In particular the present invention relates to a crystalline compound consisting of nolomirole hydrochloride polimorphic Form I of at least 95% by weight of chemical purity, preferably equal to or higher than 97%, more preferably 98% and of at least 90% w/w polymorphic purity, to the process for its preparation and isolation as well as to pharmaceutical preparations thereof for the treatment of patients suffering of cardiovascular diseases such as congestive heart failure.

()-5, 6-diisobutyroyloxy-2-methylamino-1, 2,3, 4-tetrahydro- naphthalene hydrochloride, (hereinafter indicated with its approved INN nolomirole hydrochloride) is a DA2 dopaminergic receptor/oc2-adrenoceptor agonist, which has been claimed to be useful for the treatment of cardiovascular diseases (WO 96/29065) and in particular for the treatment of congestive heart failure.

Nolomirole hydrochloride is conveniently formulated in tablets for oral administration. The hydrochloride salt is particularly suitable for the preparation of tablets.

The daily dosage is comprised between 2.5 and 20 mg.

Nolomirole is a pro-drug which, after oral administration, is rapidly and completely converted, during absorption, by the esterases contained in the intestinal mucosa into its desesterified form, namely ()-5, 6-dihydroxy-2- methylaminotetralin, indicated hereinafter with the experimental code CHF 1024.

CHF 1024 also turned out to be one of the main occurring impurities and degradation products. Although the CHF 1024 is the active moiety, it is nevertheless important for pharmaceutical and therapeutic purposes that the drug product (nolomirole hydrochloride) is present in the formulation with the highest as possible chemical purity.

Nolomirole has been first described as hydrobromide salt in GB 2,123, 410 among a series of aminotetralin derivatives (tetralin is another name for 1,2, 3,4-tetrahydro-naphthalene) and disclosed as potential antibronchospastic agents. In the description, an indication for the preparation of the hydrobromide on a laboratory scale is provided in analogy to the pivaloyl derivative. Said procedure envisions precipitation from a mixture of ethyl ether and petroleum ether. The product has been characterised in terms of NMR spectrum in solution and melting point. The solvents used for its preparation cannot be utilised on an industrial scale; moreover, although it is reported that the product is obtained as a white crystalline powder, once moving on a bigger scale, a significant percentage of amorphous is obtained.

EP 788472 in the name of the applicant and EP 534536 in the name of Zambon refer, respectively, to processes for the preparation of 5,6 dihydroxy-2-amino-tetralins and N-alkyl derivatives thereof and 5,6- dimethoxy-2-amino-tetralin as intermediates useful for obtaining pharmacologically active chemical compounds. In none of them processes for the preparation and isolation of acyl derivatives such as nolomirole are mentioned.

In a study presented as a poster at the XXth National Congress of AICAT (Rome, December 14-18,1998), mainly aimed at investigating the thermal behaviour of nolomirole hydrochloride racemate (quoted with its experimental code CHF 1035) and its enantiomers, preliminary results about

its polymorphism were disclosed. In the poster it is stated that Form I can be obtained from acetone and ethanol after fast cooling, Form II from acetone after slow cooling and from III from methyl-ethyl-ketone. No details about the crystallisation conditions are reported nor on the process of preparation of nolomirole hydrochloride.

In Giordano et al (J Pharm Sci 2001,90 (8), 1154-1163), the polymorphism of nolomirole hydrochloride has been thoroughly investigated. Thermal, spectroscopic, and X-ray diffraction analysis confirms that three differing crystal forms by recrystallization procedures from common organic solvents can be obtained.

Taddei et al [Biopolymers (Biospectroscopy) 2002,67, 289-293] used vibrational spectroscopy coupled with thermogravimetry and differential scanning calorimetry to investigate the possible presence of different polymorphic forms of CHF 1035 and their relative stability. Crystallized CHF 1035 was obtained from an acetone solution by fast crystallization as a-form and from acetone solution by slow crystallization at a low cooling rate as (3-form. According to the spectra, a and P-form in Taddei correspond to Form I and Form III in Giordano.

Recrystallizations have been performed in the prior art on a laboratory scale and (in Giordano) according to the following procedures: 10 ml of the solvent under examination were saturated with the product, holding the temperature slightly below the boiling point. The hot suspension was then rapidly filtered into a flask maintained at room temperature (RT) or ice- cooled (IC). In all cases the filtrate was allowed to reach spontaneously RT and to equilibrate overnight.

From ethanol and methanol as well as from methylethylketone, a single solid phase has been obtained whatever recrystallisation procedure is used; on the contrary, from acetone two solid phases were obtained depending on

the suspension was maintained at RT or IC. According to Giordano, Form I can be obtained from ethanol and methanol or acetone at room temperature, Form II from methylethylketone and Form III from acetone ice cooling.

We have now found that: Form I can be prepared in high chemical pure form by crystallization from acetone by ice cooling. It cannot be prepared by using ethanol/methanol since when operating on an industrial scale this kind of solvents can give rise to trans-esterification reactions and thus to significant amounts of de-esterified degradation products.

Form II can be obtained from acetone at a temperature of about 20-25°C (room temperature), in any case not lower than 18°C ; Form III is obtained from methylethylketone.

Form II does not possess the chemical and physical stability characteristics required for a pharmaceutical product and is easily oxidised.

Moreover it has been found that Form II has not the desirable characteristics with respect to the manufacturing process since during isolation it is obtained as powder crystals that are indeed hardly filtered off to detriment of the product yield; moreover, said form strongly retains the solvent (s) of crystallisation so they cannot easily be dried.

The only form of nolomirole hydrochloride suitable as a medicament for pharmaceutical preparations is Form 1. Accordingly, there is a need of a nolomirole hydrochloride Form I with high chemical and polymorphic purity and of a process for its preparation in order to fulfil the requirements described above.

In general terms, chemical purity is a very important issue for pharmaceutical products. Impurities should be kept as lowest as possible as they could be detrimental to the potency of the active ingredient and they could also be responsible of unwanted side effects.

According to the pharmaceutical guideline ICH Q1A"Stability Testing <BR> <BR> of new Active Substances (and Medicinal Products) "of October 1993, a 5% change in assay of the active ingredient from its initial value does not meet the criteria of acceptance.

In the case of the product of the invention, the main occurring impurities are the monoester 5 (6)-isobutyroyloxy-2-methylamino-1, 2,3, 4- tetrahydro-naphthalene (CHF 2101) hydrochloride and the free cathecol derivative (CHF 1024) hydrochloride which, during storage, is easily oxidized to quinonic derivatives as evidenced by the slight coloring of the product.

High crystallinity is another important issue as amorphous or prevalently amorphous compounds are not suitable for pharmaceutical use due to the fact that potential crystallisation during handling and storage is always present. Such crystallization, in turn, can be responsible for phenomena such as post-compression hardening of tablets (Elamin et al Int J Pharm 1994,108, 729-752). Moreover amorphous or partially amorphous materials absorb water in larger amounts than crystalline ones (Hancock et al. J. Pharm. Sci. 1997,86, 1-12) ; so formulations containing active ingredients such as nolomirole hydrochloride, whose chemical stability is particularly sensitive to the humidity content due to the presence of ester bonds which can be subjected to hydrolysis reactions, could face stability problems during long term storage.

Polymorphic purity is a further important issue since different polymorphs have different physical properties which in turn can affect both stability and bioavailability. Among others, it has been reported that different physical forms (e. g. polymorphs) can have different hydrolysis and rate profiles (Waterman K et al Pharm Dev Tech 2002,7, 113-146) so that the stability of molecules such as nolomirole hydrochloride could be

dramatically affected by the polymorphic purity.

The process for the preparation of nolomirole hydrochloride Form I needs to be suitable for operating on an industrial scale and the crystallization solvent (s) should be readily and almost completely removable. Moreover, the product should be in a form that is readily filtered off and easily dried.

Finally, it has been found that it is highly advantageous to obtain a product with a particle size less than 400 um, preferably less than 300 llm, and more preferably between 100 and 300 llm. Said particle size is optimal for having either good flowability characteristics and an homogenous distribution of the active ingredient in the preparation of pharmaceutical solid dosage forms and especially tablets.

It has also been found that a solid material with a particle size of about or higher than 400 um is easily oxidized.

OBJECT OF THE INVENTION It is a first object of the invention to provide nolomirole hydrochloride of at least 95% chemical purity. It is a further object of the invention to provide nolomirole hydrochloride polymorphic Form I of at least 95%, preferably 97%, more preferably of at least 98% chemical purity. In a preferred embodiment of the invention it is provided nolomirole hydrochloride Form I of at least 97%, preferably of at least 98% chemical purity containing an amount equal or less than 0.3% by weight of 5, 6-dihydroxy-2-methylamino-1, 2,3, 4-tetrahydro- naphthalene (CHF 1024) hydrochloride and/or a content of 5 (6)- isobutyroyloxy-2-methylamino-1, 2,3, 4-tetrahydro-naphthalene (CHF 2101) hydrochloride equal to or less than 1.0% by weight.

Advantageously, nolomirole hydrochloride Form I (also referred to as drug product) will have a polymorphic purity of at least 90%, preferably of at least 95%.

Form I and Form II according to the invention are identified from the Raman spectra and the powder X-ray diffraction pattern reported in Figures 1,2, 3,4 respectively.

The present invention also provides a manufacturing process, which can be applied on an industrial scale for preparing nolomirole hydrochloride of at least 95% chemical purity. Said process comprises the steps of : i) reacting () 5, 6-dihydroxy-2-methylamino-1, 2,3, 4-tetrahydro- naphthalene (CHF 1024) hydrochloride with isobutyroyl chloride optionally in the presence of a suitable solvent to yield raw nolomirole ; ii) removing any volatile substance from the raw reaction product and dissolving the oily residue with an organic solvent ; iii) precipitating nolomirole as hydrochloride salt from the solution by adding hydrochloric acid ; wherein the organic solvent of step ii) is an ether solvent, preferably isopropyl ether or mixtures thereof with non-alcoholic solvents and step iii) is carried out by bubbling gaseous hydrochloric acid to avoid the use of water which might favour the hydrolysis of the ester bonds.

The synthesis of 5, 6-dihydroxy-2-methylamino-1, 2,3, 4-tetrahydro- naphthalene (CHF 1024) hydrochloride is described in EP 788472.

The conversion of CHF 1024 hydrochloride into its isobutyryl ester is effected by reaction with isobutyroyl chloride, using a suitable solvent. The elimination of the solvent excess from the reaction raw product leads to the formation of an oily mass. It has been found that nolomirole can be precipitated as hydrochloride from its oily mass by addition of gaseous hydrochloric acid in the presence of an ether solvent. It has been found in this respect that, among the possible ether solvents, isopropyl ether is particularly suitable. In fact in the presence of another widely used ether solvent, i. e methyl-tert-butyl ether, nolomirole might experience a

significant degradation to the monoester (CHF 2101) and free cathecol (CHF 1024) hydrochloride derivatives. We have indeed found that methanol can form due to the degradation of methyl tert-butyl ether in acidic environment: the formed methanol reacts with nolomirole by parasitic trans- esterification giving rise to the two aforementioned degradation products.

Although raw nolomirole hydrochloride is further subjected to a purification step by crystallization, nevertheless the amount of the above mentioned impurities should be maintained as low as possible since they are difficult to be completely eliminated from the finished product due to their close structural similarity.

A further object of the invention is a purification process of nolomirole hydrochloride to obtain the Form I characterized by high crystallinity as well as high chemical and polymorphic purity, at the same time fulfilling the other desirable features described above.

There is so provided a process for the (re)-crystallization of nolomirole hydrochloride by dissolving the product in a non alcoholic solvent with a boiling point lower than 70°C, preferably lower than 60°C, then cooling the solution to a temperature lower than 20°C, preferably lower than 18°C, more preferably equal to or lower than 5°C at a speed higher than 1°C/min.

In fact it has been found that a crystalline nolomirole hydrochloride Form I of a highly chemical and polymorphic purity, can only be obtained using a non alcoholic solvent with a boiling point lower than 70°C, preferably lower than 60°C and after cooling the solution of raw nolomirole to a temperature lower than 20°C, preferably equal to or lower than 18°C, more preferably equal to or lower than 15°C, even more preferably equal to or lower than 5°C, at a speed higher than 1°C/min.

The preferred non alcoholic solvent is acetone. Contrary to the teaching of the prior art when the crystallization from acetone is carried out

at room temperature, at about 20°-25°C and in any case at a temperature higher than 18°C, it predominantly gives rise to the form II, which is unsuitable for pharmaceutical utilization.

Although nolomirole hydrochloride polymorphic Form I can be obtained from ethanol and methanol as well, such solvents, as reported above, are not suitable as they give rise to trans-esterification reactions and thus to significant amounts of the de-esterified degradation products mentioned above, namely CHF 2101 hydrochloride and CHF 1024 hydrochloride.

The re-crystallization process of the invention, instead, allows to obtain predominantly polymorph I of nolomirole hydrochloride with a polymorphic purity of at least 90%, preferably of at least 95%, in a highly crystalline form with a very high chemical purity, higher than 95%, preferably 97%, more preferably 98%.

Advantageously, the above mentioned (re) -crystallization process gives rise to particles with an inherent particle size optimal for nolomirole hydrochloride to be conveniently formulated in tablets for oral administration. The particles of the active ingredient are uniformly incorporated in the mixture before tabletting by simple mixing so avoiding any further treatment such as milling which may disturb their crystallinity.

The present invention also provides a process for the conversion of Form II of nolomirole hydrochloride to Form I.

The process can be carried out using similar conditions of (re) crystallisation as those described above which give purified Form I.

According to this way, Form II is dissolved in a non alcoholic solvent having a boiling point lower than 70°C, preferably lower than 60°C, by warming, then cooled at a temperature lower than 20°C, preferably lower than 18°C, more preferably lower than 15°C till complete crystallisation.

The preferred non alcoholic solvent is acetone. In order to speed up the process, the solution may be seeded with few crystals of Form I prior to the initiation of product crystallisation. Alternatively, the process can be carried out by: i) suspending Form II in a non alcoholic solvent having a boiling point lower than 70°C, preferably lower than 60°C, such as acetone, in the presence of Form I ; ii) keeping the suspension under stirring at a temperature lower than 20°C, preferably of about 10°C for several hours, preferably for at least ten hours, then filtering the resulting product. In a preferred embodiment the suspension has been stirred for 30 hours.

A particular object of the present invention is the use of nolomirole hydrochloride Form I of at least 95%, preferably 97%, more preferably 98% chemical purity as a medicament for the preparation of pharmaceutical compositions for the treatment of patients suffering form cardiovascular diseases, in particular congestive hearth failure.

A further object of the invention are pharmaceutical compositions, in form of tablets for oral administration, further comprising pharmaceutically acceptable excipients, advantageously containing between 2.5 mg and 10 mg of the active ingredient per unit dose, preferably 2.5 mg or 5 mg per unit dose.

DETAILED DESCRIPTION OF THE INVENTION The characteristics of the process for the preparation of nolomirole hydrochloride and nolomirole hydrochloride Form I and the features of the product obtained will be more apparent from the following detailed description.

The synthesis of nolomirole hydrochloride is carried out by conversion of 5,6-dihydroxy-2-methylamino-1, 2,3, 4-tetrahydronaphthalene hydrochlo- ride into its 5,6-diisobutyryl ester by reaction with isobutyryl chloride, using a suitable solvent, followed by the elimination of the solvent excess from

the reaction raw product till an oily mixture is obtained. The term suitable solvent means any volatile polar acidic solvent, preferably halogenated acetic acid. The preferred one is trifluoroacetic acid.

Advantageously, nolomirole is precipitated as hydrochloride from the oily mixture by bubbling gaseous hydrochloric acid in the presence of an ether solvent. Preferably, gaseous hydrochloric acid is bubbled for at least 15 minutes, more preferably for 60 minutes keeping the temperature under 20°C, then optionally lowering the temperature to about 10°C and then to about 5°C.

As an ether solvent, isopropyl ether, ethyl ether, dioxane, tetrahydrofurane, 2-methoxyethyl ether and 2-ethoxyethyl ether can be advantageously used. Preferably, pure isopropyl ether or mixtures thereof with other non alcoholic solvents such as acetone and toluene, preferably in a ratio comprised between 10: 1 to 3: 1 v/v are used. More preferably, a mixture of isopropyl ether: acetone in a ratio 5: 1 is used.

Advantageously the process of (re) -crystallization for the preparation of nolomirole hydrochloride Form I starting from either raw nolomirole hydrocholoride or nolomirole hydrocholoride Form II is carried out as follows: i) dissolving in a suitable flask the product in a non alcoholic solvent having a boiling point lower than 70°C, preferably lower than 60°C such as acetone at a temperature from about 30°C to reflux temperature, preferably at 50°C ; ii) cooling the solution, preferably under stirring, by standard methods and/or by concentration under vacuum to a temperature lower than 20°C, preferably lower than 18°C, more preferably lower than 15°C, even more preferably lower than or equal to 5°C at a speed higher than 1 °C/min, preferably equal to or higher than 2°C/min. Although theoretically suitable halogenated solvents such as chloroform are to be avoided for environmental reasons.

The amount of solvent is at least 3 part by volume per part of product.

Higher amounts of solvents and generally up to 10 parts by volume can be used. Amounts higher than 10 volumes are not useful from an economical point of view because large size apparatus would be necessary. The most preferred solvent is acetone.

The flask will be advantageously maintained at 5°C and the precipitation will typically be accomplished within 5 hours. However the time required will vary depending on such factors such as total volume of solution, size of batch and presence or absence of stirring. Methods known in the art may be used to enhance any aspect of the process. For example, as reported above for crystallization of Form I starting from Form II, the solution may be seeded with few crystals of Form I prior to the initiation of product crystallisation ; nolomirole hydrochloride Form I can be collected by any standard method known in the art such as by filtration, filtration under vacuum, or decantation and drying.

Nolomirole hydrochloride Form I obtained by the process of the invention has a chemical purity, as determined by HPLC of at least 95% by weight, preferably of at least 97%, more preferably equal to or higher than 98%, with a melting range of 198-206°C as determined by Differential Scanning Calorimetry (DSC). The main impurities are detected: the content of CHF 1024 hydrochloride is less or equal than 0.3% by weight and/or the content of CHF 2101 hydrochloride is less or equal than 1.0% by weight.

Accordingly, it is provided a method of testing the chemical purity of a sample of nolomirole hydrochloride Form I or a pharmaceutical dosage form comprising nolomirole hydrochloride Form I assaying it for the presence of said derivatives.

The drug product and the pharmaceutical dosage form may be analyzed for purity or stability to degradation by a conventional analytical technique

and preferably by high performance liquid chromatography (HPLC).

The analytical testing will confirm that the main impurities or degradation products CHF 1024 hydrochloride and CHF 2101 hydrochloride are present at the above defined levels.

Advantageously, the polymorphic purity and the degree of crystallinity are both higher than 90% by weight, preferably higher than 95% as determined by powder X-ray diffraction. The crystal structure of nolomirole hydrochloride Form I has been determined. Unique indexing and lattice parameters values (a=29. 73 (2) A, b=7.748 (5) A, c=18.479 (13) A and B=104. 901 (9) °) were obtained from single crystal X-ray experiments performed on small (0.19 x 0.15 x 0.06 mm) specimen selected from the crystalline powder. The observation of systematic absences gave monoclinic C2/c space group and eight closely packed molecules in the unit cell.

Advantageously, at least 95% of the particles of nolomirole hydrochloride Form I has a diameter lower than 400 jum, preferably equal to or lower than 300 um, more preferably comprised between 100 and 300 m, as determined by laser diffraction (Malvern).

Form I of nolomirole hydrochloride produced according to the process of the invention can be characterised by its Raman spectrum and its X-ray powder diffraction (XRD) pattern (Figs 1 and 2). The FT-Raman spectrum, obtained by simply packing the powder into a cup, shows the following main peaks in the 3500-700 cm-l range (accuracy 1 cm-1) : 2937 cm-1 (vs); 1771 (s); 1614 (s); 1588 (s); 1446 (s); 1426 (s); 1302 (s); 1274 (m) ; 1221 (m) ; 1255 (m); 1098 (br, m) ; 1009 (w); 966 (w); 856 (s); 818 (m) Legend: vs = very strong; s = strong; m = medium; w = weak; br = broad The interplanar distances and relative peak intensities (in brackets) of

the powder XRD pattern are reported as follows (depending on the packing conditions, the relative intensities can change): 14.35 d/A (64); 8.93 (18) ; 8.63 (6); 7.46 (34); 7.19 (100); 7.13 (5); 7.04 (3); 6.46 (19); 5.55 (6); 5.40 (12); 4.82 (4); 4.66 (3); 4.62 (7); 4.52 (11); 4.27 (18); 4.07 (5); 3.90 (3); 3.80 (28); 3.60 (6); 3.55 (3); 3.24 (4); 2.86 (3).

For comparison Figures 3 and 4 show the Raman and XRD fingerprints of Form II.

The following examples better illustrate the invention.

EXAMPLES Example 1-Process for obtaining ()-5, 6-diisobut royloxy-2- methyl amino-tetralin hydrochloride (nolomirole hydrochloride) starting from () 5, 6-dihydroxy-2-methylamino-1, 2n3 ^4-tetrahydro-naphthalene (CHF 1024) hydrochloride.

Slowly add, in 2 hours, a molar excess of isobutyryl chloride to a suspension of CHF 1024 hydrochloride in trifluoroacetic acid, always keeping temperature at 25 2°C.

Then heat the solution to 85 2°C for 1 hour, thus obtaining a full dissolution.

Cool to 50 5°C, distil the maximum part of trifluoracetic acid under vacuum and add toluene to the oily residue: then, distil again to oil.

Repeat three times both addition and distillation of toluene, then dissolve the oily residue in a mixture of isopropyl ether: acetone 5: 1 v/v. Let gaseous hydrochloric acid bubbling for 60 minutes keeping temperature under 20°C.

Raw nolomirole hydrochloride precipitates as a white crystalline solid and the suspension is kept at 10 2°C for three hours, then at 5 3°C for further five hours and finally centrifuged. The obtained raw nolomirole

hydrochloride is dried under vacuum at 60 2°C.

The purity of the compound obtained is about 95% both upon lH NMR and HPLC analysis.

1H NMR (CH30H-d4, ppm): 1.28 (d, 6H); 1.35 (2 x d, 6H) ; 1. 82 (m, 1H), 2.30 (m, 1H); 2.6-3. 0 (m, 5H) ; 2.80 (s, 3H); 3.30 (dd, 1H); 3.48 (m, 1H), 7.0-7. 2 (AB syst, 2H).

13C NMR (CH30H-d4, ppm): 19.3 ; 19.4 ; 22.9 ; 25.6 ; 30.9 ; 32.2 ; 35.0 ; 55.9 ; 122.5 ; 128.2 ; 130.5 ; 132.4 ; 141.6 ; 142.5 ; 175.5 ; 176.6.

Legend: d = doublet; dd= doublets of doublet; m = mutiplet; s = single Example 2-Process for obtaining nolomirole hydrochloride Form I starting from raw nolomirole hydrochloride Raw nolomirole hydrochloride is purified by crystallisation on acetone.

The solid substance is dissolved in 10 volumes of solvent at 50°C, filtered, then the limpid solution is cooled to a temperature of 5°C upon concentration under vacuum at a speed of 2°C/min. The temperature is kept for five hours at 5 2°C, then centrifuged. The solid is dried under vacuum, at 60 2°C.

Assay = 99. 1% (HPLC); melting range = 199-202°C (DSC).

Operating in the same conditions as described in Example 2 nolomirole hydrochloride Form I can be obtained starting from nolomirole hydrochloride Form II as such or in presence of Form I.

Example 3-The crystal structure of nolomirole hydrochloride Form I has been determined. Unique indexing and lattice parameters values (a=29. 73 (2) A, b=7. 748 (5) A, c=18.479 (13) A and ß=104. 901 (9) ° ; cell volume=4113 (5) A) were obtained from single crystal X-ray experiments performed at ambient temperature T=293 (2) on a small specimen (0.19 x 0.15 x 0.06 mm) selected from the crystalline powder on a Bruker diffractometer using molibdenum Ka radiation (0.7107 A). The observation of systematic

absences gave monoclinic C2/c space group and eight closely packed molecules in the unit cell. The bond distances and angles are reported in Table 1 and the structure of the molecule is reported in Figure 5, wherein the thermal vibration ellipsoid of all non-hydrogen atoms is indicated.

Tab} ce w v t : C6 ï+3ætì3 » ~ cle ci7<ìs ~ l 1 l. S ») 01-C161. 3S48 (176) <C18-C : 17-C16 114. 08 (4) 02-CS l 3 (14 Cl9-c17-Ct6 14t$4) 2-C51. 4193 (146) C19-C17-C16 109. 24 (4) 02'C : 121. 3660 (176) CH-t-C2 114. 62 (4) <03-C : 121. 2058 (177) C15-C13-CI4 113. 29 (4) 04<C161. 1860 (179) C15-d3-C12 113. 25 (4) Nl-Cl 4990 (124) C14-C : 13-C12 107. 6S (3) NI-C2 4877 (14 !) CS-02-C12 117. 94 (4) 'Ni-Cl 1 5230 (160) C6-<01-C16 1172 (5) Cl-C1. 516 (14 : 8) <02-C : 5-C : 6 119. 9 (4) M G-C3 1. 5171814~ C&C5ZID 122. < C : 2'. C313214 (157) 02<C5-C10 H7. <64 (4) C4-C3". 5171 (146) C<S-C5-C : 10 122. 44 (4) C4-C10. 5032 (13) Ot-C6-C5 H9. 3<S (4) C4-CIO 1. 5032 (163) (>I-c6-c5 119. 36 (4) .-c o x. c. x s . -cs x ts. C5-cfi 1. 4M5 (l72) 01-CSC7 t C6-C7. 3489 (189) C10-C4-C : 3 112. 09 (4) C ! 8-C7. 3743 (161) <>4'C16-C17 125. 03 (4) C6-C7 1. 3489 (189) CIOC4-C3 112. 09 (4) v C10-C91. 3765 (175) C17-C : 16-01 111. 69 (4) C8"C9 1. 4968 (215) CS-C10-C : 4 118. 54 (4) C : 14-C131. 4792 (225) CS-C ; 10-C9 1103 (4) C13-cl 1. 4239 (230) C4'CtO-C9 123. 3S (4) C'17-CKS I. 47w=t5) C5410-CP 7 I I M 03 (4) C1C17 1. 4956 (236) CC12Q2 122. 8 (5) C19-C17 1. 5379 (244) C13-C12-02 111. 39 (4) C2-C1-C9 109. 41 (4) 1C2-C : 1 109. 69 (4) Mt-< : : 2C3 108. 59 (4) C2-Cl-C9 109. 41 (4) C1 : 2-C3 110. 44 (3) 109. 59 (4) C1oC243-l 10. 3) c-c- x . a :, C9-C$-<C7 122. 02 (4) C : 10-C9-C1 122. 16 (4) ...... w lls C1-C9. C8 118. 83 (4) C6-C7-C119. 87 (4) 6-yC ?- ! 1' ! (4