CA2128621A1

CA2128621A1 - Biodegradable polycarbonates and their use as drug carriers

Info

Publication number: CA2128621A1
Application number: CA002128621A
Authority: CA
Inventors: Murat Acemoglu
Original assignee: Individual
Current assignee: Novartis AG
Priority date: 1992-03-27
Filing date: 1993-03-23
Publication date: 1993-10-14
Also published as: WO1993020126A1; JPH07505420A; US5849859A; GB9206736D0; EP0633905A1

Abstract

A biodegradable and biocompatible polycarbonate comprising (C3-10) alkylene carbonic acid ester units, each alkylene group being a C3-alkylene group having 1 oxy substituent or a (C4-10) alkylene group having 2-8 oxy substituents, each of the oxy substituents occurring individually as a hydroxyl group or as a derivatized hydroxyl group comprising an ester or an ortho ester or an acetal residue. The polycarbonates may be used as matrices for the sustained release of pharmacologically active compounds, e.g.
peptides or proteins, in the form of microparticles or implants.

Description

WO 93/20t26 PCI`/~:P93/00699

2~862~.

BIOOEGRADABLE POLY~ARBONATES ~ TE~EIR USE AS DRUG CARRIERS

The ~tiorl relates to bi~egradable and b o~tible polyesters ;~
and to phar~oeutir ~ oSi~iQns ccntaining th~.

qhe f~ctio;l of the polyesters in the ph~sceuti~ ositio3~s is to corstrol the rate of the rel ~e of pba~acolo~ir~lly ac~
~3~ds fmn the ~ositio~s and the charation of the acti~rity in the ani~l bo~ to whi~h the c~ositions are ~in~stered. ~

Alt~ough we do not wi~h to b~und by any ~eorSr, qt is belie~?ed that ~; ;
when a~nistered to the bo~ the polyes~ers can initially soreen off t~e pba~scologically active ~1ds fmm the a~ueous me~ia, present -~
is~ ~e body, whereaf~er dlle to biode~radatio~ Oc the polsresters or tO - ~:
diffusio~ of the drug a~s throu~ ~ Dolyesters, ~e dn~g ~:
r~eases and beca~s ~dically act~. ~s may be an ir~teres~ g me~2ani~n eOg. w~en the polyes~ers are ~aate- :Lnso~le.

In the ca~ositio~s the drug ccsz~aund may also be ~nic~lly bound to ~che po~y~ers, ~reafter due to biodegra~atiQn of th~ polye~er n~lecule pa~:, ~ dmg releases framthe c~ositiQns. Th~s may be an irsterestis~g mecban~n e.g. ~Oen the polsresters are ~ater soluble and the polyes~er - drug 3~0and c~ination ~cti~ns as a wa~er solu~le pre-drug.

Dep~t on ~che type of rel~?ce mechar~ ~e drug m~d can be set free e.g. tri~hin one or ~re hours or aays if ~mically bound to poly~ers or w~hin cne or ~re days, weeks or ~ths if screened ofC
by the polyesters.

2~621 .
The invention provides biodegradable, biocompatible polyesters comprising ~C3_l0) alkylene carbonic acid ester units, each alkylene group being a C3-alkylene group having 1 oxy substituent or a (C4_10) alkylene group having 2-8 oxy substituents, each of the oxy substi-tuents occurring independently as a hydroxyl group, or as a moiety independently comprising an ester or an ortho ester or an acetal group.

Thus the polymers may contain e.g. mixtures of different oxy substitutents. Preferably the oxy substituents are the same.
Representative compounds may contain however a hydroxyl group and an oxy substituent, e.g. up to 30 or 20% hydroxyl groups. `~

,..
The polyesters of carbonic acid are in principle biodegradable since ~
their bick- bone chains contain carbonic acid esters bonds -0-C~=0)-0- ~ -which are hydrolysable in the human body's aqueous media, at suitable pH, e.g. in the presence of hydrolytic enzymes, e.g. esterases.
Polyesters containi~g carbonic acid ester groups are generally known as rather stable polymeric materials. Exceptions reported so far are poly(ethylene carbonate)s, which decompose within approxim~tely 2 - 4 weeks in rivo.
The next higher homologue, namely poly(trimethylenecarbonate), is not completely decomposed in vivo even after 6 months. Both, polylethylenecarbonate) and poly(trimethylene carbonate) are polymers, in which the alkylene group is unsubstituted.

The polyesters of the invention comprise preferably C3-alkylene groups or ~C~_10) alkylene groups situated between the carbonic acid ester groups, each having 2 tenminal -CH2- groups. (C4_l0)alkylene groups have a (C2_8) alkylene central part carrying at least 2 and at most 8 hydroxyl groups in free form or in a form in which at least one of them is a derivatized hydroxyl group, comprising an ester or an orthoester or an acetal residue. A C3-alkylene group has a methylene central part, carrying 1 hydroxyl or derivatized hydroxyl group.
Polyesters having such C3-alkylene or (C4_l0) alkyLene units between the carbonic acid ester groups are novel.

W O 93/20126 PCTiEP93/00699 21~:86;2~.

They are in principle biodegradable, many quickly, others slowly, depending on their structural type. Preferred are those, which -biodegrade within 1-90 days.

Preferably all the carbon atoms belonging to the IC2_a~ alkylene central part of the IC4 10)alkYlene groups are oxysubstituted.

The polyesters of the invention can be prepared by methods known per se, e.g. by reacting:

- a diol with phosgene 1. ~rench Patent 905,141 (1945) 2. US Patent 2,999,844 ~1961)

3. German patents 117,625; 118-536-7;

- a diol with a bislchloroformate) - ;~

4. German patent 857,948 ~1952) - a diol with a dialkyl carbonate

5. W.~. Carothers and F.J. Van Natta, J. Amer. Chem. Soc. 314, ~2, (~930)

6. J.H. Hill and W.H. Carothers, J. Amer. Ch~m. Soc. 5031, 55, llg33~

7. S. Sarel, L.A. Pohoryles and R. Ben-Shoshnan, J. Org. Chem.
1673, 24, 1959.

- a diol with urea

8. EP 0,057,825 Al and by W O 93/20126 P ~ /EP93/00699 X1~621.
- polycondensation of bis ~alkyl carbonates)

9. US Patent 2,789,968 (1957) - ring opening polymerization of cyclic carbonates: see 5. and 6.
- ring opening polymerization of spiroortho carbonates ~..

10. S. Sakai, T. Fujinami and S. Sakurai, J. PQ1Ym. Sci. Polym.
Lett. Ed. 631, 11, ~1973)

11. T. Endo and W.J. Bailey, J. Polym. Sci., Polym. Chem. Ed., 2525, 13, (1975) - copolymerization of epoxides

12. S. Inoue, H. Xoinuma and T. Tsuruta, J. Polym. Sci. B, 287, ~, (1969)

13. US Patent 3,900,424 (Inoue et al).

14. US Patent 3,953,383 ~Inoue et al~.

15. US Patent 4,665,136 (Santangelo et al).

The nvention thus also provides a process for the production of a polyester of the invention by reacting a bifunctionally reactive carbonic acid ester derivative with a bifunctional reactive sugar alcohol or glycerol having one or more protected secondary hydroxyl groups and 2 free primary hydroxyl groups.

Depending on the type of the production process the polyesters may _e prepared having a molecular weight of several hundreds up to more million daltons (Da).

Generally diol or bis (alkyl) carbonate polycondensations gi~e l-~.e_:
polyester chains ha~ing lower molecular weights of 1000 - 50,000 Z~
Daltons.
.:..
Anionic ring opening polymerizations of cyclic carbonates generally lead to products having higher molecular weights, e.g. up to more than 100,000 Daltons:

16. H. Keul, R. Baecher and H. Hoecker, Makromol. Chem. 187, 2579 (1986) - Cationic ring opening polymerization --

17. H.R. Kricheldorf et al., Makromol. Chem. 18B, 2453, ~1937) - and also polymerizations in the presence of complexing catalysts

18. H.R. Kricheldorf et al., Makromol. Chem. 192, 2391, ~1991) , ~' however lead to polycarbonates of lower mole~ular weight. Polyesters ^ha~ing the highest molecular weights of e.g. more than 1,000,000 Daltons may be obtained by copolymerization of epoxides with carbon -~
dioxide (12-lS). When prepared accordi~g to the same production processes, the polyssters of the invention have basically molecular weights of the same ranges. Preferred ~re polyesters having 5-1000, e.g. up to S00 back bone alkylene carbonic acid ester units.

Typical polyesters have Mw from about 5000 to about 25,000 Da. Typicai Mw/Mn are from 1.2 - 1.9.

As indicated above, for the production of the polyesters a diol may be used. Since preferably all the b~c~bone chain carbon atoms are oxy substituted in the polyesters of the invention, preferably a sugar alcohol (reduced sugar, particularly reduced mono saccharides, e.g.
threitol) or glycerol is chosen of which the secondary hydroxyl groups may be protected.

A preferred process feature is thus using bifunctionally reactive su-X12~6Z~.

gar alcohols or glycerol having one or more additional, protected, secondary hydroxyl groups. In case of glycerol 2-benzyloxy-1,3-propandiol can be used as a known starting compound.

Except where otherwise mentioned, carbon containing moieties preferably contain up to 12 carbon atoms, and if they are substituted contain one substituent or conveniently no substituent.

Protection in sugar alcohols may occur by methods known per se, e.g.
by the pre-protection of the primary tenminal hydroxyl groups, e.g. by converting them into benzoic acid ester groups, by converting the secondary hydroxyl groups to e.g. acetals orrhemiacetals e.g. with acetone giving rise to O-isopropylidene residues and by splitting off the benzoic acid ester groups with e.g. methanol in the presence of sodium methylate. The thus obtained sugar alcohols have two free tenminal primary hydroxyl groups and protected secondary hydroxyl groups and can be used as diol starting compounds for the production of the polyesters of the invention.

The obtained polyesters, having protected secondary hydroxyl groups in the form of an acetal and/or a hemi-acetal residue, are compounds according to the invention.

The hemi-acetal or acetal groups m3y be r~moved by metho~s known per se, e.g. by water and trifluoro acetic acid, leading to polyesters having free secondary hydroxyl groups, which are also compounds of the invention.

A further, optional, process feature for the preparation of compounds of the invention other than hemi-acetals or acetals is thus deprotecting the secondary hydroxyl groups in the formed polyesters.

A derivatization of secondary hydroxyl groups is broadly described in the chemical literature, e.g. in

19. Houbén-Weyl, "Methoden der Organischen Chemien, Bd. VIII ~1952), `.''.. ' 2~ 62~

Pages 75 and 503.

20. Houben-Weyl, "Methoden der Organischen Chemien, Erw. Bd. E4, ~1983), Page 66.

21. Harrison, "CompendiuT; of Organic Synthetic Methodsn,Vols. I-IV, ~1971-1980).

22. S.G~ Wilkinson in "Com~rehensive Organic Chemistry", D. Barton and W.D. Ollis, Eds., Vol. I, p. 579, (1979).
:
For a derivatization to carboxylic ester residues, the polyesters having free hydroxylic groups are preferably dlissolved or suspended in ;
an inert~ aprotic solvent e.g. in tetrahydrofuran, methylene ~-chloride, toluene or dimethylformamide and reacted in the presence of a catalyst~ e.g. a tertiary amine, with an active carboxylic acid -derivative.

Active carboxylic acid derivatiYes are e.g. carboxylic acid anhydrides and carboxylic acid chlorides. These derivatives may be obtained by reacting the carboxyclic acid with an activation reagent and can often be brought i~to contact with the hydroxyl groups when formed in s.tu.
Reaction with keterles leads also to the introduction of carboxylic acid ester residues.

Exam~les of activation reagents are dicyclohexyl carbodi~mide

23. A. Hassner et al., Tetrahedron Lett. 4475 (19~8) di-(N-succinimidyl)-carbonate -

24. a) H.Ogura et al., Tetrahedron Lett. 4745 (1979) b) T. Tokubo et al., J.Amer.Chem.Soc. 109, 606 (1987) Jr^ ~ ~ 8 -. .
1Z~621 bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride

25. a) J. Diago-Meseguer et al., Synthesis 547 (1980) b) E.J. Corey et al., J. Amer.Chem.Soc. 104, 6818 ~19~2) l,l'-carbonyl-diimidazole and further diazoles, as well as thionyl-diazoles ~ -

26. H.A. Staab, Angew. Chem. 74, 407 (1062) Polyesters according to the invention are those in which the carboxylic acid ester residues comprise those of formuc acid and/or saturated or unsaturated ~C2_20) fatty acids, e.g. of lauric acid, oleic acid or stearic acid. Conveniently the carboxylic acid residues are unsubstituted.

Further polyesters according to the invention include those in which the carboxylic ester residues comprise moietiss of a hydroxy carboxylic acid, e.g. those of lactoyl or glycoyl or of polylactoyl, polylactoyl-co-glycoyl or polyglycoyl, such with the pre-fix "poly"
however not having chain lengths enabling the polyester to form a hydrogel in an aqueous m~dium, to exclude hydrogels described in the EP 92918.

Based upon the methods in the literature and choosing the appropriate reagents, polyesters may b~ obtained and are in the scope of the invention, in which the derivatized hydroxyl groups comprise substituted carboxylic acid ester residues, e.g. oxo carboxylic acid ester residues, or dicarboxylic acid ester residues.

For a derivatization to carbonic acid ester residues the polyesters having free hydroxyl groups are reacted with active carbonic acid derivatives, preferably with chloroformic acid esters or pyrocarbonates ~= carbonic acid anhydrides).

The polyesters according to the invention thus also comprise those ir.

Z~ 36~1.

which the derivatized hydroxyl groups are carbonic acid ester residues, e.g. those containing hydroxy carboxylic acid ester residues or being cyclic carbonate residues.

Further polyesters according to the invention are such having carbonic acid ester residues, e.g. comprising those containing a steroid alcohol, like cholesterol or a (Cl_20) alkanol residue. ;

Additionally polyesters according to the invention are those in which the derivatized hydroxyl groups comprise such carbontc acid ester residues which contain carbamlc acid or a derivativ~ thereof. ~-Carbam2tes of hydsoxy compounds are generally made e.g. by their conversion with isocyanates or with carbamoyl chlorides. ~--The residues may al~o comprise ortho ester residues, e.g. those of an ortho carboxylic acid ester or an ortho carbonic acid ester, which are acid sensitive and thus increase the biodegradability of the poly-esters of the invention.

Polyesters according to the invention may be those in which the derivatized hydroxyl ~roups comprise those of an ~mino acid or peptide. The amino acid residue can be prese~t as a part of a carboxylic acid es~er residue or as a part of a carbonic acid ester residue, if the amino acid contains hydroxyl, e.~. serine, or as a ~art of a carbamio acid ester residue.

If the amino acid residue is a carboxylic acid ester or a carbonic acid ester derivati~e, the amino group mdy be present in free condition, in a protected fonm or in a ~alt foDm.

The polyesters of the invention may e.g. thus be obtamed by react the secondary free hydroxyl groups or a reactive derivative thereo~
with mono- or bifunctional carboxylic acid or carbonic acid derivatives. ;~

The termm al groups of the polyesters of the invention are free hy-,, -- 1 0 6Z~. .
droxyl and/or esterified hydroxyl groups, depending on the preparation method applied. If an anionic ring opening polycondensation is applied, the starter molecule will be incorporated as a terminal group into each polyester chain.

In the polycondensation examples described hereinafter products are obtained having ethoxycarbonyloxy and/or hydroxyl termlnal groups.

Terminal esterified hydroxyl groups are e.g. those which have been formed during the preparation step of the polyester back bone chain, e.g. ethoxycarbonyloxy.

Other tenminal esterified groups are those obtained from terminal hydroxyl groups during the esterification step of the secondary hy-droxyl grou~ps.

Further derivatization of terminal groups may be obtained by selectively reacting terminal hydsoxyl groups with e.g. esterification agents or by splitting the polycarbonate chain by transesterification reactions, before splitting off the groups protecting the secondary hydroxyl groups, e.g. acetal residues. In such manner lipophilic residues, like stearoyl groups can be introduced as terminal groups.
After splitting off the protecting groups amphiphilic products are obtained characterized by hydrophilic secondary hydroxyl groups and lipophilic terminal residues.

The invention thus additionally provides a process for the production of the polyesters of the invention by a) reacting a bifunctionally reactive carbonic acid ester derivative with a bifunctionally reactive sugar alcohol or glycerol having one or ~ore protected secondary hydroxyl groups and 2 free primary hydroxyl groups, and optionally, b) for the production of end-group modified polyesters treating the polyester obtained with an esterification or transesterification WO 93/20126 PCriEP93/00699 - 11 - 212~62~.

reagent and, optionally, c) for the production of polyesters having free secondary hydroxyl groups, deprotecting the secondary hydroxyl groups in the fonmed polyester, and, optionally, d) for the production of esters and orthoesters reacting the secondary free hydroxyl groups with mono or bifunctional carboxylic acid or carbonic acid derivatives. --A typical sugar alcohol has e.g.~ carbon atom5, e.g. threitol or mannitol.

The invention further provides a process for the production of polyesters having an acetal residue by choosing for reaction step a) a bifunctionally reactive sugar alcohol having secondary hydroxyl groups protected by an acetal residue.

The polyesters comprise generally alkylene carbonic acid ester units in homopolyester arrangement, although other configurations may be contemplated.

If their alkylene parts contain free hydroxyl groups as well as derivatized hydroxyl residues, their distribution over the alkylene uni~s of the polymer chain is preferably random. The arrangement is then that of a randomized homopolycarbonate.

Preferably the number of alkylene carbonic acid ester back bone units, also when partially or completely derivatized, is 5 to 1000.

The novel alkylene carbonate units can however also be chemically combined ~ith known ester units e.g. also of the carbonic acid ester type and/or of the hydroxy carboxylic ester type to foDm a polymer chain. If so, the novel alkylene carbonate units form with the known ester units a polycarbonate 9r a polyester chain having a randomized co-polyester or a block-co-polyester arrangement respectively.

W O 93/20126 P ~ /EP93/00699 2I~3~21. -12 -Preferably the number of ester units, inclusive the known ester units, is S to lO00, e.g. 5 to 500.

The polyesters of the invention are preferably prepared from sugar alcohols, particularly those of natural sources, which are optically active and thus are stereomeric isomers. Their chiral, asymmetric centres are the carbon atoms to which secondary hydroxyl groups are bounded. When the sugar alcohol molecules are converted to polyesters and the hydroxyl groups are derivatized, no significant change in the asymmetric arrangement takes place, although the type of ;~
derivatization may influence the size of optical rotation of each ~ ;
asymmetric carbon atom involved.
This means that the polyesters will have corresponding asymme~ric -arrangements.
The sugar alcohols can be used in any stereomeric enantiomer form, in racemate fonm, in meso form or in mixtures in which one of the enantiomers preponderates over the other. ~
,.-' ' '.
In the Examples hereinafter it is indicated, which optically active sugar alcohols (D,L,DL-isomer~ were used for the polyester synthesis.

The polyesters of the invention contain cleavable bonds and are of a type, biodegradable in neutral or acidic or basic media.
Although in fact all the different residue types mentioned can be present together in one polyester molecule, for reasons of a slmpler production method preferred polyesters, if derivatized, those are taken which contain only one type of residue. Further, preferably p~lyesters are taken which have only one ester bond type, i.e. the carbonate bond, in their back bones.

Preferred are thus polyes~ers in homopolyester arrangement, especially in randomized homopolycarbonate arrangement.

The amino acid and the steroid alcohol residues can be the active part of a drug compound. ~3 - 13 - 2i~3621.

The polyesters thus also include such in which the derivatized hydroxyl groups comprise drug compound residues, e.g. further those of a peptide or a protein. The polyester structures have then a pro-drug character. They can be used in pharmaceutical compositions.

Water soluble polyesters, e.g. those of Examples 4-6, are preferred for pro-drug formation, enhancing drug solubilization andlor releasing drugs by cleavage of a labile bond.

If the terminal groups are modified, e.g. by stearoylation, the ~;~
polyester is capable of being incorporated into liposomes by lipophile - lipophile interaction in an aqueous medium, leaving the m~in hydrsphilic polymer chain in the outer sphere of the liposome.

This may result in an enhanced circulation period in the blood, similar to that obtained for polyethylene glycol ~US Patent 5,013,556) or ganglioside GM1-modified ~US-Patent 4,837,028) liposomes. ~ -~However, the pharmaceutical compositions of the invention preferably contain a polyester of the invention mixed with a drug compou~d, especially in such manner that the polyester is a solid matrix for the drug compound e.g. in the form of a microparticle or a Lmpl nt. The polyesters however can also be used as a capsule wall material, e.g.
for normal size or microcapsules.

In W0 89/05664 polyesters have been described containing alkylene carbonic acid ester units as weLl. However, the carbon atoms of the alkylene groups art not oxysubstituted and have thus no adjacent hydroxyl nor hydrolysable ester, ortho ester or acetal residues. They are thus less biodegradable. The polyesters are used for medical devices, e.g. implants, to aid in tissue regeneration, growth and/or healing and do as mQdical devices not contain ~rug compounds.

In the german patent application 1.921.866 polyesters are described, prepared by reacting a) diphenyl carbonate, b) a diol, like neopenty:
glycol and c) a triol, e.g. hexanetriol-1,2,6 (Example 40) or a 212~3~2~ - 14 -. , .

tetrol. They were said to have an undefined structure.
The polyesters are used for the preparation of weatherproof and ultra-violet light resistant protective coatings. ;
The structure of the compounds of the invention is well defined and different, since those having ~C4_l0)alkylene groups possess at least 2 oxy substituents compared with l oxy substitutent in the C6-alkylene unit of Example 40.

~he preparation of the pharmaceutical forms according to the invention may be carried out by methods known per se, the microparticles and microcapsules by appropriate spray drying or emulsifying techniques, the implants by mixing the drug compound and the polyesters both in particulated, solid state at higher temperatures at which the poly-esters become liquid, followed by cooling the mixture to solid state and modelling it to a suitable shape. It is also possible to mix the drug compound in dissolved or dispersed state with a solution of the polyester and to evaporate the solvent, after which the solid residue is shaped to suitable implant forms.

Pharmaceutical compositions containing microparticles may be made by working them up with suitable galenical excipients and optionally bringing them in appropriate dispensers.

Whereas in Lmplants the drug loading content can vary between wide limits, in the order of O.OOl to about 70%, the loading content of microparticles and microcapsules can - due to the method of their production - vary between narrower limlts, e.g. O.OOl to 8% of weight.

The choice of pharmacologically active compound to be used in combination with the polyesters of the invention is not critical. ~n the case of microparticles or microcapsules preferably those types drug compounds are used, which are pharmacologically active in low amounts and need to have an uninterrupted blood level during extec~ei periods, e.g. peptides or proteins, e.g. somatostatins or interleukins, but especially such of honmonal types, in particular those that will desintegrate after oral use in the gastro-intestina!

- 15 - 2~

system and thus preferably are administered parenteraLly. ~-:;~
The depot formulation according to the invention may be used to ad-minister a wide variety of classes of active agents, e.g~ pharmaco- ~;
logically active agents such as contraceptives, sedatives, steroids, sulphonamides, vaccines, vitam;nes, anti-migraine drugs, enzymes, bronchodilators, cardiovascular drugs, analgesics, antibiotics, anti-gens, anti-convulsive drugs, anti-inflammatory drugs, anti-parkinson drugs, prolaction secretion inhibitors, anti-asthmatic drugs, geriatrics and anti-malarial dNgs.

The depot formulations may be used for the known indications of the particular drug compound incorporated therein.

The exact amounts of drug compound and of the depot formulation to be administered depends on a number of factors, e.g. t~e condition to be treated, the desired duration of treatment, the ra~e of release of drug compound and the degradability of the polyester mat~ix.

The desired formulations may be produced in known manner. The amount of the pharmacologically active agent required and the release rate --thereof may be determined on the basis of known in vitro or in vi~o techniques, e.g. how long a particular active agent concentration in --the blood plasma remains at an acceptable level. The degradability of the matrix may also be obtained by in vitro or especially in vivo techniques, for example wherein the amount of matrix materials in the muscle is weighed after particular t~me periods, e.g. in comparison with o~her matrix materials.

The depot formulations of the invention may be administered in the form of e.g. microparticles, e.g. orally or preferably subcutaneously or intramusculary, particularly as a suspension in a suitable liquid carrier or in the form of Lmpiants, e.g. sub-cutaneously.

Repeated administration of the depot formulations of the invention may bç effected when the polyester matrix has sufficiently been degraded, . ' W O 93/20126 P ~ /EP93/00699 :.

;~1;2~6Zl ~

e.g. af ter 1, 2 or 3 weeks or 1 month.

An example of a dose is as follows:-20 mg of octreotide in a polymer as described in Example 37 to be administered s.c. once a month against acro ~ aly.

An advantage of the polyester matrices of the invention is that during and after the release of the drug compound many of them may be quickly degraded to a molecular size, which may be transported by the body fluids from the site of administration.

W 0 93/20126 PCT/EP93/00699 ;~
- 17 - Z~286~

OEN~RAL -, Materials To each prepared polyester a number was given. On the formula page the corresponding alkylene carbonic acid ester unit has been designed, related to this num~er. Letter (a), ~bl, or (c) as a suffix to the ;-compound number denotes t~at the polymer was derived from L-, D-, or ;~-~
DL-sugar alcohols.
;~
2,4:3,5-and 2~3:4,5-di-0-isopropylidene-D-mannitol were prepared by a ~;
modified version of the procedure described in:
,~ ~
127] K. Gavronska, Carbohydr. Res. 176, 79, (1988).

The starting material was 1,5-di-0-benzoyl-D-mannitol: ~;
: ' [28] P. 8rigl and H. Gruner, Berichte 65 641 (1932).

Hyflo (Super) Cel (Kieselgur, 2-25 microns, Fluka 56678) was used as filtration aid.

Molecular weights (Mw= weight average molecular weight; Mn= number average molecular weight) were determined by gel permeation chromatography on a Waters 840 system with a refraction index detector Waters 410 and W detector Waters 490. Columns:
polystyrene-divinyLbenzene crosslinked gels, Polymer Laboratories, UK~
combination of columns with pores of 105, 104 and 500 Angstroms, at 35C. Calibration with standard polystyrenes, Polymer Laboratories, UK, for a molecular weight ra~ge of 1.75x106 to 580 Daltons.

Glass transition temperatures ~Tg) and melting points (Tm) were measured on a DSC 7 instrument of Perkin Elmer with data station ana intracooler at a scanning rate of 10C/min. heating. The sample was ;~12~3621.
heated in a first run above the glass transition temper~ture followed by fast cooling to -30C and a second run to give the Tg-value.

Inherent viscosities (= ~lnh) were measured at 20C on an AVS 350 instrument with a Micro-Ubbelohde capillary.

NMR spectra were obtained on a Bruker AM 360 spectrometer. ~) in NMR-data means the chemical shift delta, given in ppm. The assignments of the NMR-signals to the nuclei are not proved. Therefore, some of ~-the assignments may be interchangeable.

The empirical fonmulae in the microanalysis results are those of ~he correspondi~g monomer units of the polyesters.

Formula pages are to bs found at the end of the examples.

m~L~ 1:

The polyester from (+)-2,3-0-Isopropylidene-L-threitol and Diethyl carbonate (Monomer unit la, see formula pages) 39.7g (245 mmol) of ~+)-2,3-0-isopropylidene-L-threitol ~see formula pages) were placed in a dry, round bottom~d flask, which is a part of a distillation appara~us. 190 ml ~1570 mmol) of diethyl carbonate and 0.794 g of di-n-butyl-tin-oxide were added while in an atmosphere of argon. The reaction mixture was stirred at 120C for 20 hrs., durins which tim~ distillation occurred. After cooling down to room temper~ture, the distillate was removed under argon and then the pressure was carefully reduced to 45 m~ars. The mixture ~as heated t~
65C and stirred at this temperature for 4.5 hrs. to distill the excess of diethyl carbonate. After the distillation was completed, .~e pressure was set to atmospheric pressure with argon and the distili~-e was removed while under argon. Then the pressure was reduced to 8 mbars and the temperature was increased stepwise to 120C during 1 The reaction mixture was stirred for 48 hrs. at 120C t 8 mbars ar.d .

W O 93~20126 PCT/EP93/00699 - 19 ^ ~ ~ 8 for 20 hrs. at 130C / 0.3 mbar.
For working-up, the reaction mixture was cooled down to room temperature, dissolved in 150 ml of dichloromethane under reflux and 3 g of Hyflo Cel were added to the solution. After stirring for 15 min.
at room temperature, the suspension was filtered and the polymeric product was precipitated by slow addition of the dichloromethane solution into 2000 ml of methanol. The brownish-beige precipitate was dissolved in 600 ml of acetone and treated slowly while continously stirring, with 1 ml of a 30% solution of hydrogen peroxide in water.
The mixture was stirred at room temperature for 20 hours. Then, the solution was treated with 4 g of a filtering aid (Hyflo Cel), stirred for another 1 hr. and filtered. The solvent was evaporated under reduced pressure, the residue dissolved in 70 ml of dichloromethane and the product precipitated by dropwise addition of the dichloromethane solution into 2000 ml of methanol. The precipitate was dried in vacuo for 48 hrs. to gi~e the polyester in almost colourless, -~
white solid form.

~nh~dllg)= 0.115 in CHCl Mw= 11350 Da, Mn= 8250 Da, Mw/Mn= 1.38 Tg= 51.3C

~alpha]D= -34O (c=1 in CHCl3, 20C) IR ~KBr): 2992m, 2942w, 2908w, 17~7s,broad, 1460m, 1386s, 1235s,broad, 1169m, 1092s, 992m, 964m, 845m, 786m, 607w, 514m [cm~ll.

~H-NMR (CDCl3, 360 MHz): ~= 1.42 ppm (s, 6H, 2CH3~; 4.096 (m, 2H, 2CH); 4.245 (d.m, 2JAB= ca.ll.5 Hz, 2H, 2H3 of 2 CH2); 4.357 ~d.d, 2JAB= ca. ll.S Hz and ~= ca. 3.3 Hz, 2H, 2HA of 2 CH2).

13C-NMR (CDCl3, 90 MHz): ~= 154.59 ppm (O-C~O)-O); llO.S5 (O-C-O);
75.34 ~CH); 67.17 ~CH2); 26.83 ~CH3).

X12~6~1.

Microanalysis: Calc.for C8Hl20s : C 51.08 ~, H 6.38 %
found : 50.90 %, 6.50 EXAMPLe 2:

The polyester from (-)-2,3-0-Isopropylidene-D-threitol and Diethyl carbonate ;~
(Monomer unit lb) PQlycondensation of 40.0 g (247 mmol~ of ~ 2,3-0-isopropylidene-D-threitol with diethyl carbonate according to the procedure described in example 1) gave the polyester having the monomer unit lb.
.. ~ .
~lnh (dl/g)= 0.145 in CHCl3 Mw= 14700 Da, Mn= 9950 Da, Mw/Mn= 1.48 ~Tg= 52.2C

~alpha]D= +33.5 (c=1 in CNCl3, 20~C) IR- and NMR-Spectra of the polymer of Ib wece identieal with the spectra of the polymer of la.

Microanalysis: Calculated for CaHi20s. C 51.08 ~, H 6.3B %
found: 50.80 %, 6.50 %

EXANPLe 3:

The polyester from 2,3-0-Isopropylidene-DL-threitol and ~iethyl ~arbonate (Monomer unit lc) 39.53 g (244 mmol~ of (+J-2,3-0-isopropylidene-L-threitol and 39~53 g ~ 2,3-0-isopropylidene-D-threitol were placed in a dry, round bottomed flask, as a part of a distillation apparatus. 370 ml (3050 W O 93/20126 PCT/EPg3/00699 - 21 - X~ 6~Jl mmol) of diethyl carbonate and 1.6 g of di-n-butyl-tin-oxide were added in an atmosphere of argon. The mixture was stirred for 16 hrs.
at room temperature and for additional 20 hrs. at 120C, during which period distillation occurred. After cooling to room temperature, the distillate was removed under argon and the pressure was carefully reduced to 50 mbars. The temperature was increased stepwise to 100C
during 3 hrs. to distill the excess of diethyl carbonate. After the distillation was completed, the pressure was set to atmospheric pressure with argon and the distillate was removed in an argon atmosphere. Then, the pre~sure was reduced to B mbars and the temperature was increased stepwise to 120C during l hr. The reaction mixture was stirred for 20 hrs. at 120C / 8 mbars and for 20 hrs. at 140C I O.S mbars.
For workinq-up, the product mixture was cooled down to 40C and dissolved in 6~0 ml of dichloromethane under reflux. The solution was treated with 6g Hyflo Cel, stirred for 1 hr. at room temperature and filtered. The solvent was evaporated to a final volume of ca. 250 ml under reduced pressure and the polymeric product was precipitated by dlopwise addition of the solution to 4000 ml of methanol. The brownish-beige precipitate was dissolved in lS00 ml of acetone and 2.2 ml of 30% hydrogen peroxide in water were added slowly to the stirred solution. The mixture was stirred at room temperature for 20 hours.
The solution was then treated with 6 g of Hyflo Cel, stirred for another l hr. and filtered. The solvent was evaporated at red~ced pressure, the residue dissolved in ca. 250 ml of dichloromethane and the product was precipitated by dropweise addition of the dichloromethane solution to 4000 ml of methanol. Drying of the precipita~e in vacuo for 48 hrs. gave the polyester as an almost colourless white solid.
The mother liquor was evaporated, the residue dissolved in 20 ml of dichloromethane and precipitated from 1000 ml of methanol to give, after drying in vacuo, an additional amount of polyester.

~nh ~dl/g)= 0.145 in CHCl3 Mw= 16550 Da, Mn= 10300 Da, Mw/Mn= 1.61 . .. ,. ~ ., , 621 ~

Tg= 47.50C ~ -~

IR (KBr): 2990m, 2940m, 2907m, 1757s,broad, 1576w, 1457m, 1385s, 1233s,broad, 1169m, 1092s, 993m, 963m, 8~5m, 786m, 737w, 607w, 513m [cm-l ] .

H-NMR ~CDCl3, 360 MHz): ~= 1.42 ppm ~s, 6H, 2CH3); 4.10 ~m, 2H, 2CH);
4.24 (d.m, 2~A~= ca.ll.5 Hz, 2H, 2HB Of 2 CH2); 4.357 (d.d, 2JAB=
ca.ll.S Hz and J= ca. 3.3 Hz, 2H, 2HA of 2 CH2).
.
l3C-NMR (CDCl3, 90 MHz): ~= 154.61 ppm ~O-C(O)-O); 110.57 (O-C-O);
75.34 ~CH); 67.20 (CH2); 26.86 (CH3). ;

Microanalysis: Calculated for C~H1205: C 51.08 %, H 6.38 %
found : 50.60 %, 6.30 ~
. .
Additional polyesters of different molecular weights having the ~
monomRr unit lc were prepared by varying reaction conditions such as ;~ -temperature, pressure and reaction time, see next table.

Temp. Mw Mn M~/Mn Tg [Cl [Da] ~Da]

120,0~ 10700 6450 1.~6 42.0 140tO* 20300 11100 1.83 47,0 150,0* 23400 12700 1.84 50,1 ~* 42000 27200 1.54 54,5 ~:24h,120C/1013mbar, then 3x 24h at given temperature and 400 mbar,lOOmbar and 0.2mbar respectively (total reaction time 96 h~urs for each co~pound) **:24h/120C/1013mbar,24hll20C/8mbar,30h/140C/0,35mbar, 30h/160C/0,35mbar - 23 - X1~ 2~.

EXA~PLE 4:

Synthesis of the polyester having the monomer unit 2a To a stirred solution of 18.82 g (100 mmol) of the polyester having the monomer unit la (of Example 1) in 150 ml of dichloromethane were added 27 ml of ~ater and 150 ml of trifluoroacetic acid. The reaction mixture was stirred rigorously for 20 minutes at room temperature. The product was then precipitated by dropwise addition of the solution to 3000 ml of diethyl ether. The suspension was stirred for additional 10 minutes at room temperature, the precipitate was isolated under an argon stream and washed twice with diethyl ether. Drying in vacuo for 48 hours gave the polyester as a hygroscopic, white powder, which was kept under argon.
The polyester is soluble in water, dimethyl fonmamide and d~methyl sulphoxide. It is insoluble or hardly soluble in chloroform, dichloromethane, tetrahydrofuran, dioxane, ethyl acetate and acetone.
~n some solvents its dissolution may be accompanied by degradation.

~nh (dl/g)= 0.085 in H20 Tg= 31.4C

IR (KBr): 3447s, broad, 2367w, 2917w, 1750s, broad, 1460m, 1408m, 12~2 and 12Ç2s, broad, 1134m~ 1077m, 96Qmr 895w, 78am [cm~l].

lH-NMR (d6-DMS0, 360 ~Hz): ~= 3.697 ppm ~m, 2H, 2CH): 4.044 td.d, 2JAB= Ca. 10.7 HZ and J= ca.7 Hz, 2H, 2HB Of 2 CH2); 4.125 (d.d, 2JAP=
ca. 10.7 Hz and J= ca.4 Hz, 2H, 2HA of 2 C~2); ca. 4.76 (broad s, 2H, 20~).

3C-NMR ~d6-DMS0, 90 MHz): ~= 154.59 ppm lO-C~0)-0); 68~62 (CH2);
68.37 (CH).

Microanalysis: Calculated for CsH80s : C 40.56 %, H 5.40 found : 39.90 %, 5.60 P ~ /EP93/00699 24 - ~ .
ZlZ8~

EXANPLE 5:

Synthesis of the polyester having the monomer unit 2b :;

14.11 g (75 mmol) of the polyester having the monomer unit lb (of Example 2) were hydrolysed with trifluoroacetic arid (112.3 ml) and water (20.2 ml) in dichloromethane (112 ml) accordi~g to the procedure described in Example 4! to give the polyester having the monomer unit 2b. The polymer has similar dissolution propeirties as the polymer of ~:
2a.

nh ~dl/q)= O.07 in H20 Tqi=i 32.3C

IR- and NMR-Spectra of the polymer of 2b were identical to those of the polymer of 2a.
.:
Microanalysis: Calculated for C5H305 : C 40.56 %, H 5.40 %
found : 39.20 %, 5.50 %

~XANPL~ 6:

Synthesis of ~he polyester having the monomer unit 2c 58.68 g (31~ mmol) of the polyester having the monomer unit lc (of Example 3) were hydrolysed with 470 ml of trifluoroacetic acid and 8j ml of water in 470 ml dichloromethane according to the procedure described in Example 4), leading to the formation of the polyester.

h (dl/g)= O .1 in H20 Tq= 39.6C

IR ~KBr): 3468s, broad, 2968w, 2917w, 1751s, broad, 1458m, 1409m, .2 - 25 - x~ fi~

and 1259s, broad, 1132m, 1075m, 959m, 895w, 787m [cm~l].

1H-NMR (d6-DMSO, 360 MHz): ~= 3.696 ppm ~m, 2H, 2CH); 4.044 (d.d, 2JA~= ca. 10.7 Hz and J= ca. 7 Hz, 2H, 2H3 of 2 CH2); 4.125 (d.d, 2JAB= ca. 10.7 Hz and J= ca. 4 Hz, 2H, 2HA of 2 CH2); ca. 4.91 (broad s, 2H, 2 OH).

3C-NMR ld6-DMSO, 90 MHz): 8= 154.55 ppm ~O-C(O)-O); 68.58 ~CH2);
68.32 ~CH).
Microanalysis: Calculated for CsH8Os : C 40.56 %, H 5.40 %
found : 40.90 %, 5.60 %

EXUMPL~ 7:

Synthesis of the polyester having the monomer unit 3a 2 g (13.5 mmol) of the polyester havins the monomer unit 2a ~of Example 4) was suspended in 30 ml of dry tetrahydrofuran. 0.55 ml pyridine and 32 ml acetic anhydride were added ~o the suspension in an argon atmosphere. The mixture was stirred for 18 hrs.-at room temperature, then the solvent was evaporated under reduced pressure and the residue was dissolved in 10 ml of dichloromethane. The produc~
was precipitated by drop~ise addition of the solution into 250 ml of tert.-butyl methyl ether. The precipitate was wa~hed with 100 ml of water, resolved in 10 ml of dichloromethane and reprecipitated from 250 ml of tert.-butyl methyl ether. Drying off the precipitate in vacuo for 120 hrs. at 50C gave the polyester as a fine, white powder.

nh~dl/g3= 0.11 in CHCl~

Mw= 10950 Da, Mn= 7750 Da, Mw/Mn= 1.41 Tg= 56.2C

IR (KBr): 2978w, 1751s,broad, 1456w, 1410w, 1376m, 1279 shoulder, 1217s, broad, 1057m, 1015w, 951w, 847w, 787m, 632w, 603w [cm~1].

WO 93/20126 PCI`/EP93/00699 212~3621.

1H_NMR (CDC13, 360 MHZ): ~= 2.12 PPm tS, 6H, 2 CH3); 4.165 (d.d, 2JA3=
Ca. 11.8 HZ and J= Ca. 5.6 HZ, 2H, 2H~ Of 2 CH2); 4-385 ~d-d~ 2JAB=
Ca. 11.8 HZ and J= ca. 3.3 HZ, 2H, 2HA Of 2 CH2); 5.339 (m, 2H, 2 CH).

13C-NMR (CDC13, 90 MHZ): ~= 169.82 PPm (-C~0)-0); 154.22 (O-C(O)-O);
68.68 (CH); 65.67 ~CH2); 20.66 (CH3).

Microanalysis: Calculated for CgH12O7 : C 46.57 %, H 5.17 found : 46.30 %, 5.40 ~XANPLE 8:

Synthesis of the polyester having the monomer unit 3b 2 g ~13.5 mmol) of the polyester having ~he monomer unit 2b (of Example 5) were acetylated aecording to the procedure described in example 7) to give the polyester as a fine, white powder.

~inh (dllg) = O 10 in CHCl3 Mw= 11250 Da, Mn= 7300 Da, Mw/Mn= 1.54 Tg- 58.6C

IR- and NMR-Spectra of the polymer of 3b were identical to those of the polymer of 3a.

Microanalysis: Calculated for CgH12O7 : C 46.57 ~, H 5.17 %
found : 45.20 %, 5.20 %

~e~ g:
.

Synthesis of the polyester having the monomer unit 3c :
, 6.07 g (41 mmol~ of the polyester having the monomer unit 2c ~of Xl'~6~1.

Example 6) ~ere ~cetylated with 97 ml of acetic anhydride and 1.7 ml of pyridine in 90 ml of tetrahydrofuran according to the procedure described in Example 7) to give the polyester as a fine, white powder.

~lnh ~dl/g)= 0.14 in CHC13 Mw= 13800 Da, Mn= 9050 Da, Mw/Mn= 1.52 Tg= 57.8C

IR ~KBr): 2977w, 1750s, broad, 1449w, 1411w, 1376m, 1279shoulder, 1216s, broad, 1057m, lOl5w, 951w, 847w, 787m, 631w, 603w [cm~1].

1H-NMR ~CDCl3, 360 MHZ): 8= 2.12 ppm ~ s, 6H, 2CH3); 4.17 ~m, 2H 2HB
of 2CH2)-; 4.38 ~d.m, 2JAB= ca. 12.1 HZ, 2H, 2HA of 2CH2); 5.328 (m, 2H, 2CH).

3C-NMR (CDCl3, 90 MHz): ~= 169.79 ppm ~-C~O)-O); 154.21 (O-C(O)-O);
68.70 (CH); 65.66 (CH2); 20.66 ~CH3).

Microanalysis: Calculated for Cg~l2O7 : C 46.57 %, H 5.17 % ;~
found : 46.70 %, H 5.40 %

~XA.~LE~ 10:
. .

Synthesis of the polyester having the monomer uni~ 4c B6.31 g tl.R75 mol) of formic acid were added dxopwise into 177.6 g ~1.25 mol) of acetic anhydride. The temperature was kept below 40C
during this exothermie step. After the addition was oompleted, the mixture was stirred for 1 hr. at 50C, then cooled down to room temperature and 7.4 g ~50 mmol) of the polyester of Example 6 ~monomer unit 2C) were added. The suspension was cooled in an ice bath and 59.3 g ~0.75 mol) of pyridine were added dropwise to the suspension at 05C. ~.
When the addition of pyridine was eompleted, the suspension was stirred ~or 1.5 hrs. at 0C and for additional 18 hrs. at room ZlZ8621 temperature then filtered and the product was precipitated by dropwise addition of the filtrate into 1500 ml of diethyl ether. The precipitate was resolved in 15 ml of acetone and reprecipitated by dropwise addition of the solution into 1500 ml of diethyl ether. The precipitate was filtered and dried in vacuo at room temperature to yield a polyester having the monomer unit 4c as a fine, white powder.

(dl/g)= 0.065 in acetone Tg = 54.3C

IR (KBr): Strong absorptions at 1758, 1727, 1251 and 1154 cm~l.

lH-NMR (d6-DMSO, 360 MHz): ~= 4.275 ppm (dd, 2JAB= ca. 12 Hz and J=
ca.6 Hz, 2 H, 2 H~ of 2 CH2); 4.34 (d, 2JAB= ca. 12 Hz, 2 H, 2 HA Of 2 CH2); 5.40 ~m, 2 H, 2 CH); 8.30 ~s, 2 H, 2 H-C(O)-O).

3C-NMR (d6-DMSO, 90 NHz): ~= 65.58 ppm (CH2); 68.11 (CH); 153.54 ~O-C(O)-O); 161.06 (H-C(O)-O).

Microanalysis: Calculated for C7~807: C 41.20 %, H 3.92 %
found : 41.30 %, 4.00 %

ESX~P~ 11:

Synthesis of the polyester having the monom~r unit 5a 1.85 g (12.5 mmol) of the polyester of Example 4 (monomer unit 2a) were dissolved in 8 ml dimethyl form~mide and the solution was diluted with 30 ml of tetrahydrufuran. 0.495 g (6.25 mmol) pyridine and 38.8 g (181 mmol) caproic anhydride were added under argon and the mixture was stirred for 20 hrs. at room temperature. The solution waâ
then diluted with 50 ml of dichloromethane, washed twice with saturated sodium bicarbonate solution and with water, the organic layer was separated and dried over anhydrous sodium sulfate. The vvo 93/20126 PCT/EP93/00699 2~;~8~

solvent was evaporated under reduced pressure, the residue was dissolved in lS ml of dichloromethane and the polymeric product was precipitated by dropwise addition of this solution into 600 ml of hexane. Reprecipitation from dichloromethane / hexane and drying in vacuo for 48 hrs. gave a polyester having the monomer unit 5a as a viscose oil. According to lH-NMR, 76 % of the hy~roxyl groups were esterified to caproate ester and 24 % were present in free condition.
Thus, the product comprised approximately 52 % di-caproate ester units (di-units) and 48 ~ mono-caproate ester units (mono-units). The ratio of di-units and mono-units was determined from the integrals of the signals at 5.352 ppm (2 CH of di-units) and 5.205 ppm (1 CH of mono-units).

~lnh ~dl/g)= 0.08 in CHCl3 Mw= 7550 Da, Mn= 5000 Da, Mw/Mn= l.Sl Tgz 9.9C

IR (film): Strong absorptions at 1750, 1246 and 1164 cm~l. -1H-NMR (CDC13, 360 MHz~: ~= 0.~99 ppm (t, J= 7 Hz, CH3 of caproate side chain); 1.317 (m, 2 CH2 of caproate side chain); 1.55-1.70 (m, CH2 of caproate side chain); 2.26-2.44 (m, CH2 of caproate side chain~; 4.02-4.56 ~m, 2 CH2 of di-units, 2 CH2 of mono-units, 1 CH of mono-units ~nd OH of mono-units); 5.205 ~m, 1 CH of mono-units); 5.3i2 (m, 2 CH of di-units).

3C-NMR ~CDCl3, 90 MHz): ~= 172.9 and 172.6 ppm (-C(O)-O); ca. 154.5 (multiple signal, O-C(O)-O); ca. 70.1 (multiple signal, CH); ca. 6~.
~multiple signal, CH); ca. 65.8 (multiple signal, CH2); 33.97 (CH2 s-caproate side chain); 31.17 (CH2 of caproate side chain); 24.46 (C 2 of caproate side chain); 22.26 (CH2 of caproate side chain); 13.87 (CH3).

XlZ~362 ~eLE 12:

Synthesis of the polyester having the monomer unit 6a 1.48 g ~10 mmol) of the polymer having the monomer unit 2a (of Example 4) and 1.7 ml pyridine were dissolved in 60 ml of dimethyl formamide /
tetrahydrofurane (1:1). A solution of 12.12 g ~40 mmol) of stearoyl chloride in 30 ml of tetrahydrofuran was added dropwise over 15 minutes to the stirred solution at room temperature and stirring was continued for additional 20 hours. The solvent was then evaporated under reduced pressure, the residue dissolved in 200 ml of dichloromethane and washed with aequous 5% sodium bicarbonate ~2x) and water. The organic layer was dried over anhydrous sodium sulfate, the solution concentrated to a final volume of 100 ml and the product was precipitated by dropwise addition of the solution to 2000 ml of ~;~
methanol. The precipitate was dissolved in 350 ml of ethyl acetate at 60C and the stirred solution was allowed to cool to room temperature.
After 2 hours stirring at room temperature, the white, powdery precipitate was isolated and dried in vacuo for 48 hours at room temperature to give the polyester. The reprecipitation from ethyl acetate was repeated to give the product with a low polydispersity. ~-According to lH-NMR, ca. 95% of the hydroxyl groups were stearoylated and ca. 5% were in free condition. Thus, the product comprised ca. 90%
of di-stearoylated units (=di-units! and ca. 10~ of mono-st~aroylated units ~=mono-units). The ratio of di-stearoylation and mono-stearoylation was determlned from the integrals of the signals at ca. 5.34 ppm (2CH of di-units) and ca. 5.20 ppm (lCH of mono-units).
Other signals of the minor mono-units were either overlapping with the signals of the major di-units or were too small to observe. Thus, the lH-NMR spectrum of the product is mainly attributed to the major di-units. -~lnh (dl/g)= 0.11 in CHCl3 Mw= 15850 Da, Mn= 13500 Da, Mw/Mn= 1.17 X1~6Z~.

. , Tm= 55 to 75C.

IR ~KBr): Strong absorptions at 2918, 2850, 1751 and 1250 cm~1. ;
. :
H-NMR ~CDC13, 360 MHz): ~ = 0.88 ppm lt, J= ca. 6.8 HZ, various CH3);
1.20-1.35 ~m, various CH2); 1.605 (m, various CH2); 2.33 (m, ~arious CH2); 4.05-4.25 (m, 2HB of 2CH2-0 of di-units and various H of mono-units); 4.375 (d.m, 2JAB= Ca.11 HZ, 2HA of 2CH2-0 of di-units and various H of mono-units); ca. 5.20 (m, lCH of mono-units); 5.34 (m, 2CH of di-units).

~XANPI~ 13:
.

Synthesis of the polyester having the monom~r unit 7G

2.96 g t20 mmole) of the polyester having the monomer unit 2c (of Example 6) were dissolved in 90 ml dimethyl formamide /
tetrahydrofuran (1:5) and the solution was cooled to 0C in an ice ~bath. 3.56 g (45 mmole) pyridine and a solution of 9.23 g ~50 mm~le) Benzyloxyacetyl chloride in 60 ml of tetrahydrsfuran were added subsequently to the stirred solution at 0C and stirring was continued .~l-for additio~al 6 hours at this temperature. Then, the mixture was dissolved in 300 ml of dichloromethane, the dichloromethane solution was washed with aqeuous 5~ sodium bicarbonate (2x) and water ~2x) and dried over anhydrous sodium sulfate. The 501~ent was then evaporated under reduced pressure and the residue was dissolved in 30 ml of dichloromethane. The polyester was precipitated on dropwise addi~ion of this solutio~ into 1000 ml of methanol and dried for 4B hours in vacuo.

~nh (dl/g)= 0.12 in CHCl3 Mw= 17550 Da, Mn= 11200 Da, Mw/Mn- 1.57 Tg= 32.2C

X~2~fi21 - 32 -IR (film~: Strong absorptions at 1762, 1246, 1185 and 1125 cm~l.

l~_NMR (CDCl3, 360 MHz): ~ = 4.00-4.19 ppm (m, 6H, 2H~ of 2 chain CH2 and 2 CH2); ca. 4.35 (m, 2H, 2HA Of 2 chain CH2); 4.555 (m, 4H, 2 benzyl CH2); 5.383 tm, 2H, 2CH); 7.20-7.40 (m, lOH, arom.H).

3C-NMR (CDCl3, 90 MHz): ~ = 169.41 ppm (-C(O)-O); 154.06 ~O-C(O)-O);
136.87 (arom.C); 128.41 and 127.94 ~arom. CH); 73.27 Ibenzyl CH2);
69.00 (CH); 66.73 (CH2); 65.54 (chain CH2).

Microanalysis: Calc. for C23H24O9: C 62.18 %, H 5.40 %
found: Çl.50 %, 5.60 %

EXaMPLe 14:

Synthesis of the polyester having the msnomer unit 8c lg of 5~ palladium on charcoal was suspended in 250 ml of dioxane and dimethyl formamide (9:1) while under argon. Hydrogen gas was bubbled through the suspension during 30 minutes.
To the stirred suspension was added dropwise, while the bubbling of the hydrogen gas was continued, a solution of 5 g (11.25 mmol) o~ the polyester having the monomer unit 7c (Mw = 12200, Mn = 8~00) in 250 ml of dioxanetdLmetnylformamide ~9:1). The mixture was stirred for additional 2 hours under a gentle stream of hydrogen, then purged with argon. The catalyst was removed by filtration. The filtrate was evapora~ed in vacuo to a final volume of ca. 75 ml. and by addition of this solu~ion into 500 ml of isopropyl ether a product was precipitated. The precipitate was dissolved in 50 ml of dioxane and stirred with 150 mg of activated charcoal at room temperature. After filtration, the filtrate was evaporated in vacuo to a final volume Or ca. 15 ml and a product was precipitated by dropwise addition of this solution into 500 ml of isopropyl ether. The product was dried in vacuo for 48 ho~rs to yield the polyester having the monomer unit 8c.

~inh. (dl/g) = 0.105 in CHCl3 PCI`/EP93/00699 ~VO 93/20126 Zl~fizl. `~. .

Tg = 44, 8C

IR (KBr): Strong absorptions at 3446, 1757, 1255, 1193 and 1094 cm~l.

H-NMR (d6-DMS0,360MHz): ~ = 4.05 ppm (m, 4H, 2 side chain CH2);
4.15-4.24 (m,2H,2H~ of CH2): ca. 4.29 (d.m, J = ca. llHz, 2H, 2HA of 2 CH2); ca. 5.35 (m,2H,2CH); 5.42 (t,J = 6.5Hz, 2H, 20H).

3C-NMR (d6-DMSO, 90 MHz): S = 172.00 ppm (-C(O)-O~; 153.72 (O-C~O)-O); 68.62 (CH); 65.68 (CH2); 59.33 (side chain CH2).

Microanalysis: Calculated for C9Hl2O9: C 40.92% H 4.58%
found : 40.85% 4.85%
.. .~
Additional es~erifications with active lactic- or glycolic acid derivatives lead to products having oligo- and poly-co-glycolide-lactide side chains.

Polyesters having monomer units 2a-2c are alternatively derivatized with glycolic- or lactic acid ester residues by treatment with the corresponding chloroforma es, utilizing the hydroxyl grsups of glycolic respeetively laetic acid residues. The conversion sf e.g.
ethyl lactate into ethyllactyl chloroformate i5 described in the literature [29~: US Patent 3,742,022 (1973) and [30]: German Pater.~ 2 58 254 (1977). Treatment of the polyester having the monomer unit 2c with ethyllactyl chloroformate according to thé procedure described in examples 21 or 22 gives the corresponding ethyllactyl carbonate derivative.

aMp~ 15:

Synthesis of the polyester having the monomer unit 9c ~-2.22 g tl5 mmol) of the polyester of Example 6 (monomer unit 2c) were dissolved in 12 ml dLmethyl formamide, the solution was diluted with W O 93/20126 P ~ /EPg3/00699 Xl~l~fi21 60 ml of tetrahydrofuran and 3.34 g (33 mmol) of 4-methylmorpholine were added. The solution was cooled down to 0C in an ice-bath and treated dropwise with a solution of 3.17 g (30 mmol) pyruvoyl chloride in 17 ml of tetrahydrofuran. The mixture was stirred for 4 hrs. at 0C, the solvent was removed under reduced pressure and the residue was taken up in 400 ml of dichloromethane. The solution was washed twice with water, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in 15 ml of dichloromethane and the product was precipit~ted by dropwise addition of the solution into 500 ml of diethyl ether. The product was reprecipitated from dichloromethane / diethyl ether and dried in vacuo for 48 hrs. to give a polyester having the monomer unit 9c as a brownish-yellow powder.

~n~(dl/g)= 0.05 in CHCl3 Mw= 5950, Mh= 3750, Mw/Mn= 1.59 'Tg= S0.3C

IR (KBr): Strong absorptions at 1768, 1739, 1251 and 1135 cm-1.

1H-NMR ~CDCl3, 360 ~Hz): ~= 2.47 ppm (m, 6 H, 2 CH3); 4.33 (m, 2 H, 2 H3 of 2 CH2); 4 . 51 (m, 2 H, 2 HA of 2 CH2); 5.47 ~m, 2 H, 2 CH).

l3C-N~ (CDCl3, 90 MHz): ~= ca. 190.3 ppm (-C(0~-); 159.41 (-C(0)-0):
153.39 ~0-C(0)-0); 70.60 (CH); 65.15 (CH2); 26.69 ~CH3).

Microanalysis: Calculated for CllHl209: C 45.84 %, H 4.20 ~
found: 45.40 %, 4.20 %

EXAMPLX 16:

Synthesis of the polyester having the monomer unit lOc 9.12 g ~60.B mmol) of benzoyl formlc acid were treated slowly wi~.

~VO 93120126 - 35 - z~fi~

6.99 g ~60.8 mmol) of dichloromethyl methyl ether and the mixture was st -red at 50C Ibath temp.) for 90 minutes, until HCl-evolution was almost ceased. The mixture was then cooled down to room temperature, dissolved in 60 ml of THF and the solution was added dropwise to a cooled solution ~0C) of 2.0 g ~13.5 mmol) of the polyester of Example 6 (monomer unit 2c) and 12.3 g (121.5 mmol) of 4-methylmorpholine in 120 ml of tetrahydrofuran-dLmethyl formamide (5:1). The mixture was stirred for additional 4 hrs. at 0C, then the solvent was evaporated under reduced pressure and the residue was disso}ved in 500 ml of dichloromethane. The dichloromethane solution was washed twice with ~-water, dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure. The polymeric product was precipitated twice by dissolving in 35 ml of dic~loromethane and dropwise addition of the dichloromethane solution into 1500 ml of t-butyl methyl ether to give, after drying in vacuo for 48 hrs., a polyester having the monomer unit lOc as a brownish-yellow powder.

inh ~dl/g)= 0.07 in CHCl3 Mw= 9370 Da, Mn= 4690 Da, Mw/Mn- 2.0 Tg= 51C

IR (KBr): Strong absorptions at 1756, 1689, 1243, 1194, 1172 and g81 cm-~H-NMR (CDCl3, 360 MHz~: ~= 4.36-4.47 ppm (m, 2 H, 2 H~ of 2 CH2~;
4.58-4.69 Im, 2 H, 2 HA Of 2 CH2); 5.755 Im, 2 H, 2 CH); 7.39 (m, 4 H, 4 arom. H); 7.52 (m, 2 H, 2 arom. H); 7.B85 (m, 4 H, 4 arom. H).

l3C-NMR (CDC13, 90 MHz): ~= 184.73 ppm (-C(0)-); 162.48 (-C(0~-0);
153.93 (0-C(0)-0); 135.12 (arom. CH) 131.73 (arom. C); 129.94 (arom.
CH); 128.93 larom. CH); 70.43 (0-CH); 65.48 (0-CH2).

Microanalysis: Calculated for C~1Hl609: C 61.18 %, H 3.88 %
found: 60.60 %, 4.30 %

W O 93/20126 P ~ /EP93/00699 2128~;21.

EXAHPLE 17:

Synthesis of the polyester having the monomer unit llc 30.4 g (264 mmol) of dichloromethyl methyl ether were added slowly t~
34.4 g ~264 mmol) of 4-methyl-2-oxovaleric acid and the mixture was heated to 50C (bath temp.). After stirring for 60 min. at this temperature, the crude product was fractionated on a vigreux column to `
give the 4-methyl-2-oxovaleryl chloride (b.p. 41C/14 mbar). 14.7 g ~99 mmol) of 4-methyl-2-oxovaleryl chloride were dissolved in 144 ml of tetrahydrofuran and the solution was added dropwise at 0C to a ~`
solution of 6.66 g (45 mmol) of the polyester of Example 6 (monomer unit 2c) and 7.83 g (99 mmol) of pyridine in 514 ml of tetrahydrofuran/dimethyl formamude ~5:1). The reaction mlxture was stirred at 0C for additional 3 hours, then filtered through Hyflo Cel and the filtrate was concentrated under reduced pressure.
~he polymeric product was precipitated by dropwise addition of the resulting solution into 1000 ml of isopropyl ether / n-hexane (1.~
The precipitate was stirred several tLmes in tetrahydrofuran/diethyl ether ~1:2) and the insoluble part was removed by filtration. The resulting clear solution was added dropwise into 500 ml of isopropyl ether, the precipitate was redissolved in tetrahydrofuran and precipitated from 1000 ml of n-hexane giving a polyester ha~ing the monomer unit llc.

~lnh ~dl/g)= 0.10 in CHCl3 Mw= 15300 Da, Mn= 9050 Da, MwlMn= 1. 69 Tg= 30.3C

IR ~KBr): Strong absorptions at 1763, 1740, 124B and 1047 cm-l.
1H-NMR (CDC13, 360 MHz): ~= O.g52 ppm ld, J= 6.5 Hz, 12 H, 4 CH3);
2.16 ~sept., J= 6.5 Hz, 2 H, 2 side chain CH); 2.705 ld, J- 6.5 Hz, 4 - 37 - 212~21.

H, 2 side chain CH2 ); 4.30 (m, 2 H, 2 HB of 2 CH2 ); 4.522 (dm, J- ca.
12 HZ, 2 H, 2 ~A of 2 CH2 ); 5.453 ~m, 2 H, 2 CH).

3C-NMR (CDCl3, 90 MHz): ~= 192.42 ppm t-C(O)-); 159.96 (-C(O)-O);
154.00 ~O-C~O)-O); 70.45 ~CH); 65.12 lCH2); 47.85 ~side chain CH2);
24.13 (side chain CH); 22.38 ~CH3). .

EXANPLE 18:
:"
Synthesis of the polyester having the monomer unit 12c 2.96 g ~20 mmol) of the polyester having the monom~r unit ~c (of Example Ç) was dissolved in 15 ml of dimethyl fonmamide, the solution was diluted with 80 ml tetrahydrofuran and cooled to 0C in an ice bath. 3.16 g 540 mmol) pyridine and a solution of 5.99 g ~44 mmol) ~-Ethyl oxalyl chloride in 40 ml of tetrahydrofurane were added subse~uently and dropwise over 15 m1nutes to the stirred solution at 0C. The reaction mixture was stirred for additional 7 hours at this temperature, then dissolved in 300 ml of dichloromethane and the dichloromethane solution was washed with aqeuous 5% sodium bicarbonate ~2x) and water. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residue was dissolved in 20 ml of dichloromethane. The product was precipitated by dropwise addi~ion of the dichloromethane solution into 1500 ml diethyl ether.
The precipitate was dried in vacuo for 48 hours at room temperature to give the polyester.

~lnh (dl/g)= 0.09 in CHCl3 ~w= 15000 Da, Mn= 9850 Da, Mw/Mn= 1.52 rg= s3.aoc IR tKBr): Strong absorptions at 1779, 1~49, 1313, 1249, 1181 and 1155 W O 93/20126 PCT/EPg3/00699 2~fi21.
cm~l H-NMR (CDC13, 360 MHz): 8= 1.364 ppm (t, 3J= ca.7 Hz, 6H, 2C~3);
4.346 (q,3J= ca.7 Hz, 4H, 2 ethyl CH2); 4.295-4.410 (m, 2~, 2HB of 2 CH2); 4.475-4.575 (m, 2H, 2HA of 2 CH2); 5.522 ~m, 2H, 2CH).

13C-NMR (CDCl3, 90 MHz): ~= 156.69 ppm (-C(O)-O); 156.59 (-C(O)-O);
15~.88 (O~C~O)-O); 71.09 (CH); 65.01 (CH2); 63.48 (CH2); 13.84 ~CH3).

Microanalysis: Calc. for Cl3Hl6Oll: C 44.85 %, H 4.60 %
found: 44.70 %, 4.80 %

}Ka~L~ 19:

Synthesis of the polyester having the monomer unit 13c 5.18 g ~35 mmol) of the polyester having the monomer unit 2C ~of Example 6) were suspended in 250 ml of tetrahydrofuran. 7.1 ml (6.958 g; 88 mmol) of pyridine and 51 ml (57.22 g; 353 mmol~ of diethyl pyrocarbonate were added while under argon. A gentle evolution of CO2 started simul~aneously on addition of diethyl pyrocarbonate. The mixture was stirred for 3 hours at room temperature, after whicn m~e the evolution of CO2 was slowed down. The solvent was then evapora~ea at reduced pressure at 30C, the residue was dissolved in 25 ml o-^
dichloromethane and the produc~ was precipitated on dropwise ddi.icn of the dichloromethane solution nto 1000 ml of hexane. The precip--tate was resolved in 25 ml of dichloromethane and reprecipitated -rom 1500 ml of diethyl ether/hexane (2:1). The precipitate was dried -.
~acuo for 48 hours to give the polyester.

(dl/g)= 0.12 in CH~13 Mw= 15650 Da, Mn= 10550 Da, Mw/Mn= 1.4B

Tg= 49.8C

PCT/EPg3/00699 ~VO 93/20126 Z~862~1.

IR ~pfr) strong absorptions at 1752 and 1245 cm~~

H~ CDC13, 360 MHZ): ~= 1.315 ppm (t, J= ca.7 HZ, 6H, 2CH3); 4.222 (q, J= ca.7 HZ, 4H, 2 CH2); 4.16-4.32 tm, 2H, 2H3 of 2 chain CH2);
4.42-4.52 (m, 2H, 2HA Of 2 chain CH2): 5.175 ~m, 2H, 2CH).

13C-NMR tCDC13, 90 MHZ): ~- 154.13 ppm tO-CtO)-O); 72.43 and 72.38 tCH); 65.47 tCH2); 64.81 tCH2)i 14.11 (CH3).

Microanalysis: Calc. for C9Hl20~: C 45.21 %, H 5.52 %
found: 45.50 %, 5.60 %

EXAMPL~ 20:
':~
Synthesis of the polyester having the monom~r unit 14c 2.96 g t20 mmol) of the polyester havin~ the monomer unit 2c (of Ex-ample 6) were suspended in 150 ml of tetrahydrofuran. 3.3 ml (3.2 g;
'41 mmol) of pyridine and 5.8 n~ ~6.5 g; 40 mmol) of diethyl pyrocar-bonate were added while under a.gon. A gentle evolution of C02 started simultaneously on addition of diethyl pyrocarbonate. The mixture was stirred for 30 min. at room temperature, then the solvent was evapo- ;~
rated at reduced pressure at 30C and the residue was dissolved in 25 ml of dichloromethane. The product was precipitated on dropwise addi-tion of the dichloromethane solution into 1500 ml of diethylether. The precipitate was dried in vacuo for 48 hours to give the polyester, f_~
which according to lH-NMR ca. 76.5% of the hydroxyl groups were ethoxyearbonylated and ca. 23.5% were in free condition. Thus the ratio of di-ethoxycarbonylated units to mono-ethoxycarbonyla~ed uni~s was ca. 53% : 47~, according to the integral ratio of the signals ~:
5.18 ppm ~m, 2 CH of di-ethoxycarbonylated units) and 5.02 ppm (m, ' CH of mono~ethoxycarbonylated units).

~lnh (dl/g)= 0.10 in CHCl3 Mw= 11450 Da, Mn= 79S0 Da, Mw/Mn= 1.44 P ~ /EP93/00699 212Rfi21 Tg= 45.4C ;

IR (KBr): 3508 (OH-Absorption) and strong absorptions at 1757, 1234, 1005 and 786 cm-l. -lH-NMR ~CDCl3, 360 MHz): ~- 1.312 ppm (t, 3J= ca.7.2 Hz, 2CH3 of di-units and lCH3 of mono-units); 2.75-3.35 ~m, OH of mono-units):
4.22 (q, 3J= ca.7.2 Hz, 2CH2 of di-units and lCH2 of mono-units);
4.08-4.40 ~m, 2H of di-units and 4~ of mono-units); 4.40-4.54 ~m, 2H
of di-units and lH of mono-units); 5.02 tm, lCH of mono-uni~s); 5.18 ~m, 2CH of di-units).

~XAHPLB 21:

Synthesis of the polyester having the monomer unit 15c 1.48 g ~10 mmol) of the polyester having the monomer unit 2c (of ~xample 6) were suspended in 80 ml of toluene and the suspension was stirred for 1 hr. at room temperature. After the addition of 1.76g (22 mmol) pyridine, a solution of 9.88 g (22 mmol) cholesteryl chloroforma~e in 70 ml of toluene was added dropwise over 10 min. tO
the stirred suspension and stirring was continued at room temperature for 50 hrs. The reaction mi~ture was then dissolved in 400 ml of dichloromethane, the dichloromethane solution was washed with aequous 5~ sodium bicarbonate (2x) and with water, and dried over anhydrous sodium sulfate. Then, the solvent ~as evaporated under reduced pressuret the residue was dissolved in ca. 50 ml of dichloromethane and the product was precipitated on dropwise addition of the dichloromethane solution into 2000 ml of 2-propanol. The product was further purified by dissolution in 50 ml of dichloromethane and pre-cipitation from 1~00 ml of n-butanol. The fine, powdery polyester was isolated by filtration and dried in vacuo for 48 hrs.

~lnh (dl/g~= 0.12 in CHCl3 ~VO 93/20126 PCI`/EP93/006g9 Xl;;~86Z~
Mw= 18150, Mn= 11600, Mw/Mn=1.56 Tg= No Tg was observable from -30C to +240C.

IR ~KBr~: Strong absorptions at 2951, 1758 and 1249 cm~l.

1H-NMR (CDC13, 360 MHZ): ~= 0.684 ppm (s, 6H, 2CH3); 0.869 (d.d, 3J-ca. 6.5 HZ, 12H, 4CH3); 0.921 (d, 3J= ca. 6.2 Hz, 6H, 2CH3); 1.0B3 ~S, 6H, 2CH3); 0.75-2.10 ~m, 52H, various CH2 and CH); 2.28-2.47 (m, 4H, 2CH2); 4.241 (m, 2H, 2HB of 2 chain CH2); 4.40-4.55 (m, 4H, 2HA of 2 chain CH2 and 2CH of cholesteryl residue); 5.153 ~m, 2H, 2 chain CH); ~-5.396 (m, 2H, 2 olefin H).

EXAMPLe 22:

Synthesis of the polyester having the monom~r unit 16c 2.96 g (20 mmol) of the polyester having the monomer unit 2c (of Example 6~ were suspended in 150 ml of toluene and the suspension was stirred for 1 hr. at room temperature. After the addition of 3.48 g ~44 mmol) of pyridine, a solution of 10.68 g ~50 mmol) 4-methoxycarbonylphe~yl chloroformate in 50 ml of toluene was added to the stirred suspen~ion over 15 mm. and the reaction mixture was stirred for additional 65 hrs. at room temperature Then, the solvent was evaporated at reduced pressure, the residue was diluted with dichlorom~thane and the dichloromethane solution was washed with aequous 5% sodium bicarbonate ~2x~ and ~ater. The organic layer was then dried over anhydrous sodium sulfate, filtered and the solvent was evaporated at reduced pressure. The residue was dissolved in 50 ml of dichloromethane and the product was precipitated by dropwise addition of the dichloromethane solution into lOOOml of diethyl ether. The precipitated polyester was resolved in 50 ml of dich}oromethane, reprecipitated from 1000 ml ethanol and dried in vacuo for 48 hrs.

~lnh (dl/g)= 0.12 in CHCl W O 93/2012~ PCTJEP93/00699 212~621.
,i.
Mw= 22600 Da, Mn= 13500 Da, Mw/Mn= 1.67 Tg= 90.9C

IR (KBr): Strong absorptions at 1772, 1723, 1282, 1235, 1211 and 1112 cm~l H-NMR (CDCl3, 360 MHz3: ~= ca. 3.86 ppm ~broad s, 6H, 2CH3);
4.28-4.45 (m, 2H, 2HB of 2 CH2); 4.64 (m, 2H, 2HA of 2 CH2); 5.319 ~m, 2H, 2CH); 7.18 7.30 (m, 4H, 4 arom. H); 7.95-8.09 (m, 4H, 4 arOm. H).

3C-NMR (CDCl3, 90 MHz): ~= 165.85 PPm (-C~O)-O); 154.23 (arom. C);
154.04 IO-C~O)-O); 152.19 (O-C(O)-O); 131.22 ~arom.CH); 128.20 ~arom.
C); 120.73 (arom. CH); 73.50 (CH-O); 65.32 (CH2-O); 52.19 (CH3).

Le 23:

Synthesis of the polyester in which the monomer unit is 17c -2.0 g ~13.5 mmol) of the polyester of Example 6 ~monomer unit 2c) were suspended in 120 ml of tetrahydrofuran 24.2 g (203 mmol) of phenyl isocyanate and 0.5 ml of pyridine were added under an argon stream and the mixture was stirred for 96 hrs. at room temperature.
The product was then precipitated by dropwise addition of the solution into 1500 ml of hexane. The precipitate was dissolved in 20 ml of tetrahydLofuran and the solution was added dropwise into 500 ml of diethyl ether. The reprecipitation from tetrahydrofuran-diethyl ether was repeated once again and the product was dkied in vacuo at room temperature for 48 hss. to yield a polyester having the mo~omRr unit 17c. According to lH-NMR, the product comprised 7% free hydroxyl groups, whilst the remainder ~3% of the hydroxyl groups were derivatized as carbamate est~r.
Thus, the product comprised 86% di-carbamoylated units ~di-units) and -14% mono-carbamoylated units ~mono-units). The ratio of mono-carbamoylation and di-carbamoylation was determined from the integrals of the signals at 5.04 ppm ~1 CH of mono-units) and 5.30 ppm PCT/EPg3/00699 2i~862~.

~2 CH of di-units).

~lnh(dl/g)= 0.115 in acetone Mw= 17700 Da, Mn= 10900 Da, Mw/Mn= 1.62 Tg= 86.7C

IR ~KBr): Strong absorptions at 1744, 1602, 1530, 1446 and 1211 cm~l.

1H-NMR ~d6-DMSO, 360 MHz): ~= 3.85-4.50 ppm (m, 1 CH and 2 CH2 of mono-units and 2 CH2 of di-units); 5.04 ~1 CH of mono-units): 5.30 (m, 2 CH of di-units); 5.63 (m, OH of mono-units); 6.96 ~m, 2 arom. H);
7.23 ~m, 4 arom. H); 7.44 (m, 4H, 4 arom.H); ca. 9.80 (m, 2 NH).

l3C-MMR ~d6-DMSO, 90 MHz): ~= ca. 154.0 ppm (multiple signal:
O-C~O)-O); 152.5 ~O-C~O)-NH); 138.6 ~C~1')); 128.6 ~C~3')); 122.7 ~C~4')); 118.5 ~C~2')): ca. 69.5 ~broad, CH); ca. 66.5 ~broad, C~2).
~ome additional, weak signals of the minor mono-carbamoylated units are also present.

EXA~PLB 24:
~; _ .

Synthesis of t~e polyester having the monomer unit l~c 444 mg ~3 mmol) of polyester having the monomer unit 2c o~ example 6 was dissolved in 8 ml of dimethyl fonmamide. ~he solution was diluted with 32 ml of tetrahydrofuran. To the stirred solution subsequently were added at room temperature 4.78g (18 mmol) of BOC-L-phenylalani.., 3.71g (18 mmol) of N,N'-dicyclohexyl-carbodiimide and 135 mg ~1.2 mmol) of 4-dim~thylaminopyridine. The mixture was stirred for additional 2 hours at room temperature.
After filtration of the forme~ suspension, the solvent was evaporat~d under reduced pressure, the residue was dissolved in dichloromethane and the solution was washed subse~uently with water, aqueous lM acet~^
acid, 5% sodium hydrogencarbonate and saturated brine. The P ~ /EP93/00699 X~2~62~.
dichloromethane solution was then dried on anhydrous sodium sulfate and evaporated to a final volume of ca. 20 ml. By dropwise addition of this solution into 200 ml of hexane a precipitate was formed. The solid product was reprecipitated from dichloromethane/hexane and dried in vacuo to give the polyester of which the amino groups are protected by tert.-butyloxycarbonal groups.

~ lnh . ~dl/g) = 0.09 in CHCl3 Mw = lS000 Da, Mn = 10800 Da, Mw/Mn = 1.3 Tg = 82.4C

IR (KBr): Strong absorptions at 1760, 1717, 1499, 1251 and 1166 cm~1.

H-NMR (d6-DMSO, 360 MHz)~ ppm (m, 18H, 6CH3); 2.78 - 2.94 ~m,2H, 2 side chain CH2~; 4.04 - 4.30 (m,6H, 2 chain CH2 and 2 side chain CH); 5.24 - 5.50 (m,2H, 2 chain CH); 7.12 - 7.3~ (m,12H, 2NH and ro arom. H).

13C-NMR ~d6-DMSO, 90 MHz): ~ = i71.49 and 171.04 ppm (-C(O)-O); 155.34 and 155.24 (O-C(O)-O); 153.60 (HN-C(O)-O~; 137.22 (arom. C); 128.93, 128.04 and 126.34 (arom. CH); 78.3B and 78.31 ~side chain C); 69.07 ~chain CH); 65.43 ~chain CH2); 55.05 (side chain C~); 36.2 and 35.9 (benzyl CH2); 28.0 ~CH3).

Microanalysis: Calculated for C33H42N2Oll: C 61.67% H Ç.59% N 4.36%
found: 61.40% 6.40% 4.30%

The tert.-butyloxycarbonyl protecting groups are removed by known methods, e.g. by treatment of the product with an acid, e.g.
trifluoroace~ic acid, to give the trifluoroacetate salt or, after neutralisation, to give the polyester wi~h free amlno groups.

Polyesters having monomer units 2a-2c are alternatively derivatized with amino acid ester residues by treatment with their correspondir.q ~vo 93/20126 Xl;~6Z~.

.
isocyanates. Amino groups of amlno acid ester are readily converted into isocyanates: [31]: Japanese Patent 53018515 (1978) and [32]:
Shoichiro Ozaki et al., Bull. Chem. Soc. Jpn. 50, 2406 (1977).
Subsequent treatment of the isocyanates according to the procedure described in example 23 leads to the formation of the carbamic acid esters of the corresponding amino acid residues.

EXANPL~ 25:

Synthesis of the Polyester having the monomer unit l9c 444 mg ~3 mmol) of polyester having the monomer unit 2c from example 6 was dissolved in 8 ml of dimethyl fonmamide. The solution was diluted with 32 ml of tetrahydxofuran. To the solution were added subsequently 4.78 g (18 mmol) of Z-L-leucine, 3.71 g (18 mmol) of N,N'-dicyclohexyl-carbodii~de and 135 mg (1.2 mmol) of 4-dimethylaminopyridine. The mixture was stirred for 2 hours at room temperature. After filtration of the formed suspension, the solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane and the solution was washed subsequently ~ith water, aqueous lM acetic acid, 5~ sodium hydrogencarbonate and saturated brine. The dichloromethane solution was then drie on anhydrous sodi~m sulfate and evaporated to a final ~olume of ca4 20 ml. By dropwise addition of this solution to 200 ml of hexane a precipitate is fonmed.
The solid product was reprecipitated ~rom dichlorom~thane/isopropyl ether and dried in vzcuo to give the polyester, in which the ~m1no groups are protected by benzyloxycarbonyl groups (Z-group).

Mw = 1~000, Mw = 10800, Mw/Mn - 1.39 IR (KBr): Strong absorptions at 2960, 1760, 1723, 1529, 1264 and 1048 cm-l lH-NMR (d6-DMSO, 360 MHz): ~ = 0.70 - 0.97 ppm (m, 12H, 2CH3); 1.34 -1.70 ~m,6H, 2 side chain CH2 and 2 side chain CH); 4.00 - 4.30 tm~6H~

X12f~62~ 46 -2 chain CH2 and 2 side chain CH); 5.00 ~m,4H, 2 benzyl CH2); 5.32 ~m, 2H, 2 chain CH); 7.18 - 7.42 ~m,lOH, 10 arom. CH); 7.19 (m,2H, 2NH).

3C-NMR ~d6-DMS0, 90 ~Hz): ~ = 172.18 and 171.70 ppm ~-C(0)-0); 155.99 ~0-C(0)-0), 153.54 (NH-C(0)-0), 136.66 ~arom. C); 12~.18, 127.84 and 127.65 ~arom. CH); 69.20 (CH); 65.56 (CH2); 52.28 ~CH); 24.16 (CH);
22.70, 22.51, 21.19 and 20.96 (CH3).

The esterification was also performed using Z-L-leucyl-L-alanin, under the same reaction conditions to give the corresponding dipeptide ester derivative.

The benzyloxycarbonyl protecting groups are removed by known methods, e.g. by hydrogenation on palladium/charcoal, to give a polyester with free amino groups or, if an acid is added, the corresponding ammonium salt.

~X~MPIB 26:

Synthesis of the polyester in which the monomcr unit is 20 c 7.5 ml of trifluoroacetic acid and 29 g (150 mmol) of tetraethyl orthocarbonate were a~ded at room tem~erature to a suspension of 2.22 g (15 mmol) of the polyester of Example 6 ~monomer unit 2c) in 150 ml of tetrahydrofurane under an argon stream. The mixture was stirred for 18 hrs. at room temperature. The resulting solution was treated with 3.5 g of powdered sodium bicarbonate, stirred for 30 min. and after filtration, the solvent was evaporsted under reduced pressure~ The residue was dissolved in 3ao ml of dichloromethane and the dichloromethane solution was washed with 300 ml of aequous 5% sodium bicarbonate by stirring for 15 min. at room temperature. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated to a final volume of ca. 20 ml and the product was precipitated by dropwise addition of the solution to 1000 ml of h~xane. The precipitate was dried in vacuo for 48 hrs. at room t~mperature to W O 93/20126 PCT/EP93/0069g yield a polyester having the monomer unit 20c.

~inh (dl/g)= 0.1 in CHCl3 Mw= 11750 Da, ~n- 7750 Da, Mw/Mn= 1.52 Tg= 10.8C

IR tfilm): Strong absorptions at 2982, 1755, 1266, 1214t 1145 and 1047 ~H-NMR (CDCl3, 360 MHz): ~= 1.21 ppm ~t, 3J= 7 Hz, 6 H, 2 CH3); 3.715 ~q, 3J= 7 Hz, 4 H, 2 side chain CH2); 4.27 (m, 2 H, 2 HB Of 2 CH2);
4.315 ~m, 4 H, 2 HA Of 2 CH2 and 2 CH);

3C-NMR ~CDCl3, 90 MHz): ~= 154.39 ppm ~0-C~0)-0); 127.48 ~orthocarbonate C); 74.74 ~CH); 67.38 ~CH2); 60.~6 5side chain CH2);
14.98 ~CH3).

Microanalysis : Calculated for CloH167 C 48.39 %, H 6.50 %
found: 48.10 %, H 6.50 %

EXaNPLe 27:

Synthesis of the polyester in which the monomer unit is 21c 2.5 ml of trifluoroacetic acid and 44.5 g (300 mmol) of triethyl orthoformate were added at room temperature under an argon stream to a suspension of 4.44 g (30 mmol) of the polyester of Example 6 (monomer unit 2c) in 300 ml of tetrahydrofuran. The mixture was stirred for 4 hrs. at room temperature, the resulting solution was treated with 4.5 g of powdered sodium bicarbonate, stirred for another 30 min. at room temperature and after filtration, the solvent was evaporated under reduced pressure. The residue was dissolved in 300 ml of dichloromethane and the solution was washed with 300 ml of aequous 5%
sodium bicarbonate by stirring for 15 min. at room temperature. The organic layer was separated, dried over anhydrous sodium sulfate and W O 93/20126 P ~ /EP93/00699 X~ 362t.

concentrated to a final volume of ca. 50 ml. The product was then precipitated by dropwise addition of the solution to 1200 ml of hexane. The product was reprecipitated by dissolving in 15 ml of dichloromethane and dropwise addition of the solution into 500 ml of isopropyl ether. The reprecipitation was repeated and the product was dried in vacuo for 48 hrs. at room temperature to give a polyester having the monomer unit 21c.

~lnh (dl/g)= 0.10 in CHCl3 , Mws 10650 Da, Mn= 6650 Da, Mw/Mn= 1.60 .
Tg- 23.5C -IR tfilm): Strong absorption at 1753! 1263 and 1069 cm~1.

H-NMR ~CDCl3, 360 MHz): ~= 1.217 ppm tt, 3J- 7 Hz, 3 H, CH~); 3.60 (q, 3J= 7 Hz, 2 H, side chain CH2); 4.15-4.40 ~m, 6 H, 2 CH2 and 2 ~ffl; 5.87 (s, 1 H, side chain C~

13C-NMR ~CDCl3, 90 MHz): ~= lS4.43 ~O-C~O)-O); 115.93 (ortho ester CH); 75.05 (CH1; 68.22 (CH23; 66.93 (CH2); 60.77 (side chain CH2);
14.g6 (CH3).

Microanalysis: Calculated for C9H12O6: C 47.06 %, H 5.92 %
found: 46.70 %, 6.00 %

EXUNPL~ 28:

a) Synthesis of 2,3:4,5- and 2,4:3,5-di-O-Isopropylidene-D-mannitol 273.5 g ~1.37 mol) of 1,6-di-O-benzoyl-D-mannitol (Ref: E28]) and 2.-g of p-toluolsulfonic acid were suspended in 1650 g (16 mol) of 2,2-dimethoxy- propane and the mixture was heated to reflux for 1 hour. After cooling to room temperature, the solution was diluted wi~.

- 4~ -21;~2~;.

diethyl ether, washed twice with aequous 5% sulfuric acid and with saturated NaCl-solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield a crude product, being mainly a mixture 3 compounds on TLC.
The crude mixture was dissolved in 5000 ml of chloroform and a solution of 10 g (0.18 mol) sodium methylate in 1500 ml of methanol was added. The mixture was stirred for 20 hrs. at room temperature, then the solvent was evaporated under reduced pressure and the residue was washed several times with light petroleum. The crude product muxture was dissolved in a minimum amount of chloroform and su~jected to flash chromatography on silica gel. Elution with diethyl ether ~
containing 0.1% triethylamine gave 45 g of pure -2,4:3,5-di-O-isopropylidene-D-mannitol. Subseque~t elution with ethyl acetate and 0.1% triethylamine gave a m~xture of 2,4:3,5 - and 2,3:4,5-O-isopropylidene-D-mannitol, followed by pure 2,3:4,5-di-O-isopropylidene-D-.nannitol. The third, more polar component of the mixture, being presumably 3,4:0-isopropylidene-D-mannitol, was not isolated.
The products gave satisfactory spectroscopical data.

b) Polyester from 2,4:3,5-di-O-Isopropylidene-D-mannitol and diethyl carbonate, ha~ing the monomer unit 22b.

5.25 g (20 mmol) of 2,4:3,5-di-O-isopropylidene-D-mannitol was polycondensed with diethyl carbonate according to the procedure described in Example 3) to give the polyester.

~lnh (dl/g)- 0.19 in CHCl3 Mw= 16000 Da, Mn= 11700 Da, Mw/Mn= 1.37 Tg= 105.6C

~alpha3D- +14.3 (c=1 in CHCl3, 20C) IR (KBr~: Strong absorptions at 1756, 1384, 1266, 1219 and 1173 cm-:

W O 93/20126 P ~ /EP93/00699 212~362~ - 50 -lH-NMR 5CDCl3, 360 MHZ)~ .32 PPm (5, 6H, 2CH3); 1.39 ~s, 6H, 2CH3); 3.80-3.96 (m, 4H, 4CH); 4.22 (d.d, 2JA~= Ca. 11.5 HZ and J= 6.2 HZ, 2H3 of 2CH2); 4.28 (d.d, 2JAB= ca. 11.5 HZ and J= 2.7 HZ, 2HA of 2CH2 ) .

3C-NMR (CDCl3, 90 MHz): ~=155.02 ppm (O-C(O)-O); 101.14 ~O-C-O);
67.88 and 67.76 (CH); 67.54 (CH2); 27.55 and 23.64 (CH3).
.
Microanalysis: Calc. for Cl3H20O7 : C 54.19 %, H 6.94 %
found : 54.00 %, 7.10 ~ .

Polyester from 2,3:4,5-di-O-Isopropylidene-D-mannitol and Diethy?
carbonate, having the monomer unit 23b:

lO.Sg (40 mmol) of 2,3:4,5-di-O-Isopropylidene-d-mannitol ~see Example 28a) was polycondensed with diethyl carbonate according to the procedure described in ex~mple 3) to give the polyester.

~lnh. (dllg): 0.185 in CHCl3 Mw = 20500 Da, Mn = 17700 Da, Mw/Mn = 1.16 Tg = 80.8C

IR ~KBr): Strong absorptions at 1758, 1267, 1091 and 972 cm-1.

1H-NMR (CDCl3, 360 MHz): ~ = 1.35 ppm (s, 6H, 2CH3); 1.495 (, 6H, 2CH3); 4.22 - 4.37 (m, 6H); 4.38 - 4.47 (m, 2H).

13C-NMR ~CDCl3, 90 MHz): ~ = 154.53 ppm (O-C(O)-O); 109.59 (acetal C);
74.67 (CH); 74.10 (CH); 67.07 (CH2); 27.18 ~CH3); 25.38 (CH3).

- 51 - 2~2862~.

Microanalysis: Calculated for Cl3H20O7: C 54.19%, H 6.94%
found: 53.50% 6.90%

~XA~PLe 30:
:
Synthesis of the polyester having the monom~r unit 24b 5.0 g (17.3 mmol~ of the polyester having the monomer unit 22b (different batch with Mw-- 6650 Da and Mn= 5270 Da) were hydrolysed with 46 ml of trifluoroacetic acid and 7 ml of water in 46 ml dichloromethane, according to the procedure described in Example 4, to give the polyester.

(dl/g)= 0.07 in H20 Tg= 47.2 and 58.9C (from the 1. run) IR (KBr): Strong absorptions at 3408, 1741, 1282 and 1074 cm~1. :
.
H-NNR (d6-DMSO, 360 MHz): ~- 3.59 ppm (d, J= 9 Hz, 2 H, 2 CH); 3.68 ~m, 2 H, 2 CH); 4.07 (m, 2H, 2 H~ of 2 CH2); 4.33 (d, J= 10.5 Hz, 2 H, 2 ~A of 2 CH2); 2.8-4.8 (broad m, 4 H, 4 OH).

~ C-NMR (d6-DMSO, 90 MHz3: ~- 155.16 ppm ~O-C(O)-O); 70.36 (CH2);
68.72 (CH); 68.10 (CH).

Microanalysis: Calculated for C~H12O7: C 40.39 %, H 5.81 %
found: 39.60 %, 6.00 %

~X~MPL~ 31:

Synthesis of the polyester having the monomer unit 25b 1.04 g t5 mmol) of the polyester of Example 30 (having the monomer W O 93/20126 P ~ /EP93/00699 ,~ - 52 -2i2~fi;~1 unit 24b) were acetylated according to the procedure described in Example 7, to give the polyester having the monomer unit 25b. :~
', lnh= . 075 in CHCl~

Mw= 6200 Da, Mn= 5050 Da, Mw/Mn= 1.23 Tg= 54.7C (from the 1. run) IR ~KBr): Strong abso~ptions at 1753, 1373, 1268 and 121B cm~1.

lH-NMR ~CDCl3, 360 MHz): ~= 2.05 ppm (s, 6 H, 2 CH3); 2.09 (s, 6 H, 2 CH3); 4.11 (dd, 2JAB= 12 Hz and J= 5.5 HZ, 2 H, 2 HB of 2 CH2); 4.24 ~`
(dd, 2JAB- 12 Hz and J= 3 ~z, 2 H, 2 HA of 2 CH2); 5.08 ~m, 2 ~, 2 CH); 5.41 (d, J= 8 Hz, 2 H, 2 CH~.

~C-NMR ~CDCl3, 90 MHz): ~= 169.72 ppm ~-C(O)-O); 169.60 (-C(O)-O);
154.29 ~O-C(O)-O); 67.54 (CH~; 65.80 (CH2~; 20.76 ~CH3); 20.S3 (CH3).
icroanalysis: Calculated for C1sH20oll: C 47.88 %, H 5.36 %
found: C 47.50 %, H 5.50 %
XA~PL~ 32:

Synthesis of the endgroup-stearoylated polyester 26b 2.88g ~10 mmol) of the polyester having monomer unit 22b (Mw = 6650 Da, Mn = 5270 Da) were dissolved in 53 ml of tetrahyrofuran and treated subsequently with 0.95g (12 mmol) pyridine and 1.51g ~5 n~ol) stearoyl chloride at room temperature. The reaction mlxture was stirred for 20 hours at room temperature, filtered and the product was precipitated by dropwise addition of the filtrate into 500 ml of n-Butanol. The product was reprecipitated twice from tetrahydrofuran- -/n-Butanol and dried in vacuo for 48 hours to yield the endgroup-stearoylated polyester 26b.
The lH-NMR-spectrum of compound 26b clearly showed the presence of a ~1;286~

stearate ester function ~triplett at 2.33 ppm, J = 7.5 Hz, multiplett ~;
at 1.59 ppm, singulett at 1.25 ppm and triplett at 0.88 ppm, J = 7 Hz) in addition to the monomer unit 22b (showing all characteristic signals of the polyester having the monomer unit 22b). No free stearic acid was detectable in the product).

EXANPIE 33:

Synthesis of the endgroup-stearoylated polyester 27b 0.85g of endgroup-stearoylated polyester 26b was dissolved in 7 ml of dichloromethane and treated subsequently with 7 ml of trifluoroacetic acid and 2.3 ml of water. The solution was stirred for 15 minutes at -room temp~rature and poored slowly into 350 ml of ethyl acetate to -~
precipitate the product. The precipitate was washed well with ethyl acetate and with water and dried in vacuo for 48 hours to obtain ~he amphiphilic polyester 27b According to lH-NMR, the product comprised ca. lÇ monomer units 24b per stearate ester endgroup.

This ratio was calculated from the integrals of the signals at 2.28 ppm tt, 2H of the stearate residue) and at 4.34 ppm ld, 2~ of the mono~er unit 24b). The IR-spectrum (KBr) of 27b showed strong absorptions at 3391, 1740, 1283 and 1076 am~1.

~XAHPL~ 34:
, Polyester from 2-Benzyloxy-1,3-butandiol and Diethyl carbonate, havi~.g the monomer unit 28 1.822g (10 mmol) of 2-benzyloxy-1,3-propandiol were suspended in 7.3Qg (62.5 mmol) of diethyl carbonate and 37 mg of di-n-butyl-tinoxide were added while under argon. The mixture was stirred 24 hours at 120C a~.~
atmospheric pressure, and 24 hours at 130C/400mbar, during which ~
distillation occurs. The distillate was removed while under argon a.~
the mixture was stirred for additional 24 hours at 130C/5mbar. The P ~ /EP93/006g9 X12862~.
resulting viscous slurry was dissolved in S0 ml of dichloromethane and after removal of the insoluble part by filtration, the solution was evaporated to a final volume of 10 ml. The product was precipitated by dropwise addition of this solution into 200 ml of methanol. The precipitate was further purified by dissolving it in acetone, treatment of this solution with hydrogen peroxide and florisil (magnesium silicate), and working up as described in example 1~.
Finally, the product was reprecipitated from dichloromethane/methanol to give the polyester having the monomer unit 28, in which the secondary hydkoxyl groups are protected as benzyl ethers.

~lnh . ~dl/g) ~ 0.11 in CHCl3 Mw - 91S0 Da, Mn z 6100 Da, Mw/Mn l.S0 ~g = 20-C

IR ~film): Strong absorptions at l?Sl, 1554 and 1239 cm-l.
lH-NMR ~d6-DMSO, 360 MHz): ~ - 3.88 ppm ~m, lH, CH); 4.165 ~d.d, 2J
= 11.5 Hz and 3J = 5.5 Hz, 2H, 2HB of 2 CH2); 4.2~5 ~d.d, 2J = ll.S Hz and 3J = 4 Hz, 2H, 2HA Of 2 CH2); 4.565 (s, 2H, benzyl CH2); 7.13 -7.33 ~m, SH, arom. CH).

l3C-NMR (d6-DMSO, 90 MHz): ~ = lS4.14 ppm (O-C(O)-O): 137.87 (arom.
C), 128.0 and 127.32 (arom. CH); 73.92 ~CH); 70.87 ~benzyl CH2); 6O.'4 (chain CH2).

Microanalysis: Calculated for C1lHl2O4: C 63.45% H 5.81%
found: 63.20% 5.80%

The protecting groups are removed by catalytic hydrogeneration on palladium - charcoal to give a polyester with free hydroxyl substituents.

35:

_ 55 _ 2~2~36Z

Co-polyester from 2,3-O-Isopropylidene-L-threitol and 1,4-Butan-diol, having the monomer units la and 29 9.73g (60 mmol) of 2,3-O-Isopropylidene-L-threitol and 5.41g (60 mmol) of 1,4-Butandiol were added to 45.5 ml of diethyl carbonate. 0.3g of di-n-butyl-tin-oxide were added to the mixture. The mixture was stirred for 24 hours at 120C/atmospheric pressure and for another 24 hours at 140C/400mbar, during which time distillation occured. The distillate was then removed and stirring was continued for 24 hours at 140CIlOO~ar and 96 hours at 140C/lmbar. The mixture was then allowed to cool to room temperature and the pressure was set to atmospheric pressure. The c~ude product was dissolved in 50 ml of dichloromethane, the solution was treated with HyfloCel and filtered.
The filtr~te was evaporated to a fitlal volume of ca. 20 ml and the product was precipitated by dropwise addition of this solution into 500 ml of methanol. The precipitate was further purified by dissolving it in acetone, stirring of the solution with hydrogen peroxide and florisil, and filtration. The solvent was evaporated. The residue was dissolved in dichloromethane and the produet was precipitated from methanol. The product, dried in vacuo for 48 hours, gave the co-polyester.
According to lH-N~, the co-polyester co~rised ca. 52.8% of monomer units 29 and 47.2% of ~onomer units la.

This ratio was calculated from the integral ratios of the sigslals at 1.425 ppm (6H of the monomer UIlit la) and at 1.775 ppm ~4H of the monomer unit 29). The remainder protons of both monomer units gave several multipletts between 4.05 and 4.40 ppm (6H of the monomer unit la and 4H of the monomer unit 293.

lll"h, (dl/g): 0.325 in CHCl3 Mw = 33600 Da, Mn = 18700 Da, Mw/Nn = 1.80 Tg = 25.7C

Z12~36Zl. - 56 -IR (filmJ: Strong absorptions at 1747 and 125B cm~l.

Microanalysis:
Calculated for ~CsH803)l.l2 ~C3H1205)1.0: C 51.33% H 6.64%
found: 51.00% 6.50%

EXANPLE 36:

a) Degradation of polymers in vitro using sterile conditions PolymQtr samples of compounds having the monom~tr units 4c, 9c and 11 c Itimplants of 5 mm diameter and 25 mg of weight) were special dried, weighted, and transfered to glass bottles containing 4Q ml phosphate buffered saline sterile buffer (SP8S p~ 7.4; ionic strength 0.17) to be shaken at 120 rpm and 37C for different times.
At weekly intervals the buffer was replaced by sterile P8S.
After selected time points the remaining implant mass was again dried and ~eighted to determine the mass loss. If possible, the molecular mass of the remaining implant m2ss was measured using GPC and polystyrene as standard.

The degradation results are shown in Figures 1, 2 and 3.

b) Degradation of polymers in rats usin~ sterile conditions To test biodegradatiQn of polymers male ~istar rats (body weight about 250 g) were used having free access to food and drinking water before and during the exper~ment. The rats were anaesthesized by inhalation of Isofluran ~Forene~). Polymer samples of the polyesters having the monom~r units 4c and llc respectively we~e Lmplanted in subcutaneous skin pouches undtr laminar flow conditions right or left to the bac~bone for different times. After specified time points the remaining Implant mass was explanted, freed of adhering tissue, dried and weighted to determine mass loss. If possible, molecular mass was determined W O 93/20126 PC~/EP93/0069g - 57 ~ 3,6 by GPC using polystyrene as standard.

The degradation results are shown in Figures 2 and 3.

Results:
The degradation kinetics of polyesters in vitro and in vivo are of a comparable level (Fig. 2 and 3). The time point for complete mass degradation can be varied between 24 hours and about 9D days (Fig. l and 2) depending on the chosen structural polyester type.

In some cases the loss of molecular weight is faster than the loss of polyester mass ~Figure 3) which means that first the polyester chains will be cleaved to a certain degree throughout the whole implant, and thereafter water soluble molecule fragments will be removed.

However, ~here are also examples of derivati~es in which the speeds of the molecule degradation and the removal of water soluble molecule fra~ments are more equal (Fig. l). In these cases, presumably, at each step of hydrolytic degradation a water soluble fragment is generated, reducing the Implant mass and the molecular weight of the remaining polyester.

EXAMPLE 37:

Drug compound release from an implant containing the polymer having the monomer units 4c.

For the release octreo~ide was taken as a drug compound.

Preparation of the implant:
1 g of the polyester was dissolved in 3 ml of methyl acetate. 81.8 mg of Octreotide-pamoate powder (= 52.19 mg Octreotide base) was homogeneously suspended in the solution and the solvent was evaporated under reduced pressure.
The residue was milled in a SPEX-mill at the temperature of liquid ~12862~
nitrogen to give a fine powder which was then compressed at 59C
and 7 bar during 15 min. to implants of 5 mm diameter and ca. 25 mg of weight.

In vitro degradation of dNg loaded polymer implants was measured using the same conditions as described in Example 36a for the unloaded polymer.
Release of octreotide was detected from the buffer solution using ~PLC techniques.

Results: .
The drug compound release correlated with the polymer mass loss in a satisfactory manner, although a very simple technique was used to prepare the implants.

The retardation of the polymer mass loss may be attributed to the presence of the drug compound, since the degradation of the unloaded polymer is faster ~see Fig. 4 and 2).

21;~62~. ~

N/~H /~

>3<CH3 C~3 CN3 2, 3-O-Isopropy~ d~ L-tbseitol 1~
lb (D) S ,S )-Conf igur~tion lc ( DL) C~3 o 2~ (L) ~/
2b (D) 2c ( DL) }~3C

3a (L) O 3b (D) 3c ~DL) 0~
4c: Rl R2 C ( Sa Rl8 _~ (~o) (C~2)4 3 R2 ~1 or ~
6a: Rl' -(C'O)-(C~2)16 3 ~2~ ~1 or 7c: R1--R2-- -C( L~)~2~2 8c: Rl--RZ~ )~2--SUBST~TUTE StlEET

Z1286Zl ~ J~
o~o /\
Rs gc: Rl'R2' -~:( O )~ O )~3 lOc: Rl-R2-- --C( o)~ p~ 20c~ R2' ~2C~s3 L~c: Rl~R2-- --c~)-c(-ol~2~1C~3)2 ~lc: R~ ~d R2 ~2C~3 12CS Rl-R2--' -C( ¢1 )-C( O ) ~2C~3 - 13cs R~--R2 ~C(~)~2C~3 l~CS R~ 0)~2c83 R2 Rl or ~
15c: ~ styl R2 ~ 11 ~ oryc ~bonylpll~yl9 ~7c~ P~
~2' Rl or ~
1 8c: Rl--R2 ~C ~ ~ 3 ~ t ~{2~ ) 3 19~ 2c~ 3)~ o)~

SUBSTITUTE SHEET

`~'O 93/20126 PCr/EP93/00699 FORMULA PAGE 3 - 61 - 2~;28621.

~H~

0~ ~3~5~H, H 0~0 / \ H--O O--H
c~, C~

2, ~: 3 ,, 5-di~Isopropyl~den~- 2, 3: 4, 5-di~Isoprc~pylidone-D-~nn~tol D-~nsaitol J'~ 4 0~0 O
~ -- ' 22b 23b ~, C~, O Q~ O 0~00~0 J~0~ 0 0}~ 0~ Oq~O 0~0 ~ ~, 24b 25b SUE~8TITUTE SHE~T

WO 93/20126 PCI/EPg3/006g9 :12~621.
_ ~ _ . J~ ~ ( CH2 ) 16 CH3 C~, C~ n 26b ~~(CH2316-C~3 0~-- 0~ 0 n 27b J~o~o- `' O
J~o~9`

SUBSTITUT~ SHEET

Claims

CLAIMS:

1. A biodegradable and biocompatible polyester comprising (C3-10) alkylene carbonic acid ester units, each alkylene group being a C3-alkylene group having 1 oxy substituent or a (C4-10) alkylene group having 2-8 oxy substituents, each of the oxy substituents occurring independently as a hydroxyl group or independently as a moiety comprising an ester or an ortho ester or an acetal moiety.

2. A polyester according to claim 1, in which all the carbon atoms belonging to the (C2-8) alkylene central part of the (C4-10)alkylene group are oxysubstituted.

3. A polyester according to claim 1, comprising the alkylene carbonic acid ester units in a randomized copolyester, in a block co-polyester or in homopolyester arrangement.

4. A polyester according to claim 3, in homopolycarbonate arrangement.

5. A polyester according to claim 1 in which the oxy substituent comprises carboxylic acid ester residues.

6. A polyester according to claim 5, in which the carboxylic acid ester residues comprise such of an oxo carboxylic acid.

7. A polyester according to claim 5, in which the carboxylic acid ester residues comprise such of a dicarboxylic acid derivative.

8. A polyester according to claim 1 in which the oxy substituent groups comprise carbonic acid ester residues.

9. A polyester according to claim 8 in which the carbonic acid ester residues comprise such of a hydroxy carboxylic acid derivative.

10. A polyester according to claim 8, in which two oxy substituent comprise a cyclic carbonate residue.

11. A polyester according to claim 1, in which the oxy substituent comprise such of an acetal or a hemi-acetal residue.

12. A polyester according to claim 1, 5 or 8 in which the oxy substituent comprise such of an ortho carboxylic acid ester or an ortho carbonic acid ester residue.

13. A polyester according to claim 5 in which the carboxylic acid ester residues comprise those of formic acid and/or a saturated or unsaturated (C2-20) fatty acid.

14. A polyester according to claim 8, in which the ester residues comprise those of a steroid alcohol.

15. A polyester according to claim 14 in which the ester residues comprise those of cholesterol.

16. A polyester according to claim 8 in which the ester residues comprise those of a (C1-20) alkanol.

17. A polyester according to claim 1 with a number of 5 to 1000 alkylene carbonic acid ester units.

18. A polyester according to claim 5, in which the carboxylic acid ester residues comprise such of a hydroxy carboxylic acid or its derivative.

19. A polyester according to claim 18 in which the carboxylic acid ester residues comprise those of lactoyl or glycoyl.

20. A polyester according to claim 5, in which the carboxylic acid ester residues comprise polylactoyl, polylactoyl-co-glycoyl or polyglycoyl, the chain lengths being such that the polyester does not to form a hydrogel in an aqueous medium.

21. A polyester according to claim 8, in which the carbonic acid ester residues comprise a carbamic acid ester derivative.

22. A polyester according to claim 5, 8 or 21 in which the ester groups comprise those of amino acid or peptide residues.

23. A polyester according to any one of claims 1 to 22, in which at least one of the terminal groups is a lipophilic residue.

24. A polyester according to claim 23 in which the lipophilic residue is a stearoyl group.

25. A pharmaceutical composition comprising a polyester according to any one of claims 1-25 mixed with a drug compound.

26. A pharmaceutical composition according to claim 25 comprising the polyester as a solid matrix for the drug compound.

27. A pharmaceutical composition according to claim 25 in microparticle or implant form.