FI103794B - (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-didydro-4-oxo-3-quinolinecarboxylic acid O3, O4) -bis (acyloxy-O) borate and a process for its preparation - Google Patents

Description

103794 (6,7-Substituted 8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-03.04) bis (acyloxy-O) borate and its salt and process for its preparation - (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylsyr-03.04) bis (acyloxy-O) Borat and dess salt and derivatives. This invention relates to a novel compound which is an important intermediate in the preparation of a novel quinolone carboxylic acid having an alkoxy group at the 8-position and useful as a drug, (6,7-substituted 8-alkoxy-1-cyclopropyl-1,4-dihydro -4-oxo-3- [Quinolinecarboxylic acid-O) bis (acyloxy-O) borate, a salt thereof, a hydrate thereof and a process for its preparation.

As a process for the preparation of a quinolone carboxylic acid derivative having an alkoxy group at the 8-15 position, two processes are known as follows.

(1) (described in Kokai Sho 62-252772, JP)

r2 o R2 O

X AkxOOR

^ TT | ζήβ [

o r · - ^ 0 A k''0 A

V ·: 20: \: (2) (described in JP Patent Kokai Sho 63-198664) • · «• · · .bf2 O O’ o V; X. .COOR10: T: I || T I T T 0: F N F N —►

r-R R 'R

• • • • • • • • • • · · · · · · · · · · 10 103794 f 'BF2 N, n

O 'O O

| HF Addition I

r · R R1 R

\ /

However, since process (1) has an alkoxy group at the 8-position, which is an electron donating group, its reactivity at the 7-position is reduced, and therefore, under mild reaction conditions, the desired 8-alkoxyquinolone carboxylic acid derivative can be obtained only in extremely low yield. Moreover, when the reaction conditions are stringent, the alkoxy group at the 8-position is dealkylated and becomes a hydroxyl group and, as a result, the target product cannot be obtained in high purity.

10

Since process (2) is carried out via a boron fluoride chelate compound, the target product can be obtained in high yield. However, fluorinated boronic acid is so expensive that it is costly and still difficult to produce using conventional industrial equipment, since hydrofluoric acid is a by-product at the time of preparation of the intermediate.

In these circumstances, the inventors have discovered, as a result of an unremitting study on the industrial process for the preparation of quinolone carboxylic acid in its 8-position, that the above problem can be solved by using the intermediate (6,7-substituted 8-alkoxy-1-cyclo-). 1: 1. Propyl 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-O 03.04) bis (acyloxy-O) borate, its salt and its hydrate represented by the general formula (I).

• · · • · · · · 1

In other words, not only is the chelate compound of the present invention suitable for its industrial production because it does not produce hydrofluoric acid, which as a by-product, which · · ·,! f corrodes the reaction vessel and other components at the time of synthesis, but also exists: a feature that the target product can be obtained in high yield and in high: · 'purity using this chelate compound.

In addition, the process has the advantage that the compound can be prepared at a significantly lower cost than the known process.

3 103794 R \

'BC

s> Λ R'X ZA (I) (wherein X represents a halogen atom, R represents an aliphatic acyloxy group having 5 to 6 carbon atoms, an aliphatic acyloxy group having 2 to 6 carbon atoms optionally substituted by a halogen atom, or an aromatic acyloxy group having 7 11 carbon atoms, R 'represents a lower alkyl group, R 2 represents a hydrogen atom, a halogen atom, an amino group or a nitro group, Z represents a halogen atom, Z 1 - R 4 represents a hydrogen atom, a lower alkyl group, an aryl group , '* alkoxycarbonyl or aralkyl group, R 4 and R 5 each independently represent a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group or a phenyl group) or: 3 Ριχ1 / *'. is 0, 1 or 2.1 is 0, 1 or 2, m is 0 or 1, R6 represents a hydrogen atom, a halogen * n-20 atom, a lower alkyl group or a hydroxyl group, R represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, R8 represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or a * * * * aralkyl group) or an azetidino group, a pyrrolidino group, a pyrrolidino group, a pyrrolidino group;

The chelate compound of the present invention may be prepared according to the following reaction process.

X

r2 O R2 O o X, .COOR9 X. .A.

v ^ Il ιί ^ B ^ l li li 0

The A

cn> {rv>

R.R.

X

ΖΉ R2 9 O

(V) x. ^ A. X.

^ o Γ'Υ ^ 'Ν ^

r "° A

. ·. : 5 '(where X' represents a halogen atom, R 9 represents a hydrogen atom or a lower alkyl

,., X, R, R ', R 2 are the same as above and Z' is the same as Z

* ;;; * with the exception of a halogen atom).

1) A compound of general formula wherein Z is a halogen atom can be prepared by reacting a compound of general formula (II) with a triacyloxyborate derivative of general formula (III) in the presence of a solvent. The triacyloxyborate derivative of general formula (ΠΙ) may be used in an amount of 1 to 50 equivalents, preferably 5 equivalents: '·'; with respect to a compound of general formula (II).

. An organic acid (for example, acetic acid, propionic acid, trifluoroacetic acid) may be used as the reaction solvent. At this stage, the reaction temperature is between 20 and 200 ° C, and preferably between 20 and the boiling point of the solvent used. The triacyloxyborate derivative of the general formula (III) may be prepared by reacting boric acid in an organic acid (e.g. acetic acid, propionic acid, trifluoroacetic acid) or an organic anhydride (e.g. acetic anhydride, - 5 in the face of 103794. The amount of boric acid used is 1.1 to 2 equivalents, preferably 1.5 equivalents relative to the compound of general formula (Π). In this case, the resulting triacyloxyborate derivative can be used without isolation for reaction with a compound of general formula (II).

2) A compound of general formula (I) wherein Z is other than a halogen atom may be prepared by condensing a compound represented by general formula (IV), which is a halogen atom, with a cyclic amino compound represented by general formula formula (V).

10 ΖΉ (V) (where Z 'represents -N N-R3 R3 * (where n is 1 or 2, R represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group, R4 and R5 each independently represent a hydrogen atom, a lower alkyl group , substituted lower alkyl (c): 20, cycloalkyl or phenyl), or · · O Pry '* 6 / r7 ·; ··· Λ V- (CH2> k-N- ^ R8 · · # • « (Where k is 0, 1 or 2, 1 is 0, 1 or 2, m is 0 or 1, R6 represents a hydrogen atom, a halo: 25 gene atom, a lower alkyl group or a hydroxyl group, R7 represents a hydrogen atom: : an atom, a lower alkyl group, or a substituted lower alkyl group, R 8 represents: a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or a (? , morphino group, or thiomorphine oryhmää.

: **. · 30: '* *: The reaction of a compound of general formula (I) wherein Z is a halogen atom with a cyclic amino compound represented by general formula (IV) can be carried out without a solvent, 103794 or with a polar solvent such as water. , alcohol, acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoramide (HMPA), pyridine, picoline and the like.

The reaction temperature is optionally selected between room temperature and 200 ° C, and preferably between room temperature and 100 ° C.

More specifically, it is convenient to react a compound of general formula (I) wherein Z is a halogen atom with 1 to 5 times the molar amount of the cyclic 10 amino compound represented by general formula (IV) in 2 to 10 times the volume of the above solvent at a temperature from room temperature to 50 ° C for 1-50 hours. In this case it is also advantageous to use triethylamine, diazabicyclo base or potassium carbonate, etc.

The following examples are provided to further illustrate the present invention, but the present invention is not limited to any of these examples.

Example 1 To a mixture of 57.2 g (0.925 mol) of boric acid and 1.24 g of zinc chloride was added 300 ml of acetic anhydride, which was then stirred at 110 ° C for 1.5 hours.

To this reaction mixture was added 400 ml of glacial acetic acid and stirred for a further 1 ':' hour at the same temperature.

25 µl: ***: After allowing the mixture to cool, 200 g (0.619 mol) of ethyl 1-cyclopropyl-6,7-? · · Difluoro-1,4-dihydro-8-methoxy-4-oxo-3 quinolinecarboxylate was added thereto at 50-60 ° C and then 200 ml of glacial acetic acid was added thereto and the reaction was allowed to proceed for 5 hours.

30 • ·

The reaction mixture was concentrated under reduced pressure and the oily residue was poured into 8 liters of · · · * · [* ice water. The resulting precipitate was collected by filtration and suspended in 3 liters of water: and collected by filtration and then dried to give 249 g of (1-cyclo: "': propyl-6,7-difluoro-1,4-dihydro-8-methoxy). -4-oxo-3-kmolinecarboxylic acid 353.04) bis (acetate-0) borate as a light orange-yellow powder.

· · · * ··· * Melting point 113-117 ° C.

7 103794

Elemental Analysis (%) (Formula C18H16BF2N08.l / 4H20)

Calculated C, 50.56; H, 3.89; N, 3.28

Found: C, 50.32; H, 3.71; N, 3.33 NMR Spectrum (CDCl3, delta) 1.12-1.60 (4H, m) 1.92 (6H, S, -OCOCH3) 4.2 (3H, d, J = 2H2) -OCH3) 4.33-4.73 (1H, m) 7.97-8.28 (1H, dd, J = 8Hz, 10Hz, 5-H) δ 9.24 (1H, s, 2-H) .

Example 2 To 12.3 g (29.1 mmol) of (1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-15-oxo-3-quinolinecarboxylic acid-03.04) bis ( acetate-O) borate was added a mixture of 4.38 g (43.7 mmol) of 2-methylpiperazine, 8.2 ml of triethylamine and 30 ml of acetonitrile and then stirred overnight at room temperature.

The residue obtained by distilling off the solvent was dissolved in 40 ml of ethyl acetate. After washing with water, it was dried over anhydrous sodium sulfate. It was concentrated and dried under reduced pressure to give 12.9 g of [1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3 -quinolinecarboxylic acid '·': 03.04] bis (acetate-O) borate (91.0% yield).

M.p .: 126-129 ° C.

• · · • · «· • · ·: * ·. · Elemental Analysis (%) (Formula C23H27BFN3O8.3 / 4H2O)

Calculated for C, 53.45; H, 5.56; N, 8.13

Found: C, 53.36; H, 5.46; N, 7.93.

30 NMR Spectrum (CDCl 3, delta) 0.84-1.47 (7H, m): δ: 2.04 (6H, s, -OCOCH 3) 2.47 (1H, = NH) 2.82-3 , 66 (7H, m) 35 3.80 (3H, s, -OCH3) 4.10-4.35 (1H, m): ···: 7.93 (1H, d, J = 12Hz, 5- H) 9.12 (1H, s, 2-H) δ 103794

Example 3 2.0 g of (1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxyl-5-ylacetic acid-03.04) bis (acetate-O) borate, 1.4 g of cis -3-t-butoxycarbonylamino-4-methylpyrrolidil, 6 ml of acetonitrile and 1.6 g of triethylamine were charged together and stirred at room temperature for 24 hours.

The Kim mixture was dissolved in ethyl acetate, washed with water.

10

After drying over anhydrous sodium sulfate, it was concentrated and dried to give 2.8 g of [7- (cis-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-methoxy -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-0,304] bis (acetate-O) borate (98.2% yield).

15

Melting point 146-148 ° C.

Elemental Analysis (%) (Formula C28H35BFN3O10.1 3 / 4H2O).

Calculated C, 52.97; H, 6.11; N, 6.62. Found: C, 53.01; H, 5.73; N, 6.57 [1-Cyclopropyl-7- (3-methyl-1-piperazinyl] -1-cyclopropyl) -6-fluoro-8-methoxy-1,4-dihydro-4-oxo 3-quinolinecarboxylic acid-03.04] bis- (acetate-O) borate and [7- (3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-: ... 25-fluoro-1, 4-Dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid-03.04] bis (acetate-O) borate can be converted to 8-alkoxyquinolinecarboxylic acid which is industrially useful in the following process.

• · · • · · · ·

Comparative Example 1 To 30 · · · 14.2 g (29.1 mmol) of [1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-

• 1 1 'X A

of methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid -0.0] bis (acetate-O) borate was added a mixture of 50 ml (0.36 mol) triethylamine, 264 ml ethanol and 66 ml. ml of water and then refluxed with stirring for 6 hours.

After the reaction solution had cooled, the insoluble material was filtered off and the filtrate was concentrated and dried to give a yellow oily substance. It was dissolved with heating in 240 ml of ethanol and after cooling, the resulting precipitate was collected by filtration: ·! 35 9 103794 club to give 9.1 g of 1-cyclopropyl-7- (3-methyl-1-piperazinyl) -6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (yield) 83.4%).

Comparative Example 2 2.8 g of [7- (cis-3-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4- Oxo-3-quinolinecarboxylic acid-03.04] -bis (acetate-O) borate was dissolved in dichloromethane and 40 ml of trifluoroacetic acid was added dropwise thereto while cooling with water.

10

After stirring at room temperature for 30 minutes, the mixture was concentrated. After addition of 40 ml of water to the residue and neutralization with aqueous NaOH, it was extracted with ethyl acetate.

After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate and concentrated and then dried.

After adding 10 ml of ethanol, the product was dissolved by heating and after cooling, the precipitate obtained was collected by filtration and then dried to give 1.0 g (57.4%) of 7- (cis-3-amino-4-methyl-1 pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

M.p. 214-215 ° C.

«·« · • 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 • · · • · · · <• · • «·

Claims (4)

103794 1. (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-03.04) -bis (acyloxy-O) borate, its salt and its hydrate, characterized in that it is represented by the general formula (I) R 2 O '-O / ° R' Z-^ (I) wherein X represents a halogen atom, R represents an aliphatic acyloxy group having from 2 to 6 carbon atoms , an aliphatic acyloxy group having 2 to 6 carbon atoms optionally substituted with a halogen atom, or an aromatic acyloxy group having Λ 7-11 carbon atoms, R 'represents a lower alkyl group, R represents a hydrogen atom, a halogen atom, an amino group, or a nitro group, R4, · *. * ·: -N N-R3 ·: · <; n; ··. (Where n is 1 or 2, R represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group, R 4 and R 5 each independently represents a hydrogen atom, a lower alkyl group, substituted an alkyl group, a cycloalkyl group or a phenyl group) or a group · · ·? ·? r * x * /> '/ ··. (where k is 0, 1 or 2,1 is 0, 1 or 2, m is 0 or 1, R6 represents a hydrogen atom, a halogen atom, a lower alkyl group or a hydroxyl group, R represents a hydrogen atom, a lower alkyl group of 103794 or substituted a lower alkyl group, R8 represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group), or an azetidino group, a pyrrolidino group, a 3-hydroxypyrrolidino group, a piperidino group or a thiourino group. 2. A process for the preparation of a compound of general formula (I) wherein Z is a halogen atom, characterized by administering a compound of general formula (II) R 2 O X wAsy / N / 000119 annetaan R '^ (II) wherein X, X' represent a halogen atom, R 'represents a lower alkyl group, R 2 represents a hydrogen atom, a halogen atom, an amino group or a nitro group, R 9 represents a hydrogen atom or a lower alkyl group, react with a triacyloxyborate-15 derivative of general formula V B (R) 3 (III) wherein R represents an aliphatic acyloxy group having 2 to 6 carbon atoms, an aliphatic. 20 acyloxy groups having 2 to 6 carbon atoms optionally substituted with halo. ♦. *: with a gene atom, or an aromatic acyloxy group having 7-11 carbon atoms. Process for the preparation of a compound of general formula (I) in which Z is a halogen atom, characterized in that boric acid is reacted in an organic acid or in an organic acid anhydride and in zinc chloride. in the presence of v to give a triacyloxyborate derivative and without isolation it is reacted with: a compound of the general formula (H) <· · * t · 103794 r 2 h R '^ 0 AR (II) wherein X, X' represent a halogen atom, R 'represents a lower alkyl group, R 2 represents a hydrogen atom, a halogen atom, an amino group or a nitro group and R 9 represents a hydrogen atom 5 or a lower alkyl group. A process for the preparation of a compound of general formula (I) wherein Z is other than a halogen atom, characterized in that a compound represented by general formula (IV) which is a compound of general formula (I) wherein Z is a halogen atom > {R2 OO v ·; o A ·: ·: R A a (IV) where X, X ′ represent a halogen atom, R represents an aliphatic acyloxy group having 2 · 6 carbon atoms, an aliphatic acyloxy group having 2 to 6 carbon atoms and having • · 15 optionally substituted with a halogen atom, or an aromatic acyloxy group having 7-11 carbon atoms, R 'represents a lower alkyl group, R 2 represents a hydrogen atom, a halogen atom, an amino group or a nitro group fused to a cyclic amino compound represented by general formula (V) • · * * i 20 ΖΉ (V) • «I · '' • · • .. * where Z 'represents the group •» * «· • · 103794 _ ^ R4 -N \ i-R3 V | ^„ R5 (where n is 1 or 2, R3 represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group, R4 and R5 independently represent 5 hydrogen atoms, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group) or a group of 10 (where k is 0, 1 or 2.1 is 0, 1 or 2, m is 0 or 1, R 6 represents a hydrogen atom, a halogen atom, a lower alkyl group or a hydroxyl group, R 7 represents a hydrogen atom, Q a a lower alkyl group or substituted a lower alkyl group, R represents a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an Aralyl group) or an azetidino group, a pyrrolidino group, a 3-hydroxypyrrolidino group, a piperidino group, a morphorino group. • · ....: Patent Application • <'· · <' 1. (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate). xylsyra-03,04) -bis (acyloxi-0) Borat that you därav och ett hydrat därav, • · kännetecknat av att det representeras av den allmänna formeln (I) r2 9 '9 • * * lv II I • · · Xv> v \. :! ·: III / O R: R, ^ «37 37 37 37 vä vä 37 37 37 37 37 37 37 37 37 37 37 37 37 vä 37 vä 37 37 37 37 37 37 37 bet bet 37 37 94 37 37 37 37: 103794 Color X betecknar en halogenatom, R betecknar en aliphatic acyloxigrupp med 2-6 kolatomer, en aliphatic acyloxigrupp med 2-6 kolatomer möjligen substituents med en halogenatom eller en aromatic acyloxyl group 7-11 collatomer, R 'betecker alkyl group, R2 betecker halogen atom, amino group eller nitrogroup, Z betecker member halogen atom, en R4 group, -N N-R3 R5 (color 1) eller 2, R 3 is alkyl, alkyl, acyl, alkoxy-10 carbonyl, aralkyl, R 4 and R 5 are substituted, alkyl, substituted with alkyl, cycloalkyl; 15 (color at 0, 1 eller 2, 1 at 0, 1 eller 2, at 0 eller 1, R6 betecker alkyl group, halogen atom eller hydroxyl group, R7 betecker group, alkyl alkyl group, substituents for the alkyl alkyl group, R8 betecknar en acyl, alkoxycarbonyl, eller aralkyl), azetidinogroup, pyrrolidinogroup, 3-hydroxypyrrolidinogroup, piperidinogroup, • ♦ morphorinogroup eller thiomorphinogroup. 2. "Förfarande för framställning av en förening med den allmänna formeln (I), Color Z halogenatom, kannnetecknat av förening med den" «· v : 25 allmänna formeln (II) • 1 · «· · * · 1 • · <· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · about: 103794 R2 TXT X Λ R ΖΛ (II) color X, X 'betecknar en halogen atom, R' betecknar en alkyl group, R 2 betecknar alkyl group, halogen atom, aminogmpp eller nitrogroup, R 9 betecknar en alkyl group, med triacyloxiboratderna med den allmän ) B (R) 3 (III) Color R is a substituent on an aliphatic acylloxy group of 2-6, an aliphatic acylloxy group of 2-6 alkyl substituents of a halogen atom, an aromatic acylloxy group of 7-11. 3. Förfarande för framställning av en forening med den allmänna formeln (I), shade Z halogenatom, kanknetecknat av att man omsätter borer i en organic salt 15 eller organic cyanohydride and nickel chloride, colors man erhäller et triacyloxibat isolering omsätter detta med en forening med den allmänna formeln (II) R2 0 X. XT XOOR9. ···. YY • · • · · R./° x ..... (11) :: i .: 20 * 1 1 λ * ·) 1 color X, X 'betecknar halogenatomer, R' betecknar en lägre alkylgrupp, R2 betecknar : :: en substituent, halogen atom, amino group eller nitrogroup and R9 betecknar en substituent :: eller en lägre alkylgroup. • «· · • · 25 4. Förfarande för framställning av en forening med den formen (I), color '···' Z betecknar annan halogenatom, kännetecknat av att man condenserar 103794 förening som representeras av den allmänna formeln (IV), som är en forening med den allmänna formeln (I), color Z is an halogen atom, V R 2 O '') Λ R 'Δα (IV) 5 color X, X' is a halogen atom, R is a aliphatic acyl group of 2-6, aliphatic acyloxyl group 2-6 kolatom möjligen substituents med en halogenatom eller en aromatic acylloxy group med 7-11 kolatomer, R 'betecknar en alkyl group, R 2 betecknar en heteroatom, halogen atom, amino group eller nitro-10 group, med en cyklisk aminof. representeras av den allmänna formeln (V) ΖΉ (V) 15 colors Z 'betecknar en grupp ·: ··: __k .R4 r ~ x 3' ... · -N N-R3 O VlV5 n: R • · • » I «·» (((3 ((v eat ell ell ell (((((((((((((( xi -... 20 carbonyl moiety eller aralkyl moiety, R4 and R5 betecknar moiety, alkyl moiety, substituted alkyl moiety, cycloalkyl moiety eller en mo 9 xr7 25 103794 (color) O 1 eller 2, 1 ell O, 1 eller 2, O eller 1, R 6 betecknar en substituent, halogen atom, slag alkyl group eller hydroxyl group, R 7 betecknar en group, alkylgroup eller substituents slurry alkyl group, R betecknar en group, alkylgroup , acyl, alkoxycarbonyl eller aralkyl) eller azetidinogroup, pyrrolidinogroup, 3-hydroxypyrrolidinogroup, piperidinogroup, morphorinogroup eller thiomorphinogroup. • · · * · · • • • • • I (• 1 · • »· · ·