PL100315B1 - METHOD OF MAKING NEW DERIVATIVES OF 1-PYRIDYLOXY-2-HYDROXY-3-AMINOPROPANE - Google Patents

Description

The patent description was published: February 29, 1980 100315 [IF and £ LNIA] U- edu Patenlwc! ^ 1 t ¦ • ¦ »!> • -. ¦: ¦ 1 1 Int. Cl.2 C07D 213/38 Inventor: Patent holder: Ciba-Geigy AG., Basel (Switzerland) The method of producing new derivatives 1-pyridyloxy-2-hydroxy-3-aminopropane One aspect of the invention is the manufacturing process new l-pi'iydyloxy-2-hydix derivatives> xy-3- an aminopropane of formula I, wherein R 1 is a hydrogen atom or a methyl radical, R2 is low a lower alkyl radical of at most 7 in-5 atoms carbon or lower phenylalkyl radical by at most lower 7 carbon atoms in the lower alkyl chain an optionally substituted lower alkyl group alkoxy or alkoxy of at most 7 te atoms gla, trifluoromethyl or chlorine-10 ca, R8 is alkoxycarbonylamino or alkanoylamino of 7 or fewer carbon atoms or alkoxyalkylDonylaminoalkyl or al- canoylamirioalkyl having 00 at most 7 jn atoms gla in the aflkoxykai-bonyl alkanoyl chain 15 and with a maximum of 4 carbon atoms in an alkali chain and R4 is hydrogen or halogen, or their salts, especially pharmacologically acceptable salts of acid addition salts.

The new compounds show valuable drug properties macological. Their main action is to block vats of adrenergic ^ -receptors, which is possible stated in various organs, e.g. as an action restraining compared to the known effects β-receptor stimulators, such as the action of 25 inhibitory isoproterenol tachycardia on the isolated heart of the guinea pig and the relaxation of iso- proterenol in an isolated pig trachea Marska at a concentration of 0.001 ^ 3 g / ml, action of inhibitory isoproterenol tachycardia and 30 2 spreading vessels in a dormant cat at intravenous injection administration of 0.01-30 mg / kg i.v. The discussed compounds na¬ either belong to the class of non-cardioselective substances blockers that block ^ -receptors, that is, they block them /? - receptors in vessels or in the trachea in similar or even lower doses or concentrations than ^ -receptors in the heart, or belong to a class of so-called cardioselective substances blockers, that is, blockers cardiac pathways already within this dosage range relative concentrations that do not yet cause a problem any preceptors in the vessels relatively in breath vicy. Some of these compounds are shown as additive the so-called "Intrinsic sympatho- minetic activity (ISA) ", that is, these compounds are referred to big next to ^ -block (main action) partially /? - stimulations. Substances that block the can receptors for use, for example, for the treatment of Angina pectoris, nad¬ pressure and heart rhythm disturbances.

Dioselective preparations also have superiority over non-cardioselective, with doses of not to block the heart receptors still await blocking of ^ -receptors in others organs. So there is a slight risk of development Side effects, for example, skin feel the bronchi. Contrary to cardiovascular preparations dioselective, not kaindioselective preparations or they block the receptors in all organs approximately equally or preferably 100315s block ^ -receptors in specific organs, na example in dishes.

The compounds listed in Table 1 given were tested in vitro in terms of their blocking effects on cardiac receptors-jff. In the third column, the Table 1 shows the interpolated concentrations in / tg / ml, which in the isolated heart of the guinea pig Langendorff debt causes a 50% deterioration tachycardia interaction 0.005 µg / ml dose of Dl ^ isoproberenol sulphate (EC50).

Table 1 No. 1 2 3 4 6 Name of the active substance 3-chloro-2- (3 / -isopropyl- fumarate) amlmo-2 / -hydrok! sypitopakHy) -5- (2 / - -methoxycarbonylamino-ethyl) -py ryidines Va-fumarate 5- (2'-n-bu1 »(ksykairbo- nylaminoethyl) -2 - ^ '- isopropyl- amdno-2 / - ^ hydroxyipax) poksy) -piiry- Pumpkins 5- (2'-ethoxy-carbonyl- fumarate) amino-ethyl) -3-chloro-2- (3'-isopro- pylamino-2'-hydroxypropoxy) - -pyridine V «-rumaran 2- (3'-isop (ropylamino- -2 / -hydroxypropotes) -5- (2 '^ metho- xycarbonyl- (unano-ethyl) -pyridine 2- (2'-hydroxy-3'-isopix) fcylamino- -propoxy) -5- (n-butoxycarbonyl- -amJnomethyl) -pyridine 1 / * - 1,2-Isopropylamino-3- fumarate - (pyridinyl-4-oxy) -propanol-2 [known ny from J. Med. Chem. 15, 1321-1324 (1972)] • EC * 0.057 0.075 0.03 0.6 M. 0.9 From the table 1 given, it appears that the products were tested new compounds created according to the invention Nos. 1-5 are due to the concentration of the effective attack ECM speech up to about 64 times more effective than the known comparative pyridine compound No. 6 with a structure similar to new substrates of the formula rze2. ^ Further pharmacological properties of some new ones Compounds of Formula 1 are summarized in the following tabula 2.

Table 2 Relationship with for example clade II III IV V VI VII 1 viii Action blocking ^ - (recept¬ tracks cardiac in vitro 1) 1 0.6 0.075 0.057 1.3 0.4 0.03 Blocking action / ^ - cardiac receptors in vivo 2) AND 1.5 0.5 0.16 1.2 0.24 B average 30 average 3 8.5 average 3 > 3 those 7 > 13 > 6 53 > 3 > 13 ) 315 4 Table 2 legend: 1) Blocking action of ^ -re¬ cardiac receptors in vitro: are given (interpolated n) the concentrations of the preparations in g / ml, which are guinea pig heart beat according to Langendórff's method 50% containment often of the contractile action of the dose of 0.005 µg / ml sulfate DL-isoproterenol; 2) Blocking effect on cardiac receptors and blood receptors in vivo: A. doses of the preparation are (interpolated) given in mg / kg i.v., which in a dormant (pentdbarbital) the cat 5 minutes after injection high 50% inhibition of tachycardia is working at a dose of 0.5 µg / kg i.v. DL ^ zoprotere- sulphate nolu; ' B. the doses of the preparation are (interpolated) given in mg / tag Lv., which in a dormant (penlobarbdtalem) the cat 5 minutes after it has started it results in 50% suppression of a vasodilator (reduction of perfusion pressure in hind limbs constant blood volume) effect doses of 0.5 µg / kg Iv. DL-isoproterenol sulfate; B C. The quotient C = - indicates whether in the case of AND of the given preparation is a cardioselective sub¬ -blocking state (preferably -recept blocking of the cardiac pathways in comparison with N-receptors workmanship) or not. And so C <1 means na- makes selective ^ lock; C = 1-5 is non-selective block and O 5 stands for cardiac disease active, blockade, the degree of selectivity the greater the higher the number.

The method of producing new compounds of formula at 1, in which all symbols have the above a given meaning, according to the invention, is that with a compound of Formula 2, wherein R5 is primary amino group or primary an aminoalkyl group of at most 4 atoms carbon, and Rj, R, and R4 have the meaning given above, is reacted with alkyl chloroformate with at most 6 carbon atoms in an alkyl chain or with an alkane carboxylic acid for which at most 7 carbon atoms, or reactive derivative. The alkyl chloroformate used is e.g. methyl or ethyl chloroforman which is is reacted in a suitable solvent for the above purpose. As a suitable solvent for example, an isopropanol-water mixture is used. Down The 50 lower alkanoic acids are included in particular acetic acid, moreover, acid is used vertical, n-butter and valerian.

Reactions with the lower alkanecarboxylic acid, in particular with acetic acid, carried out I am intentionally using His reactive derivative, for example with a halide such as ace chloride as many as or with an anhydride such as anhydride acetic water, or by means of mixed anhydrides aquifers, such as ccto anhydride you. The reaction with the halide takes place in a known manner man. Reactions with an anhydride such as anhydrous acetic acid, runs in an inert environment a solvent such as dichloromethane. Dec- pa of formula (B * -) (R, -) (CH8) ^ C- is the preferred 65 isopropyl or tert-butyl radical. Ja-5 100315 6 a halogen atom is a fluorine atom, bromine atom, especially chlorine.

For an embodiment of the method according to the invention also include those proceedings in which the components of the reactants are optionally in the form salt.

Depending on the conditions of conduct and sub¬ final products are obtained in free form or in the form of their additive salt with acids. And so you can get on e.g. alkaline salts, neutral or mixed, optionally also their hemi-, mono-, sesqui- or pcflihydrates. Addition salts of new compounds with acids can be converted into free compounds in a known manner, for example by means basic, such as alkali or ion exchangers new.

The obtained free bases can form salts with organic or inorganic acids. Down the preparation of acid addition salts is used such acids as are suitable for exclusion saline preparation with therapeutic use. As acids are therefore used, for example, chlorinated hydrocarbons, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, ali- cyclic, aromatic or heterocyclic acids carboxylic acid or sulfonic acid such as formic acid acetic, propionic, amber, glycolic, lactic, apple, wine, lemon, ascorbic new, maleic, fumaric or pyruvic, after moreover phenylacetic acid, benzoic acid, anthranilic acid, n-hydroxybenzoic, salicylic, emibonic, me- tanosulfonic, ethanesulfonic, hydroxyethanesulfonic phonics, ethylene polyphonic, halobenzenesulfon new, toluenesulfonic, naphthalenesulfonic, sul- fanilic acid or cyclohexylaminosulfo- speech. These and other salts of novel compounds such as pictrates or perchlorates, may also serve for purifying the obtained free bases, with the aqueous bases are converted into the salts, from splits them from salt again frees the bases. Due to there is a close relationship between the new relationships in free form and in salt form under the term vol different relationships throughout the description should be understood also the corresponding salts.

New compounds depending on the type of substance the initial and procedural conditions may exist as enantiomers or racemates, or in the event that they contain at least two asys metric carbon atoms, also as mixtures isomers (mixtures of racemates).

The resulting mixtures of isomers (mixtures of r cematów) can be based on physico-chemical differences separate components into both stereo isomeric (diastereomeric) pure racemates in a known manner, for example by chromatography and / or fractional crystallization.

The resulting racemates can be in a manner known per se for example by recrystallization with optically active solvent, with the aid of a microorganism speak or by reacting with an optically active acid a salt-forming compound with a racemic compound and separating the salts thus obtained, into example based on their different solubilities, separate into diastereomers from which it can be released nothing enantiomers by treatment with appropriate means cows. The optically active acids are usually used The D and L forms of acids such as viral acid new, di-o-toluoyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, gluco acid taminic, aspartic or quinic acid.

Preferably a more active method is identified both enantiomers.

In the process according to the invention, it is preferably used u> in taffeta the starting substances that lead to receipt of the end products discussed in introduction to the description, especially for specialty products not described and emphasized as beneficial.

Starting materials can be obtained as known way. For example, the compound of formula II, wherein R5 denotes an amino group, may be obtained yeast by reducing the corresponding nitro compound with the aid of Raney nickel in methanol as solvent.

A compound of Formula 2 wherein RB is a group amphinomethyl is available on the same route from the corresponding cyano compound, whereby reduction The operations are carried out in the presence of ammonia Sub¬ the output states can also occur in half enantiomeric forms.

The new compounds can be used as drugs, e.g. in the form of pharmaceutical preparations, which include contain these compounds or their salts in a mixture, e.g. with or without an organic pharmaceutical carrier organic, solid or liquid, suitable for for example for intravenous or parenteral use this. Substances such as that do not react with new compounds, such as water, gelatine, milk sugar, starch, steary magnesium nanate, tailfc, vegetable oils, gasoline alcohols polyethylene, rubber, polyalkylene glycols, petroleum jelly, choline sterol and other known drug carriers.

Pharmaceutical preparations can occur on example in the form of tablets, dragees, capsules, suppositories, ointments, creams or in liquid form as 40 solutions (for example elixirs or syrups), incl livid or emulsions. They are possibly sterilized and / or contain excipients such as preserving, stabilizing, wetting agents or emulsifying, salts that change the osmotic pressure 45 or buffer substances. They may also include other therapeutically valuable substances Mo ¬ preparations also seeking to find use in veterinary medicine are produced in a known manner.

The daily dose is about 40-150 mg in 50 fall of a steel-blooded organism about weight away about 75 kg. The examples below show a closer look according to the invention. In the examples, tem perature is given in degrees Celsius.

Example! 12.5 g 2- (3'Hisopropylamano-2'-hy- 55 drok) sy ^ propoxy) -5 - <^ ano-pyridine is dissolved in 100 ml of methanol, 5 to 7 g of ammonia are added and a decomposition of water dornia in the presence of 3 g of Raney nickel at a temperature of bend 70-80 °, at an initial pressure of 40 bar hydrogen tide until hydrogen absorption ceases. Ka- 60 the talcum is filtered off, the solution is evaporated and evaporated the residue is distilled in a vessel with a ball cooler at a temperature of 140 ° under a pressure of 0.01 mm Hg.

There is obtained 5-amino-methyl-2- (3M-hemopt) pylaine no-2'-hydroixy (prop6k)) pyridine in pale form 65 yellow oil 100 315 8 bl pr in Tl £ bl ki for m Example II. 28.7 g 2- (3'-isopropylamino-2'- the hydroxy-pral-oxy) -5-nitro-pyridine dissolves in 300 ml of methanol and hydrogenated in the presence of 3 g Raney nickel at room temperature and atmospheric dream until the theory is absorbed the amount of hydrogen. The catalyst is withdrawn at in a nitrogen atmosphere and the filtrate evaporates. Received crude mana 5-amino-2- (3'-isopyapylamino-2 / -hy- Droxy-propoxy) -pyridine is dissolved in 150 ml of dichloromethane and is infused dropwise during the night with 14.3 ml of acetic anhydride, the solution being diluted the formation warms up to rain. After dripping without the reaction mixture is stirred further for 20-30 minutes. After shaking the solution with 90 ml of 2N sodium carbonate solution, organic phase 200 ml of total hydrochloric acid are extracted dreams, the water extract treats with activated carbon (about 10 g) and evaporates in a vacuum. Received dark oil dissolves in as little as possible necessary amount of water and alkalizes with concentrated slurry sodium. A strict rule was distinguished by the ex with dichloromethane. It crystallizes from butanone -acetone ^ and d | o-2- (3'-isopyrc) phenyaniino-2 / -hydbxy-pro poxy) - pyridine, mp 138-141 °.

The hydrochloride formed melts at temperature 204-206 ° (from methanol-acetone).

Example III. 12.4 g of 5 ^ (2'-aminoethyl) -2-3'-iso- propylamino-2'-hydroxypropoxy) pyridine, sol dissolved in a mixture of 45 ml of isopropanol and 45 ml of water, mixed with stirring at the temperature of temperature 20-35 °, dropwise 3.5 g of methyl ester chloroformic acid, but in the event of it needs to be cooled by ice water. Reaction mixture stirring is continued for 1 hour at the temperature room, evaporates in a vacuum and the residue after After evaporation, it dissolves in about 30 ml of water. Chap the product is extracted with 20 ml of ethyl acetate and acidic, the aqueous phase is made alkaline with concentrated sodium liquor.

The precipitated oil is extracted into dichloromethane.

After drying the solution over magnesium sulfate and evaporation of the solvent gives 2- (3'- -isopropylamlin-2'-hydroxy-propoxy) -5- (2'-me- toxycarbonylaminoethyl) -pyridine, which after Crystallization from a small amount of butanone melts at 97-99 °.

Example IV. Using 8.9 ml of n-butyl ester of chloroformic acid instead of 5.4 ml chloroformic acid methyl ester, ana logically as in example III one gets 5- (2'- -n-butoxycarbonylamdnoethyl) -2- (3'isopropyl- amino-2'-hydroxy-propoxy) Hpyridine, which after after recrystallization from butanone, it melts at a temperature 93 ° -95 ° C and forms an inert fumarate with a temperature of mp 145-147 °.

Example V. Similarly to the example III, but using 14.1 g of 5- (2H-aminoethyl) -3-chlorb- -2- (3'-isopropylammo-2'-hydroxy-propoxy) -pyr- dynes instead of 5- (2 H-aminoethyl) -2- (3'Hisopropylami- no-2'-hydroxy-propoxy) Hpyridine is obtained 3nchlom-2 ^ (3 / -iJzopyropylamino-2-hydroxy-p £ petroleum) xy) -5- (2'-methoxycarbonylaminoethyl) -pyridine, o mp 99-101 ° (from ether). Formed Neutral fumarate melts at 197— 180 ° (from ethanol). 19 40 45 50 55 60 65 The output is produced as follows way: a) Crude 5,6-dichloronicotinic acid chloride was obtained from 279 g of 2-hydroxy-5-pyramidal acid dynecarboxylic acid, 185 g is reduced with boron sodium hydride in 3.2 liters of water (F. E. Ziegler and J. G.

Sweeny, J. Org. Chem. 34, 3545 (1969)) to 2,3-two- chloro-5-hydroxymethyl-pyridine, at a temperature of mp 72-75 °. b) 2,3-dichloro-5-hydroxymethyl] pyridine was introduced It is reacted in a manner known per se with chloride thionyl, obtained 5-chlioramethyl-2,3-dhloro -pyridine is processed without further purification reaction with sodium cyanide (analogous to in L. A. Cairlson et al. Acta Pharm, Suecica 9, 411 (1972)). The resulting 5,6-dichloro-pyridine-3-aceto the nitrile melts upon recrystallization from ether at 72-75 °. c) 85.5 g of (5,6-dichloro-3-pyridine) acetonitrile in 200 ml of methanol, 18.5 g of borohydride are reduced sodium in 65 ml of concentrated sodium hydroxide solution and presently carries 20 g of Raney nickel. The raw material thus obtained of this product, 5- (2'-aminoethyl) -2.3- -dichloropyridine by distillation in the vessel with a ball dephlegmator at bath temperature 95-11570.08 mm Hg. d) 44 g of 5- (2'-ammoethyl) 2,3-dichloronpyridine and 55 g of 5-hydroxymethyl-3-isophenyl-2-phenyl-oxa- zolidine, dissolved in 500 ml of 1,2-dimethoxy- ethane is added while cooling with ice at a temperature of At 0-10 °, portions of 55% of a suspension of 12 g of water sodium chloride. Then the reaction mixture it is stirred for 2 hours at room temperature for 16 hours at boiling point under reflux cooler. The rework produces a raw 5- (2'- -aminoethyl) -3-chloro-2- [3 / -isopropylamino-2 / -phe nylo-okEazolidinylJ-S ^ Hme ^ toxy-pyridine, which without further purification hydrolyzes to 5- (2'-amino- noethyl) -3-chloro-2- (3) -isopropylamino-2) -hydro xy-propoxy) -pyridine, boiling point 165-18570.06 mm Hg.

Example VI. 6 g of 5-aminomethyl-2-N -hydro xyl'-isopropylaminopropoxy) -β-iridine, dissolved it is recovered in 25 ml of isopropanol and 25 ml of water and the like It reacts as in example III with 2.3 ml of chloroformic acid methyl ester wego and processes it further. Obtained 2 ^ (2'-hydro- xy-3'-isopropylamino-propoxy) -5-non-nitoxy-carbo- nylaminomethyl-pyridine, m.p. 96-97 ° (from ether). The inert fumarate melts in temperature temperature 138-140 °.

Example VII. Same as in the example VI is obtained with 3.7 ml of n-butyl ester chloroformic acid with methyl ethers go, 2- (2-hydroxy-3 / -isopropylamine-propoxy) -5- - (n-B, t-oxycarbonylaminomethyl) pyridine, with a temperature of mp 85-87 ° (sintering from 79 °) after recrystallization from dichloromethane - ether.

Example VIII. 5.3 g 5- (2 / Aminoethyl) -3-chloro -2 -. (3'-isoprc-4-yl-amino-2H-hydroxy-propoxy) -pi- ridines are reacted in the same way as in example III with 2.2 g of acid ethyl ester chloroformic acid in a mixture of 25 ml of isopropa nol and 25 ml of water and is obtained after pre-crystallization-9 100315 from acetone-ether 5- (2H-ethoxy-carbonyl- amihoethyl) -3-ohloro-2 - ^ - azopropylamino ^ '- hy- drx3 ^ y-pvapicBssy) panrinine, melting point 120-122 °. The inert fumarate melts in temperature Temperature 149-151 ° (from ethanol-acetone).

Claims (12)

Patent claims 1. The method for the preparation of the new 1,3-dyloxy-2-hydroxy-3-aminopropane derivatives of the formula I, wherein Rt is a hydrogen atom or a methyl radical, Rj is a lower alkyl radical of at least 7 carbon atoms or lower phenylalkyl radical of at most 7 carbon atoms in the lower alkyl chain, optionally substituted lower alkyl or alkoxy group of at most 7 carbon atoms, trifluoromethyl or halogen, Rs is an alkoxycarbonyl alkoxy group of at most 7 carbon atoms or an alkali ByphylAninealkyl group with a maximum of 7 carbon atoms in the alkoxy carbonyl portion and with a maximum of 4 carbon atoms in the alkyl chain and R4 is hydrogen or halogen or a salt thereof, characterized by the compound of formula II, R5 is a primary amino group or a primary aminoalMyl group with a maximum of 4 carbon atoms, and RA, Rj and R4 are as defined above, reacted with an alkyl chloroformate having at most 6 carbon atoms in the alkyl chain, the resulting salt is optionally converted to the free compound or the obtained free compound is optionally salified, or the resulting racemate is optionally cleaved into enantiomers. 2. The method according to claim The process of claim 1, wherein the reactions are carried out in a solenoid. 3. The method according to p. The process of claim 2, wherein the solvent is dichloromethane. 4. The method according to p. The process of claim 2, characterized in that an isopropanol-water mixture is used as the solvent. 5. The method according to p. A process as claimed in any one of the preceding claims, characterized in that 5- (2'-aminoethyl) -2- (3'-isop (phenylalanino-2'-hydroxypropoxy) -pyridine is reacted with methyl moroformate, prepared by 2- (3'-isopropylamino-2'-hydroxypropoxy) -5- (2'-methoxycarlxmylamoyl) n-pyridine. 6. The method according to p. A method as claimed in any one of the preceding claims, characterized in that 5- (2H-aninoethyl) -3-chloro-2- (3H-isopropylaminoc2H-hydlicylpyridine is subjected to reaction with methyl chloroformate to give 3-chloro-2- (3) -isopropylamino-2H-3-hydroxy-polypropoxyl) -5H (2-methoxycarbotnylamino-methyl) -pyridine, 5 7. The method according to p. A process as claimed in any one of the preceding claims, characterized in that 5- (2'-aminoethyl) -3-chloro-2- (3'-isopropylaonincK2'-hydiro) is reacted with ethyl chloroformate to give 5- (2'- ethoxycarfoonylamino-ethyl) -3-chloro-2- (N-α-propylammo-α-hydroxypropoxy) -pyridine. 8. The method according to p. Reaction as claimed in claim 1, 2, or 3 or 4, characterized in that 5- (2'-aminoethyl) -2- (3'-isopropylamido-2'-hydroxyp (ropoxy) -pyridine is reacted with n-butyl chloroformate, to give 5- (2'-n-bu1-xycarbonylamino) -2- (3'-isopropylarciino-2-hydroxypropoxy) pyridine. 9. A method for the preparation of the new 1-pyridyloxy-2-hydroxy-3-ammopropane derivatives of formula I, wherein Bt is a hydrogen atom or a methyl radical, and R2 is a lower alkyl radical of at least 7 carbon atoms or lower. a phenylalkyl radical of at most 7 carbon atoms in the lower alkyl chain, optionally a substituted lower alkyl or alkoxy group of at most 7 carbon atoms, trifluoromethyl or halogen atoms, Rj is an alkanoylamino group of at most 7 atoms a carbon or an alkylaminoalkyl group with a maximum of 7 carbon atoms in the alkanoyl chain and with a maximum of 4 carbon atoms in the alkyl chain, and R4 is hydrogen or halogen or a salt thereof, characterized by the compound of formula II, wherein R5 represents a primary amine or primary amdnoalkyl group of at most 4 carbon atoms and Rx, Rj and R4 are as defined above, are reacted with an alkanecarboxylic acid of at most 7 atoms With carbon, or with a reactive derivative thereof, the resulting salt is optionally converted to the free compound "or the obtained free compound is optionally cleaved into enantiomers. 10. The method according to p. 9. The process of claim 9, wherein the reactions are carried out in a solvent. 11. The method according to p. The process of claim 10, wherein the solvent is dichloromethane. 12. The method according to p. The process of claim 10, wherein the solvent is an isopropanol-water mixture. 15 20 25 30 35 40 45 \ 100 315 ^ 'PM R3-t ^ rR4,. T "3V" O-CH2-CH (OH) -CHr NH- C- R2 Ri Formula 1 11 Rffi ^ VR4 and 3 WLo-CH1-CH2 -CHf-NH-C-R. Pattern from PZG Bydgoszcz, residing in 185/79, nakl. 95 + 20 Price PLN 45