LU80531A1 - 4-ANIMO-2-PIPERIDINOQUINAZOLINE DERIVATIVES, THEIR PRODUCTION PROCESS AND PHARMACEUTICAL COMPOSITION CONTAINING THEM - Google Patents

Description

OC 5ο.125

8 ~ γΥΊ £ ï G ^^ ND-DUCHÉ DE LUXEMBOURG

V0 J I

du 15 nQV.eïSbJT.Q l.S.7.8 (fâWffy Minister, I of the National Economy and the Middle Classes

Industrial Property Service

Λ 7 / LUXEMBOURG

yrs Patent Application; r // o I. Request ..... La ... socdii £ ..â ^ ....... U) e ...... / A / h / il 6'-Αλ1 / ρ /// Α ^ ..................

...... 1Ο2 ... Α: υ ^ ι..ίΓ4Α & ο ^ .Α ^ .οΓ0..4Α ..... Æ / rpsa..dal * tysogf aei sisafc <? Λ cy ^ lAtg ân lur .fhfcaJ-re .............................................. ......................................

deposit ........ this „^ jinZ-Q_J.tOVvsZbr.3 ... 1 2.20 .......................... ...... (3) at .......... 15 ............. hours, at the Ministry of National Economy and the Middle Classes, in Luxembourg : 1. the present request for obtaining a patent of invention concerning: ....... ”Mi \ iiÎÊs ..... Ô5 ..... 4 ~ c: -. Iuo ~ 2 ~ plngrj.diitoc · ulna soline, ...... leux ..... pxcc $ d ^ de {4) ........... ί / ^ ο £ \ ια / 1ο: ι .... ^ .... ο.ο ~. / £ 54 £ 1οη ....: / 4. ^ ...................... ........

déelafe, assuming responsibility for this declaration, that F (es) inventeuris) is (are): .....: · *: .n ', "o ............. .................................................. .................................................. .................................................. .................................................. (5)

2. the delegation of power, dated ds 1. ‘Ν '.,;, ......... on ..XL · ..... // 4 / éé .... / éad ... <·. -a./ J

3. description in language ....... 'ivt t'p tl ............................ of invention in duplicate; 4.. / .. / ............. drawing boards, in two copies; 5. the receipt tax case ver.-a had Sureau ds i'Em agis :: -ment à Luxembourg, le ....... 15 .... s .J 44 / .S ..... .................................................. .................................................. .............................................

ifcV '.- r:' i: c for the aforesaid Cz ::. h ~ -lz of patent 'has priority dhma des) requested} of (3) ............... ...... · '' ......................................... ....... deposited sis) in (T) ... ri d ... -. -. .. é .......................................

the 15th ... die. 1,; - ¾ ... .1.417 ........... Γ'Ο * ...... 44.4.4.4/.7) ............ .................................................. ........................................; 3) ^ bu sm from ... -adé, .ddr.: 4 ... aaba4.aétéa.Q .................................. .................................................. .................................................. .............................. (9) elect for him / her and, if designated, p · ..r his mtndstaire, in Luxembourg .......................................

"" is requesting the issue of a patent c'i.manllon fear l'ob’at described and represented in err. ·; · c-s> above, - same mounaement of that emlivmnee to · month.

:, tiidl / elb 1. 4 ^ b. rrnie-r; ’R! M 'd / ôf / L' The aforesaid request for haaret "'a. ”E è hua mb mag. Dated: ML> 1. Pr. Le d'irdmre.

at .......... L.3 .......... hours / · '>' '* -v .é; de Ineovomie jTsdkemm el des Cleraas é-Peyerm es,; 7 / M; a .. 44 ·. P · / · - - r -: / 4 v · A 4.7 - ‘........., D. 50.125

CLAIM OF PRIORITY

* _______ of the patent application / fifafiYtfî /

' ' In Great Britain

NOVEMBER 16, 1977 ^ ----> '_______

UPDATE

Brief Description I filed in support of one of Iceland

! PATENT

4 to 4

Luxembourg i

2U name of: bFiSeR COrPOrAYION

for: "4-a derivatives; -ninc-2-pip * Sridinoquinazol.lne / their process αβ prcauccion and. cc ~ iposi 1ion ph ίππ a c en i i cj s containing them

The present invention relates to therapeutic agents which are novel derivatives of 4-amino-2-piperidino-quinazoline and relates in particular to derivatives carrying a substituted alkoxy group in the 4 position of the 5 piperidino group. These compounds have the property of exerting a regulatory effect on the cardiovascular system and can be used in particular in the treatment of hypertension.

The new compounds in accordance with the invention correspond to the general formula:% l / \ R0 N N / - X (I) πτ ^

RO

5 Π * * ίΗ2 10 wherein R is a lower alkyl group; and X is a group of formula: O-alk-OR1 in which the alk represents an eventual ethylene lover group killed by 1 or 2 lower alkyl radicals: and R · * · is a hydrogen atom; lower alkyl group; "M C 1-6 cycloalkyl group; or a group this for-

J O

ru le: - / T ”20 in lacquer! pa R and R-";.-have, independently of one another, of hydrogen, a lower alkyl or alkoxy / t I. 2 5 * ) '1' i, 'lower} a halogen, a trifluorcméfchy) t group, 4 5 454 l | a group -CONR R or a group -SO ^ NR R, R and *} a independently representing one of the another one has hydrogen, or a lower alkyl group. These compounds also exist in the form of their pharmaceutically acceptable icic addition salts.

; In the present specification, the term "halogen" denies fluorine, chlorine, bromine or iodine. The term "inferior or>" qualifying an alkyl or alkoxy radical means that this radj '..-, χ 10 contains 1-to β carbon atoms, preferably 1 to 4 atoms: *, · -.

'of carbon and, when co radical contains 3 to 6 carbon atoms, its chain can be straight or branched.

Pharmaceutically acceptable acid addition salts are the salts formed from acids qm.j X5 give non-toxic addition salts containing pharmaceutically acceptable pommons, such as hydrochlorides, hydrobromides , sulfates, bisulfates, phcspha * .. <· -., acid phosphates, steelworks, maleates, fumarates, lactates, * .; r_ tratas, citrates, gluconares, saccharates or p-toluenesulfu - .. * PQ Compounds invention having one or more: ..- existing asymmetry centers; : r> t in the form of one or more -; .--, pairs of enantiomorphs r: these pairs or the isomers mci /: ~ dual can be separated by these physical methods, by pie by crystallization · .- actuated to know suitable. L ’: .- -p 5 vent ion concerns separate pairs of the same with their me! ·: 'Y ·, in the form of a mixture? racamiquas or in the forms i: v,; optically active of e: 1 separate.

R is preferred. · Is a methyl group.

X represents a group: 30 CH CH3 -OCH2CH2OR, —0CH2 — CH - C3 · or -V .Lru-L-’Jrl.

r * uu "3 R · *" is preferred - a hydrogen atom, a crc-pe alkyl having 1 to 4 carbon atoms, a perreyla group or a "jpe pn 'nyle, possibly j_er. = - 3nr run. · ..

killed by a ra \ i '~ -l si, lower cyle, ..rue. <halogen, trif-aromethyl or carbamayl.

/ 3

In a preferred group of compounds, R ^ represents something other than a C 1-6 cycloalkyl group and R and R and R represent something other than a trifluoromethyl group.

The two individual compounds which are preferred are those in which (a) R is a group CH-., Nalk "is a group i -3 -CH-jCHg- and R is a group and (b) R is a CH ^ "alk" group is a group - C ^ CH ^ - and R is a phenyl group.

The compounds of the invention can be produced by various methods, for example by the following methods: 2q (1) The compounds can be prepared by reaction of i quinasoline of formula:

RO -N. / Q

rt V

I - (ii)

RO

im2 (in which Q represents an easily eliminating group such as quechl; brorno, iodo, lower alkoxy (lower aikyl) thi or (lower alkyl) sulfonyl) with a piperidine · formula:

X

Λ „---- (III).

V K /

H

in which Q preferably represents a chloro or oror radical

The reaction is usually carried out in close proximity to a base such as triethylamine or an excess of reactant of formula (III).

Living room in normal operating roca, the reactio bodies are heated together, for example to a temperature of 70 to 130 ° C, with reference to the flow in an organic solvent in a 4 such as n-butanol, for periods reaching approximately 48 hours . The product can be isolated and purified by conventional operations. For example, the product is normally obtained in the crude form by evaporation under vacuum of the reaction-5 nal mixture, and the crude product can be purified by recrystallization from a suitable solvent or by conversion, for example, into hydrochloride by reaction with hydrochloric gas, for example in ethanol, followed by recrystallization of the salt. Naturally, the reaction product is sometimes the hydrochloride. It also happens that the crude product can be purified by chromatography, for example by alkalinizing and extracting it with chloroform, by evaporating the chloroform extracts and by chromatographing the residue for example on neutral alumina, the product being eluted with chloroform and with a mixture of chloroform and methanol. The eluted product can be purified by conversion to the hydrochloride followed by recrystallization, as above.

The intermediate compounds of formula (II) are generally known compounds or can be prepared by analogy with known methods.

The intermediate compounds of formula (III) are known compounds or can be prepared by standard methods! sics, for example as indicated below: 1 (a) I Λ A ΙΛ j Γ I (1) KaH / PMP ____ hyarolye -AA. \ I A J (2) I (acid Ot?

j I RjO-alk Cl \ K / basic) \ n A

5 ~ or B O-alk-mesyl [OR H

I? = ° (bJ n ".is. Not c = 0 | [1’ hyarogene). .

; 3 ch3; - O ii o L.îiy]. £ o XTèCiin i cl o / \ ”: Ά

* U

5

The piperidines in which "alk" is an ethylene group substituted by 1 or 2 lower alkyl radicals can also be prepared via the corresponding 1-acetyl-4-alkenoxypiperidines, for example according to the following diagram ( R * can be a hydrogen atom in this operating mode? · H och2.ch-ch2 o.ch ^ hor1 (1) KaH / DMF ^ (l) HgOÂc / R1OH ^

(2) CH2 = CH.CH2Br ^ (2) RaBH ^ ^ J

S> v 'N ^ ^ N ^ ^ μ ^

l, I I

C = H c = o c = o

1 I I

CK-CH3 CH3 hydrolysis - 4 / Cacxd.e or 'basiqUe; 1

O.CH CHOR

> R P ”

H

(rj La 4— (2-hydroxyéthcxy) pipéric '?. cannot be prepared _-r i _ from the procedure already described, according to the scr.ama:

POL AT L

- / \ OCH0CHoOH OCH CH OH

ί), λ. λ ".

LiAlH4 / fc.Cl, ^ Ho on Pd ^ N

"->

\ N S \ K S

I K

CB „Ph I 2 GH2? H 7 t I” i, 6 1 '% (d) The 4 ~ (2-hydroxyalkoxy) piperidines can also be prepared by the following conventional procedures: 1 R- OEt f ° Et' p -ex * ™ "Wbcr / ° ch-c \! "Ô -“ Ô '

I I

· .; Prot. Prot.

H + / H O N / R "R" I!

OCH.CH OH OCH.CHO

Λ Λ I I <·

j N ^ \ K

! 1 1 ‘Prot. Prot.

ii ["Prot'1 denotes a suitable group protecting the arota atom, i for example an acetyl or benzyl group, and this group can be removed by conventional operations at the final stage, and H" is an atom hydrogen or a lower alkyl group] / 7, * or ^ R "* 0H OCH CH \

(iii) JL '· I ^ OH J

f \ (i) NaH, DMF, THF

(ii) s ° 7 / ^ N ^ ^ 4- R "^ Γ /

Pi'ot. Prof-, (5îProt. ”And R” have the definitions given above) or R ”,. ., OH . lT. _ (H). P.

^ (i) K.Æ / CÎP

"—-T11 - \ N ^ (ii) BrtHC02H u | (üi) StCB / H + |

Prot.

srïZO c.

OC ^ CH ^ OH

^ '\ K ^ * Vd * · ti ("Prot.” St R ”have the definitions given above).

* (e) your 4- (2-all: oxyalkoxy) piperéines can be prepared by reaction of a 4- (2 ~ hycsoxyslioxy) sipéricine port-and a protective orouc s on 1 * sluggish "obi" sr.us r-; r I * ·. * η c .-. s. i * above processes with a halo cesium of elkyis ru rr ·; i.ésy “s.te alkyl in the presence of a strong basa” by srrrrle according to! s scheine: 8 R "R" * pu R ...

oin-l? î rA 0H _ / k '-1 I I (i) KaK / DMF ^ ^ (Ü) Rll, Rlßr

I GU RÎOSO CH. I

Prot. 2.3 Prot.

'4 \ i

Removal of the protecting group \ / R "R'11

I I

; OCH-CH

. X v i ^ N '.

! H · (-: Prot. ”And R” have the definitions given above; R '*' is I a hydrogen atom having a lower alkyl group) and | <-f) The 4 ~ (2-aryl oxyalkoxy) piperidines can be pre-; trimmed: 5 (i) by reaction of an N - scy t 1 - 4 - (2 - hycrc>; there is 1 kb>: y) piperine obtained as above, with a phenol suitably: substituted , in the presence of tripheny! phosphine and diethyl asodicarfcexyl ("DEAD"), according to the scheme:. Ls ~ \ 9

("D.E.A.D."): OH

R "R" 'R "R"' c-Λ AR

i "r I i // OCH-CH-OH I OCH-CH-O - ('H2 ^" 3 ^ vhJ V1 ·' · * · '1 ·' 1Νχ \ j A THF. j c = o? '°

I I

‘CH

c 3 I 3, ^ hydrolysis Acid eu 'basiaue) R "R" ‘

I I

OCH -CH / --- λ 3 A, χ · / - ¥ \ rr5> ^ R2 K, y H.

(R "and R''1 have the definitions given above) (ii) the 4 ~ (2-aryloxyalkcxy) piperidines can be prepared as this variant from a 4- (2-hydroxyalkoxy) -piperidins bearing a protective group on the atom of asohe, obtained co.Tur.e above, and of fluorobensene or of a substituted fluorobensene, in the presence of sodium hydride or dimeinyl-fonna.Tdde, from the diagram: 10 R "R" 'R »R" "OCII-CH-OH 0CI1-CH / Λ' Λ I -> x — 7

NaH / D.M.F. N ^ ·

i i

C = 0 9 “°: I 1 i CH r CH0 3 I, ioo ° c 3 hydrolysis

V

R "R" 'I i, _.

Λ, '-Ο! C, J w

; H

'(R "and R' * 'have the definitions given above) (2) The addition salts of pharmaceutically acceptable acids * * * from the pharmaceutical point of view of the compounds of formula (I) can be prepared by conventional operations, for example by mixing Ί i 5 the free base with the chosen acid in a suitable solvent such as Isopropanol, filtering and if necessary recrystallizing the salt thus produced, until it is pure Naturally, the product in the operating mode (1) is often in the form of an acid addition salt.

The invention also relates to the pharmaceutically acceptable bioprecursors of the compounds of formula (I) thus having their salts.

The expression "bi cpr eeu s eu r acceptable from the pharmaceutical point of view" requires exegesis exéleica. It is well known in pharmacautic chemistry to remedy an undesirable physical or chemical property of a midica. By transforming this drug into a chemical derivative which does not exhibit this undesirable property but which, when it is administered to an animal or a human being, returns to its initial form. For example: -, - 20 pie, if the medication is not well absorbed when i! is administered to the animal or patient orally, it is possible ί 11 to convert it into a chemical derivative which is well absorbed and which; in serum or tissue, resumes the form of the original drug. Again, if a drug is unstable in solution, it is possible to prepare a chemical derivative of this drug which is stable and which can be administered in solution but which returns to its original form in the body. The specialist in the field of pharmaceutical chemistry is fully aware of the possibilities available to him for remedying the intrinsic defects of a medicament by chemical modifications which are only temporary and which are reversible during administration to animals or to the patient.

For the purposes of this specification, the expression "pharmaceutically acceptable bioprocessor" of a compound of formula (I) designates a compound whose structure is different from that of the compounds of formula (I) but which, however, when administered to an animal or a human being, is transformed in their organism into a compound of formula (I).

The antihypertensive activity of the compounds of the invention is demonstrated by their ability to lower the blood pressure of rats not anesthetized in spontaneous hypertension and of dogs not anesthetized in renal hypertension, when they are administered orally at doses up to 5 rng / kg.

The compounds of the invention may be administered alone, but they are generally administered in admixture with a pharmaceutical carrier or vehicle chosen taking into account the desired route of administration and pharmaceutical practice. normal. For example, they may be administered orally in the form of tablets containing excipients such as starch or lactose or in capsules, alone or in admixture with excipients, or in the form of ilixirs or whatever. suspensions containing perfumes or dyes. They can be injected parenterally - for example, per intravenous or intravenous or intra-venous air * For parenteral administration, they are best used on the farm with a solution 35 sterile aqueous solution which may contain dissolved body felts, such as sufficient amounts of this eucosa salt to make the solution isotonic.

Accordingly, the invention also relates to a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable acid addition salt of this compound in combination with a diluent or carrier acceptable from the point of view pharmaceutical.

The compounds of the invention can be administered to humans for the treatment of oral or parenteral hypertension, and they can be administered orally in doses which are approximately in the range of 1 to 20 mg / day for an adult of average weight (70 kg), in a single dose or in several doses, the number of which may be up to 3. The doses administered intravenously must represent a fraction ranging approximately from the fifth to tenth of the daily oral dose. Thus, for an adult of average weight, individual oral doses in the form of a tablet or capsule may be approximately in the range of 5 to 100 mg of | active compound. Variations are inevitable depending on the weight] and the condition of the subject being treated and the particular route; of administration which one chooses, as is known to those skilled in the art.

The compounds of the invention and the compositions containing them make it possible to treat an animal or a human being suffering from hypertension by administering to the animal or to human beings an antihypertensive amount of a compound 1 of formula (I) or of a pharmaceutically acceptable acid addition salt of this compound or of a pharmaceutical composition as defined above.

The invention is illustrated in the following examples.

: / U

"\ 13. EXAMPLE 1

Preparation of 4-amino-6,7-dimethoxy-2- [| 4- (2-ethoxyethoxy) piperidinolguinazoline hydrochloride.

och ^ c ^ cx ^ Hç- CH 0 co 1 / \ yx ^ \ N y ~ OCH2CH2OC2H5

/ <N A / N L J jL

NH2 nh2

The mixture is refluxed for about 16 hours under a nitrogen atmosphere 4.3 g of 4-amino-2-chloro-6,7-diraethoxy-quinazoline, 3.2 g of 4- (2-ethoxyethoxy) pipeiidine and 10 ml of triethylamine in 400 ml of n-butanol. The mixture is then cooled, evaporated in vacuo and the residue basified (aqueous sodium carbonate solution) and then extracted three times with chloroform. The combined chloroform extracts are evaporated and the residue is chromatographed on 150 g of neutral alumina (quality I, deactivated with 5 ml of water). Elution with chloroform gives the crude product (3.6 μg) which is converted into the hydrochloride by treatment with a solution of this hydrochloric gas in ethanol. The hydrochloride is then recrystallized from a mixture of ethanol and isoprGpsnol, giving 3.4 g of 4-amlnc — 6,7-dnnéthcxy-2- [4- (2-ethoxyethoxy) pioeridino ~] guinrzoline hydrochloride 219-220 = C. Analysis: 20 Ç ±% 1 H {%) N (%)

Calculated for C] _9H28N4 ° 4 * HC ~ 55.3 7.1 13.6

Find; eb, 4 7.2 13.5.

EXAMPLES 2-7

The following quinazolines were prepared ccrr.ms 25 in Example 1, starting from 4 ..... ami no-2 ~ chloro-6,7 ~ di methc xy- quir.ssoline and piparidir.e horn. v in ab 1 -rr. in t substituted, and they have been isolated in the form indicated.

ί I14

. f * l> CPi σι M

M * “r K *“. NOT

. ΟΙ OJ 'a * «3 · CM CM

! w ^ H H H H

OJ

I t! c O - w C! Φ Π tn CD ίΓίΰ vd m in in> i. ^ - - r- r- -r-r ~ r-r-

1 HOC

ci 'dj O

- C Æ î-t i <-U fij a

1 U

! g H ldcnj ov £> r- o U * x ^ ^ ^

> r ^ · h o ^ LO

v- / LO LO LO O m lD

t * * - * ‘’ 1 1, _ 'Λ "q. <v φ a ~ d „. ~ vQ) vd); · '- o ûi o and 4J o

j— î-i - * L'Cn r.ij ^ D

1 Ç-i- '0 g Q o .. ^ ^ V

ο Λ v oj <pj ^ -Ό oj

10 C Μ i · 1 ^ I ^> V I

-: 'C' -r ^ h -o c .c -c LJ,.,,. 0 ~ î -> o o »c \ Ë.5 -3 g ° i / y ~ 2 oj S a υ Q .u & J— ^

J

/AT

__ / ΙΊΓ ”* ο ο χ -u aF w1 V '' υ b cl i I o

ÿ r'i Ö. ,,? :; T

o__ G — ΰ - ΰ ° ~ V °. y u 0 V ο o 1 I 1 r »i — î .a%? .. rj '"' ^ *; ____J j 15 co vr ο 3 nj · -s · ^ • 'ο *** N N Γ \

ΓΟ -ίΓ CN η ΓΌ CN

. "-Η 1- <., · <1-1

CJ

U

-3-> ιη iîcil Ci ta * ω <U <a x; W 2 -iJ K r- Γ- VD “N sf> i C1 c ^ ^ ^ rH-HO ωιΰ

C U U

NECK

<> 0 a rC i 4-1 fit r i CT> ΙΓ) v-i Γ ^ Ο Π _Zr ^ "^ ^ 1-

* “J O 1n O O> CO

(ü V £> \ £> vD VD L "iT>.> v - -" _ <· θΐ5 ~ "os Jj Z- X 3. ·." 0 ° ^ - '

‘4 '-H ^ O ^ K S.- C

S ni ^ ^ ^ r0 CM ~ <->. r z 'U -H>, 1>.

, rt ^ O <~ t V r I '- ^ C- ’1'J o -: c4 û. o

SC> - ro ο SN C .H

• ~ C "ri t" '-! . - CM d— -M

0 0 Π3 - - ^ -c, J ^ u

* CM

K. "Z ™ I / Λ U i /> 8 8",

ü 0 ~ G

CM; N

"- <. - 'a Π;'

0 C

1 1 33 r-î

21 iO VD

.— o

G Z

X

a / 'î /' "j ·. 16 i

The following minor differences which exist in the procedure should be mentioned from Example 1.

! In Example 3, the product of the chromatographic purification is recrystallized directly without prior conversion to the hydrochloride. In Examples 5 and 7, silica is used for chromatographic purification. In Example 6, the residue which remains after the evaporation of the initial reaction mixture (which is a hydrochloride) is recrystallized from dimethylfortr.amide and then chromatographed directly on silica.

EXAMPLE 8

4-amino-6,7-dimethoxy hydrochloride ~ 2 "[4 ~ (2 ~ methoxy-“ n --- proDOXV) -piperperinolquinazoline.

3.6 g of 4-15 smino ~ 2 — chlorine — 6, 7 — dimethaxyquinacoline, 3.0 g of 4— (2 ~ methoxy— n-propoxy) piperidine and 1.5 g of are heated at reflux for 30 hours. triethylamine in n-butanol. The solvent is evaporated in vacuo, the residue is stirred with diethyl ether, the solid is collected and it is recrystallized twice from isopropanol to ofcie-20 nir hydrochloride 4 - ami η o - 67 - d 1 metox y- 2 -f 4 - (2 -me th oxy · n propoxylpiperidinolcuir.aaoli ne (2.3 g) icncant at 2rS-241 ° c. Analysis: ç (% 1 jii% ln (% )

Calculated for C19H28N4 ° 4'HC1 65.2 7.1 13.6 25 Found: 55.1 7.2 13.6 1 / i ^ EXAMPLES 9-22

The following quinazolines were prepared in the same manner as in Example S, starting with 4-aminc-2-chloro-6,7-dimethoxyquinamoline and from the factory; not suitably substituted, and they were isolated in the form indicated.

17? —I cî CD VO Op.

K "'s" V * S * s.

4- * sr * - »* - <OJ x-t

C / “N H * r-1 Ύ ~~ ι ▼“ <T — I tH

03 W ü (13 "^ 3-G3 CT £ j a -h -u i s? K * S θ ') Γ- ^ 31 r" cr> m ^ 0 CJ V * s. K ^ K ".

c — i 'O î-t CD CD Ö “m Lf) ß SZ ß C4J a

U

3 m CD CO ο ΰ CD 0 ~ ß »h» <—io cn ο- ο- J> mm κν m mm v '^ ^ - Λ ---- ^ - {^ 1 C3 OG> a G) CJ Ί »" · £ · *% v £ '03 π öVCjO 0 ^ 0 r.3 LV. Y ί- * η, ß (-1> * "t" y '. <' R-! Olijm C ΙΪ w Ooj \ 8a0u N3 7 Νί 7 ·>?

V- z ijl-S 'ÏS

/ J κ \ ™ C O .-- Î <N O c \ O CN3 V \\? ç £ ii C r-ί \ '/ Ο OR "ü ~ u \ __ / ··· —I -------------------------- -------------------------------, o. δ-, Ο O!.

D * 1

° “- Π Π I

V V: ta 1 o

"· M Ο O

S oi Ol

A

where u

23 Ol ΓΜ O ts 23 0 u u 1 c o

I I

GJ |

CL

£ 0 CH | O ^ C? ^ 1 i * ^ *! ! / t 18 <u ί {* -ι τ- (ο r- co ο in -! J <2 "ν · ^

C '* ~ 1 ^ Ο CD Ή * —I

^ ^ Η * -Μ Η <Η ^

W Ο GJ 0¾ 2 0J

ί σ, α> "Ι · Η £ Î -" u υ ^ G C ^ cm ιη nsr m Ν '

r-T'OiCU * - ^ V * V

fTr ^ J_ [V.0VD Ο l0 Û a c 3 2 <α I 3 '; U co νο in “JD ν! ί> ιο νο t "r- r- r ~ • '- * m in in lo mm • j * r V_J'; ΠΥ i 0 ^ <o cj Ό '® ™ -ÎJ -U jj o 1' <u 2 neither rs do &

<U, * J 'f, 0 f.-iJ O

. k-i -3 o r0 /; NT (3 CN

1 O _ O-p en Ο o Om 07 OJ r% Π3>! CM SO 1 vl τι ^ sz ^ i _o I <-> 1 "-" ci'O "λ T, m t *. Cs r '¢ - -rJ ^ p ncn o ^ -ho

μ C * ^ r’Z V ~ <* - / CN 0 F = CsJ

G, ._ -: .-; , - c 0 0 -J f. ^ -:

t, α vJ u G

I “i - ': ^ ro § m i ^ §

x ^ ll i ^ Y

UU o °: Y sT Y kv γ

Y u y

o o o

* _JN CM CM

ö U U

CN CM CM

; ^ '- *

u Π G

o û o

I I

___________________________ _ __ _ ___ _____ __ 0 t-i cx r- _ cm m nt S »A v-i * -t ü 2

K

fc3 / 7

’/> EY

19 Φ i? CT U) ο r- -.- sr 1 K. s, ^ ** S. . k C. ο ο ^ ct ^

Ci ^. —T H —I ”H ^ ^ ta Φ Φ ^ ~ n cvsj φ · η .c n 'j u„

H'0 G CT CT CT CT vD vT

Φ JC U

a 4J vs <a u 3 φ

, -i o_CT ST ^ CS CS, S

u s? ^ ct ct "dd-T

> mm mm m w v- / φ a?,. .¾ <y

* * η * -J M

& ’Rf £ fi (3 vri w] f f f, ·”; u

^ 3 ~ 0 ^ 'GO

- n CT? DD CT Π C CT

"„ RS> ·) π; Γ · “V, 4- vT

1/5 ^ U Ä “a H CS. Γ- * K -

* - i Ό o t, '· U- -TJ I -J J-' I

SL '-J w,, rî ^ .q r- £ js vT

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/ î / 'f {_ I 22 ί,'. The following examples illustrate the preparation of some of the starting compounds used in the previous examples.

ί EXAMPLE A

| ‘5 Preparation of 4- (2-methoxyethoxy) piperidine.

A solution of 30.5 g of | N-acetyl-4-hydroxypiperidine in 200 ml of dimethylformsmide in a suspension with stirring of sodium hydride (11.26 g, 50% dispersion in mineral oil) in 300 ml of dimethylformamide under atmosphere of 'nitrogen. The reaction temperature is kept below 30 ° C by external cooling and, when the addition is complete, stirring is continued for another 1 hour and 15 minutes. A solution of 32.6 g of 1-bromo-2-methoxyethane in 100 ml of dimethylformsmide is then added dropwise with external cooling and the resulting clear solution is stirred for about 16 hours at room temperature. The reaction mixture is then evaporated in vacuo, the residue is partitioned between water and chloroform, the organic extracts are dehydrated over sodium sulfate and then they are evaporated leaving a crude residue (16.1 g). The above aqueous phase is saturated with sodium chloride, it is reextracted with chloroform and the organic phase is dried over sodium sulfate and then evaporated, leaving another residue (9.2 g). This residue is added to the initial residue and the mixture is heated in a boiling water bath for about 16 hours with 243 ml of 2N hydrochloric acid. The reaction mixture is extracted with chloro-. Formed to expel residual mineral oil, the aqueous phase is concentrated, alkaline! see with sodium hydroxide (pH 30 12) then re-extracted with chloroform. The organic extracts are washed with brine, dried over sodium sulfate and evaporated leaving 8.3 g of 4 - ^ - rethoxyethcxy) piperidine.

A sample of this product in ethyl acetate is formed to form an oxalate by the addition of oxalic acid in solution in ether, followed by recrystallization from ethanol, the oxalste having a point this fusion from 86 to 68 ° C.

'·> ^ 23 4 Analysis: C (%) H (%) N (%)

Calculated for CQH. „N0 _. (CO_H) 0: 48.2 7.7 5.6 ο 1 / ά ά ά

Found: 48.1 7.6 5.6.

The following piperidine derivatives were prepared by procedures similar to that of Example A, starting with N-acetyl-4-hydroxypiperxdin and the corresponding bromide. The hydrolysis of the N-acetylated intermediate compounds in Examples B and D was carried out using sodium hydroxide in place of dilute hydrochloric acid.

IN V— Y

vv f. ^ y Isolated form and Analysis%

Example melting point (Theoretical value 'between, brackets)

C H N

B -OCH CH OC B Cxalate 58.5 6.8 4.3 144 - 145 ° (57 * 9 6; 8 4 ^ 5) C -OCH CH 0-nC H „Cralate 52.4 8.4 4.8 hemihvörste (52,0 8.7 4.7) .86-88 ° * ““ - —---------------- - i ___ - - 1 1 D -OCH CH 02 K Oxalate 50, 5 0.2 5.2 93-95 ° (50.2 8.0 5.3) / / / ”

EXAMPLE E

P re d a r ation of the? - -_a_cé t vl -_4 - a 1 ly 1 oxv p. ijo é r idine -

A solution of 100 g of N ~ acefcyl ~ 4 * -hydro> is added dropwise; ypiperid5ne cens 250 ml of cinethyiformemide 15 to sodium hydride (33 g, dispersion at 50% like mineral oil) in operating under a nitrogen atmosphere. The mixture is stirred for 2 hours and then 93 g of allyl bromide are slowly added thereto while maintaining the temperature of this reaction at 25 ° C., cooling externally. The reaction mixture is then stirred at room temperature after about 16 hours, (/ / ..-- x) 24. Diluted with 20 ml of isopropanol and 500 ml of ether, filtered and filtered. evaporates under vacuum. The distillation of the residue gives 108, Qg of N-acetyl-4 ~ allyloxypiperidine melting at 128 ° C / 2 mm, this compound having been identified by spectroscopy.

5 EXAMPLE F

Preparation of 4- (2-ethoxy-n-proooxy) piperldine.

A solution of 6.4 g of N-acetyl-4-allyloxypiperidine in 10 ml of absolute ethanol is added dropwise to a suspension, with stirring, of 11.5 g of mercuric acetate 10 in 50 ml of ethanol with ambient temperature. After 20 minutes, the mercuric acetate has dissolved and the mixture is stirred for another 40 minutes, cooled with a mixture of ice and water and then supplemented with 20 ml of 5N sodium hydroxide. A yellow precipitate forms during the addition. A solution of 1.3 g of sodium borohydride in 20 ml of 5N sodium hydroxide is then added, the mixture is stirred for 10 minutes and acetic acid is added to adjust the pH to 6. The filter is filtered. mixture to separate the precipitated mercury, the ethanol is evaporated in vacuo and the resulting aqueous phase is extracted with chloroform. The organic extracts are dried over soc ·: um sulphate, evaporated under vice and the resulting crude residue (7.5 g) is taken up in 50 ml of ethar.ol and its solution is heated at reflux for about 16 hours with 20 ml of 5N sodium hydroxide and 20 ml of water. Most of the ethanol is then removed under vacuum, the aqueous phase is extracted with ether, the extracts are dried over sodium sulfate and then they are evaporated leaving a residue (5 g).

Thin layer chromatography indicates that the hydrolysis of the acetyl function has been incomplete, so that the residue is treated with 20 ml of hydrochloric acid 2ii and heated in boiling water for 10 hours. The mixture is then washed with ether, the aqueous phase is alkalinized with sodium carbonate, it is extracted with ether and the organic extract is dried over sodium sulfate and evaporated, leaving a residue weighing 4, 3 g. The eyelash til it: we had ra if had gave 3.0 g of 4— (2-ethoxy-n-prcpcxyipipéricine boiling at 112—116 ° C / 10 mm, of which the sescuioxalate is prepared by reaction f *! '' - '-N, 25 between a solution of piperid <ne in ether and a solution of acid oy =, jfqUe in ether, then recrystallization from ethyl acetate, the oxalate ay * "nt un melting point of G8-70 ° C.

5 Analysis: C (%) H (%) N (%)

Calculated poi, r r H. N0 „. 1.5 (C0oH) ·, 48> 4?> 5 4.4, -LU 41 d c.

Finds: 48.3 7.5 4.7.

EXAMPLE G

10. Preparation of 4- (2-hydroxy - n-uropoxy) piperidine.

| Λη added drop by drop 18 g of h '~ scétyl-4-al lyloxy-pipéridine in 30 ml of tetrahv! Rofuranne to the yellow suspension with stirring of 34 g of roercuric acetate in a 1-me angel: 0 ml of water and 120 Ί of tetrahydrofuran. The suspension dissolved during i * eition and the resulting clear solution is stirred at room temperature for 20 minutes. if it is added .. · '^ sodium hydroxide 5N, e · same time as r-' ·:; η9- Gst cooled with ice e ·; some water. The comp '' -nrernieaiaire thus obtained 20 is then reduced by adding -'3 2 g of sodium borohydride c ^ ns 40 ml of hydroxide this sodium 3 '·. * The excess hydride being destroyed in 10 minutes Lout c- acaition acetic acid cry suai 1 is - bie. The liquid phase followed by decantation, its chloride urea from the organic phase is separated and the aqueous phase rei · - -te is extracted 4 times with "chloroiorir". The chlorine phases: "* '' --ü’Jés rassenrlées are dehydrated .r s Sl5r sulphate" "-u: n evaporated under vacuum, in Idissan: a colorless oil. Ai ~ nt 23 g.

'"act oil is stirred · -'V3C cs 1 * sodium hydroxide 30 5N at room temperature pr 2 6 hours then at lGûcC

uSiicant 2 ’. heures. The solution then follows up on chloro-form (4 f.-is), the extracts c --ormiopues collected are dehydrated. ^ On sulfate sulfate. · Pu - s lilies are evaporated under vacuum, leaving 16.1 g c-; üit gross crystalline. This j5 proaum are taken up in chloride .emyler.a, -liter, evapc-re er the resi.-u is crushed in 1 -: '-r Ge paarole (Eo »40 / 60cC) • εη ooun = nr 11,0 g of 4- (2-nydra '•' • “? roPc'xy) P- p = r. \ iir“ e fendant / (26.

. At 55 ~ 57 ° C. The oxalate of this compound is prepared as in Example F and recrystallized from isopi'opanol; it melts at 104-105 ° C.

Analysis: 5 Ç (%) H (%) N (%) j Calculated for CgH ^! ^. (C02H) 2: 48.2 7, 7 5.6 | Found: 48.2 7.7 5.6.

EXAMPLE H

Preparation of N-acetyl ^ -tg-raethylallylc ^ Piperidine.

This compound is prepared as in Example E, starting with N ~ acetyl ~ 4-hydroxypiperidine and 2-methylallyl chloride, then it is distilled and dissolved therein. It is used directly in the following step. Its boiling point tic- "1 under vacuum; 1 mm is equal to 128 ° C.

15 EXAMPLE I

Preparation of 4- (2-en, ethcx'-r-2-methyl-n-r '-noxy) oipgridir.

This compound is prepared as in Example F starting from N-acetyl-4- (2-r.ethylallyloxy} piperine and mercuric acetate in methanol. The compound is: sscterisé in the form of 1 ' h & mi exa1a basing you at 2CS-21C-.

Analysis:: c (%) '- ·'%) N (%)

Calculated for c10h2iHCV 1/2 (C ° 2H) 2: 56.9 S, û

Found: 56.7 “-'5 5.9.

v

25 EXAMPLE J

; . Preparation of 4 ~ (2-hydrcxy-2-ri Ȏ thyl-n-r .: oxv) r-ioeridine.

This compound darkening at èO — o2 ° east; rare crm.ma cens example G from L'-acetyl —-.- (2-r.eth: '· -ly2oxy) pipéri ~ dir.e and rnercuric acetate in a milanç:; this ta— trahydrofuran.

Analysis: c [%) -H%)

Calculated for CQH. >; 0 „: 62.4 -» 1 3.1 9 19 2

Found: 62.2 -’1 p, 3.

/ /

.'"*NOT

27

EXAMPLE K

Preparation of 4- (2-ethoxy ~ 2-methyl-p.-Dropoxy) aperidine.

This compound is prepared as in Example F, starting with N-acetyl-4- (2-methylallyloxyipiperidine and mercuric acetate in ethanol, then basic hydrolysis is carried out to remove the acetyl group protecting the nitrogen. transforms the sample to the hemioxalate which is recrystallized from a mixture of ethyl acetate and methanol; it melts at 184-185 ° C.

10 Analysis: c (%) H (%) N (%)

Calculated for cnH23N02-1 / 2C2H204: 58.5 9.8 5.7

Found: 58.6 9.7 5.8

EXAMPLE L

Preparation of 4- (2-isoDropoxyethoxy) pioeridine.

This compound is prepared as in Example A from N-acetyl-4- * hydroxypiperidine and l-bromo ~ 2-isopropoxy-ethane. This compound has been characterized by spectroscopic techniques.

20 EXAMPLE M

Preparation of 4 ~ (2-â.éthcxv-n - DroDcxv î pioerioine.

These compounds are prepared as in Example F from N-acetyl ~ 4 ~ allyloxopiperidine and mercuric acetate in methanol. To improve the rate of notches * ma ci of the starting compound in product, the treatment with mercuric acetate in methanol is repeated twice to obtain N-acetvl-4- (2-methoxy ~ n ~ propcxy) pi peri d 5. ne which is hydrolyzed in a solution of * hyoroxyoô üô sooiu.t »cô -n ^ nol to · obtain 4- (2-methoxy-n-oropoxy) Dirérldine. A sample 30 characterized in the form shingles za a c9-91 “C.

Analysis: C (% 1 H (%). N (%)

Calculated for 'C2H2 ° 4 s S0; 2 8.1 5.3

Found: 49, c 7.9 5.3.

/ (. /. 1 ~~ 28

EXAMPLE N

Preparation of 4— (2-phenoxy-n-propoxy) piperidlne.

12 g of N-acetyl-4- (2-hydroxy-n-propoxy) piperidine in 50 ml of anhydrous dimethylformamide 5 are added dropwise to a suspension with stirring of sodium hydride (5.0 g, dispersion at 50 % in mineral oil) in dimethylformamide (50 ml) at 60-70 ° C under a nitrogen atmosphere. The suspension is stirred for 3 hours and then 6.4 g of fluorobenzene in 50 ml of D.M.F. is added dropwise. and the suspension is stirred XQ at 100 ° C. for 50 hours - The cooled solution is treated with 20 ml of isopropanol then 200 ml of water, extracted with three times 200 ml of petroleum ether then three times 200 ml of chlororoform . The combined chloroform extracts are dried over sodium sulfate and the solvent is evaporated X5 under vacuum. The residue (9.0 g) in 20 ml of sodium hydroxide; SN supplemented with 20 ml of methanol to carry out the dissolution is heated under reflux for 5 hours. The methanol is evaporated, the residue is diluted with water and then extracted with three times 50 ml of chloroform. The combined chloroform extracts are washed with three times SC ml of 2N hydrochloric acid, the combined aqueous extracts are alclinized to pH 12 by addition of a sodium hydroxide solution and they are extracted with three trots oO At this point, the combined chloroforms are dried over sodium sulfate, the solvent is evaporated in vacuo then the residue is triturated with ether and filtered. The filtrate is concentrated and then distilled giving 0.5 g ce 4— (2-ohénoxy-n-propoxy) omerrcxne boiling at 118-122 ° C / 0.3 mm, characterized by spectroscopy.

/ 29 EXAMPLE Ο 4- (2- [2, 6-Dimethoxyphenoxy ~ lethoxy) pi peri-dinner.

90¾ och3 AT OCH CH OH ^ OCH CH OSO „CH, Γ Π CH3S02C1 2 2 2 3 Γ J | - * - * -> I | O.

“’ Go / b dp. , Jhv ° é3

cro hyorolysis f> CH

3 ----------------- 3

. ^ '· K N J

. -. I

- /. " Zi Q

/ Ac = CH3CO- /

23 g of methane-sulfonyl chloride are added dropwise to a stirring solution of 20 g of 2- ^ 2,6-5 dir.ethoxyphenoxy ^ ethanol (nJ. Med. Chem. * '1969, 1-2, 326) in 50 ml of pyridine. The solution is kept at room temperature for 60 hours and then the solvent is removed by evaporation under reduced pressure. The residue is taken up in. chloroform, it is washed with three times 100 ml of water and with a sodium bicarbonate solution (5%, three times 100 ml), then it is dried and the solvent is evaporated. The residue is triturated with n-hexane and the solid is collected, which gives 11.3 g of 2 ~ rnesylate [2, S-direthcxyphencxylethyl] characterized by spectroscopy.

15 4.3 g ce M-acetyl-4-- hydrcxypiperidina in 50 ml of dirnétnylforrerice is added dropwise to a stirred mixture of sodium hyoride (3.0 c, dispersion / / 3 ° il | ί I at 50% in mineral oil) in 50 ml of dimethylformamide

Under a nitrogen atmosphere. After stirring for 3 hours at room temperature, 9.0 g of 2 - 2,6-dimethoxyphenoxy] ethyl mesylate in 50 ml of methylformamide are added dropwise and the stirring is continued for 20 hours. at room temperature. The solvent is evaporated in vacuo, the residue is again taken up in water, it is extracted with three times 100 ml of chloroform, the organic phase is dried over sodium sulfate and the solvent is evaporated. 6.0 g of N-acetyl-4- (2- [2, 6-dimethoxyphenoxy ^ jethoxy) piperidine 1 are obtained by distillation! boiling at 200 ° C under a vacuum of 1 mm.

| i This product (6.0 g) in 40 ml of methanol and 20 ml 1 of 5N sodium hydroxide solution is heated to reflux! for 20 hours. The methanol is evaporated under reduced pressure, | The aqueous residue is extracted with three times 30 ml of petroleum ether and three times 30 ml of ether. The ether extraction phase is dried over sodium sulfate and the solvent is evaporated. The ether residue is treated with a solution of hydrochloric gas in ether and the above solid substance; 20 pity is recrystallized from isopropanol giving 1.4 g of 4- hydrochloride (2- [2? S- dimét] -> cxvρhé-ηo>: v 1 ethoxy) oioér 1 dins - fondant at 143 ~ - 1450C.

Analysis: i £ (% W H (%) N (%) 1 25 Calculated for c15H23N04 * HC: L: 56.7 7.6 4.4

Found: 56.4 7.6 4.3.

EXAMPLE P

:, (A) P repair a tion of K'-acetyl-4- (2,2-6 :. ethoxyethoxy) oioerid i no.

Cn is added drop to short 57.2 g of N-acéyl-^ - hydroxy-30 piperidine in 250 ml of di.v.ethy) so ~~ a, r-ide anhydrous to a suspension with stirring cïcride this soaium ( 23.2 g, dispersed at 50% in mineral oil) in 5 50 ml of anhydrous dimethylformamide under nitrogen atmosphere and cooling externally in an ice and water bath. The suspension is allowed to warm to room temperature and then stirred for o hours. 94.7 g of dielectric is slowly added to this alfalfa-bromoetaldehyde to the reaction mixture with stirring, with cooling, then the mixture is stirred at room temperature for 18 hours. Another 23.2 g of sodium hydride is added in portions and the mixture is stirred until the effervescence 5 has ceased. An additional 100 ml of anhydrous dimethylformamide are added and the mixture is cooled in an ice-water bath while slowly adding a second batch of 94.7 g of bromacaldehyde diethylacetal. The mixture is stirred at room temperature for 3 hours and then 150 ml of isopropanol 10 are added to destroy the excess sodium hydride. The suspension is filtered, the filtrate is concentrated under reduced pressure and then the residue is taken up in water and extracted with chloroform. The chloroform extract is dried over sodium sulfate, the solvent is evaporated in vacuo and the residue is distilled to give 61.5 g of N-acetyl-4- (2,2-diethoxyethoxy) nioeridine boiling at 142-145 ° C / 3mm, characterized by nuclear magnetic resonance.

(3) Preoaration of N-acetyl ~ 4 -_ (2-hydr oxvethoxy) olceridine.

Stirred at room temperature for about 16 to 20 hours 12 g of N-acetyl-4- (2,2-diethoxyethoxy) piperidine in 50 ml of 0.5N hydrochloric acid. The solution is saturated with sodium chloride and extracted several times with chloroform (500 ml in total). The chloroform extract is dried over sodium sulfate and the solvent is evaporated under vacuum at a bath temperature below 30 ° C. The resulting intermediate aldehyde (9.8 g) is immediately reduced with 0.75 g of sodium borohydrvre in 75 ml of ethanol, at pH 5. After stirring for 3 hours at room temperature, the reduction is complete. Water is then added to the solution with stirring and the organic solvent is evaporated in vacuo.

The residue is taken up in 30 ml of water, it is extracted with 10 times 30 ml of chloroform, the combined chloroform extracts are dried over sodium sulfate and the solvent is evaporated in vacuo. The residue is taken up in 70 ml of water and its solution is washed with water in 10 times 10 ml of petrel ether a. The aqueous phase is concentrated by horning 6.9 g of this N-acety-4- (2-hydroxvethoxv) pioeridina, characterized by methods / '! '· T 32 spectroscopic. A distilled sample boils at 139-140 ° C / 0.3 mm. Analysis: C (%) H (%) N (%)

Calculated for CgH ^^ NO ^: 57.8 9.1 7.5 5 Found: 57.5 9.1 7.6.

(C) 4- (2-Cyclopentyloxyethoxy) piperidine.

5.0 g of N-acetyl-4- (2-hydroxyethoxy) piperidine in 25 ml of dimethylformamide are added dropwise to a stirred suspension of sodium hydride (1.28 g, 50% dis-persion). in mineral oil) in 50 ml of anhydrous dimethylformamide, under a nitrogen atmosphere. When the effervescence: has ceased, 4.4 g of cyclopentyl mesylate ("Tetrahedron" 1972, 2B, 2469) are slowly added in 10 ml of dimethylformamide and the mixture is stirred at room temperature for 40 hours. Another 0.64 g of sodium hydride and then 2.2 g of cyclopentyl mesylate are added and the mixture is stirred at 60 ° C. for 7 hours and then at room temperature for 64 hours.

Isopropanol is added, the mixture is filtered and the filtrate is concentrated in vacuo. The residue is heated at reflux for 3 hours in 30 ml of ethanol and 30 ml of 5N sodium hydroxide solution. The ethanol is removed in the vice, the residue is diluted with ether and extracted with chloroform. The chloroform extract is dried over sodium sulfate, the solvent is evaporated in vacuo then the residue in chloroform is treated with a solution of hydrochloric gas in ether. The solvent is poured off by decantation and the residue is triturated with ether, giving 4-C 2-cyclopentyloxvethoxy) piperidine hydrochloride in the form of a gum. The product is contaminated with a small amount of 4- (2-hydroxyethoxy) piperidine, but it is used directly.

EXAMPLE Q

Preparation of 4— (2 — p — fluorophenoxyethoxy) piperidine.

A solution of 5.0 g of N ~ acetyl-4- (2-hydroxyethoxy) piperidine, 8.4 g of triphenylphosphine, 5.6 g of diethyl azodicarboxyate lr ^ 33 is stirred in an ice bath for 2 hours. and 3.36 g of p-fluorophenol in 75 ml of freshly distilled tetrahydrofuran, then the solution is left to stand for 48 hours at room temperature. The solvent is evaporated in vacuo, the residue is taken up in chloroform and washed twice with 1N sodium hydroxide solution and twice with water, dried over sodium sulfate and the mixture is evaporated. solvent under vacuum. The residue is taken up in the minimum volume of ether at reflux and then allowed to cool in the refrigerator. The precipitated solid is collected, the filtrate is evaporated and the residue is taken up in ether and set aside to allow it to cool. The precipitated solid is again separated, the filtrate is evaporated and the residue is extracted with five times 100 ml of petroleum ether (60-80 °) at reflux. The solvent is evaporated in vacuo and the residue in 50 ml of ethanol and 50 ml of sodium hydroxide solution is heated at reflux for 5 hours then neutralized by addition of 2 H hydrochloric acid and the organic solvent is evaporated.

The aqueous residue is acidified to pH 2 by addition of 2N hydrochloric acid and extracted twice with ether. The aqueous phase is basified to pH 12 by addition of a 2hr sodium hydroxide solution and then extracted with three times ml00 ml of chloroform. The combined chloroform extracts are dried over sodium sulfate and the solvent is evaporated in vacuo to give 1.3 g of 4- (2-p-fluorophencxyethoxy) piperidine.

A sample of this product in chloroform is converted to the hydrochloride by treatment with a solution of hydrochloric gas in ether; it melts at 144-145cC.

Analysis: c (%) n (%) n (%) 30 Calculated for: 56.6 6.9 5.1

Found: 56.1 6.8 5.5.

EX5LFLES R h U

The following niDericine derivatives are prepared as a procedure similar to that of Example Q, starting with 35 KT-acetyl-4- (2-hydroxyc'noxy} piperidine and corresponding phenol. l. · r • / fl i 34 h μ cry 1 * M * \ \ N • 'v

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EXAMPLE V

1 Preparation of 4- [2- (4-piperidvloxy) ethoxylbenzamide.

Stirred at room temperature for 66 hours 1.0 g of N-acetyl-4- (2-hydroxyethoxy) piperidine, 0.82 g of! j 5 4-hydroxybenzamide, 1.12 g of diethyl azodicarboxylate and 1.68 g of triphenylphosphine in 30 ml of tetrahydrofuran.

The precipitated solid is collected and dried to obtain 0.72 g of 4- [2- (N-acetyl-4-piperidyloxy) eth: xy] benzamide melting at 154-155 ° C.

10 Analysis: C (%) H (%) N (%)

Calculated for C- ^ 5H22M204: 62.7 7.2 9.2

Found: 62.7 7.1 9.1.

4.3 g of 4- [2- (N -acetyl ~ 4 ~ piperidyloxy) ethoxy3benzamide in 60 ml of ethanol, 30 ml of water and 10 ml of 2N hydrochloric acid are heated at reflux for 24 hours. the solvent is evaporated under vacuum. The residue is taken up in water and extracted three times with chloroform, the pH and the aqueous phase are adjusted to 12 by addition of a sodium carbonate solution and it is extracted three times with chloroform. chloroformic extracts collected are discarded, the sawing phase is saturated with sodium chloride then it is extracted with chloroform, the chloroformic phase is dehydrated over sodium sulfate and the solvent is removed because 25 giving 0.36 g of 4- ~ Ç2- (4-piperidyloxy) ethoxvlbencamlda. The aqueous phase is concentrated in vacuo and the residual solid is extracted with 200 ml of ethyl acetate at reflux. The solid substance is separated by filtration and the filtrate is evaporated under vacuum to give another 0.30 g of 4- [d 2- (4-30 pipé rid y1oxy) é th ox y] was obtained above. A one-year sample of this product of chloroform and methanol is transformed into hydrochloride rar treatment with a solution of hydrochloric caz in ether, then recrystallization from a mixture of ethyl acetate and Isopropanol; the product characterized by a sreccrcr c-pique method melts at 244-246 ° C.

/ / ·· __ 3 7

EXAMPLE W

Preparation of 3- | ~ 2- (4-pjperidyloxy) ethoxylbenzamide.

Agitation is carried out at 0 ° C. for 2 hours and then at room temperature for 64 hours 5 × 10 g of N-acetyl-4- (2-hydroxyethoxy) -5 piperidine, 4.4 g of 3-hydroxybenzamide, 5.6 g of diethyl azodicarboxylate and 8.4 g of triphenylphosphine in 100 ml of anhydrous tetrahydrofuran. The solvent is evaporated under vacuum and the residue is then treated with three times 100 ml of ether at reflux and the mother liquors are separated there by decantation. The oily residue 10 is taken up in chloroform and the solution is washed with 40 ml of dilute sodium hydroxide solution and 40 ml of water.

The chloroform phase is dried over magnesium sulfate and then the solvent is evaporated in vacuo. The residual oil is treated with 50 ml of ether and left to stand in a re-refrigerator. The solid substance is collected, suspended in 30 ml of ether, filtered and the solid substance is washed with 30 ml with ether, giving 3.7 g of 4-d ~ 2- (N ~ acetyl-4 ~ piperidyloxy) ethoxylbenzamide containing a little triphenylphosphine oxide (about 25% according to nuclear magnetic resonance analysis). The product in 43 ml of ethanol, 24 ml of water and 8 ml of 2N hydrochloric acid , is heated under reflux for 24 hours then the ethanol is evaporated in the empty direction. The aqueous residue is extracted with those times 100 ml of ether then 100 ml of chloroform, then the aqueous phase is adjusted to pH 12 by addition of '' a sodium hydroxide solution and it is extracted with twice 100 ml of chloroform. The organic phase is dried over magnesium sulphate and the solvent is * r evaporated under vacuum, giving 0.55 g of 3 - [_ 2— (4 ~ pfpéridyloxy) - éthoxy] ben zami de. The aqueous phase is saturated with sodium chloride and extracted with three kings 100 ml oe cnlQrQ “Qj-fi, gt The combined chloroform extracts are dried over magnesium sulfate and 3 solvent is evaporated in vacuo giving a second harvest te ce 0.26 g of 3 2- (rr;, vo oxv) - sthoxy] bensa: nest identical to that which was obtained above.

This sample is characterized in the form of hydrochloride by treatment of an ethanolic solution with a solution of hydrochloric gas in ether; hydrochloride fc.n, j at 144-146 ° C.

/ ï · 35 I! ! · Analysis: I C (%) H (%) N (%) | Calculated for c14H2QN203.HCl: 55.9 7.1 9.3 d Found: 55.0 7.2 9.2!) -! î!

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Claims (7)

2. Compound according to Claim 1, characterized in that R is a methyl group, X is a group CH3 CH3 -OCH ^ CH ^ OR1, -OCH ^ -CHOR1 or -OCÎ - ^ - C-OR1 and R1 is a CH3 I hydrogen atom or a C -C alkyl, cyclopentyl or phenyl I X 4 group; optionally substituted with a lower alkyl, lower alkoxy, halo, trifluoromethyl or carbamoyl radical. : 3. Compound according to claim 1, characterized: in that R is a methyl group, "alk" is a group —CH ^ CH ^ - and R is an ethyl or phenyl group. 4. Compound according to claim 1, characterized in that it represents something other than a cyclo-2 3 -alkyl group C 3 ~ C 6. and R and R represent something other than a trifluoromethyl group. 5. Process for the production of a compound of formula (I) according to claim 1, characterized in that it consists in reacting a compound of formula: R ° 2 • I - - (II). RO N NH2 (in which „R has the definition given in claim 1 and Q is an easily removed group) with a piperidine of the formula: H t— / X --- (III). 41 (in which X has the definition given in claim 1. 6. Method according to claim 5j characterized in that Q is a chloro or bromo radical. 7. A bioprecursor acceptable from the pharmaceutical point of view of a compound of formula (I) according to claim 1. 8. Pharmaceutical composition, characterized by the fact that it contains a compound of formula (I) according to one; Any of claims 1 to 4 or a pharmaceutically acceptable acid addition salt of this compound or a pharmaceutically acceptable bioprecursor according to claim 7, in combination with a diluent or carrier acceptable from a pharmaceutical view. UOvlAXU Jk îi