 g of 2- (3-chloropropyl) -2- (p-fluorophenyl) -1,3-dioxolane in 20 ml of dimethylacetamide is then added dropwise with vigorous stirring and the temperature is maintained at 100 ° for k hours: in. The solution is cooled, the potassium carbonate is filtered off and the filtrate is evaporated under reduced pressure. The compound in the residue is still used as such.

According to Example 5 or 1, the following compounds can also be prepared by reacting the corresponding (1-hydroxy-1-piperidyl) carboxylic acid amides prepared according to Example 1a and b with the corresponding 1-chlorobutyrophenone derivatives or by cleaving the corresponding 2-phenyl-2 prepared according to Example 5a-c. - E 3- (1-hydroxypiperidyl) propyl] -1,3-dioxolane derivatives: 20 58328 cö -— · -P ci cd 01 pp

I ^ · Η to CO

Ο * H Ρ Ή Ή CO H O ft Ο • ho a o o

P - · Ö cö BP

O cö -P eö <D

• H LA -P CU -P CO

Ai "O) O cö> on o co

H- O Pt Pt O O

Ρ I OJ O T- NO pj

CD O O CM I ON

CO ON CM I NO CM h—

• H ’I CO pj- I I

H O O <- LA CM

cö ·· O CM • -ON

CÖ · CM ·· CM h-

Ai ft ...

• H co · Pj CO · ft CO · ·> a β ft co ft ft

ft -H CO C CO CO

X * C -H

«· Η β -H -p β B

P S CÖ · Η P CÖ -H -H

cd o ρ Ό ^ cö cö x) xl CO Sh CO -H: (Ö CÖ β · Η · Η

Ad ρ -H a P U -H Sh Sh

3 · η ft O CO cö O O O

P COOi — l * H B i — I i — I i — I

B Ai B Ai a 3 CÖ Ai Ai CÖOCÖOO ft g O o a Sh ft Sh P>, s Sh Sh oxsoop p p xj x) 3 >> a>, CD CU CL) i >> s P K ft EB CD>> W S3

•B

«—I I

, s a • h B> s

-H <D S

S >> ft P I

> s I 0) I · Η co b a a h

Ai I I I »>»

<D Β -H Β B

P - H I I P

3? S ö Ö g

Ai f-A P H Η I

S · Η '<D S>, CM

CO ft g S S I

I I x) x) f--, B B -H -H -H1

I rO I Sh Sh i — I

Ι '-' η · Η ΙΆ CD 0) S

• H 'Sh · Η> ft ft h I — I O (—l · Η · Η ft ft £ »> ft ft · Η -H k I I Sh ft ft xl Pt Pt (1) • H I · Η I I ft

Sh -3 Sh · Η · Η * H

OI CD CO CO ft

ft · Η ft AI Ai I

• H CO · Η O 0-3

ft Ai ft Sh Sh I

I O I ft ft hh -3 Sh pS >> ί >> · Η I X) I Ρ P ft >> ^ 1 I> »• H p Ή -3 Pj · s r — I I f — I I I p

”T έ · Η · Η P

P · - ‘P i — lp * H

3 · Η 3 fo to H

P H P >> S S »> • H>» · Η P P i >> (UH Po H 3 3 Ö S S P >> P P 0) • H? >> 3 s O O ft

«Ö Π P O co CO I

Φ O CU Ai Ai Pt

ft CO ft o O I

I Ai I I I Ή O

pf O Pf Pf pt Xl cfl I I I I I · Η Ai · Η 0 -3 o -h -h a o a CO I CO 1 — I H 8 I · Η

Ai -H -H -H Ai S-H j >> o Pt · Η OXJHXÖ O t >> XJ Λ ft - Ό 1 · Η Ρ> · Η I a · Η Ö ft I · Η

pta >> a pf <d a cuaj’-H

- a as --- ftSftp io I aoa I · η a · η · η · η a h- o ft o> - ao ao ma I · Η · Η · Η I Ο · Η O> Ai >> • Hftaft- H 3 ft 3 0 Oft

C0O OO CO * H ft O H · CO ShTS

pa 3a p xi ft a ft · η ft -h1 O ft ft Ph O -h I Οι I I >> ft

Sn * h ft * h a a ft * H ft * H P Ρΐ Ο H I ft xl 3 IP IP I!> »'8 fc Λ? § e £: * £ g ip ip ι · η I a I +> I · η, t-l. <υ I- ·, <D vf, ft Want-. CD r \ 0) iCM ft i u v 4 a - 4 o 1 i ft m a - I o li I · P ia ii ip I a P B CM P CM ft CM B CM Xl> - ft 21 58328

Example 6; 2- (4-Hydroxy-1-phenethyl-N-piperidyl) -N, N-dimethylpropionamide According to Example 3, 2- (k-hydroxy-U-piperidyl) propionic acid Ν, Ν-dimethylamide and phenethyl bromide are reacted. The crude title compound obtained is dissolved in ethanol, the required amount of fumaric acid is added, followed by ether until the solution is cloudy. The hydrogen fumarate of the title compound obtained is recrystallized from ethanol / ether, the melting point of hydrogen fumarate being 188-189 °.

According to Example 6, the following compounds can also be prepared by reacting the corresponding (1+ -hydroxy-U-piperidyl) -carboxylic acid amides prepared according to Example 1 + a and b with the corresponding β-halophenethyl derivatives: 1. '22 58328 ^ s? ΐ,

^ -ρω tn I

• H tn · Η · Η CtJ

Ö * H Ö «H ^. i — I -P O -H

o Sh ο h · η o φ one

P OJ-POHÖ— 00 O

Φ -P Φ C O cd OJ -p -PM -P M Cd C -P O I φ O cd —- o cö-pcd Φ and cm tn • H - 'CÖ Φ -— Φ -p -' "CO ert

Jd -P ^ 'Φ CM ^ - cd OM · Η O —'Of— o> on-Hö eno m * - 40 ·· o on rH O CM CO O OI OCO f- · j- -Ρ'-Ο- ρ <- un en (Mun o \ oj OM ft αο Φ 1 C Φ I t— I "CO I T- W r- ω cm cd m r- i oj un o - on I cd i • Hon-ped oj mo i «e— Leo mo-pccmj h ·> - o- 'un oo on r- mw onm-hco cd —- i- T- o an · h -pi— di * · ·· ·· c \ jc \ i r- .. a cd M · · · · O cd • HP * · P <· - · ·· p, .. pH 4 ^> p · M en ft en ω ft · -en · ιη ft φ o ft> im ω ft ft (¾ ω ω V m

via a a m ωα mc cdH

• ha ή ha * h ή a - aa "-p -h -p -p -haa -pa Td -hm .h -P cd -PO cd Cd -p -rl · Η tfl · Η · Η -PO -H -—- _p Φ cd —- cd and cd cdcd '~' rO '~ - Td <d td Sh cd cd on Td cd cd r— tn a: cd cd "ao a cd: cd · γ-ι: cd ή a -h O -p cd on .h -p cd: cd -H-pao-Hun -na-pa-p a · η από aa en s. -pa φ ω cd no φ *> φ cd ω o ω ο ad o ad · η cd ι · η · η ^ μ

-P I — I · H a '' —l'- rH Ö * H Sh 'rl Cl H d i — I O i — I S CM -Hi — I e -H

a cd sh 3 t cd -4 cd 3 Sh jo Sh jn cd -p χ mo 3 on ho 3 si cd ö 11 'h ^ β'πΦΟΦ o ä mo Td av' -cdavai a pn-PCn ^ Pnl >> - P Sh -p Sh S · η Sh S cd S pd>, + o O -P -P -P On -p O -P -P -P Ό -p Td -PH d £ J -p · V -P. p nj g φ φ φ and φ 4 φ φ φ >> φ> n φ o · η φ φ ft cd φ φ φ m> φ> i—> <->> φ m φ a> aa ρ —-> en a - ·> o I -ii * hai ^ i — i

• H -H · γ-Ι Td O · γ-Ι · Η I S

Td i — I Td * H -H i — I rH Γ * -> - I

• H S -H S ft V s' .h · a M

ι e tn, e 53 ι o S S h ι jd • HOcd-pS-HOSi-P-P S cm φ

TdHaoaHHftoo S ι a • HjdoaoSad-HBa a -h o

a S Ή I Ή S S rH I I Oi — Il — I

roMft3ftMMt>, a-M · · η S Jd Öl OI O ftd I Si I I ftSfn 0 cm Ch * h sh φ cm α -h r-, a o a tn

• Hl ft ft ft and I <D H · H * Λ Sh (D I

ft · Η · Η> 5 · Η Ο · Η V S rH s ft V on

OrHrHCnrHi — IrHI SSl’HI I

ch SSm: >> jd S a m S o h a ia S S jd >>> s S ι m a Pt S I · η

• H-P-p Ο-p M-P-H Φ O ft S · Η I — I

p a g a φ I Oved-Hcd-pHS SgjjooacMaSoft.aaiSS

rn * H -H rH · Η I * H jn rH O * HBS Td -pTdTdJdTd-HTd-pjdSnO I -p -h 3 II dnIHI Φ ft> CM Φ Sh vasMiaSaaMi oi ε φ 1 *> »I '• S · '! t -— 'to · - I ft aaaaa -paaa · η -η · η a -h IIIII CD III r — II r-1 I ft • Η · Η · Η · Η · Η · Η · Η · Η · Η Ή ^ · Η -J "

rHrHi— | ι— | ι — I Td. — Il — I rH Td ι — I Td i — I I

SSSSSi rnSS * H S * h S ή S S S S fn a S S S p S Ch S m

Td Td t) Td Td «• TdTdTdtDTdOTdiM

• H · Η -H · Η · Η a · Η * Η · Η ft · Η ft · Η Ο ρραααι αρα · Ηα · Ηαα α> ο <υ (υ <υ -— '<υ <υ ο ft cd fttUTd ftftftftft.pftftftl ftl ft>, • Η * H · Η · Η Ή ι — I · Η · Η · Η -ei · Η -Μ "· Η ftftftftftSftftfti fti fti IIIIISIII -HI -HI -3-

Η4444ά-ί44 M-4 MJ- I

I I I I I · Η I I I J4 I J4 I -H

Η · Η · Η · Η · Η · Η C-l * Η · Η · Η Ο Ή Ο · Η ι—!

aMMcnMCGtDMcntnc-iMi-iMdn • H J4 Jc! Ai Jd J4 ftJdJdJdTdJdTdJd S CO O O O O * H O O O CnO SO-P

PPPPCHftc-iPiHjaaaao TdTdTdTdTd I TdTdTd I Td I Tda

rn rn fn rn —4 Cn>, t >> -4 C >> -4 dn O

ad-timer ι divider ι and ι jav

ι ι ι ι ι -h ι ι ι -H ι · η I -H

-4-4-4-4-4 Η-4-4_4Η-4Η-4 P

iiiiiSiiiSiSio

• H -H · Η · Η · Η |> 5 · Η * H · Η ϊ> ΐ · Η C> i · Η O

rHi — li — IrHi — 1-PrHrHi — l-pi — I -PrHi — I -H

bbbbb S bbb S bebf Ή iO r *> r * ^ Vh Pi Ρϊ Pä Vh P> Vh r * ^ 1 · Η -p + J + o -p * h -p <u -p -p -po -po - P Ob

ai φ · η o <u Td φ V φ · ηφ cu v Φ v φ i ro a a Td a a · η a ι aTda a · η a · η a-Hr-Q

o aj-Htu φβφ · - <υ · ΗΦ ω a o a φ Td - ^ o

Cm VBV VroV I ChÖV V O V * HO V-hI.h • H -H 3 · Η · ΗΟ · Η * H ’HCÖ * H * H O * H Td O · H B CM ft. p a-pa afta tn in-pp Sh · η i — ι · η a · η γ-η ρφι o O ΟΦΟ OftO M ΟΦΟ OTdJdÖOÖJd-HOP-H ^ o omo Oedo o omo 3 · Ηΐ · Ηθ3ιαοΦιΗρ,

ι — I rHedi — I ι — I JI rl Sh rHCdrH rHBO · Η ι — I Ή O * H rl CO «H

, T; rti -H M jd -H Jd Td Jd -h Jd V Cd ι tn jd V l -h Jd cd S rH

ι irHi ιαι irHi ια · --ρ iS’-Td ι · η μ ·> _

0 0 >> 0 O O O and.-OSO ΟΟ— edOS ^ -HOH-pS

1 I S ι I -ΓΗ I I I s I · Η I · Η I Sh I +0 I Sh I fn a -P

.- · - M '- r-ftr- -Ct r® rifl rftiftl® rHJiMU r>, φ ^ —- - —- -ro—- —-jd ^ -H — ovjft- ^ a ^ JPi ^ HiO a II Φ II Si III OJ is I ft I -rH 1 -rH I -rH IOI t CM CM Jd CM CM ft CM CM CMJdCMSCMftr-ftCMTd ^ -ftCM-pas; 23 58328?

swim

· H I

• H rH O I

G O -P O

0 G CU a

+3 .p p m G

o CD -P P Ui

• H Ui G —'G

a P -— ^ _

P - · O O O O

> oo f- O 0 0-0 co „„ „„ O C \ O ro - NO - CM -P) o o o o o o a PN ^ ON 00 OI U3 ftl oo ON - t— a LTN OO ΙΟ) a | OO I I NO I r-Ot ^ CVJt—

Ui OJ C— CM Lf \ I I I On I - LO CM CM - CM -

• H I On I OO C— a On - a luo II I I I

H a OO - CM CM UN W 00 t- r- ΙΛ C \ J P - ND

p a oo NO -— O t— CVJ C-—

CÖ CM - · - CM -— ·· Γ- · OI RJ W

a ·: P: P ..........

• H ·· ftp ·· +3 ft · · · ft .. ft .. "ui ui ui · m ui ftftftm ft · ui · · · b ft -H ft-H Ui Ui Ui Ui ft ftftftftft ft m G Sh mh GG ui a en ui ui m ui • HGO -HG GG-H G. t! _ ^ _

n G ft H-3 G ft ft * H -H -H ft -H O G ft G G G G G

ft -H G ft -H ft cd ft ft ft te ft - ~ · Η G · Γ- | -ft · Η · Η · Η G Κ · —- Ρ G -ϋ G Ρ G Ρ Ρ Ρ G Ό Ρ ΗΌ Ό ft ft

ui Ή G Ρ G -H G G G GGG G <- -HP -H -H T1 T1 ', H

M g .p -h G -H G S-i G · Η G I S -H G E i ^

3 O CO G -H O -H G G GGG G O O G OO O O O

ft G * Hr — IGiHiHrH g E g ft § - * h ft 3¾ 3 3 3 G ft H P O a O G P p p G -> P —-— ft G ftft a a a

G OOEftOGö ft ft ft g tö ft P O E OO O O O

g g ρ b g g p b >> S3 S3 b a Sn a - g b £ i il i i

OftPatOHaa ft ft ft ft G ft G · Oft ftft ft ft ft p S3 a G P S3 G G G G G G -H G -H ft >> <U>?>? >? >? >?

ffi KG> --- K'- '>>>>> P> P CO W> KW K K K

•B

π3 «Η * H T3 m I ft G I §

pi · Η I I * H Ο -Η Ρ I

O ft O I · Η Ö · Η Ρ O I -H

H b G -H H G ft O -H O H I

1 G S3 ft H b G P i R * 3 fc1 ^

k Eft o b ^ i, ° R P v L

«I G to b a ft l-H ft O G S3 a -H

a ftE-Hft g-h a ft ι ft g ft g gh I I I I G g E - O S H ft · H I E b • HCNjassiG kgi b 3 -L b hi I I I a c I ft · η Pa · ρ> 3 I a -p

> 3 · Η · Η -H a I Ο · Η -H H G H PO '- I G

S H H H I -H · Η H Hb ab ftft -H, S

G bbb 'HH ft bb'> 5Ra? P3 3'3 G bbb H b O -H b bP -g ft gbb 3 tp G Ui Ui bb G ft ω CO Ρ 0 · Η ft b S b "H a pH ab Ui ft · Η M a GHG Oft Ui S3

G GG G ft pj · Η g G G ft a G G-H PJ G

o aa a o g HG a ao Ss ft -h g g pj

0 o o o g a bc o oh g-h ι g a G

hhhh ft o bo h na .Hft-Hft ci aa aa aohg -haa> 3fti 3 2 1> 3> 3> 3 gag ft> »>> >> ia- ifta h p4U] CO CO» H ^ jChO to CO I ^ 1 SI >> ri ^ I | | I I CO Ik I IS * · Η Λ - = t w >>

OO S S S S 1 ÖftOOSI S CO SI I CO

Λ 1 Λ Λ Λ 1 2 3 4 5 6 7 8 9 ΛΑΛΛ ^ -Lo ^ s

• H »H · H · · · Η ^ · Η · Η · Η · Η Η · Η J-j Ή Λί I

ι — I f — if — I rH f — I · Η r — I rH ι “Ή Ή Ό 1 I Ο · Η SSSSSoSSSSfSfllbi ft ft ft ft ft bftft ft ft -H ftl ft> 3 i> 3 b • Η - Η -Η -Η -H ft -H -H »H -HG * H a * -pa ft S3 GGGG GH GG G GG Gl GI -H ft

G G G G G G GG G G ft G-H Ga G-H

ft ft ft ft ft G ftft ft ft-H ft H ftl G G

• Η -Η -Η -Η -H ft -Η -Η -Η -H ft -H b -Η -H ft G

ft ft ft ft ft-H ftft ft ft! ftS ft ft -H ft

ι ι ι ι ι ftii ι ia la i> 3ft.H

aa-aaa I a-aaai aGas I ft 1 1 1 1 1 a 11 1 1 -h 1 c ι -pa ι • H -H -H -H -HI -H -H -H -H Ui -HG -HGI a-

m ui ui ui Ui -H m ui ui tna Toft mp-Η I

aaaaanaaaaoai ag gh 0 0 0 0 0 boo 0 og o 3— oh a to GG Gi GG b GGG GK GH O a -β Η a Η Ή P Kt) Ό O ^ ai hg go>,>,>, S> S »G b &>? fe> SP Ϊ a a-na aa ft aa a ai ai ao> 3 κ GII 13 III -H II I la I -HIH a> 3 ca a-na aam aa a ai an aa 1 a • HI ι a II 1 a II ι I - ib 11 1 <3j -Η -H CO -Η -Η -Η Ο -Η -Η -Η -Η Ή -Η? 3 -HOI a-

H H-PH Η Η -P HH Η -H Hi — I ι — I -P ι — Il -H I

SS a ft ft £ ftft 62 ft ft · - ft% ft OS t P.H

+ 3.paP-p -pa 1 aa aaaaOai a 1 -h> 3 bO GHG-HG G-HG 0 GG GOTGG-HGK G CM E +3 b Ή P-HPHC-HPOC I CP PPPPE ^ 1 PIcdG as 2 GEGSsGHG -HG - GG GO GG cg GH G-HPP Geo

ft 3 ft b ft -H ftl a 'hh I ftft ft -H ft ft P ft H ft H 0 G P P

• Η Η-3 Ή 4-3 -H E * H CO Ή * H * H Ή * H ft -Η * H Ο -H Ss -H S3-H ft G O

3

G G G G G c3 G P G-H Ui -H G G GO G G-H G b G b ft · Η -H ft -H

4 omosoooooKa-öoo OGOOftOtn oaoaO-pft 5

OP 01 OftO-H O-H O-H O O O ft O OO oa-p O PG O-H GO

6

ι — I · H r — I Εΐ ι — I p. H ft ι — IE ^ hS i— * 1 — I 1 — l-H Η ι—! G <—I OK 1 — I P ft GE OG

7 Anai acoaoaSOpaa anaaftaa-na i-Paro oft 1 S3 1 ή 1 a 1 g 1 p S3 p .. 1 1 1 b 1 1, H 1 0 a 1 * ft 1 p η -η 8

OS3OH o-η oftooao ftft obooHOHPoabi ^ oaH

ia 1 S3 1 ο 1 -π 1 -π 1 -π 1 1 la ι ι b 1 a ο ι G b ι -η i b

‘-G’-Si’-S’-Hr-ftaPH-— T- I— G S3 - Ssft-— G G - ft O S

- E —- e —- o- ^ Ss- ^ o— O '--'-' - ^ E '--'- ^ a ^ Gft' - aa ^ o —- a 9

l-H IG IP IS3IG IG I I l-H I I G I IP I IGIGIG

CJH CM ft CM-H CM ft CM ft CM ft CM CM CM H CM CMg CM Ka CM S a CMftCMS

2k 58328

-P

O

•B

X

3

> O O O

o σ \ o t— c—

• P t ~ - OJ O -4 * VO CO

O ** - C \ J - OJ 1- - W OJ I T- T- | |

• H I 00 OJ I IA o IA

H LA OJ I CO LO C— CO

3 - OJ O - - - -

3 OJ - - OJ

X ·· OJ I

• H ·· · IA

<n. p, · Pj pj.>! Pj in P <ft ω OJ in <n in in in _ Ö O · Ö

'C -H O p e -H Pj -H

-P -H -P -P -H -H-P in 4J

P -d 3 · -P -d -d 3 3 tn -h 3 - -h -h 3 c cd x ccicb ^ -hc C OCÖOOOOP-PCÖ -P rHÖ- ^ rI C g 3 a P, ^ 3-- ^, 033: 3 cö O Vi OOVtf-jtp

O Π3 + 3 · -d -d -p S -P

P> jPPj>, i> 5PpP

w K> cnpM> ijj>

I I

• Hl —-III

rH -H -H -H -H -H

'—I i — I r-H rH rH

5 £ jj £ £ £

oi -p -d -p -p -P

a <i> -h pop i a i e a a a a a f -h p r r r I 3 H Pj 3 3 3 s ή i i i i • H -H r * L Pj -H -H -h 3

H H Pj I H r — I H I

jj £ S -f £ £ £ H

-dinPi-HtnininS

h X O v> X χ χ> »CP W JcJ P P P tn PÄ-H ΟΛΛΛΛί

Pj O I C O O O P

• H (—I -H -d I — Ji — I rH jC

Pj- ^ iP! >> Λ! PJ Ai O

I >> I HP >> S H

-P tn 3 l in tn tn, m II *> -p III >> • ha 3 iaaam in i I -hiiii Λί— '^ H - r ^ r ^ a 0 -H -H -H -H -H 1 P rH rH ί> ϊ fH rH rH ''% a js ΐ ss S c

X! -d -d C -d -d -d S

1 -H -H P -H -H -H i >>

Hfpppjppp-o

I P P -H P p p -H

• HpjpjtnpjOjPjP rH -H -H X -H -H -H P

> iPjPjO PjQjPjPj

!> a I I -P I I I -H

-P -P -P P pj "-P Pt Pj p i -h i a i i i i C -H -d -H I -H -H -H Pt p in -h in o ω in in l

<H Ai g A! 1 Ai X X -H

• h o 3 o - o o O en 5 £ g · £? j? 1st £ 3-0 P I X5 I -H I I I -H> »P a Pt -H Pt rH Pt Pt p Ö J3

Cl I rH I s I | I 3 I

• H Pj -H Α »ϊ -H,> s -H -H -H P -P

<1 I H Λ H -P rH rH rH Ai I

0 SJi S a S-H fe SS 3¾ 1 -ρο-p i jj-d + s -pc s-h

OJ PJ2P a P -H P -H P 3 Λ B

i cc c-h i -h cg c τί c a! -p 3 • hp 3 pdHd p3 ph ph po rH <jJ. * i <»- JH rH -H« HO Cjgl-lC CPj f >> -H -H -H g SS -H Pj -H 3 -H CÖ P pj Ϊ >> · Η cc C® k S CPjCO C 3 Cj cd

tn-d 03 OO eno 03 OPjO-P-hjC

Ai -h 03 O pj Ai Pj O £ OPjOC C-h

Pg H Oj i — I Pj P Pj * —l-H rH3 <—IP OO

Ä 3 H! O A! 3 Ä3 Ai C A! Λ X Pj O i>

O C 1C I C O rC IP l-H I O H -H

i — IO OPj O-h rH * H pjrH, O C O H Ai i — I

X -H IO I O Ai O 13 10- IA! I>,

ί-iPi - H ->!>;> r> rO rf », OS

I »O --Ai ^ O MO ^ O ^ jj ICI >> liniinitni3ll IP apjoiin oj-h a-h οι-h οι λ oj— oja 25 58328

Example 7 '2- (4-Hydroxy-1-phenethyl-4-piperidyl) propionic acid ethyl ester To a solution of Ν, Ν-diisopropyllithium amide (prepared from 8.9 ml of diisopropylamine in 60 ml of anhydrous tetrahydrofuran and 25 ml of 20%: solution of n-butyllithium in hexane at -75 °), a solution of 6.4 g of propionic acid ethyl ester in 25 ml of anhydrous tetrahydrofuran is added dropwise at -75 °, the mixture is stirred for 1 hour at the same temperature and added over 20 minutes. containing 12.5 g of 1-phenethyl-4-piperidone in 50 ml of tetrahydrofuran, and the reaction is allowed to proceed for 2 hours at about -70 [deg.] C. The reaction temperature is allowed to rise to about -10 [deg.] C. and the reaction mixture is decomposed at 100 The mixture is extracted twice with ether and the crude product is isolated by evaporation of the extracts dried over magnesium sulphate, the red oil formed is dissolved in acetone, the required amount of maleic acid is added and the precipitated crude crystals are recrystallized. setonista. Hydrogen maleate of the title compound with a melting point of 138-139 ° is obtained.

According to Example 7, by reacting the corresponding 1-phenethyl-4-piperidone derivatives with the corresponding carboxylic acid esters, the compounds described in Example 3 (pages 15-18} can also be prepared.

Example 8: 2- (4-Hydroxy-1-phenethyl-4-piperidyl) -M, N-dimethylpropionamide To a solution of Ν, Ν-diisopropyllithium amide (prepared from 8.9 ml of diisopropylamine in 75 ml of anhydrous tetrahydrofuran and 25 ml of a $ 20 solution of n-butyllithium in hexane at -75 °), a solution of 5.05 g of N, N-dimethylpropionic acid amide in 25 ml of anhydrous tetrahydrofuran is added dropwise with stirring. Stir for 1 hour at 7575 ° and then dropwise at the same temperature a solution of 10.2 g of 1-phenethyl-4-piperidone in 30 ml of anhydrous tetrahydrofuran. The reaction is allowed to proceed for 1 hour at -75 °, the temperature is raised to about -10 °, and the reaction mixture is decomposed with 50 ml of $ 20 potassium carbonate solution. The mixture is extracted twice with ether, the dried extracts are evaporated and the semi-crystalline crude base is dissolved in ethanol. Add the required amount of fumaric acid and ether until the solution is cloudy and the crude crystals obtained are purified by recrystallization from ethanol. Hydrogen fumarate of the title compound with a melting point of 188-189 ° is obtained.

According to Example 8, the following compounds can also be prepared by reacting the corresponding 1-phenethyl-4-piperidone derivatives with the corresponding carboxylic acid amides: 26 5 8 3 2 8

te te I

-p -po te tn tn ö -p \ • H \ -H te tn p

G P \ f — t p p O p C

p o ρ ρ o φ h m α p o o pöpö-- 'o co o a p ö φ g o g G ojpoo G ω te a p o te lopen

• HO G p G Φ ltn p c \ J tn φ G

te lpv o —op'— ·> φ cocetn ^ -

> "J" N Φ OJ - G

te o »o '—of- __ o

Λ ^ Ο’-ΟΟΟ Lf \ * - O O "O OO

'-p-CXJOOO OI O pi t— · p-O ON

Pl '-'- laOnCMLTN On CO On ft CO ltn <- tD UO I lr-T- | «CO OJ ^ M r- p- | tn * o r- ι oj uo o »- i ite icMf—

• H Os ft "OJ NO I ·> t— I CO NO P G CM I ON

Pl / NT- i- U> CO ΓΟγ- CO CO ON tn P CO -P t- G> - · - · - o co oj <- ρ ρ »- p- te ·· ·· cvj c \ j * · 1— g te oj ·· g! ·· ·: ce · · ·· o te • H ftp ft. ·· .. Oh .. ft · p G · ·· ft n ft ra in in ft · · tn · tn ft φ o ft · tn> jtn -H cnftft ft tn tn ft tn ft ft GGG tncnG tnG G ft ra c

G -H O -H G Ή P G - G G -H

·> Ρ ρ ρ ρ p G Gp GO -H tn p CP

p P ^ G P G P · Η -H G · Η · Η p o · Η - p · Η G

O G G G Φ G G ^ O ^ -O G Ό P G rOföGG ^ tÖ ^ G ^ - '

ω G P G 01 G G: G · Η: G · Η G · Η O G co ρ ρ G: G P G G sG

-¾ G tn Ρ P ppgpg · Η ppp r-Ctnppgp.Hp GG ρ Φ ρ Φ G tn o tn o Φ O Gi G l ρ ρ G tn o to Φ tn P g ft PG Ρ Θ · ΗΡ · p P p O β OJ ft ft g ft G · Η ft p

G GO GO G GP ^ OPrQ G ^ G! P G mpoGPPPGP

G ft G g P g ft Φ O Φ O g G O X) lp r-GCPCDOOSO

S G S Φ S P P P P S S -P P> s >> PG> sP PC S -P

O ppp tn p ρ p ft ρ ft p in ft jC p · ft ρ ρ p ft et) ρ p G φ φ φ G φ φ φ> 5 φ; >> οι · η>, · η φ ftGooo> ipoo K > φ w φ m> pmo> MS '-'> otGo> o

I G

• H · Η · Η O II

ft ft ft · Η · Η Γ '' -, I

* H S · Η ft ft ft 'g ι g S g ι o s ρ i i

0 G P G ft p S S S

P G Φ G P ft P S I I "

G! O g O S -H Φ G ft O 3 I

S · Η I ft S PllgOPPIft

en ft 3 ft tn S 3 -G- ft ft S Gi -h I

1 OI O pe! I Si I ft Ph S! >> ft OJ

OJ Ρ · Η Ρ φ CM G · η cS I O G tn!>, I

I ft H ft X I Φ Ρ ft '3 Ρ Φ I S · Η

• η · η s ρ ο · ηρ S ρ λ Ρη ρ oj cp ppSpppi S S 3 · η ι ι φ S SS0}> j G! S3 tn Si ρ 3 -—- ft S

S S G! S ί> 5 S ι g! G o s 1 * h p G -Ρ -Ρ φρ tn P ft φ O ft S Ρ ι— | ΡΛί GGPO I Φ ι — I, G * H ft p p O Φ rO-poaoiaSopHGo ^ So.c • H · H P · H I p S P O P g S TG P o ft ^ ÖGiftftftPG! PP I P ft G! ft I I> ilpl Φ £> »Ph O OJ Φ G I G! 33G3S3gGI> gOft >> "“ I * 'S *' I I -— 'O · - I ftl tn

3333P333 P tn ft 3 ft OJ I

ι ι ι ιφι ι ι p h p -h ρ ι ft ι a • H · Η · Η · Η · Η · Η · Η · Η ^ · Η · Η -G · Η · Η

ι — I I — If — ir-t ^ i — f ι — li — lpÖrHrÖrH I r — f ι — I

£ £ j? FtftftoftoftGjftft • Η · Η · Η · Η 3 · Η · Η · Η ft · Η ftp Ο · Η Ρ ΡΡΡΡΙ Ρ Ρ Ρ Ρ Ρ ρ ρ Ρ ρ ρ ΦΦΦΦ ^ - 'ΦΦΦΟίΦΛΦ'ϋφφ ftftftftpftftftl ftl ft> s ft ft Ρ Ρ Ρ ρ ι — l Ρ Ρ · Η -G- P -Ρ · Η JC Ρ p ftftftftS ^ P <P <i ftl fti ftft

1 I I I S I I I P I P I -G Γ I

-GP'-G-G'd-GG-G- WG- ω-G I _G- _G

I I ι I Ρ I I I M I Λ! I Ρ I I

ρ ρ ρ ρ ρ ρ ρ ρ op ο ρ η ρ ρ p tntntnwotntntnptnptnStntnO ΛίΛίΛΛ! ftGclGiJ * iOG! O> i S-MGiP

Ο O o OP O O O> 5 Ο >> Ο -PPO og

P h ΐ P ftp Ρ P Ä P JG P OTGP PG

OotGtG I tGtGtG I x) I xl GPnGOP

φ >> S S> 3-g> s i >> >> - g- t >>. *> 5 φ s ί> »>» φ

GjGägGjG I G3G3jG I Xl I ÄftGÄÄtn

p I I I I P l I l P I P I P G I I G

<Jnt -G- -G -G H -G -G -G H -G H -G pO-G ^ GP

I I I I S I I I S I S I Ο · Η I I ft

P * H Ρ Ρ p >> Ρ · Η Ρ P S * H S · Η O ft P p S

ιΗ Η Η Ρ -Ρ (ΗΌΗ Ρ -Ρ Ρ ρ P POP pS

SSSS ο S'dr * »SS φ S jiipS S - * - 'SSSS c SsS S * hcp S ö S iftS So ρ p ppp φ pGp ΡΌΦΟΡ Φ Ρ ΟΡΡΡΡΒ φρφ φρφ ft φρφ φ ρ ft ρ φ ft φ ιρφόφι GX) G tl ρ GIG Φ GG g Ρ · Η GPG Ρ, SGPG 3 φρφ Φ0Φ r- ΦΐηΦ oGGtno g φ xi - Stnaoi ftMft a-toift I ft G ft ft GOP ft O ft ρ ι ρ ft G ft p

• r l G Ρ Ρ O Ρ Ρ Ρ Ρ P P O O G Ρ O Ρ Θ CNJ Φ Ρ Ρ P rH

Gpi-t GftG tn GrHG CPr-IGt-H P Gw IBGOigS

ΟΦΟ OftO A! OS © Oft> SOO Λί Ρ O Ρ Ρ I O tn O S

OWO O G O O OSO GO I ft O IG ΟΦΗ3 OG OC

ι — IG' — I rH, Ci — I G Ρ p tn H PGOPi — I O P P tn S I '—IP Ρ Φ M -H M yp Λ ftftlftA; | P> | G S-H ϋ P Gi ft

I <—Il I G I ·> »>, Ρ I Φ I IP r— Ρ I Ip tni — I lS IP

0> j0 OO O rGg O G Ο O P ^ ft O '-'P oppSoSotn iSi ι-H I IG IO IP iSlSlP IG iScSlP IG! '-Tn · - · ft · -Gp'-P'-O'— S 11c \ i S »- x) ιοί <l> r- S otn <-φ <- ο

- G! '· - Ο'-' ^ ω ^ X ^ .Hwp '^ vlp P VJ ft p PGi ^ a' - 'P

ΙΦΙ I C I ΙΜΙ> »ΙΘΙΦΙΦΙ0ΙΡΙ0ΙΦΙΡΙΦ OJPOI CNJ ft OJ OJGOJmOIGCUg’-gOjG ^ -ftOJPSrGOJTaCNia 27 58328

CD

a '' “S * A ®

CD A

<D ω · η

\ · Η G

• H d O

H O -P

0 -P CD

-PC CD ω O ® ω a! • h -p ¢ 0 ---

A <D

® -— O O O

> c · - o o on ao o o on 1— o vo oo o cm o o o o o o o \

CT \ i-POVDOOt- is «-c— pfiAcnt— t ^ CM

aion i «- cvj '- i md i - o c— cm e— r- cm

en CM ir \ I * - I CM »- LA CM CM r— CM r— CM I

hi on c— i -a · m ιι ^ ι ι i ι i ico

H CO t— CM pf on> - £ - r-lTcCMH · '- MOLTNCM

COΟ T-CM> - Ά 1-OD-CMr— '-CM

CÖ CM ·· * - ·· '- •• CMCM'-CM' ~ CM

• H .4 · ... ·· Ph · »·· ·· ·· ·· ·· · en m ft · ft ω · m · · · · · · ft> a ft M ft M ft ft ft ft ft ft ft tn

Am C tn C tnCtntntntntntn

H G G · Η · Η G

- e -p * H C * H A GAGGGGGG-HO

-p · Η cd -P · Η -P cd · Η CÖ Ή · Η · Η · Η · Η · Η A A

cd d cö®A®® ^ - 'd®dddddd®-3-en · Η C cd cd cd C: cd · Η C · Η · Η · Η · Η · Η · Η «ν Α Ρ · Η Ρ cd Ρ · Η Α θ · Η Ρ I Ρ Ρ Ρ ^ · CO ID ¢) CD cdCDcn O CD Ο Ο Ο Ο Ο Ο ® 00

pi — I rH ÖH a ι — I Ή Ρ H H ft «—I ι — I <—j —j g A

G A cd 3 cd 3 ® P A Cd A A Ai A! A! A! 3 <- edOced g ft i ft Ö CD O Ö OOOOO Oft ap -p F>> 5> -> -p P >> ft ft ft ft ft ft O d tn -p -p -p + 3 + 3 + 3 d +3 dddddd -p 3Ϊ >> · Η CD CD CD CD CD CD> »CD .51

BAP>>> >> (D A> A A A A A A> CO

• H

B

• H I

ι d ι -p ft a · η · η ι cd η ι ι 1 I '' ÖIHI-HiaSSIft a cm ι a ® s >> - h s ι ι s h

ι ι ι -hi g ι >> · η >> ι a -ρ -ι> s • H a · Η Η · Η Ο · Η ΜΗ S '- I <D · Η · Η S

H I H! >> H · Η H A t ^ ftHiH S H d £ c £ 3 £££ & ££! & £££ h £££ cnSMAlMf-i-PO'HftPsAs ^ -i'dtn ft

A! ! >> A CD A ft G H P O d tn ί> »· Η A O

CD ft CD A CD · Η CD A CD Μ · Η A ® P <D M

A O A O A H ftSft-H P OA OA-H

ΟΜΉκόΟΜΉ I CD A CD ft O I

H ft H A H P "i Η * H ft · Η Λ O ^ * H r — j · H

A OA A A A d I d-HH O ftAd

>> M> jM> j3> 5lPtl ft A H I> a I

cn-HMI m A tn SISI> 5 A A- tn a III a III * · Η ·> ΑΜί> 5ΙΙ · 'aas ι oossaens ι ι w · η aa ι II -' ι ι ι ι A ι · η s ι OT ι ι

--—- -—- —- · η -—- -—- -— '-—- O - tn I a A

H * H -H rH 'Η * H * H · Η P * HA "' I Ο * H Ή HHH i> a HHHH d ι IO * H - Ρ Π Π ddd-Hdddd I d S!> A >> A dd • H · rH · ιΗ Ρ Ή · Η Ή · Η A «HA d As t · Η · Η PPPDPPPPI Ρ I · Η d A Ρ Ρ <D <DCDft (D <DDCD * HDAP-H I (DO) ftftft -H ftftftftH ft I CDP-Hftft • Η · Η »H ft Ή · Η · Η · Η · Η · Η ft CD ι — f · Η · Η ftftftl ftftftftt», ftH-Hft> sftft

I I I A I I I I -PI S, ft · Η >> I O I

AAA I A A A A (DA!> J I ft-pAftA

I I I -H -H I I I I C I A A I CD I ft I

• Η · Η · Η Γ0 hH · Η · γΗ »H · Η d)» H d) I P · H Cu * H

M M Μ-Ηίχ, Μ M M M ft M 0 · Η I <D MAM

A A aöKa A A A I A cd tn -h ft A -h A

0 O Oö-P O O O O’- O ft A tn -h OHO

ρ p p-poi ρ ρ pp, H o fp iöhiö ddd (DC dddd I d Ρ PO> jdl> jd CD> i> 5 >> tn cd S t >>> y S ± 1> »>?“]> ?

CA A A CÖ ft A Ä A A I A O & T1 A

Hl I I · Η · Η I I I I · Η I Η · H A> 5 ω I O I

<A-HA AHtn A A A A H H Adi A S AAA

Idi I A I I I I * *> I 1 · η A I I 'b1 • Η · Η · Η · Η? >> Ο · Η · ιΗ * Η · Η? >> · Η 0 g I A ft · Η CÖ · Η

ΗΒΗ ΗΑΑ · ΗΗ · ΗΗ Η Η -Ρ Η | 3 · Η I · Η I HAH

δΐ δ, δ§ §3 S3 δ S-η S ρ S - ° S il τβ Βί Β

AftAdftl I a A a a Ad A I -HA l-Hi> j> jSldACÖA

CD ft CD Ή CD a O 3 CD® CD (D-Η CD ad CD CMftA> 53 <Μ · Η IDcd CD

acdödöi idGCG a & Λ ι · η ö iocd AdiSöftö-H

(DA CD® CD Ή r— O (DO CD CD CD CD · Η0 CD -HP C CDO-H® (DO CDd ft »H ft d ft HI · H ft H ft ftdft H 3 ft H ft CD Π · ΗΗΰΡιΡ 'Η Η ·

• H O * H O * H * H ft · Η ft Ή · Η Ο Ή 0 · Η · Η ft ® ft f> s O * H ft · Η B

Ρ · Η pp ^ tnO PO Ρ Ρ * Η Ρ Ή r> j ft Ρ · Η?) Η Ή Ή ft O r ^ * H PO Ρ®

ΟΟ OftOGAP OP Ο OftOd MftOdA ^ Bd-HP MftOH OO

OM OO O CD Oft Oft O OO O-HAcd 0 · Η di> iO-H P ft AO OA Oft Η · Η ι — IP H ft Ρ Ή ι — I · Η ι — I ι — I Ρ ι — lg CD A ι — IBAM PS C3 · Η CD Ρ ι I ι I ft AI AftA-HdHAHA Aft A® Α · Η A® IAA ® OHAftAMA® 1 »HI · Η I g >>> 5 III * H IdOd Id CD ΙΠΗ> OH · Η ι · η ia OH OH 00Al> a0i >> 0 OH OOHO OOAA ftOAi> »HH OH O Ή

I ί >> I> 3 I 3 I A 'I A I | S, | -H A · Η I · Η PO I -H I A A I >> I O

‘-S *>’ - >> '- H- = r <DH <D * -> -i >> ^ ft>, ftT-ft (DH'-ftOO> s? *> -R— * ->

—'0- ^ —- A - O ® O —- O A A '-' O - g tn A - A - O

I OJ I CU II II I -H I l (DIPIPIPI | | jlPII ICDICDIM

CM a CMS CMftCVia CMd CM CM B CMftaftCMfta® CMftCMa weather CM-H

58328 28 p

•B

> o o o r— o -P * - -3- VO t ~ -

<U CM i- CO

M CM i- I O

• HI I LO f- I

HO CO VO »- tO

cd> - r- CM oo nj CM «- I · - X" to CO · ft CM Ph> j ft ft co co ft m tn S. ö * GO · η ft · Η -P · Η · Η -Ρ CO Η O Td H cd cd ω · η · η cd ö cd .¾ ti Θ (h -hg po O cd -p cd

-ph ti B cd S

P X o P cd P

n3 O O ft t ft S ti Si> 4 cd> »

OH H -P B -P

P> 3> j 0) P 0) KW K> ft>

•B

B

£

B

• H

Tue

Olli ft K K K

• Carbon ft · Η · Η · Η K

I H H I — 1 I

Η "> 3> 3> 3 · Η I> 3? Ϊ́ Η • H CO CO M> 3

CO χ X Ai S

X (V CL) O CO

0 K K K X

U O O Ό <D

H H H H K

>, Ai Ai AS O

• G> 3> 3> 3 H

1 co co co Λ! - = r i i i> s

I S S S CO., LTD

• Carbon H ^ · - · B

£> 3 · Η · Η · Η I

P3 H H H - ~ -

• P> 3> 3 S -H

0? »3 i> 3> 3 H

Ö H H H> 3 Ο -H · Η · Η> 3

ft P in tl H

• H 1) O flj -H

co ft ft ft ti

Pi · Η · Η · Η 0) Ο ft ft ft ft -PI I I · Η 0) Ht χ- _cr · Η ft

1 I I I H I

I · Η · Η · Η · Η

0 CO CO tO B I

1 χ x x cd -h

3- O O O CO CO., LTD

t ti ti X X

I H H H O O

U CM> 3-H> 3> 3 K G

Ö I K H K K U H

H · Η I · Η I I CD> 3 <Ch - =) s j- · η -a- .¾ κ

! >> I a I H I -H I

> 3 · Η O · Η · Η · Η C -H-

-p H ft H B H cd I

0)> 3 ft S M t>, cd · H · H

B> 3 cd> 30 S-PHH

| -p Ä -P ft -p C >> · Η

B ΟΙ · Η 1) ft O O> 3 S

i · η c ti c cd c ft -p ro • HH 0) 0 ΦΛ 0) 0 no H * H ftH ft · Η ftH G ft> 3 S · Η od · Η C -HXO ft S ro ti> ti o ti> 3 ft cd ω o OO OSh o to -h ö

Λ! ft O M OftOI ti * H

0) ft i — I · Η H cd H * - O O

K cd. «I Λ Ä I o> 0 d I Ή I · H I * H H Ή

Η · Η Οι — I Οι — I OH .Pi H

X Ο I> 3 I f-ι I> 3 I> 3> 3> 'k * 3'> 3 1> 3 O P3 tOO --- -P ------- '-P' 4-J '1 CO I <U ΙΟ 10) I 1) η, ή cm a rvi a cm a cm a 29 58328

Example 9- 2- (1-o-Chloro-phenethyl-4-hydroxy-4-piperidyl) -N-phenyl-propionamide

To a solution of 9 g of N-phenylpropionamide in 90 ml of anhydrous tetrahydrofuran is added dropwise, under stirring under a nitrogen atmosphere at 0 °, 48 ml of n-butyllithium dissolved in hexane. Stir for 2 1/2 hours at 45-48 °, and add dropwise over 50 minutes a solution of 10.5 g of N-o-chlorophenethyl-4-piperidone in 25 ml of anhydrous tetrahydrofuran. The heating (oil bath) is removed and the reaction mixture is stirred slowly with cooling for 1 hour. To the reaction solution is then added, with stirring in an ice bath, 10 ml of 20% potassium carbonate solution, the solution is diluted with ether, and the organic phase is decanted, dried over magnesium sulfate and evaporated under reduced pressure. The crude compound obtained is filtered through silica gel (eluent: chloroform containing 3% methanol), and ethanol and an equivalent amount of fumaric acid are added to the resulting title compound, and the compound is crystallized as hydrogen fumarate. The hydrogen fumarate of the title substance has a melting point of 159-161 °.

Example 10: 2- (1-O-Chloro-phenethyl-4-hydroxy-4-piperidyl) -propionamide

To a solution of 17.5 g of 2- (1-o-chlorophenethyl-4-hydroxy-4-piperidyl) -propionitrile in 100 ml of 95 ml of ethanol and 20 ml of 3N sodium hydroxide is added dropwise with stirring in an ice bath for 15 minutes During 20 ml of a $ 40 hydrogen peroxide solution, the mixture is then allowed to stand at room temperature for 18 hours, after which the ethanol is evaporated off under reduced pressure. With stirring in an efficient ice bath, 100 ml of 4.4N sodium bisulfite solution are slowly added to the aqueous phase, the reaction mixture is allowed to stand for 20 hours at 20 ° and made alkaline with an excess of 5N sodium hydroxide. The mixture is extracted several times with chloroform, the organic phase is washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The crude title material obtained crystallizes from acetone with a melting point of 141-142 °. The melting point of the hydrogen maleate of the corresponding title compound is 219-221 °.

The starting material can be prepared as follows: a) To a solution of 17 ml of diisopropylamine in 250 ml of anhydrous tetrahydrofuran is added dropwise, with stirring under a nitrogen atmosphere at 0 °, 48 ml of n-butyllithium dissolved in hexane. Stir for 15 minutes at 0 °, cool to -70 °, and add dropwise, with stirring, 4.2 ml of propionitrile in 10 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 1 hour at -70 °, and then a solution of 14.2 g of o-chloro-3o 58328 phenethylpiperidin-U-one in 25 ml of anhydrous tetrahydrofuran is added dropwise, and the mixture is stirred for 1 hour at -70 °. :in. The temperature is raised to 0 °, 5 ml of 20% potassium carbonate solution are added to the reaction mixture and the organic phase is decanted. The residue is washed twice with ether, the combined solvent phases are dried over magnesium sulphate and evaporated under reduced pressure. To the obtained 2- (1-o-chlorophenyl-U-hydroxy-4-piperidyl) propionitrile, acetone and fumaric acid are added, followed by ether, whereupon the fumarate crystallizes. The melting point of fumarate is 187-189 °.

Example 11: 2- (1-O-Chloro-phenethyl-N-hydroxy-N-piperidyl) -N-butyl-propionamide

A solution of 5 g of 2- (1-o-chlorophenethyl-U-hydroxy-N-piperidyl) -propionic acid phenyl ester and 50 ml of n-butylamine is refluxed under nitrogen for 18 hours. The excess n-butylamine is then evaporated off under reduced pressure, the residue is dissolved in chloroform and the organic phase is washed twice with water and dried over magnesium sulfate. The chloroform is evaporated off under reduced pressure, and an equivalent amount of maleic acid is added to the residue dissolved in ethanol, and the residue is recrystallized from acetone / ether. The hydrogen compound of the title compound has a melting point of 132-133 °.

According to Example 11, the amide compounds described in Examples U-7 (pages 18-25) can also be prepared by reacting the corresponding (1 + -hydroxy-t-piperidyl) -carboxylic acid phenyl ester derivatives with the corresponding amines.

31 58328 R, R. R3 R * R, 3 \ / 4 \ X "i 3. / k HO C-CO-R HO ^ O-CO-R ^ HO ^ C-C0-Ro

X X X

Xr / \ s / R 1 '1 I (CH2) 2 la (CH2) 3 lb a Λ ^ "jr R8 I - R8

xx XX

R R R R

HO ONH HO (<CoX 6 H0>. C-COOR

X 1 (X X

XX X

»1 R, Ic R1 Id R1 Ie

I R3 RU

V / 01 * H0 '"' C ^ CO-N '^^

Hrr-coR2 \ r ^ r7 I 1 X-R1 X ^ II? Ila 111

B

i r XX HO.

*, Λ XX cox ^ w H-C-CO-R2 r2 I x /

1 N

(CH) V

X Bi If I - R8 iv

XX

32 56328 R3 Λ XXX ’ΧΧ ΧΧΧ

Nc CO-N-v ^ 'y HC - co-kh-A' X

O © ^ - === / Va \ / Vb

-I R3 rU

XX HO> -CN HO c-CH

HO Cf-C0-H „\ X X

> <2 rS π --O VI 1 Jn2 E VIIa -f — r8 V / ^

HO C-COR

6 R3 \ X

\ r VIII r> HO C-CORl k * / Γι CH \ / xk2 1 r "ll CH2 ix I IXa

X A

Κ3 \ χ ^ XR6 HO C-CO-N b X '5 1 / ΐ k [xk. VI lb

I IXb RT

33 58328 X- (CH2) 3-A- ^ y ^ E0 xi

B

HO \ V <^ 'C ~ CN

R3 / ¾ \ s'

H-C-CN XII I

ch2

XIII

Claims (1)

A process for the preparation of therapeutically useful α-hydroxy-1- (phenethyl and U-oxo-4-phenylbutyl) piperidine derivatives of the formula HO C-CO-R 11 wherein R 1 is a phenethyl group, fluorine, chlorine, bromine , a phenethyl group monosubstituted by methyl or nitro, a butyrophenone group or a butyrophenone group monosubstituted by fluorine, and is an OR group in which R 1 is lower alkyl, allyl or phenyl, or R 1 is of the formula ✓R 6. . . A group according to N, in which R 9 and R 8 are in each case hydrogen, lower alkyl or cycloalkyl having 5 to 6 carbon atoms, phenyl, benzyl or cycloalkylmethyl having 5 to 6 carbon atoms, or R 8 and R 6 together with the nitrogen atom to which they are attached form a saturated 5-6 ring membered heterocycle which may optionally contain oxygen as the second heteroatom, or methyl substituted nitrogen, and R 1 is lower alkyl or cycloalkyl of 5-6 carbon atoms, cycloalkylmethyl of 5-6 carbon atoms, phenyl or chlorine, fluorine, phenyl monosubstituted by methyl or nitro, and R 1 is hydrogen or methyl, or R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl ring having 3 to 6 carbon atoms and their acid addition salts, characterized in that a ) is administered to compounds of formula II, HO. C-COR2? H 35 5 83 2 8 wherein R1, R8 and R3 are as defined above, react with compounds of formula III, XR III wherein R is as defined above and X is an acid residue of a reactive ester such as a halide ion, or h) for the preparation of compounds of formula Ia, R 4 3 3 / i ho c-co-r; K W 2 r 2 S - R 8a wherein R 1 and R 1 are as defined above and R p is an OR group wherein R is as defined above, or is a group of the formula wherein R 1 is lower alkyl W 0 DX or cycloalkylalkyl, cycloalkyl, phenyl or lower phenylalkyl, R 1 is if R 9 and / or R 8 are optionally substituted phenyl, hydrogen, or is lower alkyl or cycloalkyl of 5 to 6 carbon atoms, phenyl, benzyl or cycloalkylmethyl of 5 to 6 carbon atoms , if Rg is lower alkyl, or cycloalkyl or cycloalkylmethyl having 5 to 6 carbon atoms, or R1 is hydrogen and R8 is phenyl, or R8 and R6 together with the nitrogen atom to which they are attached form a saturated heterocycle having 5 to 6 ring members, which may optionally contain oxygen as a second heteroatom, or a nitrogen substituted by a lower alkyl, and Rg is fluorine, chlorine, bromine, lower alkyl or lower alkoxy, is administered by the compounds of formula IV, 58328 3β kk kgk (C «2) 2 I - B8 wherein R 8 is as defined above, react with compounds of formula V, R 3 Λ / 4 IV HC-CO-R 1 wherein R, R 1 and R 2 are as defined above, or c) compounds of formula Ib for the preparation of ho 2 ^ c-co-r 2 ((jH 2) 3 CO Λ I - r 8 Ib in which R 2> R 2, and R 8 are as defined above, the protecting group is cleaved from the compounds of formula VI, CT-CO-R_ Ö / T ~ V 8 VI (ch2) 3-aA -Λ wherein R2> Rg, R1 and R8 are as defined above and A is a ketally bonded carbonyl group, or d) compounds of formula Ie to prepare, R-R, 3 \ X "k HO C-CONH„> <2 Ie! R 1 in which R 1 and R 2 are as defined above are hydrolysed in compounds of formula VII, R 1 where R 1, R 8 and R 2 are as defined above, the CN group NH 4 As a -CO group, or e) for the preparation of compounds of formula Id, 38 58328 „ο * 3 · - ^> 6> <>, Id R1 in which R1> Rg and Rj are as defined above, compounds of formula Ie, R 3 is H, wherein R 1 is as defined above and R 1 is phenyl or phenyl monosubstituted by fluorine, chlorine, bromine, lower alkyl, or lower alkoxy, to react with the compounds, of formula VIII, / 6 HN 'VIII wherein Rg and have the same meaning as above, and the compounds of formula I obtained are optionally converted into their acid addition salts. 39 58328 For the preparation of U-hydroxy-1- (phenethyl- and H-oxo-U-phenyl-butyl) piperidine derivatives for therapeutic use in the form of: H0 ^^^ - C0-R2 ä, with the aid of phenethyl groups, in which fluorine, chlorine, bromine, methyl or methoxy monosubstituted phenethyl group, but butyrophenone group or en fluorine monosubstituted butyrophenone group, R- for the group OR, color R_ for alkyl, allyl or phenyl, ^ R ^ for the group Rp for 6 color Rg and R „betecknar väte, lägre alkyl eller NV cycloalkyl med 5-6 kolatomer, phenyl, benzyl ell cycloalkylmethyl med 5-6 kol-atomer, eller Rg och R ^ tillsammans med den kväveatom, account of en a heterocyclic ring with 5-6 ring components, preferably with and without heteroatom can be substituted with methyl or methyl substituents, and R 5 stars for alkyl or cycloalkyl with 5-6 cholatomers, cycloalkylmethyl with 5-6 cholatomers, phenyl or with fluorine , chloro, methyl or methoxy monosubstituted phenyl, o wherein R 2 is selected from the group consisting of methyl, or R 1 and R 2 are selected from the group consisting of hydrogen atoms, cycloalkyl rings having from 3 to 6 carbon atoms, and from the following substituents, Formula HO C-C0R2 II f H 1,0 58328 for Rg, R1 and R3 are formed by the form of the compounds of the formula X-R1 III for the form of R1, R1 and R1 are formed by the reaction of the reaction mixture -benes Ester, whether or not halogenated, or in the case of b) for the preparation of compounds of formula R3 RU \ / I HO C-CO-R ^ Ia (CH) X ^ Re color R ^ och R ^ har den ovan angivna innebörden, R ^ är en OR group, color R ^ har den ovan angivna innebörden, eller för en grupp Rg color r | betecknar lägre alkyl JT z. R7 or cycloalkylalkyl, cycloalkyl, phenyl or alkylphenyl, Ry, R8 and / or R1 are optionally substituted phenyl, hydrogen, or alkyl by alkyl or cycloalkyl with 5-6 cholatom, phenyl, benzyl or cycloalkyl 6 -colatom, in which R8 is alkyl, or 5-6 -colates in the cycloalkyl or cycloalkylmethyl, or R1 is hydrogen and Rg is phenyl, or R1 and 6 are in the form of a hydrogen atom, but which are heterocyclic a ring having 5-6 ring components, optionally substituted with one or more heteroatoms in which the alkyl is substituted by hydrogen, and R0 is hydrogen, chlorine, bromine, alkyl or hydrogen, alkoxy of the formula X «jVa I - R8 iv 58328 of Rg having the same name as the form R3 h HC-CO-R ^ V for R, and R * having the form of R3 h HC-CO-R ^ V having the form R3 R1 + HO C- C0-R2 (ch2) 3 Λ I --¾ 111 där Rg, Rg, R ^ and Rg are such that, in the case of the formula V Λ HO C-CO-Rp> <'f, —v- "8 VI (ch2) 3-aT of Rg, Rg, R ^ and Rg har den ovan angivna innebörden och A star för en genom ketalbildning skyddad carbonylgrupp, avspjälkar skyddsgruppen, eller att man d) förställning av föreningar med formeln HO C-CONHo> <Ie J R1