WO2003028739A2

WO2003028739A2 - Composition for preventing or treating hyperlipidemia or hyperglycemia comprising a polymer or its salt

Info

Publication number: WO2003028739A2
Application number: PCT/JP2002/009181
Authority: WO
Inventors: Osamu Nakayama; Yuko Muramatsu; Yoshimitsu Nakajima; Akira Yamada; Hideo Sawada
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 2001-09-13
Filing date: 2002-09-09
Publication date: 2003-04-10
Also published as: WO2003028739A3; AR036512A1; AU2002326170A1

Abstract

A composition for preventing or treating hyperlipidemia (e.g., hypercholesterolemia, hypertriglyceridemia) or hyperglycemia comprising a polymer or its salt which is obtainable by polymerization of a monomer of the formula (I) or its salt in the presence of a radical initiator, or by polymerization of a monomer of the formula (I) or its salt with a monomer of the formula (II) or its salt in a molar ratio of (I) : (II) being 1:0.1 to 1:25 in the presence of a radical initiator wherein R1, R2, R3, R4 are as defined in the description as an active ingredient, in association with a pharmaceutically acceptable, non-toxic carrier or excipient.

Description

DESCRIPTION

COMPOSITION FOR PREVENTING OR TREATING HYPERLIPIDEMIA

OR HYPERGLYCEMIA

TECHNICAL FIELD

This invention relates to a composition for preventing or treating hyperlipidemia (e.g., hypercholesterolemia, hypertriglyceridemia) or hyperglycemia comprising a polymer or its salt and to their use as a medicament.

BACKGROUND ART

The correlation between hyperlipidemia and crisis of angina pectoris, myocardial infarction, etc. is observed. Therefore, it is necessary to treat hyperlipidemia for preventing or treating angina pectoris, myocardial infarction, arteriosclerosis, cerebral embolism and the like.

It is known that polymers having fluoroalkyl groups as their end groups are disclosed in Japanese Unexamined Patent Publication Hei 10(1998)-251349 and International Patent Publication

WO02/ 32974 and that other polymers such as anion exchange resins are used for treating hypercholesterolemia (for example, US Patent No.

3,499,960, US Patent No. 3,789,171, British Patent No. 929,391 and

Japanese Unexamined Patent Publications Sho 53(1978)- 10386 and Sho 60 (1985)-209523). Among them, cholestyramine is an ammonium salt-type anion exchange resin and known to accelerate catabolism of cholesterol to bile acid by binding bile acid in an intestine.

However, such polymers having weak activity for treating hypercholesterolemia are administered in a large amount, so that it is difficult to dose.

Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.

It is known that sulfonamides such as glibenclamide, glybuzone, gliclazide and the like are used to treat diabetes. However, any polymer is not known to show the potency for lowering levels of plasma glucose .

DISCLOSURE OF INVENTION

Accordingly, an object of this invention is to provide a novel composition for preventing or treating hyperlipidemia (e.g., hypercholesterolemia, hypertriglyceridemia) or hyperglycemia comprising a polymer or its salt as an active ingredient.

Further object of this invention is to provide a use of the composition for treating or preventing angina pectoris, myocardial infarction, arteriosclerosis, cerebral embolism, diabetes, obesity and so on.

The composition of the invention comprises a polymer or its salt obtainable by polymerization of a monomer of the formula (I) or its salt in the presence of a radical initiator, or by polymerization of a monomer of the formula (I) or its salt with a monomer of the formula (II) or its salt in a molar ratio of (I) : (II) being 1:0.1 to 1:25 in the presence of a radical initiator H₂C=C (I) H₂C=C (II)

R² R⁴ wherein

R¹ and R³ are each hydrogen atom or a lower alkyl group, R² and R⁴ are each an acyl group, an aliphatic silyl group, an amino (lower) alkyl group which may have one or more suitable substituent(s), a heterocyclic group which may have one or more suitable substituent(s) or a carboxy group which may be esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl.

In the above and subsequent descriptions of the present specification and claims, suitable examples and illustrations of the various definitions which the present invention includes within the scope are explained in detail in the following.

The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise indicated.

The term "one or more suitable substituent(s)" intended to mean 1 to 6 suitable substituent(s), preferably 1 to 3 suitable substituent(s), and more preferably 1 or 2 suitable substituent(s).

Preferred examples of "lower alkyl" moiety include straight or branched ones having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-butyl, pentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl or the like.

Preferred examples of the lower alkyl group for R¹ and R³ are referred to aforementioned "lower alkyl", in which the more preferred ones are methyl, ethyl, propyl, n-butyl, t-butyl, pentyl and n-hexyl.

Preferred examples of "acyl group" include aliphatic acyl, aromatic acyl, aiylaliphatic acyl and heterocyclic-aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid and sulfonic acid. More preferred examples of the "acyl group" are illustrated as follows: carboxy; carbamoyl; mono or di(lower)alkylcarbamoyl (e.g., methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, n-butylcarbamoyl or

1 , 1 -dimethylcarbamoyl) ; aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,

2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl or icosanoyl); lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl); lower alkenyloxycarbonyl (e.g., vinyloxycarbonyl, propenyloxycarbonyl, allyloxycarbonyl, butenyloxycarbonyl, butedienyloxycarbonyl, pentenyloxycarbonyl or hexenyloxycarbonyl); lower or higher alkylsulfonyl (e.g., methylsulfonyl or ethylsulfonyl); lower or higher alkoxysulfonyl (e.g., methoxysulfonyl or ethoxysulfonyl) ; aromatic acyl such as aroyl (e.g., benzoyl, toluoly or naphthoyl); ar(lower)alkanoyl [e.g., phenylfCi-CβJalkanoyl (e.g., phenylacethyl, phenylpropanoyl, phenylbutanoyl, phenyUsobutanoyl, phenylpentanoyl or phenylhexanoyl), or naphthyl(Cι-C6)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl or naphthylbutanoyl)]; ar(lower)alkenoyl [e.g., phenyl(C3-C6)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentanoyl or phenylhexenoyl), or naphthyl(C3-C6)alkenoyl (e.g., naphthylpropenoyl or naphthylbutenoyl)]; ar(lower) alkoxycarbonyl [e.g., phenyl(Cι-C6) alkoxycarbonyl (e.g., benzyloxycarbonyl), or fluorenyl(Cι-C₆)alkoxycarbonyl (e.g., fluorenylmethyloxycarbonyl)]; aryloxycarbonyl (e.g., phenoxycarbonyl or naphthyloxycarbonyl); aryloxy (lower) alkanoyl (e.g., phenoxyacetyl or phenoxypropionyl); arylcarbamoyl (e.g., phenylcarbamoyl); arylthiocarbamoyl (e.g., phenylthiocarbamoyl); arylglyoxyloxy (e.g., phenylglyoxyloyl or naphthylglyoxyloyl); arylsulfonyl which may have 1 to 4 lower alkyl (e.g., phenylsulfonyl or p-tolylsulfonyl) ; aroyl (e.g., benzoyl) substituted with one or more suitable substituent(s); heterocyclic aryl such as heterocycliccarbonyl; heterocyclicoxycarbonyl; heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl or heterocyclichexanoyl) ; heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl or heterocyclichexenoyl); heterocycucglyoxyloyl; and the like, in which suitable "heterocyclic" moieties in the terms

"heterocycliccarbonyl" , "heterocyclicoxycarbonyl" , "heterocyclic(lower) alkanoyl", "heterocyclic(lower)alkenoyl" and

"heterocycucglyoxyloyl" can be referred to aforementioned "heterocyclic" moieties.

Preferred examples of the acyl group for R² and R⁴ can be referred to aforementioned "acyl group", in which the more preferred ones are lower alkylcarbamoyl group such as methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, n-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl and

1 , 1-dimethylethylcarbamoyl; arylcarbamoyl group such as phenylcarbamoyl and naphthylcarbamoyl; lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, n-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl; aforementioned heterocyclicoxycarbonyl group, in which the preferred ones are quinolinyloxycarbonyl, pyridyloxycarbonyl and furyloxycarbonyl; and aforementioned heterocycliccarbonyl group, in which the preferred ones are morpholinylcarbonyl, pyridylcarbonyl, furoyl, thenoyl and imidazoylcarbonyl.

Preferred examples of the aliphatic silyl group for R² and R⁴ are trimethylsilyl and triethylsilyl.

Preferred examples of the amino (lower) alkyl group for R² and R⁴ are aminomethyl, aminoethyl, aminopropyl, amino-n-butyl, aminopentyl and aminohexyl.

Preferred examples of "heterocyclic group" or "heterocyclic" moiety include : unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, 1H- 1,2, 3 -triazolyl or 2H-l,2,3-triazolyl), and tetrazolyl (e.g., lH-tetrazolyl or 2H-tetrazolyl); saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl and azetidinyl; unsaturated condensed heterocyclic groups containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isozuinolyl, indazolyl and benzotriazolyl; unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl and oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl); saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl and morpholino; unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl and benzoxadiazolyl; unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or

1,2,5-thiadiazolyl) and dihydrothiazinyl; saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example thiazolidinyl, thiomorpholinyl and thiomorpholino ; unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 or 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl and dihydrodithionyl; unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl and imidazothiadiazolyl; unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing an oxygen atom, for example furyl; saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 or 2 oxygen atom(s), for example, tetrahydrofuran, tetrahydropyran, dioxacyclopentane and dioxacyclohexane ; unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing an oxygen atom and 1 or 2 sulfur atom(s), for example, dihydrooxathiinyl; unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atom(s), for example, benzothienyl and benzodithiinyl; unsaturated condensed heterocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, benzoxathiinyl; and the like, and this "heterocyclic group" may have one or more suitable substituent(s) selected from the group consisting of sulfo, lower alkyl, oxo, halogen and hydroxy.

Preferred examples for the heterocyclic group for R² and R⁴ can be referred to aforementioned "heterocyclic group", in which the more preferred ones are pyridyl, thienyl, furyl, pyrolyl, thiazolyl, oxazolyl, isoxazolyl and quinolyl.

Preferred examples of "halogen" are fluorine, chlorine, bromine, iodine and the like. Preferred examples of "lower alkoxy" moiety include straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neo-pentyloxy, hexyloxy, isohexyloxy or the like.

Preferred examples of "aryl" and "ar" moiety include phenyl which may have lower alkyl (e.g., phenyl, mesityl, xylyl or tolyl), naphthyl, anthryl, indanyl, fluorenyl or the like, and this "aryl" and "ar" moiety may have one or more halogen.

Preferred examples of "aroyl" include benzoyl, toluoyl, naphthoyl, anthrylcarbonyl and the like.

The above lower alkylcarbamoyl group, arylcarbamoyl group, lower alkoxycarbonyl group, heterocyclicoxycarbonyl group, heterocycliccarbonyl group, amino (lower) alkyl group and heterocyclic group may have one or more substituent(s) selected from the group consisting of sulfo; hydroxy; carboxy; amino; sulfo(lower)alkyl-di(lower)alkylamino such as sulfopropyl-dimethylamino, sulfomethyl-dimethylamino and sulfoethyl-dimethylamino; carboxy (lower) alkylamino such as carboxymethyl-dimethylamino; dihydroxyboraneyl; tri(lower alkyl) ammonium such as trimethylainmonium; glycosyloxy; heterocyclic carbonylamino such as (2-oxo- 1 ,2-dihydro-4-pyrimidinyl)carbonylamino, (2,4-dioxo-3,4-dihydro- 1 (2H)-pyrimidinyl) carbonylamino and (5-fluoro-2,4-dioxo-3,4-dihydro-l(2H)-pyrimidinyl)carbonylamino; heterocyckc(lower)alkylaminocarbonylamino such as

2-(lH-imida-zol-5-yl)ethylaminocarbonylarnino; -(lower alkoxy) β-lower alkoxy such as -(OCH₂CH₂)8-OCH3 ;and halogen such as chlorine and bromine.

The preferred composition of the invention comprises a polymer or its salt obtainable by polymerization of a monomer of the formula (I) or its salt in the presence of a radical initiator, or by polymerization of a monomer of the formula (I) or its salt with a monomer of the formula (II) or its salt in a molar ratio of (I) : (II) being 1:0.1 to 1:25, preferably 1:0.5 to 1:20 in the presence of a radical initiator

R¹ R³

H₂C=C (I) H₂C=C (II)

R² R⁴ wherein

R¹ and R³ are each as defined in the above, and R² and R⁴ are each a lower alkyl carbamoyl group, an aryl carbamoyl group, a lower alkoxycarbonyl group, a heterocyclicoxycarbonyl group or a heterocyclccarbonyl group, each of which may have one or more suitable substituent(s); a tri(lower)alkylsilyl group; an amino (lower) alkyl group which may have one or more suitable substituent(s); a heterocyclic group which may have one or more suitable substituent(s); or a carboxy group which may be esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/or lower alkenoyl.

The more preferred composition of the invention comprises a polymer or its salt obtainable by polymerization of a monomer of the formula (I) or its salt in the presence of a radical initiator, or by polymerization of a monomer of the formula (I) or its salt with a monomer of the formula (II) or its salt in a molar ratio of (I) : (II) being

1:0.1 to 1:25, preferably 1:0.5 to 1:20 in the presence of a radical initiator

R¹ R^J

H,C=C (I) H₂C=C (II)

R² R wherein

R¹ and R³ are each as defined in the above, and R² and R⁴ are each a lower alkyl carbamoyl group which may have one or more substituent(s) selected from the group consisting of sulfo, hydroxy, carboxy, amino, sulfo (lower) alkylamino and carboxy(lower)alkylamino, or a lower alkoxycarbonyl group which may have one or more substituent(s) selected from the group consisting of hydroxy, amino, lower alkylamino, glycosyloxy, heterocyclic carbonylamino, heterocyclic(lower) alkylaπήnocarbonylamino and tri(lower)alkylammonium; a tri(lower)alkylsilyl group; an amino (lower) alkyl group which may have one or more suitable substituent(s); a heterocyclic group which may have one or more suitable substituent(s); or a carboxy group which may be esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl.

Suitable salts of the polymers, monomers of the formula (I), the formula (la) and the formula (II) are conventional non-toxic salts such as salt with an alkali metal [e.g., lithium, sodium or potassium] and an alkaline earth metal [e.g., calcium or magnesium], ammonia, an organic base [e.g., trimethylamine, triethylamine, pyridine, picoline, dicyclohexylarnine or N,N'-dibenzylethylenediamine], an organic acid [e.g., formic acid, acetic acid, trifluoroacetic acid, maleic acid, tartaric acid, oxalic acid, methane sulfonic acid, benzenesulfonic acid or toluenesulfonic acid], an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid], an amino acid [e.g., arginine, aspartic acid or glutamic acid] or the like.

The preferred monomers of the formula (I) and the formula (II) are 2-glucosylethyl methacrylate (GEMA),

N-tris(hydroxymethyl)methylacrylamide (NAT), methylcellulose acrylate (MCA) represented by the formula :

wherein R⁶ is hydrogen, methyl or vinylcarbonyl and x is an integer of 1 or more, 2-aminoethyl methacrylate hydrochloride (AEM-HC1), εillylamine hydrochloride (AL-Am-HCl), dimethylacrylamide (DM AA), acrylic acid (AA), (acryloylamino) (hydroxy) acetic acid (AHA), 4-acryloylmorpholine (AM), 2- (acryloylamino) -2-methyl- 1 -propanesulfonic acid (AMP) ,

3-(acryloylamino)phenylboronic acid (APB), [ [3 - (acryloylamino) propyl] (dimethyl) ammonio] acetate (APD AA) , 3-[[3-(acιyloylaιnino)propyl](dim.ethyl)ammonio]-l-propanesulfonate (APDAP), calcium diacrylate (CD A), 5-chloro-8-quinolinyl acrylate (CQA), 2-{[(2,4-dioxo-3,4-dihydro- 1 (2H)-pyrimidinyl)carbonyl]amino}ethyl

2-methylacrylate (DCAEM),

2-{[(5-fluoro-2,4-dioxo-3,4-dihydro-l(2H)-pyriπιidinyl)carbonyl]amino}- ethyl 2-methylaceylate (FCAEM), N-(hydroxymethyl)acrylamide (HA), 2-{[(8-hydroxy-5-quinolinyl)carbonyl]amino}-ethyl 2-methylacrylate (HCAEM),

2 -hydroxy-3 - (methacryloyloxy) -N , N , N-trimethyl- 1 -propanaminium chloride (HMTP-HC1),

2- [ ({[2 - ( 1 H-imidazol- 5-yl) ethyl] amino}carbonyl) amino] ethyl 2-methylacrylate (IMA), lithium acrylate (LA), 2-methylacrylic acid (MAA), methyl 2-methylacrylate (MMA), 3,6,9,12,

15, 18,21,24,27-nonaoxaoctacos-l-yl 2-methylacrylate (NM), 2-{[(2-oxo- 1 ,2-dihydro-4-pyrimidinyl)carbonyl]amino}ethyl 2-methylacrylate (OCAEM), trimethyl (vinyl) silane (TVS) and 2-(2 -vinyl- 1 -pyridiniumyljethanesulfonate (VPES) .

The preferred radical initiators used for preparing the polymer are the ones having azo group in the molecule and the peroxides which may have perfluoroalkanoyl groups.

The peroxides having perfluoroalkanoyl groups are represented by the formula (III):

(R⁵COO)₂ (III) wherein R⁵ is a perfluoro(lower)alkyl group which may have one or more suitable substituent(s) or a cycloalkyl group substituted with one or more of fluorine atom(s), for example, CF₃, F(CF )2, F(CF₂)3, F(CF₂)₄,

F(CF₂)₅, F(CF₂)₆₎ F(CF₂)₇, F(CH₂)₈, .F(CH₂)₉, F(CH₂)to, HCF₂, H(CF₂)₂₎ H(CF₂)₃, H(CF₂)₄, H(CF₂)₅, H(CF₂)₆, H(CF₂)₇, H(CF₂)₈, H(CF₂)₉, H(CF₂)₁₀, C1CF₂, C1(CF₂)₂, C1(CF₂) , C1(CF₂)₄, Cl(CF₂)s, C1(CF₂)₆, C1(CF₂)₇, C1(CF₂)₈, C1(CF₂)₉, C1(CF₂)₁₀, CF(CF3)OC₃F₇₎ CF(CF3)(OCF₂CF(CF3))₁-OC₃F₇, CF(CF₃)(OCF2CF(CF3))2-OC₃F7, CF(CF₃)(OCF2CF(CF3))3-OC₃F7,

CF(CF₃)(OCF2CF(CF3))₄-OC3F_7> CF(CF3)(OCF(CF3)2CF)5-OC₃F₇, CF(CF₃)(OCF2CF(CF₃))6-OC₃F₇, CF(CF₃)(OCF2CF(CF3))7-OC₃F7 or CF(CF3)(OCF2CF(CF₃))8-OC₃F₇.

The preferred radical initiators of the formula (III) are 2,3,3,3-tetrafluoro-2-(l, l,2,2,3,3,3-heptafluoropropoxy)propanoyl peroxide (PFPO-2),

2,3,3,3-tetrafluoro-2-[ l, l,2,3,3,3-hexafluoro-2-(l, l,2,2,3,3,3-hepta- fluoropropoxy)propoxy]propanoyl peroxide (PFPO-3), trifluoroacetyl peroxide (FAP), 2,2,3,3,4,4,4-heptafluorobutanoyl peroxide (FBP), 2,3,3,3-tetrafluoro-2-{l, l,2,3,3,3-hexafluoro-2-[l, l ,2,3,3,3-hexafluoro-

2-( 1 , 1 ,2,2,3,3,3-heptafluoropropoxy)propoxy]propoxy}propanoyl peroxide (PFPO-4),

2,4,4,5,7,7,8, 10, 10, 11 , 13, 13, 14, 14, 15, 15, 15-heptadecafluoro-2,5,8, 11- tetrakis(trifluoromethyl)-3,6,9, 12-tetraoxapentadecan- 1-oyl peroxide (PFPO-5), 1,2,2,3,3,4,4, 5, 5,6,6-undecafluorocyclohexanecarbonyl peroxide (CPFP) and l,2,2,3,3,4,4,4a,5,5,6,6,7,7,8,8,8a-heptadecafluorodecahydro- 1-naphthalenecarbonyl peroxide (DPFP).

The polymer or its salt obtained by using the peroxides of the formula (III) as a radical initiator may be represented by the formula (IV)

wherein R¹ and R³ are as defined in the above, and R² and R⁴ are as defined in the above, and R² and/ or R⁴ may be intramolecularly and/ or intermolecularly crosslinked with another R² or R⁴, R⁵ is as defined in the above, and n is an integer of 1 to 5000, and m is an integer of 0, 1 to 5000.

The preferred polymers of the formula (IV) are those wherein R¹, R³, R⁵, n and m are each as defined in the above, and R² and R⁴ are each a lower alkyl carbamoyl group or lower alkoxycarbonyl group, each of which may have one or more suitable substituent(s), an amino (lower) alkyl group or a carboxy group which may be esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/or lower alkenoyl, and R² and/ or R⁴ may be intramolecularly and/ or intermolecularly crosslinked with another R² or R⁴.

The more preferred polymers (IV) are those wherein R¹, R³, R⁵, n and m are each as defined in the above, and

R² and R⁴ are each a lower alkyl carbamoyl group which may have one or more hydroxy, a lower alkoxycarbonyl group substituted with one or more substituent(s) selected from the group consisting of amino, glycosyloxy, hydroxy and tri(lower)alkylammonium, an amino (lower) alkyl group or a carboxy group esterified by esterified and/ or etherified cellulose, and R² and/ or R⁴ may be intramolecularly and/ or intermolecularly, crosslinked with another R² or R⁴. The polymers represented by the formula (IV) may contain polymers wherein only one of the two R⁵s is as defined in the above in any content.

The polymers of the formula (IV) can be obtained by polymerization of GEMA with AEM-HCl in the presence of PFPO-2 in the molar ratio of GEMA:AEM-HC1 being 1:2, 1: 1, 1:0.5, 1:5 or 1:20, polymerization of GEMA with AL-Am-HCl in the presence of PFPO-2 in the molar ratio of GEMA: AL-Am-HCl being 1:0.5, polymerization of NAT with AEM-HCl in the presence of PFPO-2 in the molar ratio of NAT:AEM-HC1 being 1:0.5, polymerization of MCA in the presence of PFPO-2, polymerization of MCA with AEM-HCl in the presence of PFPO-2 in the molar ratio of MCA:AEM-HC1 being 1:0.6 or 1:3, polymerization of MCA with AEM-HCl in the presence of PFPO-3 in the molar ratio of MCA:AEM-HC1 being 1 :3 or 1 :4, polymerization of MCA with DMAA in the presence of PFPO-2 in the molar ratio of MCA:DMAA being 1:2.6 or 1: 5.2, polymerization of MCA with DMAA in the presence of PFPO-3 in the molar ratio of MCA:DMAA being 1: 10.83, polymerization of MCA with AL-Am-HCl in the presence of PFPO-2 in the molar ratio of MCA:AL-Am-HCl being 1: 1.88 or 1:3, polymerization of MCA with AL-Am-HCl in the presence of PFPO-3 in the molar ratio of MCA:AL-Am-HCl being 1:4, polymerization of HMTP-HC1 in the presence of PFPO-3, polymerization of GEMA with AEM-HCl in the presence of PFPO-3 in the molar ratio of GEMA : AEM-HCl being 1: 1, polymerization of NAT with AEM-HCl in the presence of PFPO-3 in the molar ratio of NAT : AEM-HCl being 1: 1, polymerization of NAT with AEM-HCl in the presence of PFPO-4 in the molar ratio of NAT : AEM-HCl being 1: 1, polymerization of HMTP-HC1 in the presence of PFPO-4, polymerization of NAT with AEM-HCl in the presence of PFPO-2 in the molar ratio of NAT : AEM-HCl being 1: 1, polymerization of GEMA with AEM-HCl in the presence of PFPO-2 in the molar ratio of GEMA : AEM-HCl being 1: 1, polymerization of AEM-HCl in the presence of PFPO-3 or polymerization of HMTP-HC1 in the presence of PFPO-2.

The examples of the radical initiators having azo group or peroxides are 2,2'-azobis(2-amidinopropane) dihydrochloride (V-50),

2,2'-diamidinyl-2,2'-azobutane dihydrochloride, 2,2'-diamidinyl-2,2'-azopentane dihydrochloride, 2,2'-bis(N-phenylamidinyl)-2,2'-azopropane dihydrochloride, 2,2'-bis(N-phenylamidinyl)-2,2'-azobutane dihydrochloride, 2,2'-bis(N,N-diιnethylamidinyl)-2,2'-azopropane dihydrochloride,

2,2'-bis(N,N-dimethylamidinyl)-2,2'-azobutane dihydrochloride, 2,2'-bis(N,N-diethylamidinyl)-2,2'-azopropane dihydrochloride, 2,2'-bis(N,N-diethylamidinyl)-2,2'-azobutane dihydrochloride, 2,2^,-bis(N,N-di-n-butylamidinyl)-2₎2^,-azopropane dihydrochloride, 2,2^,-bis(N,N-di-n-butylamidinyl)-2,2'-azobutane dihydrochloride,

3,3'-bis(N,N-di-n-butylamidinyl)-3,3'-azopentane dihydrochloride, azo-bis-N,N'-dimethyleneisobutylamidine dihydrochloride, 2,2'-azobis(2,4-dimethyl-4-methoxyvaleronitrile (V-70), 2,2'-azobis(2,4-dimethylvaleronitrile) (V-65), 2,2'-azobisisobu1yronitrile (AIBN) and m-chloroperbenzoic acid (MCPBA).

The commercially available VA-545, VA-546, VA-548, VA-041, VA-044 and VA-046B therefore can be purchased from Wako Pure Chemical Industries Ltd. as radical initiators having azo group.

The preferred composition of the invention comprises a polymer or its salt obtainable by polymerization of a monomer of the formula (I) or its salt in the presence of a radical initiator, R¹

H₂C=C (I)

R¹ is hydrogen atom or a lower alkyl group,

R² is a lower alkyl carbamoyl group optionally substituted with one or more substituent(s) selected from the group consisting of hydroxy, carboxy, sulfo, N,N-di(lower)alkyl-N-sulfonato(lower)alkylammonio and N,N-di(lower)alkyl-N-carboxylato(lower)alkylammonio; an aryl group optionally substituted with dihydroxyboranyl; a lower alkoxy carbonyl group substituted with one or more substituent(s) selected from the group consisting of hydroxy, amino and tri(lower)alkylammonium; a carboxy group esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl; or pyridinium group substituted with sulfo(lower)alkyl, or by polymerization of a monomer of the formula (la) or its salt with a monomer of the formula (II) or its salt in a molar ratio of (la) : (II) being 1:0.1 to 1:25 in the presence of a radical initiator

wherein R*_a is hydrogen atom or a lower alkyl group, R² _a is a lower alkyl carbamoyl group which may have one or more hydroxy; a lower alkoxy carbonyl group substituted with optionally substituted-heterocycliccarboamido, heterocyclic(lower)alkylureido or glycosyloxy; or a heterocyclicoxycarbonyl group optionally substituted with halogen or hydroxy; R³ is hydrogen atom or a lower alkyl group,

R⁴ is a lower alkyl carbamoyl group optionally substituted with sulfo; carboxy group; a lower alkoxycarbonyl group optionally substituted with lower alkoxy in which the alkyl moiety may be interrupted by oxygen atom(s) or amino; a carboxy group esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl; an amino (lower) alkyl group; a heterocyclic carbonyl group; or a tri(lower)alkylsilyl group, provided that when R² _a and R⁴ are the same, then R^J _a and R³ are different from each other.

The polymerization is usually carried out in an organic solvent, preferably halogenated aliphatic hydrocarbons and halogenated aromatic hydrocarbons such as dichloromethane, chloroform,

2-chloro- 1 ,2-dibromo- 1 , 1 ,2-trifluoroethane,

1 ,2-dibromohexafluoropropane, 1 ,2-dibromotetrafluoroethane,

1, 1-difluorotetrachloroethane, 1,2-difluorotetrachloroethane, fluorotrichloroethane, heptafluoro-2,3,3-trichlorobutane, l, l-dichloro-2,2,3,3,3-pentafluoropropane,

1 ,3-dichloro- 1 ,2,2,3,3-pentafluoropropane,

1,1,1 ,3-tetrachlorotetrafluoropropane,

1, 1, 1-trichloropentafluoropropane, 1 , 1 ,2-trichlorotrifluoroethane, 1,1, 1 ,2,2-pentafluoro-3,3-dichloropropane,

1 , 1 ,2,2,3-pentafluoro- 1 ,3-dichloropropane, benzotrifluoride, hexafluoroxylene, pentafluorobenzene, or any other organic solvent which does not adversely affect the reaction, or a mixture thereof or a heterogeneous mixed solvent thereof with water. The reaction is usually carried out in the presence of a radical initiator at a temperature under cooling to warming, preferably at the temperature of 40^ to δO'C.

The polymer or its salt of the present invention can be intramolecularly and/ or intermolecularly crosslinked by a suitable crosslinking agent or without a crosslinking agent. An example of the partial structure of the crosslinked polymer is represented by the formula :

wherein R⁶ and x are each as defined in the above.

The reaction condition can be referred to the Examples mentioned below.

The polymer prepared by the above process can be isolated and purified by a conventional method such as washing with an organic solvent, pulverization, recrystallization, chromatography, reprecipitation or the like.

It is to be noted that the polymer of this invention may include one or more stereoisomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s), and all of such isomer(s) and mixture thereof are included within the scope of this invention. It is further to be noted that isomerization or rearrangement of the polymers may occur by the effect of light, acid, base or the like, and the compounds obtained as the result of said isomerization or rearrangement are also included within the scope of the present invention. A pharmaceutically acceptable salt of the polymer can be prepared, for example, by treating the polymer having amino group with an appropriate acid or by treating the polymer having carboxy group with an appropriate base in accordance with a conventional method. Also included in the scope of invention are radiolabelled derivatives of the polymer which are useful for biological studies.

The polymers and pharmaceutically acceptable salts thereof possess ability for lowering lipid, such as cholesterol or triglyceride in blood.

Therefore, the polymers and pharmaceutically acceptable salts thereof are useful for treatment and/ or prevention of hyperlipidemia (e.g., hypercholesterolemia, hypercholesterolia, hyperlipemia, hyperlipoproteinemia, hypertriglyceridemia) and various diseases caused by hyperlipidemia such as angina pectoris; myocardial infarction; arteriosclerosis; cerebral embolism; arterial thrombosis; arterial sclerosis; ischemic heart diseases [e.g., angina pectoris (e.g., stable angina pectoris, unstable angina pectoris including inminent infarction, etc.), myocardial infarction (e.g., acute myocardial infarction, etc.), coronary thrombosis, etc.]; ischemic brain diseases [e.g., cerebral infarction {e.g., cerebral thrombosis (e.g., acute cerebral thrombosis, etc.), cerebral embolism, etc.}, transient cerebral ischemia (e.g., transient ischemic attack, etc.), cerebrovascular spasm after cerebral hemorrhage(e.g., cerebrovascular spasm after subarachnoid hemorrhage, etc.), etc.]; pulmonary vascular diseases (e.g., pulmonary thrombosis, pulmonary embolism, etc.); peripheral circulatory disorder [e.g., arteriosclerosis obliterans, thromboangiitis obliterans (i.e., Burger's disease), Raynaud's disease, complication of diabetes mellitus (e.g., diabetic angiopathy, diabetic neuropathy, etc.), phlebothrombosis (e.g., deep vein thrombosis, etc.), etc.]; or the like.

Besides, the polymers and pharmaceutically acceptable salts thereof possess ability for lowering glucose level in blood.

Therefore, the polymers and pharmaceutically acceptable salts thereof are also useful for treatment and/or prevention of diabetes mellitus, hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, irritable bowel syndrome, inflamatory bowel disease, including Crohn's disease and ulcerative colitis, other inflammatory conditions, pancreatitis, obesity, neurodegenerative disease, retinopathy, neoplastic conditions, adipose cell tumors, adipose cell carcinomas, such as liposarcoma, prostate cancer and other cancers, including gastric, breast, bladder and colon cancers, angiogenesis, Alzheimer's disease, psoriasis, high blood pressure, Syndrome X, ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component.

In order to exhibit the usefulness of the present invention, the activities of the polymers are shown in the following.

In vitro studies on absorption of cholesterol and bile acid

For making micelle by mixing bile acid and lipids, the Journal of Japanese Pharmacological and Therapeutics (vol. 24, Supplement p.127-132, 1996) was referred.

A mixture of cholic acid (6.4 mM), oleic acid (9.9 mM), monooleilglycerol (0.93 mM), lecitin (0.06 mM), lysolecitin (0.88 mM) and cholesterol (0.3 mM) was treated with supersonic waves by ultra sonic disrupter (UR-200P, TOMY SEIKO CO., Ltd.) in saline for micelle solution. Each 3 ml of the obtained micelle solution was added to 5 mg of the test compound in the test-tube and the mixture was shaken at 37t for 30 minuets. After shaking, the solution was centrifuged at 3000 rpm for 10 minuets. Cholesterol and cholic acid in the supernatant were measured by kits made by WAKO Co., Ltd.

Absorption rates were calculated by comparing with control values.

Test Results

The obtained results are shown in Table 1. Table 1

As shown in the above Table 1, the polymers of the present invention have superior ability for absorption of cholesterol and bile acid which indicates that they have superior ability for lowering cholesterol in blood.

In vivo studies on hyperglycemia

Male db/db mice (five week old C57BL/KsJ-dbm db+/db+, C57BL/KsJ-Dbm +m/+m, purchased from Jackson Laboratories, Bar Harbor, ME, USA) were grouped according to the body weight, the plasma glucose and the plasma triglyceride concentrations. Then, the test compound (dissolved in sterilized water and mixed by using vortex mixer) was administered to the mice for 6 days (from 6 to 7 weeks old). In the morning on day 7, the blood was collected from the orbital venous plexus of the mice using heparinazed glass capillary tubes

(Chase haparinized capillary Tubes), and a plasma fraction was obtained through centrifugal separation. Plasma glucose, triglyceride and the body weight were measured on day 0 and day 7. After the final collection of the blood, the mice were killed by using CO2 gas. The mice without administration of the test compound were used as control.

The plasma glucose concentration was measured by a glucose oxidase method (Glucose CII-Test Wako made by Wako Pure Chemical Industries, Ltd.) by using 5 μ 1 of the plasma. The plasma triglyceride concentration was measured by GPO-DAOS method (triglyceride E-Test

Wako made by Wako Pure Chemical Industries, Ltd.) by using 5 μ 1 of the plasma. The above- mentioned measurements were conducted immediately after the blood collection. Test Results

The obtained results are shown in Table 2. Table 2

As shown in the above Table 2, the polymers of the present invention have superior ability for lowering the concentration of plasma glucose and plasma triglyceride.

The composition of this invention can be used in a form of a pharmaceutical preparation, for example, in solid or semisolid form, which contains a polymer as an active ingredient in admixture with a pharmaceutically acceptable, substantially non-toxic organic or inorganic carrier or excipient suitable for oral, parenteral such as intravenous, intramuscular, subcutaneous, intracavernous or intraarticular, external such as topical, intrarectal, transvaginal, inhalant, ophthalmic, nasal or hypoglossal applications. Especially, it is preferable to apply the composition by oral application. The composition of the invention can be formulated by compounding a polymer or its salt as an active ingredient with the conventional non-toxic, pharmaceutically acceptable carriers or excipients for ointment, cream, plaster, tablets, pellets, capsules, suppositories, emulsion, suspension, aerosols, pills, powders, syrups, injections, troches, cataplasms, buccal tablets, sublingual tablets or any other form suitable for use.

The carriers which can be used are olive oil, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing the above-mentioned preparations. In addition, auxiliary, stabilizing, thickening or coloring agents and perfumes may be used. The polymer or its salt as an active ingredient is included in the composition in an effective amount sufficient to show the desired effect.

While the therapeutically effective amount of a polymer or its salt in the composition varies depending upon the age and condition of each individual patient to be treated, in case of the systemic administration, a daily dose of about 0.01 mg-100 g, preferably 0.1 mg-50 g and more preferably 0.5 mg-10 g of the active ingredient is generally given for treating the diseases, and an average single dose of about 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 1 g, 2.5 g and 5.0 g is generally administered. Daily doses for chronic administration in humans is in the range of about 0.3 mg/body to 50 g/body.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Preparations and Examples are given only for the purpose of illustrating the present invention in more detail.

Preparation 1

2,3,3,3-tetrafluoro-2-[l,l,2,3,3,3-hexafluoro-2-(l, 1,2,2,3,3,3- heptafluoropropoxy)propoxy]propanoyl peroxide (PFPO-3, 2mmol) in 1 : 1 mixed solvents of l,l-dichloro-2,2,3,3,3-pentafluoropropane and l,3-dichloro-l,2,2,3,3-pentafluoropropane (200 g) was added to an aqueous solution (4.50 g) of 2-glucosylethyl methacrylate (GEMA: 6 mmol) and 2-aminoethyl methacrylate hydrochloride (AEM-HCl: 12 mmol). The heterogeneous solution was stirred vigorously at 45°C for 5 hours under nitrogen. The obtained crude product was washed well with methanol to remove the unreacted GEMA and AEM-HCl, and dried over in vacuo at 50°C to give a polymer hydrochloride (2.63 g). IR (KBr): 3450 (OH), 3100 (NH₃ ⁺); 1720 (C=O), 1639 (NH₃ ⁺), 1330(CF₃), 1243 (CF₂) cm-ⁱ. This polymer causes gelation with water and DMSO(dimethylsulfoxide). The gelation ability of this polymer was studied by measuring critical gel concentration (CGC, g/L) of this polymer in water or DMSO. CGC in water and DMSO are 123 g/L and 173 g/L, respectively.

Preparation 2

2,3,3,3-tetrafluoro-2-( 1 , 1 ,2,2,3,3,3-heptafluoropropoxy)- propanoyl peroxide (PFPO-2, 1.9 mmol) in 1 : 1 mixed solvents of l, l-dichloro-2,2,3,3,3-pentafluoropropane and l,3-dichloro-l,2,2,3,3-pentafluoropropane (17.71 g) was added to a mixture of a solution of AEM-HCl (0.95 g, 5.7 mmol) in water (9.0 g) and 3.31 g (5.7 mmol) of 50% aqueous solution of GEMA. After adding

100 g of the 1 : 1 mixed solvents of l,l-dichloro-2,2,3,3,3-pentafluoropropane and l,3-dichloro-l,2,2,3,3-pentafluoropropane, the mixture was stirred vigorously with a mechanical stirrer at 45°C for 5 hours under nitrogen.

The crude product was isolated by filtration and washed well with methanol to remove the unreacted GEMA and AEM-HCl, and dried over in vacuo at 50°C for 2 days to give a polymer hydrochloride (2.68 g).

IR (KBr): 3450 (NH₃ ⁺, OH), 1724, 1635(C=O), 1300(CF₃), 1244 (CF₂) cm-i.

CGC in water and DMSO are 267 g/L and 115 g/L, respectively. The obtained polymer causes gelation only with water and

DMSO. This polymer was insoluble in methanol, ethanol, tetrahydrofuran, chloroform, benzene, toluene, ethyl acetate, 1 : 1 mixed solvents of l,l-dichloro-2,2,3,3,3-pentafluoropropane and l,3-dichloro-l,2,2,3,3-pentafluoropropane, dimethylformamide, n-hexane, acetone or dichloromethane.

Preparations 3 to 7

Each polymer was prepared from monomers and a radical initiator in a similar manner to Preparation 1. The kinds and molar ratio of the monomers and the radical initiator used in each Preparation are shown in Table 3. Table 3

n.d. :not determined,

PFPO-2 : 2,3,3,3-tetrafluoro-2-(l, l,2,2,3,3,3-heptafluoropropoxy)propanoyl peroxide;

PFPO-3: 2,3,3,3-tetrafluoro-2-[l, l,2,3,3,3-hexafluoro-2-(l,l,2,2,3,3,3-heptafluoropropoxy)propoxy]propanoyl peroxide;

GEMA : 2-glycosyloxyethyl methacrylate ; AEM-HCl: 2-aminoethyl methacrylate hydrochloride; AL-Am-HCl: allylamine hydrochloride; NAT: N-tris(hydroxymethyl)methylacrylamide; CGC: critical gel concentration

The IR spectrum of the polymers obtained in Preparations 3 to 7 are shown in Table 4. Table 4

Preparation 8

2,3,3,3-tetrafluoro-2-(l, l,2,2,3,3,3-heptafluoropropoxy)- propanoyl peroxide (PFPO-2, 2.6 mmol) in 1 : 1 mixed solvents of l,l-dichloro-2,2,3,3,3-pentafluoropropane and 1,3-dichloro-l, 2,2,3, 3-pentafluoropropane (150 g) was added to an aqueous solution (100 g) of methylcellulose acrylate (MCA: 1.00 g;

Monomer- Polymer & Dajac Labs., Inc.) and 2-aminoethyl methacrylate hydrochloride (AEM-HCl: 2.9 mmol). The heterogeneous solution was stirred vigorously at 45 °C for 5 hours under nitrogen atmosphere. Methanol was added to the reaction mixture, and the solvent was evaporated. The crude product was reprecipitated from a mixture of methanol and ethyl acetate to give a polymer hydrochloride (0.90 g). IR (KBr): 3463 (OH), 1728 (C=O), 1641 (NH₃ ⁺), 1389(CF₃), 1271 (CF₂) cm-¹. This polymer causes gelation with water, chloroform, DMSO and DMF. The critical gel concentration (CGC) of this polymer in water is 107 g/L.

Preparations 9 to 19

Each polymer was prepared from monomers and a radical initiator in a similar manner to Preparation 8. The kinds and molar ratio of the monomers and the radical initiator used in each Preparation are shown in Table 5.

The IR spectrum of the polymers obtained in Preparations 10 to 12, 14 and 17 to 19 are shown in Table 6.

Table 6

Preparation 20

A 50% aqueous solution of GEMA (5.85 g, 10 mmol) was added to a solution of AEM-HCl (1.66 g, 10 mmol) and 2,2'-azobis(2-amidinopropane) dihydrochloride (V-50, 0.542 g) in water (16.56 g). After adding 100 g of the 1 : 1 mixed solvents of l,l-dichloro-2, 2,3,3, 3-pentafluoropropane and l,3-dichloro-l,2,2,3,3-pentafluoropropane, the mixture was stirred vigorously with a mechanical stirrer at δO'C for 10 hours under nitrogen atmosphere. The obtained crude product was washed well with methanol to remove the unreacted GEMA and AEM-HCl, and dried in vacuo at 50°C for 2 days to give a polymer hydrochloride (4.37 g). IR (KBr): 3440 (NH₃ ⁺, OH), 1718, 1635 (C=O) cmX CGC in water and DMSO are 44 g/L and 19 g/L, respectively.

The obtained polymer causes gelation only with water and DMSO. This polymer was insoluble in methanol, ethanol, tetrahydrofuran, chloroform, benzene, toluene, ethyl acetate, 1 : 1 mixed solvents of l, l-dichloro-2,2,3,3,3-pentafluoropropane and 1,3-dichloro- 1,2,2, 3, 3-pentafluoropropane, dimethylformamide, n-hexane, acetone or dichlorome thane. Preparations 21-170

Each polymer was prepared from monomers and a radical initiator in a similar manner to Preparation 20. For example, Preparation 157 was conducted as follows.

Preparation 157

2,3,3,3-Tetrafluoro-2-[l, l,2,3,3,3-hexafluoro-2-(l,l,2,2,3,3,3-h eptafluoropropoxy)propoxy]propanoyl peroxide (PFPO-3, 3.3 mmol) in 1: 1 mixture of l,l-dichloro-2,2, 3,3, 3-pentafluoropropane and l,3-dichloro-l,2, 2,3, 3-pentafluoropropane (total 831 g) was added to the solution of 2-hydroxy-3-(methacryloyloxy)-N,N,N- trimethyl-1-propanammonium chloride (39.1 g) in water (40 g). The heterogeneous mixture was stirred vigorously at 45 °C for 5 hours under nitrogen atmosphere. The resultant mixture was evaporated carefully under reduced pressure and the residue was taken up in acetone (1000 ml). The obtained crude product was washed several times with a mixture of methanol and acetone, dried in vacuo at 50 "C to give a polymer hydrochloride (18.4 g).

iH-NMR (D O, δ ): 0.7-1.3 (3H, m), 1.7-2.3 (2H, m), 3.2-3.4 (9H, m),

3.4-3.7 (2H, m), 3.8-4.3 (2H, m), 4.5-4.7 (IH, m).

The kinds and molar ratio of the monomers and the radical initiator used in each Preparation are shown in Table 7.

Table 7

Table 7 (continued)

Table 7 (continued)

Table 7 (continued)

Table 7 (continued)

Table 7 (continued)

PFPO-2 : 2,3,3,3-tetrafluoro-2-(l,l,2,2,3,3,3-heptafluoropropoxy)- propanoyl peroxide,

PFPO-3: 2,3,3,3-tetrafiuoro-2-[ 1 , 1 ,2,3,3,3-hexafluoro-2-

(1, l,2,2,3,3,3-heptafluoropropoxy)propoxy]propanoyl peroxide, V-50: 2,2'-azobis(2-aminopropane)dihydrochloride, FAP: trifluoroacetyl peroxide, FBP: 2,2,3,3,4,4,4-heptafluorobutanoyl peroxide,

PFPO-4: 2,3,3,3-tetrafluoro-2-{l, l,2,3,3,3-hexafluoro-2-[l, 1,2,3,3,3- hexafluoro-2-( 1 , 1 ,2,2,3,3,3-heptafluoropropoxy)propoxy]propoxy}- propanoyl peroxide, PFPO-5: 2,4,4,5,7,7,8, 10,10,11, 13,13,14,14, 15, 15,15-hepta- decafluoro-2,5,8, l l-tetrakis(trifluoromethyl)-3, 6, 9, 12-tetraoxapentad ecan-1-oyl peroxide, CPFP: 1, 2,2,3,3,4,4, 5,5,6,6-undecafluorocyclohexanecarbonyl peroxide, DPFP: l,2,2,3,3,4,4,4a,5,5,6,6,7,7,8,8,8a-heptadecafluorodecahydro-l- naphthalenecarbonyl peroxide,

AA: acrylic acid,

AEM-HCl: 2-aminoethyl methacrylate hydrochloride, AHA: (acryloylamino) (hydroxy) acetic acid, AL-Am-HCl: allylamine hydrochloride, AM: 4-acryloylmorpholine,

AMP:2-(acryloylamino)-2-methyl- 1-propanesulfonic acid, APB: 3-(acryloylamino)phenylboronic acid,

APDAA: [ [3 - (acryloylamino)propyl] (dimethyl) ammonio] acetate ,

APDAP:

3 -[ [3- (acryloylamino) propyl] (dimethyl) ammonio] - 1 -propane sulfonate , CDA: calcium diacrylate,

CQA: 5-chloro-8-quinolinyl acrylate,

DCAEM: 2-{[(2,4-dιoxo-3,4-dihydro-l(2H)-pyrimidinyl)carbonyl]- amino}ethyl 2-methylacrylate, DMAA: N,N-dimethylacrylamide, FCAEM: 2-{[(5-fluoro-2,4-dioxo-3,4-dihydro-l(2H)-pyrimidinyl)- carbonyl]amino}ethyl 2-methylaceylate, GEMA : 2-(glycosyloxyl)ethyl 2-methacrylate , HA: N-(hydroxymethyl)acrylamide,

HCAEM: 2-{[(8-hydroxy-5-quinolinyl)carbonyl]amino}-ethyl 2 -methylacrylate ,

HMTP-HC1: 2-hydroxy-3-(methacryloyloxy)-N,N,N-trimethyl-

1-propanaminium chloride, IMA: 2-[({[2-( lH-iπndazol-5-yl) ethyl] ammo}carbonyl) amino] ethyl

2 -methylacrylate , LA: lithium acrylate,

MAA: 2-methylacrylic acid, MMA: methyl 2-methylacrylate, MCA: methylcellulose acrylate,

NAT: N-[2-hydroxy- 1 , 1 -bis (hydroxymethyl) ethyl] acrylamide, NM: 3,6,9, 12, 15, 18,21,24,27-nonaoxaoctacos-l-yl 2-methylacrylate,

OCAEM: 2-{[(2-oxo- 1 ,2-dihydro-4-pyrirnidinyl)carbonyl]arnino}ethyl

2-methylacrylate , TVS: trimethyl(vinyl)silane, VPES : 2- (2-vinyl- 1 -pyridiniumyl) ethanesulfonate

Preparation 171 Step (1)

2,3,3,3-tetrafluoro-2-( 1, 1, 2,2,3,3, 3-heptafluoropropoxy)- propanoyl peroxide (PFPO-2, 5mmol) in 1: 1 mixture of 1, l-dichloro-2, 2, 3, 3, 3-pentafluoropropane and 1 ,3-dichloro- 1,2, 2, 3, 3-pentafluoropropane (30g) was added to a mixture of 2-{[({[(lE)-l-methylρroρylidene]amino}oxy)carbonyl]- amino}ethyl 2-methylacrylate (IEM-BO, 6 mmol), dimethylacrylamide (DMAA) (50 mmol) and 1: 1 mixture of

1 , l-dichloro-2, 2, 3,3,3-pentafluoropropane and

1 ,3-dichloro- 1, 2, 2, 3, 3-pentafluoropropane (100g). The solution was stirred at 45 °C for 5 hours under nitrogen atmosphere. After the solvent was evaporated off, the obtained crude product was precipitated from a mixture of methanol and hexane to give pure polymer (7.38g).

IR (KBr): 1730, 1625, 1320, 1242 (cm-ⁱ); iH-NMR(CDCl₃) δ : 0.80-3.20 (CH₃, CH₂, CH), 3.38-3.62 (CH₂), 3.92-4.38 (CH₂). Step (2)

The polymer obtained from Step 1 (1.0 g) and 5-fluoro-2,4-(lH, 3H)pyrimidinedione (5-FU) (0.2 lg) in N,N-dimethylformamide (lOg) was stirred at 120 t for one hour. After the solvent was evaporated off under reduced pressure, the crude product was precipitated from a mixture of methanol and hexane and dialyzed against 50% methanol solution to give an object polymer (0.67g). IR (KBr): 1722, 1625, 1350, 1240 (cm-'); iH-NMR (CDC1₃) δ :0.80-3.78 (CH₂, CH, CH₃), 3.80-4.39 (CH₂), 8.02 (IH).

Preparation 172-186

Each polymer was prepared from monomers, radical initiator and nucleophile in a similar manner to Preparation 171. The kinds and molar ratio of the monomers, nucleophile and radical initiator used in each Preparation are shown in Table 8. Table 8

PFPO-2 : 2,3,3,3-tetrafluoro-2-(l, l,2,2,3,3,3-heptafluoropropoxy)- propanoyl peroxide, PFPO-3: 2,3,3,3-tetrafluoro-2-[ 1 , 1 ,2,3,3,3-hexafluoro-2-

(l, l,2,2,3,3,3-heptafluoropropoxy)propoxy]propanoyl peroxide, PFPO-4: 2,3,3,3-tetrafluoro-2-{l, l,2,3,3,3-hexafluoro-2-[l, 1,2,3,3,3- hexafluoro-2-( 1 , 1 ,2,2,3,3,3-heptafluoropropoxy)propoxy]- propoxy}propanoyl peroxide, V-50: 2,2'-azobis(2-arninopropane)dihydrochloride, V-65: 2,2'-azobis(2,4-dimethylvaleronitrile)

IEM-BO: 2-{[({[( IE)- 1 -me thylpropylidene]amino}oxy) carbonyl] - amino}ethyl 2-methylacrylate DMAA: dimethylacrylamide ACMO: 4-acryloylmorpholine AI: 5-aminoethyl-lH-imidazole

5-FU: 5-fluoro-2,4-(lH, 3H)pyrimidinedione AHQ: 5-amino-8-hydroxyquinoline Cyt: cytosine

Example 1

The polymer hydrochloride (200mg) obtained in Preparation 1 and calcium carbonate (2 lmg) were homogeneously mixed in a mortar.

The mixture was put into a test tube to which was added water (0.88 ml) to give a gel. Thus obtained wet gel was dried by using an aspirator and further dried at 50°C in vacuo for one day to give white gel-powder containing calcium carbonate.

Examples 2 to 7

Each polymer hydrochloride (200mg) obtained in Preparations 2, 3, 4, 5, 11 and 14 was treated in a similar manner to Example 1 to give white gel-powder containing calcium carbonate.

Example 8

A 1% calcium chloride aqueous solution (2.29 ml) was added to the polymer hydrochloride (105 mg) obtained in Preparation 7 in a test tube to give a gel. Thus obtained gel was dried in a similar manner to Example 1 to give white gel-powder containing calcium chloride.

Examples 9 and 10

Each polymer hydrochloride (105 mg) obtained in Preparations 14 and 15 was treated in a similar manner to Example 8 to give a white gel-powder containing calcium chloride.

Example 11

A 2.5 % calcium chloride aqueous solution (2.29 ml) was added to the polymer hydrochloride (105 mg) obtained in Preparation 7 to give a gel. Thus obtained gel was dried in a similar manner to Example 1 to give white gel-powder containing calcium chloride.

Example 12

The polymer hydrochloride (105 mg) obtained in Preparation 14 was treated in a similar manner to Example 11 to give white gel-powder containing calcium chloride.

Example 13

A 5 % calcium chloride aqueous solution (2.29 ml) was added to the polymer hydrochloride (105 mg) obtained in Preparation 7 to give a gel. Thus obtained gel was dried in a similar manner to Example 1 to give white gel-powder containing calcium chloride.

Examples 14 to 16

Each polymer hydrochloride (105 mg) obtained in Preparation 11, 12 and 14 was treated in a similar manner to Example 13 to give white gel-powder containing calcium chloride.

Example 17

A 10 % calcium chloride aqueous solution (2.29 ml) was added to the polymer hydrochloride (105 mg) obtained in Preparation 14 to give a gel. Thus obtained gel was dried in a similar manner to Example 1 to give white gel powder containing calcium chloride.

The CGC values in water of the gel-powder obtained in some of the above Examples are shown in the following Table 9.

Table 9

Examples 18-40

Each preparation was obtained from the polymer and a calcium compound in a similar manner to Examples 1 to 17. The kinds and molar ratio of the polymer and the calcium compound are shown in Table 10.

Table 10

Claims

1. A composition for preventing or treating hyperlipidemia or hyperglycemia comprising a polymer or its salt which is obtainable by polymerization of a monomer of the formula (I) or its salt in the presence of a radical initiator, or by polymerization of a monomer of the formula (I) or its salt with a monomer of the formula (II) or its salt in a molar ratio of (I) : (II) being 1:0.1 to 1:25 in the presence of a radical initiator

R »1' D3

H₂C=C (I) H₂C=C (II)

R' R⁴ wherein

R¹ and R³ are each hydrogen atom or a lower alkyl group, R² and R⁴ are each an acyl group, an aliphatic silyl group, an amino (lower) alkyl group which may have one or more suitable substituent(s), a heterocyclic group which may have one or more suitable substituent(s) or a carboxy group esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/or lower alkenoyl, as an active ingredient, in association with a pharmaceutically acceptable, non-toxic carrier or excipient.

2. The composition of Claim 1, wherein the acyl groups for R² and R⁴ are each a lower alkyl carbamoyl group, an aryl carbamoyl group, a lower alkoxycarbonyl group, a heterocyclicoxycarbonyl group or a heterocycliccarbonyl group, each of which may have one or more suitable substituent(s) or a tri (lower) al ylsilyl group.

3. The composition of Claim 1, wherein the acyl groups for R² and R⁴ are each a lower alkyl carbamoyl group which may have one or more substituent(s) selected from the group consisting of sulfo, hydroxy, carboxy, amino, sulfo (lower) alkylamino and carboxy(lower)alkylamino, or a lower alkoxycarbonyl group which may have one or more substituent(s) selected from the group consisting of hydroxy, amino, lower alkylamino, glycosyloxy, heterocyclic carbonylamino, heterocyclic(lower) alkylaniinocarbonylarnino and tri (lower) alkylammonium .

4. The composition of Claim 1, wherein the acyl groups for R² and R⁴ are each a lower alkyl carbamoyl group which may be substituted with one or more hydroxy, or a lower alkoxycarbonyl group substituted with one or more substituent(s) selected from the group consisting of amino, glycosyloxy, hydroxy and tri(lower)alkylammonium.

5. The composition of Claim 1, wherein the radical initiator is represented by the formula (III):

(R⁵COO)₂ (III) wherein R⁵ is a perfluoro(lower)alkyl group which may have one or more suitable substituent(s) or a cycloalkyl group substituted with one or more fluorine atom(s).

6. The composition of Claim 5, wherein the polymer or its salt is represented by the formula (IV) :

wherein R¹ and R³ are each hydrogen atom or a lower alkyl group, R² and R⁴ are each an acyl group, an aliphatic silyl group, an amino (lower) alkyl group which may have one or more suitable substituent(s), a heterocyclic group which may have one or more suitable substituent(s) or a carboxy group which may be esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl and R² and/ or R⁴ may be intramolecularly and/ or intermolecularly crosslinked with another R² or R⁴, R⁵ is a perfluoro (lower) alkyl group which may have one or more suitable substituent(s) or a cycloalkyl group substituted with one or more of fluorine atom(s), n is an integer of 1 to 5000, and m is an integer of 0, 1 to 5000.

7. The composition of Claim 6, wherein R² and R⁴ are each a lower alkyl carbamoyl group or a lower alkoxycarbonyl group, each of which may have one or more suitable substituent(s), an amino (lower) alkyl group or a carboxy group which may be esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl, and R² and/ or R⁴ may be intramolecularly and/ or intermolecularly, crosslinked with another R² or R⁴.

8. The composition of Claim 7, wherein R² and R⁴ are each a lower alkyl carbamoyl group which may have one or more hydroxy, a lower alkoxycarbonyl group substituted with one or more substituent(s) selected from the group consisting of amino, glycosyloxy, hydroxy and tri(lower)alkylammonium, an amino (lower) alkyl group or a carboxy group esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl, and R² and/ or R⁴ may be intramolecularly and/ or intermolecularly. crosslinked with another R² or R⁴.

9. The composition of Claim 8, wherein the polymer is obtainable by polymerization of 2-glucosylethyl methacrylate (GEMA) with 2-aminoethyl methacrylate hydrochloride (AEM-HCl) in the presence of 2,3,3,3-tetrafluoro-2-(l, l,2,2,3,3,3-heptafluoropropoxy)propanoyl peroxide (PFPO-2) in the molar ratio of GEMA : AEM-HCl being 1:2, 1: 1, 1:0.5, 1:5 or 1:20, polymerization of GEMA with allylamine hydrochloride (AL-Am-HCl) in the presence of PFPO-2 in the molar ratio of GEMA:AL-Am-HCl being 1:0.5, polymerization of N-tris(hydroxymethyl)methylacrylamide (NAT) with AEM-HCl in the presence of PFPO-2 in the molar ratio of NAT:AEM-HC1 being 1:0.5, polymerization of methylcellulose acrylate (MCA) in the presence of PFPO-2, polymerization of MCA with AEM-HCl in the presence of PFPO-2 in the molar ratio of MCA:AEM-HC1 being 1:0.6 or 1:3, polymerization of MCA with AEM-HCl in the presence of 2,3,3,3-tetrafluoro-2-[l, l,2,3,3,3-hexafluoro-2-(l,l,2,2,3,3,3-hepta- fluoropropoxy)propoxy]propanoyl peroxide (PFPO-3) in the molar ratio of MCA:AEM-HC1 being 1:3 or 1:4, polymerization of MCA with dimethylacrylamide (DMAA) in the presence of PFPO-2 in the molar ratio of MCA:DMAA being 1:2.6 or 1: 5.2, polymerization of MCA with DMAA in the presence of PFPO-3 in the molar ratio of MCA:DMAA being 1: 10.83, polymerization of MCA with AL-Am-HCl in the presence of PFPO-2 in the molar ratio of MCA:AL-Am-HCl being 1: 1.88 or 1:3, polymerization of MCA with AL-Am-HCl in the presence of PFPO-3 in the molar ratio of MCA:AL-Am-HCl being 1 :4, polymerization of 2-hydroxy-3-(methacryloyloxy)-N,N,N- trimethyl-l-propanaminium chloride (HMTP-HC1) in the presence of

PFPO-3, polymerization of GEMA with AEM-HCl in the presence of PFPO-3 in the molar ratio of GEMA : AEM-HCl being 1: 1, polymerization of NAT with AEM-HCl in the presence of PFPO-3 in the molar ratio of NAT :AEM-HC1 being 1: 1, polymerization of NAT with AEM-HCl in the presence of 2,3,3,3-tetrafluoro-2-{l, l,2,3,3,3-hexafluoro-2-[l, l,2,3,3,3-hexa- fluoro-2-( 1 , 1 , 2,2,3, 3,3-heptafluoropropoxy)propoxy]propoxy}- propanoyl peroxide (PFPO-4) in the molar ratio of NAT : AEM-HCl being

1:1, polymerization of HMTP-HC1 in the presence of PFPO-4, polymerization of NAT with AEM-HCl in the presence of PFPO-2 in the molar ratio of NAT : AEM-HCl being 1: 1, polymerization of GEMA with AEM-HCl in the presence of PFPO-2 in the molar ratio of GEMA : AEM-HCl being 1: 1, polymerization of AEM-HCl in the presence of PFPO-3 or polymerization of HMTP-HC1 in the presence of PFPO-2.

10. The composition of Claim 9, wherein the polymer is obtainable by polymerization of GEMA with AEM-HCl in the presence of PFPO-3 in the molar ratio of GEMA : AEM-HCl being 1: 1, polymerization of NAT with AEM-HCl in the presence of PFPO-3 in the molar ratio of NAT : AEM-HCl being 1: 1, polymerization of NAT with AEM-HCl in the presence of PFPO-4 in the molar ratio of NAT : AEM-HCl being 1: 1, polymerization of HMTP-HC1 in the presence of PFPO-4, polymerization of NAT with AEM-HCl in the presence of PFPO-2 in the molar ratio of NAT : AEM-HCl being 1: 1, polymerization of GEMA with AEM-HCl in the presence of PFPO-2 in the molar ratio of GEMA : AEM-HCl being 1: 1, polymerization of AEM-HCl in the presence of PFPO-3, polymerization of HMTP-HC1 in the presence of PFPO-3 or polymerization of HMTP-HC1 in the presence of PFPO-2.

11. The composition of Claim 1 , wherein the radical initiator is the one having azo group.

12. The composition of Claim 11, wherein R² and R⁴ are each a lower alkyl carbamoyl group which may have one or more suitable substituent(s), a lower alkoxy group may have one or more suitable substituent(s), a heterocyclic carbonyl group, an amino (lower) alkyl group which may have one or more suitable substituent(s), or a carboxy group which may be esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl.

13. A composition for preventing or treating hyperlipidemia or hyperglycemia comprising a polymer or its salt which is obtainable by polymerization of a monomer of the formula (I) or its salt in the presence of a radical initiator,

R¹

H₂C=C (I)

R²

R¹ is hydrogen atom or a lower alkyl group, R² is a lower alkyl carbamoyl group optionally substituted with one or more substituent(s) selected from the group consisting of hydroxy, carboxy, sulfo,

N,N-di(lower)alkyl-N-sulfonato(lower)alkylammonio and

N,N-di(lower)alkyl-N-carboxylato(lower)alkylammonio; an aryl group optionally substituted with dihydroxyboranyl; a lower alkoxy carbonyl group substituted with one or more substituent(s) selected from the group consisting of hydroxy, amino and tri(lower)alkylammonium; a carboxy group esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl; or a pyridinium group substituted with sulfonato (lower) alkyl.

14. The composition of Claim 13, wherein the radical initiator is represented by the formula (III) : (R⁵COO)₂ (HI) wherein R⁵ is a perfluoro(lower)alkyl group which may have one or more suitable substituent(s) or a cycloalkyl group substituted with one or more fluorine atom(s).

15. A composition for preventing or treating hyperlipidemia or hyperglycemia comprising a polymer or its salt which is obtainable by polymerization of a monomer of the formula (la) or its salt with a monomer of the formula (II) or its salt in a molar ratio of (la) : (II) being

1:0.1 to 1:25 in the presence of a radical initiator

R¹a R³

H₂C=C (la) H₂C=C (II)

R^< R"

wherein R*_a is hydrogen atom or lower alkyl group,

R² _a is a lower alkyl carbamoyl group which may have one or more hydroxy; a lower alkoxy carbonyl group substituted with optionally substituted-heterocycliccarboamido, heterocyclic (lower) alkylureido or glycosyloxy; or a heterocyclicoxycarbonyl group optionally substituted with halogen or hydroxy; R³ is hydrogen atom or a lower alkyl group, R⁴ is a lower alkyl carbamoyl group optionally substituted with sulfo; a lower alkoxycarbonyl group optionally substituted with lower alkoxy in which the alkyl moiety may be interrupted by oxygen atom(s) or amino; a carboxy group which may be esterified by the residue of cellulose optionally substituted with one or more lower alkyl and/ or lower alkenoyl; an amino (lower) alkyl group; a heterocyclic carbonyl group; or a tri(lower)alkylsilyl group, provided that when R² _a and R⁴ are the same, then R'_a and R³ are different from each other, as an active ingredient, in association with a pharmaceutically acceptable, non-toxic carrier or excipient.

16. The composition of Claim 15, wherein the radical initiator is represented by the formula (III):

(R⁵COO)₂ (in) wherein R⁵ is a perfluoro(lower)alkyl group which may have one or more suitable substituent(s) or a cycloalkyl group substituted with one or more fluorine atom(s).

17. A polymer of its salt which is obtainable by polymerization of N-tris(hydroxymethyl)methylacrylamide (NAT) with 2-aminoethyl methacrylate hydrochloride (AEM-HCl) in the presence of

2,3,3,3-tetrafluoro-2-( 1 , 1 ,2,2,3,3,3-heptafluoropropoxy)propanoyl peroxide (PFPO-2) in the molar ratio of NAT : AEM-HCl being 1: 1, polymerization of NAT with AEM-HCl in the presence of 2,3,3,3-tetrafluoro-2-[l,l,2,3,3,3-hexafluoro-2-(l,l,2,2,3,3,3-hepta- fluoropropoxy)propoxy]propanoyl peroxide (PFPO-3) in the molar ratio of NAT : AEM-HCl being 1:2, polymerization of NAT with AEM-HCl in the presence of 2,3,3,3-tetrafluoro-2-{l,l,2,3,3,3-hexafluoro-2-[l,l,2,3,3,3-hexa- fluoro-2-(l,l,2,2,3,3,3-heptafluoropropoxy)propoxy]propoxy}- propanoyl peroxide (PFPO-4) in the molar ratio of NAT : AEM-HCl being

1: 1, polymerization of methylcellulose acrylate (MCA) with 2-(aciyloylarnino)-2-methyl-l-propanesulfonic acid (AMP) in the presence of PFPO-3 in the molar ratio of MCA : AMP being 1 : 3, polymerization of AMP in the presence of

2,2,3,3,4,4,4-heptafluorobutanoyl peroxide (FBP), polymerization of AEM-HCl in the presence of PFPO-4, polymerization of 2-hydroxy-3-(methacryloyloxy)-N,N,N-trimethyl-l-propanaminium chloride (HMTP-HC1) in the presence of PFPO-3, polymerization of HMTP-HC1 in the presence of PFPO-4, polymerization of 2-glycosylethyl methacrylate (GEMA) in the presence of PFPO-2, polymerization of GEMA with AEM-HCl in the presence of PFPO-3 in the molar ratio of GEMA : AEM-HCl being 1: 1, polymerization of GEMA with AEM-HCl in the presence of PFPO-4 in the molar ratio of GEMA : AEM-HCl being 1 : 1.

18. A medicament for preventing and/ or treating hyperlipidemia or hyperglycemia, which comprises a polymer or its salt defined in Claim

1 or 13.

19. A method for preventing and/ or treating hyperlipidemia or hyperglycemia by administering a composition of Claim 1 or 13 to a human being or an animal.

20. A method for preventing and/ or treating angina pectoris, myocardial infarction, arteriosclerosis, cerebral embolism, diabetes or obesity by administering a composition of Claim 1 or 13 to a human being or an animal.

21. A use of a polymer or its salt defined in Claim 1 or 13 for the manufacture of medicament for preventing and/ or treating hyperlipidemia or hyperglycemia.

22 The use of Claim 21 , wherein the hyperlipidemia is hyperlipemia, hypercholesterolemia or hypertriglyceridemia.