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(11) Patent Number: KE 611   
       
(45) Date of grant: 25/09/2013   
           
(51) Int.Cl.7:C 07H 17/00

(21)Application Number: KElP/ 2005/000312

(22)    Filing Date: 28/11/2003

(30)    Priority data:

10258008.1  12/12/2001  DE

(86)  PCT data PCT/EP03/0 13455 28/11/2003 wo 2004/052903 24/06/2004

(73) Owner: Sanofi-Aventis Deutschland GmbH of 65929 Frankfurt am Main, Germany

(72) Inventors: FRICK, Wendelin, Schornmtihlstrasse 3, 65510 Htinstetten-Beuerbach, Germany; GLOMBIK, Heiner,  Am Lotzenwald 42, 65719 Hofheim, Germany; KRAMER, Werner, Henry-Moisand- Strasse 19, 55130 Mainz-Laubenheim, Germany; HEUER, Hubert, Am Sportfeld 74, 55270 Schwabenheim, Gemany; PLETTENBURG, Oliver, Im Hohlchen 15, 65795 Hattersheim, Germany andBRUMMERHOP, Harm, Rotlintstrasse 20,60316 Frankfurt, Germany

(74) Agent/address for correspondence: Kaplan & Stratton Advocates, P.O. Box 40111-00100, Nairobi
 
(54) Title:  NOVEL FLUOROGLYCOSIDE HETEROCYCLIC DERIVATIVES, PHARMACEUTICAL PRODUCTS CONTAINING SAID COMPOUNDS AND THE USE THEREOF

(57) Abstract: The invention relates to substituted fluoroglycoside heterocyclic derivatives of a formula (I), wherein radicals have predefined bonds, to the psychologically tolerated salts thereof and to methods for the preparation thereof. Said compounds can be used, for example as antidiabetic agents.

Description
Novel heterocyclic fluoroglycoside derivatives, pnarmaceutical products containing said compounds and the use thereof
5

The invention relates to substituted heterocyclic fluoroglycoside derivatives, their physiologically tolerated salts and physiologically functional derivatives.

10    Several classes of substances• having an SGLT effect have already been disclosed in the•literature. The model for all these structures was the natural product phlorizin. From this were derived the following classes which are described in the property rights below:

propiophenone  glycosides  of  Tanabe  0JVO 0280936,  WO 0280935,

. 15    JP 2000080041 and EP 850948)

2-(glucopyranosyloxy)benzylbenzenes    of   Kissei    (WO 0244192,

WO 0228872 and WO 0168660)

glucopyranosyloxypyrazoles  of Kissei  and  Ajinomoto  0JVO 0268440,

WO 0268439, WO 0236602 and WO 0116147)

20    0-glycoside benzamides of Bristol-Myers Squibb (WO 0174835 and wo 0174834)

and C-aryl glycosides of Bristol-Myers Squibb (WO 0127128 and us 2002137903).

A.ll the known structures contain ~lucose as a very important structural

25    element.


The invention was based on the object of providing novel compounds with which it is possible to prevent and treat type 1 and type 2 diabetes. We have now surprisingly found that heterocyclic fluoroglycoside derivatives

30    increase the effect on SGLT. These compounds are therefore particularly suitable for preventing and treating type 1 and type 2 diabetes.

The invention therefore relates to compounds of the formula I


B    R6
I
X
A    .\/v•
R4    Om

R5


in which the meanings are


5 R1 and R2 independently of one another F, H or one of the radicals R1 or R20H;

R3 OH or F, where at least one of the radicals R1, R2, R3 must be F;

10

R4    OH;


A    0, NH, CHz, Sora bond;


15    X    C, 0, S or N, where X must be C when Y is 0 or S;

Y    N, 0 orS;


m    a number 1 or 2;

20

R5 hydrogen, F, Cl, Br, I, OH, CF3, NOz, CN, COOH, CO(C1-C6)-alkyl, COO(C1-C5)-alkyl, CONH2, CONH(C1-C5)-alkyl, CON[(C1-C6)-alkyl]z, (C1-C5)-alkyl, (Cz-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C5)-alkoxy, HO-(C1-C5)-alkyl, (C1-C5)-

25 alkyi-O-(C1-C6)-alkyl, phenyl, benzyl, (C1-C5)-alkoxycarboxyl, it being possible for one, more than one or all hydrogen(s) in the alkyl, alkoxy, alkenyl or alkynyl radicals to be replaced by fluorine;
 

3

    S02-NH2,    S02NH(C1-C6)-alkyl,    S02N[(C1-C6)-alkyl]2,
    S-(C1-C5)-alkyl,    S-(CH2)o-phenyl,        SO-(C1-C5)-alkyl,
    SO-(CH2)o-phenyl,  S02-(C1•-C6)-a!kyl,    S02-(CH2)0 -phenyl,
    where  o  can  be  0-6,  and  the  phenyl  radical  may  be
5    substituted  up  to  twice  by F,  Cl,  Br,  OH,  CF3,  N02,  CN,
    OCF3, O-(C1-C5)-alkyl, (C1-C5)-alkyl, NH2;   
    NH2,  NH-(C1-C5)-a!kyl,  N((C1-C5)-alkyl)2,  NH(C1-C7)-acyl,
    phenyl,  O-(CH2)0 -phenyl,  where  o  can  be  0-6,  where  the
    phenyl ring may be substituted one to 3 times by F, Cl, Br, I,
10    OH,  CF3,  N02,  CN,  OCF3,  O-(C1-C5)-alkyl,  (C1-C5)-alkyl,
    NH2,  NH(C1-C5)-alkyl,  N((C1-C5)-alkyl)2,  S02-CH3,  COOH,
    COO-(C1-C6)-alkyl, CONH2;           
    or when Y is S, R5 and R6 together with the C atoms carrying
    them phenyl;               
15                       
R6    optionally   H,   (C1-C5)-alkyl,   (C1-C5)-alkenyl,   (C3-C6)-
    cycloalkyl,  or phenyl  that may optionally be substituted  by
    halogen or (C1-C4)-alkyl;           
io   B    (Co-C1s)-alkanediyl,  it  being  possible  for  one  or  more  C
    atoms in the alkanediyl radical to be replaced independently
    of  one  another  by  -0-,  -{C=O)-,  -CH=CH-,  -C=C-,  -S-,
    -CH(OH)-, -CHF-, -CF2-, -(S=O)-, -(S02)-, -N((C1-C5)-alkyl)-,
    -N((C1-C5)-alkyl-phenyl)- or -NH-;           
25                       
n    a number from 0 to 4;           
Cyc1    a  3  to    7 membered  saturated,    partially    saturated   or
    unsaturated ring, where 1 C atom may be replaced by 0, Nor
30    S;                   
R7, R8, R9   hydrogen,    F,  Cl,  Br,  I,  OH,  CF3,    N02,    CN,  COOH,
    COO(C1-C6)-alkyl, CO(C1-C4)-alkyl, CONH2, CONH(C1-C5)-
    alkyl,  CON[(C1-C5)-alkyl]2,  (C1-C6)-alkyl,  (C2-C5)-alkenyl,
35    (C2-C5)-alkynyl,  (C1-Cs)-alkoxy,  HO-(C1-C5)-alkyl,  (C1-C6)-
    alkyi-O-(C1-C6)-alkyl, it being possible for one, more than one
    or  all  hydrogen(s)  in  the  alkyl,  alkoxy,  alkenyl  or  alkynyl
    radicals to be replaced by fluorine;           
    S02-NH2,    S02NH(C1-C5)-alkyl,        S02N[(C1-C6)-alkyl]2,
 

5


R4    OH;


A    0 or NH;

5

X    C, 0 or N, where X must be C when Y isS;
 


Y

35    Cyc1



R7, R8, R9
 


S or N;


a number 1•or2;


hydrogen, F, Cl, Br, I, OH, CF3, N02, CN, COOH, CO(C1-C6)-alkyl, COO(C1-C5)-alkyl; CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alky1]2, (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C1-C5)-alkoxy, HO-(C1-C6)-alkyl, (C1-C6)-qlkyi-O-(C1-C6)-alkyl, phenyl, benzyl, (C1-C4)-alkylcarboxyl, SO-(C1-C5)-alkyl, it being possible for one, more than one or all hydrogen(s) in the alkyl or alkoxy radicals to be replaced by fluorine; or

when Y is S, R5 and R6 together with the C atoms carrying• them phenyl;

optionally H, (C1-C5)-alkyl, (C1-C5)-alkenyl, (C3-C6)-cycloalkyl, or phenyl that may optionally be substituted by halogen or (C1-C4)-alkyl;

(Co-C15)-alkanediyl, where one or more C atom(s) in the alkanediyl radical may be replaced independently of one another by -0-, -(C=O)-, -CH=CH-, -C=C-, -S-, -CH(OH)-, -CHF-, -CF2-, -(S=O)-, -(S02)-, -N((C1-C5)-alkyl)-, -N((C1-C5)-alkyl-phenyl)- or -NH-;

a number from 0 to 4;


a 3 to 7 membered saturated, partially •saturated or unsaturated ring, where 1 C atom may be replaced by 0 or S;

hydrogen, F, Cl, Br, I, OH, CF3, N02, CN, COOH, COO(C1-C6)-alkyl, CO(C1-C4)-alkyl, CONH2, CONH(C1-C5)-
 

6

alkyl, CON[(C1-C5)-alkyl]2, (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C1-Ca)-alkoxy, I=IO-(C1-C6)-alkyl, (C1-C5)-alkyi-O-(C1-C6)-alkyl,

. SO-(C1-C5)-alkyl, it being possible for one, more than one or

5    all hydrogen(s) in the alkyl or alkoxy radicals to be replaced by fluorine;

or

R8 and R9   together with the C atoms carrying them a 5 to 7 membered, saturated,  partially  or  completely  unsaturated  ring  Cyc2, 10                where 1 or 2 C atom(s) in the ring may also be replaced by N,
0 or S, and Cyc2 may optionally be substituted by (C1-C5)- • alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, where •in each case one CH2 group may"b•e replaced by 0, or substituted by H, F, Cl, OH, CF3, N02, CN, COO(C1-C4)-alkyl, CONH2,

15    CONH(C1-C4)-alkyl, OCF3.


Further preferred compounds of the formula I are those in which the sugar residues are beta(p)-linked and the stereochemistry in the 2, 3 and 5 position of the sugar residue has the D-gluco configuration.

20

Particularly preferred compounds of the formula I are those in which the substituents A and B occupy an adjacent position (ortho position).

Particularly preferred compounds of the formula I are those in which •

25

R 1 and R2 are independently of one another F, H or one of the radicals

R1 or R2 = OH where at least one of the radicals R1 or R2 must be

30    R3    isOH


R4    isOH;


A    is 0;

35

X    is C, 0 or N,where X must be C when Y isS;

y    isS or N;
 

        7
    m    is a number 1;
    R5    is hydrogen, (01-05)-alkyl, (01-04)-alkoxy, H0-(01-04)-alkyl,
        (01-04)-alkyi-0-(01-04)-alkyl,  F,  01,  OF3;  OOF3,  OCHzOF3
5        (01-04)-alkyi-OFz-,  phenyl,  benzyl,  (01-04)-alkylcarboxyl,
        (Oz-04)-alkenyl, (Oz-04)-alkynyl, 000(01-04)-~Ikyl; or
        when Y is S, R5 and R6 together with the 0 atoms carrying
        them phenyl;
10    R6    is  optionally  H,  (01-05)-alkyl,  (01-05)-alkenyl,  (03-06)-
        cycloalkyl,  or phenyl that may •optionally be• substituted  by
        halogen or (01-04)-alkyl;
    B    is (01-04)-alkanediyl,  where  one OHz group  may also  be
1.5        replaced by -(0=0)-, -CH(OH)-, -00-NH-,  -OHF-, -OFz-, -0-;
    n    is a number 2 or 3;
    Cyc1    is unsaturated 5- or 6-membered ring, where 1 0 atom may
20        be replaced by 0 or S;
    R7, R8, R9    are hydrogen, (01-04)-alkyl, (01-0a)-alkoxy, S-(01-04)-alkyl,
        SOF3, F, 01, Br, I, OCF3, OOHzOF3, OH, H0-(01-04)-alkyl,
        (C1-04)-alkyi-0-(01-04)-alkyl, or
25       
    RS.and R9    together  are  -OH=OH-0-,  -OH=OH-S-,  OH=OH-OH=OH-,
        which  is  optionally  substituted  by  (01-04)-alkoxy,  or  -0-
        (0Hz)p-0-, with p = 1 or 2 and
30    R7    • is hydrogen.


Very particularly preferred compounds of the formula I are those in which


R1,.R2    are H or F, where one of the radicals R1, R2 must be F;

35

R3    is.OH;
 
is C and Y is S, or is 0 and Y is N, or is N and Y is N;

is a number 1;


is hydrogen, CF3, (C1-C5)-alkyl, or when Y is S R5 and R6 together with the C atoms carrying them a~e phenyl;

is optionally H, (C1-C4)-alkyl or phenyl;
 


8

15   
n    is a number 2 or 3;
Cyc1    is an unsaturated 5 to 6 membered ring, where 1 C atom can
    be replaced by S;
20   
R7,R8,R9    are hydrogen, (C1-C5)-alkyl, (C1-C4)-alkoxy, S-(C1-C4)-alkyl,
    SCF3, F, Cl, Br, I, OCF3, or
R8 and R9    together   are   -CH=CH-0-,   -CH=CH-CH=CH-,   which   is
25    optionally substituted by (C1-C4)-alk<?XY, and
R7    is hydrogen.


Further very particularly preferred compounds of the formula I are those in

30    which


R1, R2 •are H or F, where one of the radicals R1 or R2 is F;


R3    is OH;
35   
R4    is OH;
 


A    isO;
 

10

or Cl.


Pharmaceutically acceptable salts are, because their solubility in water is greater than that of the initial or basic compounds, particularly suitable for !1    medical applications. These salts must have a pharmaceutically acceptable

. anion or cation. Suitable pharmaceutically acceptable acid .addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and of organic adds such as, for example, acetic acid,
10    benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic,

•.    isethionic,  lactic,  lactobionic,  maleic, •malic, methanesulfonic,  succinic,

p-toluenesulfonic and. tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal" salts-(such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and

15    calcium salts), trometamol (2-amino-2-hydroxymethyl-1 ,3-propanediol), diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion such as, for example,

trifluoroacetate likewise belong within the framework of the invention as

20    useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.

The term "physiologically functional d.erivative" used herein refers to any

25    physiologically tolerated derivative of a •compound of the formula I of the invention, for example an ester, which on administration to a mammal such as, for example, a human is able to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.

30    Physiologically functional derivatives include prod rugs of the compounds of the invention, .as described, for example, in H. Okada et al., Chern. Ph arm. Bull. 1994, 42, 57-61. Such prod rugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or

not.

35

The compounds of the invention may also exist in various polymorphous

. forms; for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.
 

11


All references to ~compound(s). of formula I" hereinafter refer to compound(s) of the formula I as described above, and their salts, solvates and physiologically functional derivatives as described herein.
5

The compound(s) of formula (I) may also be administered in combination with other active ingredients.

The amount of a compound of formula I necessary to achieve the desired

10    biological effect depends on a numb~r of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg) per day and per
kilogram of bodyweight, for example 3-10 mg/kg/day. An intrav~nous dose

15    may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of 1 0 ng to 1 00 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter.

Single doses may contain, for example, from 1 mg to 10 g of the active

20    ingredient. Thus, ampoules for injections may contain, for example, from 1 mg to 100 mg, and single-dose formulations•which can be administered orally, such as, for example, tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For the therapy of the

abovementioned conditions, the compounds of formula I may be used as

25    the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be

acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient'shealth. The carrier may be a solid or a liquid or both and is preferably formulated with the

30    compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may likewise be present, including

other compounds of formula  I. The pharmaceutical compositions of the

invention •can be produced by one of the known pharmaceutical methods,

35    which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example
 

12

subcutaneous, intramuscular, intradermal or intravenous) administration, although• the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated

5    formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice-

resist~nt formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl-methylcellulose phthalate and anionic polymers •of methacrylic acid and
10    methyl methacrylate.


Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets or tablets, each of which contain a defined amount of the compound

15    of formula I; as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the

active  ingredient  and  the  carrier  (which  may  consist  of one  or  more

20    additional ingredients) are brought into contact. The compositions are generally produced by uniform and. homogeneous mixing of the active

ingredient with a liquid and/or finely divided solid carrier, after which the

product  is  shaped  if  necessary.  Thus,  for  example,  a  tablet  can  be

produced  by  compressing  or . molding  a  powder  or  granules  of  the

25    compound, where appropriate with one or more additional !ngredients. Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one (or more)

surface-active/dispersing agent(s) in a suitable machine. Molded tablets •30 can be produced by molding the compound, which is in powder form and is

moistened with an inert liquid diluent, in a suitable machine.


Pharmaceutical compositions which are suitable for peroral (sublingual) administration •comprise suckable tablets which contain a compound of

35    formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
 

Pharmaceutical compositions suitable for parenteral administration com-
 

13

prise preferably sterile aqueous preparations of a compound of formula I, which.-are-preferably isotonic with the_ blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or

5    intradermal injection. These preparations can preferably be proc;luced by mixing the_ compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.

10    Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose .suppositories. These can be produced by mixing a compound of formula I with one or more conventional solid
•    carriers, for example cocoa butter, and shaping the resulting mixture.


15    Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, cream, lotion,_ paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances.

The •active ingredient is generally present in a concentration of from 0.1 to

20    15% by weight of the composition, for example from 0.5 to 2%.


Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient'sepidermis. Such

25    plasters suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active ingredient to be released by electrotransport or iontophoresis as

30    described, for example, in Pharmaceutical Research, 2(6): 318 (1986).


The invention also relates to processes for preparing the compounds of the general formula I, which can be obtained as shown in the following reaction schemes for processes A, 8 and C;

35

Process A:
 
14



eu,anNCII K,CO•


R5




1. NaCNBH, I TMSCI

:z. MeONa I MeOH

D    R5


Process 8:





1
R2~~c    1. Bu,BnNCl/ K,CO,   
    CH2CI2 /H20   
AcO           
    2. NaOMe/ MeOH   
AaJ       
Br

A
5

Process C:
 

15

;-~    ~~   
Rs'l 'oH       
B    ABr   

Bu3BnNCI/ K2C03
CH2C~/H,O


J
1.    R5-l, K2C03 fj

2.    NaOMe I MeOH   Route B

The schemes depicted for processes A, B and C are self-explanatory and

can  be  carried  out  thus  by  the  skilled  worker.  More  details  are,

nevertheless,  indicated  in  the  experimental  part.  The  compounds  of

5    examples 1 to 31 were obtained by processes A, B and C. Other compounds of the formula I can be obtained correspondingly or by known processes.

The compound(s) of the formula I can also be administered in combination 10 . with other active ingredients.

Further active ingredients suitable for combination products are:

all antidiabetics mentioned in the Rote Liste 2001, chapter 12. They may be combined with the c9mpounds of the formula I of the invention in particular

15    for synergistic improvement of the effect. Administration of the active ingredient combination may take place either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ing•redients are present in one pharmaceutical

preparation. Most of the active ingredients listed below are disclosed in the

20    USP Dictionary of . USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
 

16

Antidiabetics include insulin and insulin derivatives such as, for example, Lantus® (see www.lantus.com) or HMR 1964, fast-acting insulins (see US 6,221 ,633), GLP-1 derivatives such as, for example, those disclosed in WO 98/08871 of Novo Nordisk .A/S, and orally effective hypoglycemic

5    active ingredients.

The orally effective hypoglycemic active ingredients include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones,
thiazolidinediones,  glucosidase  inhibitors,  glucagon  antagonists,  GLP-1

agonists,  potassium  channel  openers  such  as,  for  example,  those

10    disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, inhibitors of liver enzymes involved in the stimu•lation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake; compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, compounds which reduce

15    food intake, PPAR and PXR agonists and active ingredients which act on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the compounds of the formula I are

administered in combination with an HMGCoA reductase inhibitor such as

20    simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.

In one embodiment of the invention, the compounds of the formula I are

administered in combination with a cholesterol absorption inhibitor such as, 25 for example, ezetimibe, tiqueside, pamaqueside.

In one embodiment of the invention, the compounds of the formula I are administered in cornbination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, Gl 262570.

30

In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR alpha agonist, such as, for example, GW 9578, GW7647.

35    In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, AVE 0897 or as described in WO 00/64888. WO 00/64876. WO 03/20269.
 

17

In one embodiment of the invention, the compounds of the formula I are

administered    in  combination  with  a . fibrate  such  as,  for  example,

fenofibrate, clofibrate, bezafibrate.


5    In one embodiment of the invention, the compounds of the formula I are administered .in combination with an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757.

In one embodiment of the invention, the compounds of the formula I are

10    administered in combination. with bile acid absorption inhibitor (see, for example, US 6,245,744 or US 6,221 ,897), such as, for example, HMR 1741.

In one embodiment of the invention, the compounds of the formula I are

15    administered in combination with a CETP inhibitor, such as, for example, JTT-705.

In one embodiment of the invention, the compounds of the formula I are

administered in combination with a polymeric bile acid adsorbent such as,

20    for example, cholestyramine, colesevelam.


In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see US 6,342,512), such as, for example, HMR1171, HMR1586.

25

In one embodiment of the invention, the compounds of the formula I are

administered in combination with an ACAT inhibitor, such as, for example,

avasimibe.


30    In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as, for example, OPC-14117.

In one embodiment of the invention, the compounds of the formula I are

35    administered in combination with a lipoprotein lipase inhibitor, such as,. for example, N0-1886.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP-citrate lyase inhibitor, such as, for
 

18

example, SB-204990.


In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, such as,

5    for example, BMS-188494.


In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist, such as, for example, Cl-1027 or nicotinic acid.

10

In one embodiment of the invention, the compounds of the formula I are

administered in combination with a lipase inhibitor, such as, for example,

orlistat.


1.5    In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.
In one embodiment, the compounds of the formula. I are administered in combination with a sulfonylurea such as, for example, tolbutamide,

glibenclamide, glipizide or glimepiride.

20    In one embodiment, the compounds of the formula I are administered in combination with a biguanide, such as, for example, metformin.

•In  one  turther  embodiment,  the  compounds  of  the  formula I  are

administered  in  combination  with  a  meglitinide,  such  as, for  example,

25    repaglinide.

In one embodiment, the compounds of the formula I are administered in

combination with a thiazolidinedione, such as, for example, troglitazone,

ciglitazone,  pioglitazone,  rosiglitazone  or  the  compounds  disclosed  in

WO 97/41097  of  Dr.   Reddy's Research  Foundation,   in   particular

30    5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compounds of the formula I are administered in combination with an a-glucosidase inhibitor, such as, for example, miglitol or acarbose.

35    In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compounds of the formula I are administered in
 

19

combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin•, with a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
5

In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.: Hormone and Metabolic

10    Research (2001 ), 33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid {4-[( 4-aminoquinazolin-2-ylamino )methyl]-cyclohexyl-methyl}amide; hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-

1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chloro-

15    phenyl)-2-oxoethyl]-amide; (WO 01/91752)), orexin a~tagonists (e.g. _1-(2-methylbenzoxa~o~-6-yl)-3-[1 ,5] naphthyridiri-4-yh,Jrea; hydrochloride (SB-334867-A)}, H3 agonists (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetra-hydroimidazo[4,5-c]pyridin.:5-yl)propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6-

20    trimethylphenyi)-9H-1 ,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, ~3 agonists (e.g. 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1 H-indol-

6-yloxy)ethylamino]-ethanol; hydrochloride (WO 01i83451)), -MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g.

25    {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-yl-carbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed sertoninergic and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists, e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt

30    (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone-releasing compounds (6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1 H-iso-

quinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists

(see, for example, EP 0 462 884), uncoupling protein 2 or 3 modulators,

35    leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001 ),

•26(9),  873-881),  DA agonists  (bromocriptine,  Doprexin),  lipase/amylase

inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR
 

20

modulators or TR-~ agonists.


In one embodiment of the invention, the other active ingredient is leptin; see, for example, "Perspectives in the therapeutic use of leptin", Salvador,

5    Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In  one  embodiment,  the  other active  ingredient is  dexamphatamine  or

amphetamine.

10    In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.
In another embodiment, the other active ingredient is sibutramine. In one embodiment, the other active ingredient is orlistat.
In one embodiment, the other active ingredient is mazindol or phentermine.

15

In one embodiment, the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001

20    Sep-Oct), 18(5), 230-6). Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, lndustriepark Hochst, 65926 Frankfurt/Main)). Combination with Caromax® is possible in

one  preparation  or  by  separate  administration  of  compounds  of  the

formula I  and  Caromax®.  Caromax®  can  in  this  connection  also  be

25    administered in the form of food products such as, for example, in bakery products or muesli bars.

It will be appreciated that every suitable combination of the compounds of

the invention with  one or more of the aforementioned  compounds  and

30    optionally one or more other pharmacologicaJiy active substances is regarded as falling within the protection conferred by the present invention.
 
21

''•••(oyoR    .
HO~OH
 

22

The example$ de1ailed below serve to illustrate the invention without, however. restricting it.
 
23



Table 1:. Compounds of the formula I

                                                                                                                                                                                           
    Bsp    R1    R2    R3    R4    R5    R6    R7  :        R8,R9    A        B    Cyc1    X    y            m        n    MS*       
    1        H    F    OH    OH    H    -    4-0-CH3            H,H        0        CH2        Ph    c    s            1            3    ok       
    --                                                                                                                               
                                                                                                                                                                                           
    2    H    F    OH    OH    -CH=CH-CH=CH-    4-0-Cf-!a            H,H        0        CHz        Ph    c    s            1            3    ok       
                                                                                                           
                                                                                                                                                                                   
    3        F    H    OH    OH    OH    -    4-0-C~3            H,H        0        CH2        Ph    c    s            1            3    ok       
                                                                                                                   
    -                                                                                                                                                                                       
                                                                                                                                        c    s                                           
    4    H    OH    F        OH    OH    -    4-0-CI-!a            H,H        0        CH2        Ph                    1            3    ok       
                                                                                                                   
                                                                        :                                                                                                               
                                                                                                                                                                                       
    5    H    F        OH        OH    CFa    H    4-0•C~a            H,H        0        CH2        Ph    N    N            1            3    . ok       
                                                                                                                                                                                           
    6    F    H            OH        OH    CFa    H    4-0-C~3            H,H        0        CH2        Ph    N    N            1            3    ok       
                                                                                                                           
    -•7    H    F        OH        OH    CHa    H    4-F  )            H,H        0        CH2        Ph    N    N        1            3    ok       
                                                                                                                       
                                                                                                                           
    8    H    F        OH        OH    •CHa    H    2-CI.            4-CI, H        0        CH2        Ph    N    N        1            3    ok       
                                                                                                                                                                                           
    9    H    F        OH        OH    CHa    CHa    4-F            H,H        0        CH2        Ph    N    N        1            3    ok       
                                                                                                                               
    10    H    F            OH        OH    • CHa    CHa    2-CI            4-CI, H        0        GH2        Ph.    N    N        1            3    OK       
                                                                                                                       
                                   
        Ex.    R1    R2    R3        R4                R5                R6                    R(    :                R8,R9                A            B        Cyc1        X            y        m        n            MS*   
                                        -                                                       
        11    H    F    OH        OH                H                            4-CH2-CI-b            H,H    0                CH2        Ph        c            s    1        3            ok   
        12    F    H    OH        OH                H    -                        4-CH2-CHa            H.H                0                CHz        Ph        c            s    1        3            ok   
        13        F                                        0                        Ph        c        s        3            ok   
            H        OH        OH                H        -                            4-0~CH~            H,H                        CONHCH2                                1                       
                                                                           
        14    H    F        OH        OH                H    -                            4-0-CFa            H,H    0        CONHCH2        Ph        c            s    1        3            ok   
                                                                           
        15    H    F        OH        OH                            CH3            -                            4-0-CHa            H,H    0                CH2        Ph        c            s    1        3            ok   
                                                                                                                                                                                           
        16                                                                                                               
            H    F    OH        OH                H                        '   H            -CH=CH-CH=CH-    0                CHz    thiophene        c            s    1        2            ok   
                                                                                                                                                       
                                                                                                                                                       
        17    H    F    OH        OH        H                                                Ph        c        s        3            ok   
                        -                                -                            4-CHa                    H,H        0                CHz                                1                       
        18    H    F    OH        01-i                H        -                            2-CHa •            H,H        0                CHz        Ph        c            s    1        3            ok   
                                                                                                                                                                           
        19    H    F    OH        OH                        H        -                4-1                    H,H        0                CH2        Ph        c            s    1        3            ok   
                                                                                                                                                                               
        20    F            F    OH        OH                    CF3            H                    4-0-CHa            H,H        0                CH2        Ph        N            N    1        3            ok   
                                                                                                                                                                                   
                                                                                                                                                                                   
                                                                       
        21    H    F        OH        OH                    H            -                            3-Me  •            H,H        0                CH2        Ph        c            s    1        3            ok   
                                                                                                                                                                                       
        22    H    F        OH        OH                    H        -                            4-CI                    H,H        0                CH2        Ph        c            s    1        .3            ok   
                                                                                                                                                                                           
        23    H        F    OH        OH                    H        -                            4-F    :                H,H        0                CH2        Ph        c            s        1        3            ok   
                                                                                                                                                                                                       
        24    H        F    OH        OH                    H        -                            H                -CH=CH-CH=CH•        0                CH2        Ph        c        s        1        3            ok   
        25    H        F    OH        OH                    H        -                            4-0CF3i            H,H        0                CH2        Ph        c        s            1            3            ok   
        26    H        F    OH    . OH                    H        -                            4-Br    :                H,H        0                CH2        Ph            c        s            1        3            ok   
                                                                                                                                                                                               
                                                                                                                                                                                               
                                                                                                                                                                                                                   
    27    H        F    • OH.        OH                    H        -                4-CH(CH~h            H,H                0                CH2        Ph        c        s        1            3            ok•   
                                                                                                                                                                               
    28    H        F    OH        OH                    H        -                            H            -CH=CH-C(OMe)=CH-                    o.            CH2        Ph        c        s        1        3            ok   
    29    H        F    OH        OH                    H        -                            H                -CH=CH-0-            0                CH2        Ph            c        s        1        3            ok   
    30    H        F    OH        OH                    CH3            H                    2-F                    H.H        0                CH2        Ph            N            N        1        3            ok       
                                                                                                                                                                                                   
    31    H        F    OH        OH                    CH3            H                    4-CI                    H,H            0                CH2        Ph            N            N        1        2            ok   


The indication "MS is ok" means that a mass spectrum or HPLC/MS was recorded and the molecular peak M+1 (MH+) and/or M+18 (MNH4+)

and/or M+23 (MNa+) was detected therei,n. The linkages are indicated in the description of the examples in the experimental part.
 

25

The compounds of the formula I are distinguished by beneficial effects on glucose metabolism; in particular, they lower the blood glucose level and are suitable for the treatment of type 1 and type 2 diabetes. The compounds can therefore be employed alone or in combination with other

5    blood glucose-lowering active ingredients (antidiabetics).

The compounds of the formula I are further suitable for the prevention and

treatment  of  late  damage  from  diabetes,  such  as,  for  example, nephropathy,  retinopathy,  neuropathy  and  syndrome  X,  obesity,  heart infarction,  myocardial  infarction,  peripheral  arterial  occlusive  diseases, 1 0   thromboses,    arteriosclerosis,    inflammations,    immune    diseases, autoimmune dise~ses such as, for example, AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's,schizophrenia and infectious diseases, with preference  for  the  treatment  of type  1 and •type 2  diabetes  and  the prevention and treatment of late damage from diabetes, syndrome X and

15    obesity.


The activity of the compounds was tested as follows:


Preparation of brush borqer membrane vesicles from the small intestine of 20 rabbits, rats and pigs

•Preparation of brush border membrane vesicles from the intestinal cells of the small intestine was carried out by the so-called Mg2+ precipitation method. The mucosa of the small intestine was scraped off and suspended

25    in 60 ml of ice-cold Tris/HCi buffer (ph 7.1)/300 mM mannitol, 5 mM EGTA. Dilution to 300 ml with ice-cold distilled water was followed by homogenization with an Ultraturrax (18 shaft, IKA Werk Staufen, FRG) at

75% of the max. power for 2 x 1 minute, while cooling in ice. After addition

of 3 ml of 1M MgCI2 solution (final concentration.1 0 f!1M), the mixture is left

30    to •~tand at oac for exactly 15 minutes. Addition, of Mg2+ causes the cell membranes to aggregate and precipitate with the exception of the brush border membranes. After centrifugation at 3 000 x g (5 000 rpm, SS-34 rotor) for 15 minutes, the precipitate is discarded and the supernatant,

which contains the brush border membranes, is centrifuged at 26 700 x g

35    (15 000 rpm, SS-34 rotor) for 30 minutes. •The supernatant is discarded, and the precipitate is rehomogenized in 60 ml of 12 mM Tris/HCI buffer (ph 7.1)/60 mM mannitol, 5 mM EGTA using a Potter Elvejhem

homogenizer (Braun, Melsungen, 900 rpm,• 10 strokes). Addition of 0.1 ml of 1M MgCI2 solution and incubation at oac for 15 minutes is followed by
 

26

centrifugation again at 3 000 x g for 15 minutes. The supernatant is then centrifuged again at 46 000 x g (20 000 rpm, SS-34 rotor) for 30 minutes. The precipitate is taken up in 30 ml of 20 mM Tris/Hepes buffer (pH 7.4)/280 mM mannitol and homogeneously resuspended by 20 strokes

5    in a Potter Elveihem homogenizer at 1. 000 rpm. After centrifugation at 48 000 x g (20 000 rpm, SS-34 rotor) for 30 minutes, the precipitate was taken up in 0.5 to 2 ml of Tris/Hepes buffer (pH 7 .4)/280 mM mannitol (final concentration 20 mg/ml) and resuspended using a tuberculin syringe with a 27 gauge needle:

10    The vesicles were either used directly after preparation for labeling or transport studies or were stored at -196°C in .4 mg portions in liquid nitrogen.

To prepare brush border membrane vesicles from rat ~mall intestine, 6 to 10 male Wistar rats (bred•at Kastengrund, Ave ntis Pharma) were sacrificed

15    by cervical dislocation, and the small intestines were removed and rinsed with cold isotonic salirie. The intestines were cut up and the mucosa was scraped off. The processing to isolate brush border membranes took place as described above. To remove cytoskeletal fractio"ns, the brush border membrane vesicles from rat small intestine were treated with KSCN as

20    chaotropic ion.


To prepare brush border membranes from rabbit small intestine, rabbits were sacrificed by intravenous injection of 0.5 ml of an aqueous solution of

2.5    mg  of  tetracaine  HCI,  100 mg  of  m-butramide  and  25 mg  of 25   mebezonium iodide. The small intestines were removed, rinsed with ice-cold physiological saline and frozen in plastic bags under nitrogen at -80°C and stored for 4 to 12 weeks. For preparation of the membrane vesicles, •the frozen intestines were thawed at 30°C in a water bath and then the mucosa was scraped off. Processing to give membrane vesicles took place
•30   as described above.


To prepare brush border membrane vesicles from pig intestine, jejunum segments from a freshly slaughtered pig were rinsed with ice-cold isotonic saline and frozen in plastic bags under nitrogen at -80°C. Preparation of the

35    membrane vesicles took place as described above.


Preparation of brush border membrane vesicles from the renal cortex of the rat kidney.
 

27

Brush border membrane vesicles were prepared from the cortex of the rat •kidney--by the-•method of Biber et al. The kidneys from 6 to 8 rats (200 to•

250 g) were removed and -the cortex was cut off each •kidney as a layer about 1 mm ~hick. The kidneys were taken up in 30 ml of ice-cold 12 mM

5    Tris/HC1 buffer (pH 7.4)/300 mM mannitol and homogenized with an Ultraturrax shaft (level 180 V) for 4 x 30 seconds while cooling in ice.

Addition of 42 ml of ice-cold distilled water was followed by addition of 850 ).11 of a 1M MgCI2 solution. Incubation at- ooc for 15 minutes was

followed    by  centrifugation  at  4 500  rpm  (Sorvall  SS-34  rotor)  for

10    • 15 minutes. The precipitate was discarded, and the• supernatant was centrifuged at 16 000 rpm for 30 minutes. Resuspension of the precipitate in 60 ml of 6 mM Tris/HCI buffer (pH 7.4)/150 mM mannitol/2.5 mM EGTA

by 10 strokes in a Potter-Eivejhem homogenizer (900 rpm) and addition of 720 ).11  of 1 mM  MgCI2 solution  was  followed  by incubation  at ooc for 15    15 minutes.  The supernatant resulting •after centrifugation  at 4 500  rpm

. (SS-34 rotor) for 15 minutes was centrifuged at 16 000 rpm for 30 minutes. The supernatant was homogenized by 10 strokes in 60 ml of 20 mM Tris/Hepes buffer (pH 7.4)/280 mM mannitol, and the resulting suspension was then centrifuged at 20 000 rpm for 30 .minutes. The precipitate was

20    resuspended in 20 mM Tris/HCI buffer (pH 7.4)/280 mM mannitol using a tuberculin syringe with a 27 gauge needle and was adjusted to a protein concentration of 20 mg/ml.

Measurement of the glucose uptake by brush border membrane vesicles

25
The uptake of C4C]-Iabeled glucose into brush border membrane vesicles was measured by the membrane filtration method. 10 )..ll of the• brush border membrane vesicle suspension in. 10 mM Tris/Hepes buffer (pH 7.4)/300 mM mannitol were added at 30°C to 90 ).11 of a solution of

30    10 1-lM C4C]D glucose and the appropriate concentrations of the relevant inhibitors (5-200 )..LM) in 10 mM Tris/Hepes buffer (pH 7 .4)/1 00 mM NaCI/1 00 mM mannitol.

After incubation for 15 seconds, the transport process was stopped by adding 1 • ml of ice-cold stop solution (1 0 mM Tris/Hepes buffer

35    (pH 7.4)/150 mM KCI) and the vesicle suspension was immediately filtered with suction through a cellulose nitrate membrane filter (0.45 ).lm, 25 mm diameter, Schleicher & Schull) under a vacuum of from 25 to 35 mbar. The filter was washed with 5 ml of ice-cold stop solution. Each measurement was carried out as duplicate or triplicate determination. To measure the
 

28

uptake of radiolabeled substrates, the membrane filter was dissolved in 4 ml of an appropriate scintillator (Quickszint 361, Zinsser Analytik GmbH, Frankfurt •am Main), and the radioactivity •was determined by liquid scintillation measurement. The measured values were obtained as dpm

5    (disintegrations per minute) •after calibration of the. instrument using standard samples and after correction for any chemiluminescence present.

The active ingredients are compared for activity on the basis of ICso data obtained  in  the• transport  assay on  rabbit  small  intestine  brush  border 1 0   membrane vesicles for selected substances. (The absolute values may be

species- and experiment-dependent.)


Example No.    ICso [!J.M]
Phlorizin    16
1    4.
2    0.4
3    0.3


The preparation of various examples is described in detail below, and the 15 •othercompounds of the formula I were obtained analogously:
 

29

Experimental part:


Reaction scheme: synthesis of cx.-bromoglycosides
 
OH

HO
 

OAc



2. HBr/ AcOH


2
 

OH    2. HBr/ AcOH    A cO   
           
HO           
3        4   
           






HO        OH        AcO   
                   
            2. HBr/ AcOH   
               
    HO               
    5        6   
               

5

1 .. Bromo ..4-deoxy-4-fluoro-2,3,6-tri-0-acetyl..:alpha-D-glucose (2)

10    5.0 g (27.5 mmol) of 4-deoxy-4-fluoro-D-glucopyranose 1 {Apollo) are suspended in 50 ml of pyridine and 50 ml of acetic anhydride. The reaction solution is stirred at 45°C for 4 hours. This results in a clear reaction solution which is concentrated. 12.0 g of crude product are obtained. This crude product is dissolved in 160 ml of 33% strength HBr in glacial acetic
 

30

acid and l_eft to stand at room temperature for 2 ~ours. The reaction solution-is -then -poured-into a mixture of 300 g of ice--and ~30Q ml of ethyl acetate. The organic phase is washed twice with aqueous NaCI solution, filtered through a little silica gel and concentrated. The residue is separated

5    by chromatography on silica gel (ethyl acetate/heptane= 1/1). 8.19 g (80% over 2 stages) of 2 are ~btained as a pale yellow solid.

1-8 romo-4-deoxy-4-fl uoro-2,3,6-tri-0-acetyl-alpha-D-galactose (4)
    A cO
10    4

100 mg (0.55 mmol) of 3 are reacted with 3.5 ml of pyridine and 3.5 ml of acetic anhydride in analogy to the preparation of compound 2. 89 mg (44%) of 4 are obtained as an amorphous solid .

. 15

1-Bromo-3-deoxy-3-fluoro-2,4,6-tri-0-acetyl-alpha-D-glucose (6)





AcO



6


20    335 mg (1.84 mmol) of 5 are reacted with 10 ml of pyridine and 10 ml of acetic anhydride in analogy to the preparation of compound ~• 628 mg (92%) of 6 are obtained as an amorphous solid.
 
31

•Reaction scheme: Synthesis of the a-bromoglycoside 10



            1. Dess-Martin       
                           
            2.BAST       
    OMe  •                       
    1                    8   
        OAc    A~~   
1. Pd/C, H2 _    F            HBr I AcOH       
                           
                           
                           
    AcO        OAc    A cO   
    9                    10   



1-Methoxy-4-deoxy-4,4-difluoro-2,3,6-tri-0-benzyl-alpha-D-glucose (8)


3.69  g  (7 .9  mmol)  of  1-methoxy-2,3,6-tri-0-benzyl-alpha-D-glucose  7

(Tetrahedron Asymmetry 2000, 11, 385-387) were dissolved in 110 ml of

10    methylene chloride and, under an argon atmosphere, 3.6 g (8.5 mmol) of Dess-Martin reagent (Aldrich) are added dropwise. After 3 hours at room temperature, the mixture is diluted with•300 ml of ethyl.acetate/n-heptane (1:1) and washed 1x with NaHC03 and 1x with Na2S203 solution. The

organic phase is filtered throug_h silica gel and concentrated. The residue il?

15    separated by chromatography on silica gel (ethyl acetate/n-heptane 1:1 ).

2.90    g (79%) of the ketone are obtained. This is dissolved in 30 ml of methylene chloride and, under an argon atmosphere, 4.0 ml of BAST

([bis(2-methoxyethyl)amino]sulfur trifluoride, Aldrich) are added dropwise.

After 20 hours at room temperature, the mixture is diluted with 200 ml of

20    ethyl acetate and washed carefully (extensive effervescence) with cold NaHC03 solution. The organic phase is filtered through silica gel and
 

32

concentrated. The residue is separated by chromatography on silica gel -(ethyl acetate/n-heptane 1:1). 2.6 g (85%) of 8 are obtained as a colorless oil.

5    4-Deoxy-4,4-difluoro-1 ,2,3,6-tetra-0-acetyl-alpha-D-glucose (9)


2.30 g (4.7 mmol) of 8 and 2.0 g of Pd/C (1 0% Pd) are• dissolved in 150 ml of methanol and 10 ml of acetic acid and hydrogenated under an

10    atmosphere of 5 bar of hydrogen at room temperature for 16 h.• The reaction solution is concentrated and the residue is purified by flash chromatography (methylene chloride/methanol/cone. ammonia, 30/5/1 ). Yield 850 mg (83%) of 1-methoxy-4-deoxy-4,4-difluoro-alpha-D-glucose as white amorphous solid. C7H12F205 (214.17) MS(DCI): 215.4 (M+H+).

15    700 mg (3.3 mmol) of this are dissolved in 3.5 ml of acetic acid and 6.3 ml of acetic anhydride. Addition of 0.2 ml of cone. H2S04 is followed by

stirring at 60°C for 5 _h. The reaction solution is then poured into a mixture

. of 30 g of ice and 3.0 nil of ethyl acetate. The organic phase is washed twice with aqueous NaCI solution, filtered through a little silica gel and

20    concentrated. The residue is separated by chromatography on silica gel (ethyl acetate/n-heptane 1:1). 300 mg (25%) of 9 are obtained as a mixture• of anomers. C14H1aF209 (368.29) MS(DCI): 369.3 (M+H+)
 

33

1-Bromo-4-deoxy-4;4-difluoro-2,3,6-tri-0-acetyl-alpha-D-glucose (1 0)


300.mg (0.8 mmol) of tetraacetate 9 are dissolved in 13 ml of 33% strength

5    . HBr in glacial acetic acid and left to stand at room temperature for 6 hours. The reaction s~lution is then poured into a mixture of 1q g of ice and 10 ml

of ethyl acetate. The organic phase is washed twice with aqueous NaCI solution, filtered through a little silica gel and concentrated. The residue is separated by•chromatography (SiOz) (ethyl acetate/heptane 1:1). 112 mg

10    (35%) of 10 are obtained as a colorless solid. C12H15BrFz07 (389.15) MS(DCI): 389.2 (M+H+).
 
34

Reaction scheme: Synthesis of the a-bromoglycosides 14


.(I]

0~
. L (~Q
060~    BAST
=~0~OMe    orDAST
11

12

3.0  g of methyl  2,3,6-tri-0-benzoyl-a-D-galactopyranoside  (Reist et al.,

10    J. Org. Chern 1965, 30, 2312) are introduced into dichloromethane and cooled to -30°C. Then 3.06 ml of [bis(2-methoxyethyl)amino]sulfur
 

35

trifluoride (BAST) are added dropwise. The reaction solution is warmed to room temperature and stirred for 12 h. The mixture is diluted with dichloromethane, and the organic phase is extracted with H20, NaHC03 solution and saturated NaCI solution. The organic phase is dried over

5    Na2S04 and concentrated. The crude product is crystallized from ethyl acetate and heptane. 1.9? g of the product 12 are obtained as a colorless solid. C2sH2sFOs (508.51) MS (ESI+) 526.18 (M+NH4+). Alternatively, the

reaction can •also be carried out using 2.8 eq. of diethylaminosulfur trifluoride (DAST); in this case, the reaction solution is refluxed for 18 h
10    after addition. Working up takes place in analogy to the above description.



1-0-Acetyl-2,3,6-tri-0-benzoyl-4-fluoro-4-deoxy-glucose (13)

    13   
       

12.0 g of the compound methyl 2,3,6-tri-0-benzoyl-4-fluoro-4-deoxy-a-D-glucopyranoside are suspended in 150 ml of acetic anhydride. 8.4 ml of cone. sulfuric acid are mixed with 150 ml of glacial acetic acid and added to

20    the mixture while -cooling in ice. The mixture is stirred at room temperature for 60 h. The reaction mixture is poured into NaHC03 solution, and this solution is extracted with chloromethane. The organic phase is washed with NaCI solution, dried with Na2S04 and concentrated. The residue is

recrystallized from ethyl acetate and heptane. 5.97 g of the product 13 are

. 25   obtained as a colorless solid.
c29H2sFOg (536.52) MS(ESI+) 554.15 (M+NH4+).
 

37

Reaction sc;;heme A: Synthesis of Example 1


400 mg (1.7 mmol) of (3-hydroxythiophen-2-yl)(4-methoxyphenyl)-methanone (15) CDE Application Number 10231370.9 (2002/0049) and 200 mg (0.54 mmol) of bromide 2 are dissolved in 6 ml of methylene chloride. 160 mg of Bu3BnNCI (PTC =phase transfer cat~lyst), 320 mg of

10    K2C03 and 0.4 ml of water are successively added to this solution, which is then stirred at •room temperature for 20 hours. The reaction solution is diluted with 20 ml of ethyl acetate and filtered through silica gel. The filtrate

is concentrated and the residue is separated by chromatography over silica

gel (ethyl acetate/heptane.= 1/1). 160 mg (56%) of 16 are obtained as a
+    +
15    colorless solid. C24H2sF01oS (524.52) MS(ESl ) 525.12 (M+H ).

20    150 mg (0.29 mmol) of compound 16 are dissolved in 4 ml of acetonitrile. This solution is cooled in an ice bath and then 150 mg of NaCNBH3 and

.0.2 ml of TMSCl are added. The cooling is then removed and the mixture is stirred at room temperature for 2 hours. The reaction solution is diluted with 20 ml of ethyl acetate and filtered through silica gel. The filtrate is

25    concentrated, and 150 mg of crude product are obtained. •This crude product is taken up in 4 ml of methanol, and 1 ml of 1M NaOMe in MeOH is
 

41

added. After one hour, the mixture is neutralized with methanolic HCI and concentrated, and the residue is purified by chromatography on silica gel (methylene chloride/methanol/cone. ammonia, 30/5/1). 76 mg (69% over 2 stage~) of 17 are obtained as a colorless solid. C1sH21 F05S (384.43)

5    ME(Esn 403.21 (M+H20+H+).




Example 2 (compound 18}
 

10    18


100 mg (0.47 mmol) of (3-hydroxybenzothiophene-2-yl)(4-methoxyphenyl)-methanone (Eur. J.  Med. Chern.  1985, 20,  187-189) and 300 mg (0.80 mmol)  of bromide  2  are  dissolved  in  10 ml  of chloroform.  120  mg  of 16   Bu3BnNCI  (PTC  = phase-transfer catalyst)  and  1.5 ml  of 1 N aqueous sodium hydroxide solution are successively added to this solution, which is then boiled under reflux for 4 hours. The reaction solution is diluted with 20 ml  of  ethyl  acetate  and  filtered  through  silica  gel.  The  filtrate  is •concentrated and the re?idue is separated by chromatography on silica gel

20    •(ethyl acetate/heptane = 1/1). 135 mg (51%) of pale yellow solid are obtained. This is converted into compound 18 with 100 mg of NaCNBH3

and  0.2 ml  of TMSCI  and  then  with  NaOMe/MeOH  in  analogy to  the

preparation  of compound  17.  46 mg  of 18  are  obtained.  C22H23F05S

(434.49) MS(ESr) 479.18 (M+CHOi).
 

42

Example 3 (compound 19)


OH




0
HO    0   
    \   
       
    HO.   


1.9

5

178 mg of (3-hydroxythiophen-2-yl)(4-methoxyphenyl)methanone (15) and 90 mg of bromide 4 are reacted in analogy to the synthesis of example 1, and 49 mg of 19 are obtained as a colorless solid. C1aH21F05S.(384.43) MS(ESI+) 403..21 (M+H20+H+).

10


Example 4 (compound 20)


OH




0
0
\

HO


15    20


200 mg of (3-hydroxythiophen-2-yl)(4-methoxyphenyl)methanone 15 and 100 mg of bromide 6 are reacted in analogy to the synthesis of example 1, and 59 mg of 20 are obtained as a colorless solid. C1aH21F05S (384.43)

20    MS(Esn 403.21 (M+H20+H+).


Examples 11 (compound 25) and 15 (compound 21) are synthesized in analogy to the synthesis of example 1 starting from the appropriate hydroxythiophenes and the bromide 2.
 
43

Examples 16 (compound 32),  17 (compound 23),  18 (compound 22),  19

(compound 24), 21 (compound 27), 22 (compound 28), 23 (compound 29),

24 (compound 31), 25 (compound 30), 26 (compound 46), 27 (compound

47), 28 (compound 48) and 29 (compound 49)  are synthesized in analogy

5    to the synthesis of example 1 starting from appropriate hydroxythit;>phenes and the bromide 14.

Example 12 (compound 26) is synthesized in analogy to the synthesis of example 4 starting from the appropriate hydroxythiophene and bromide 6.
10

Examples 13 (compound 33) and 14 (compound 34) are synthesized in analogy to the synthesis of compound 16 by reacting the appropriate hydroxythiophenes with the bromide 2 and subsequently deprotecting with NaOMe/MeOH in analogy to example 1.
15

Example 20 (compound 35) is synthesized in analogy to the synthesis of example 1 starting from hydroxythiophene 15 and the bromide 10.
 

44

Reaction scheme 8: Synthesis of Example 5
 



200 mg of 4-(4-methoxybenzyl)-5-methyl-1 H-pyrazol-3-ol (35) (J. 1\i'led. Ghem:--1996, 39, 3920-3928) are glycosilated with •1 00 mg of bromide 2 in analogy to the synthesis of example 1 and then deprotected with NaOMe/MeOH in analogy to example 1. 49 mg of compound 36 are

5    obtained as a colorless solid. C1aH2oF4N206 (436.36) MS(Esn 437.21 (M+H+).



Example 6 (compound 37)

10

OH



HO    0
\
HO


37


200 mg of 4-(4-methoxybenzyl)-5-methyl-1 H-pyrazol-3-ol (35) and 100 mg

of bromide 4 are glycosilated in analogy to the synthesis of example 1 and

15    then deprotected with NaOMe/MeOH in analogy to example 1. 89 mg of compound 37 are obtained as a col.orless solid. C1aH2oF4N206 (436.36) MS(Esn 437.21 (M+H+).



20    Example 20 (compound 38)




38
 

11 0 mg of 4-( 4-methoxybenzyl)-5-methyl-1 H-pyrazol-3-ol (35). and 60 mg of
 

46

bromide 10 are glycosilated in analogy to the synthesis of example 1 and then deprotected with NaOMe/MeOH in analogy to example 1. 49 mg of the compound•38 are obtained as a colorless solid. C1sH1gFsNz05 (454.35)

MS(Esn 455.22 (M+H+).

5

Reaction scheme C: Synthesis of Example 8 and Example 10


            -Y--               
        ~N    OH                   
                               
39    Cl        Cl    40                       
                                       
                    F    ~ (~be&•Gi   
            MeONa/MeOH~       
                            HON,;t' I    I :   
            Route A    .           
                                ~  CHa       
    !                                Cl   
                            42 (Example 8)       
1. Mel, K2C03                                       
2. •MeOH I MeOH    Route B                                   

43 (Example 1 0)
 

47

Further exemplary compounds:

~~0                   
HO    N~           
    ~J(CH ~F           
44(Example 7)    3               
                       
F r_:H            F    :~a       
H~obc6           
•Ho    N:l' I        I ~    HON~   
    'N        h'-       
    HCH            'NJ(~ ..    llA   
50(Example30)        3        ~  CH 3    Cl   
                51(Example 31)       



5    Example 8 (.compound 42)

Cl    40

500 mg (1.73 mmol) of ethyl 2-(2,4-dichlorobenzyl)-3-oxobutyrate (39) (Bionet) are boiled with 0.21 ml of 51% pure hydrazine hydrate (3.46 mmol)

10    in 15 ml of toluene with a water trap for 1.5 h. After cooling, the solid is filtered off with suction and washed with toluene arid ether. 400 mg (90%) of the compound 40 are 'obtained as a voluminous white precipitate.

C11H1oC12N20 (257.12) MS(ESI): 257 (M+H+).
 

270 mg (1.05 mmol) of 4-(2,4-dichlorobenzyl)-5-methyl-1 H-pyrazol-3-ol (40) were dissolved in 25 ml of methylene chloride, and 0.7 ml of water, 1.2 g

5    (8.68 mmol) of potassium carbonate, 84 mg (0.31 mmol) of benzyltriethy.lammonium bromide and 428 mg (1.15 mmol) of bromide 2 were added, and the mixture was stirred at RT for 18 h. The reaction solution was diluted with methylene chloride and washed once each with
water and saturated brine, dried over MgSQ4 and concentrated. The crude
.    .

10    product was purified on silica gel. 122 mg (21 %) of the compound 41 are obtained as white solid. C23H2sCI2FN20s (547.37) MS(ESI): 547 (M+H+).

70 mg of (0.1278 mmol) of the compound 41 are dissolved in accordance

with route A in 2 ml of methanol, and  1.02 ml (0.511  mmol) of sodium

methanolate solution  (0.5M)  in tetrahydrofuran . are added.  After 5 -min,

20    27.6 mg (0.516 mmol) of ammonium chloride and 2.0 g of Si02 are added. The solution is concentrated and the product is filtered through silica gel and washed first with EtOAc and then with EtOAc/methanol 20:1. 50 mg (90%) of the compound 42 are obtained as a colorless solid.
C17H19C12FN205 (421.26) MS(ESI): 420 (M+H+).
 

49

Example 10 (compound 43)


50 mg of compound 41 are dissolved in accordance with route B in 2.0 ml of DMF and, at room temperature, 50 mg of K2C03 and 57 jJI of methyl iodide are added. After 14 days, 30 ml of EtOAc are added, and the organic phase is washed twice with 20 ~I of H20 each time and concentrated. The

10    crude product is purified by column chromatography (EtOAc/heptai:Je = 3:1) and reacted with NaOMe/MeOh in analogy to the preparation of compound
42.    9.1 mg of compound 43 are •obtained as a colorless wax. C1aH21C12FN205 (435.24) MS(ESI): 434 (M+H+).

15    Examples 7 (compound 44), 30 (compound 50) and 31 (compound 51) are synthesized in analogy to •the . synthesis described for example E (compound 42) starting from the appropriate 13-keto esters.

Example  9 (compound  45)  is synthesized  in  analogy to  the  synthesis

20    described for example  10  (compound 43)  starting from the appropriate
 
50


Patent claims


1.    A compound of the formula I


in which the meanings are


R1 and R2 independently of one another F, H or one of the radicals R1 or R2 OH;

R3    OH or F, where at least one of the radicals R1, R2, R3 must be F;

R4    •oH;


A    0, NH, CH2, S or a bond;


X    C, 0, S or N, where X must be C when Y is 0 or S;


Y    N; 0 or S;


m    a number 1 or 2;
 


25 R5 hydrogen, F, Cl, Br, I, OH, CF3, N02, CN, COOH, CO(C1-C6)-alkyl, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C5)-alkenyl,

"(Cz-C6)-alkynyl, (C1-C5)-alkoxy, HO~(C1-C6)-alkyl, (C1-C6)-alkyi-O-(C1-C6)-alkyl, phenyl, benzyl, (C1-C5)-alkoxycarboxyl, it being possible for one, more than one or all hydrogen(s) in the a!kyl, alkoxy, alkenyl or alkynyl radicals to. be replaced by fluorine;

SOz-NHz, SOzNH(C1-C6)-alkyl, SOzN[(C1-C6)-alkyl]z, S-(C1-C6)-alkyl, S-(CHz)0 -phenyl, SO-(C1-C6)-alkyl, 80-(CHz)o.:.phenyl, SOz-(C1-C6)-alkyl, SOz-(CHz)0 -phenyl, where o can be 0-6, and the phenyl radical may be substituted up to twice• by F, Cl, Br, OH, CF3, NOz, CN, OCF3, O-(C1-C6)-alkyi,_(C1-C6)-alkyl, NHz;

NHz, NH-(C1-C5)-alkyl, N((C1-C6)-alkyl)z, NH(C1-C7)-acyl, •phenyl, O-(CHz) 0 -phenyl, where o can be 0-6, where the phenyl ring may be substituted one to 3 times by F, Cl, Br, I, OH, CF3, NOz, CN, OCF3, O-(C1-C6)-alkyl, (C1-C5)-alkyl, NHz, NH(C1-C5)-alkyl, N((C1-C6)-alkyl)z, SOz-CH3, COOH, COO-(C1-C6),.alkyl, CONHz;

or when Y is S, R5 and R6 together with the C atoms carrying them phenyl;

R6 optionally H, (C1-C5)-alkyl, (C1-C5)-alkenyl, (C3-C6)-cycloalkyl, or phenyl that may optionally be substituted by halogen or (C1-C4)-alkyl;

. B• (Co-C15)-alkanediyl, it being possible for one or more C atoms in the alkanediyl radical to be replaced independently of one another by -0-, -(C=O)-, -CH=CH-, -C=C-, -S-, -CH(OH)-,. -CHF-, -CFz-, -(S=O)-, -(SOz)-, -N((C1-C6)-alkyl)-, -N((C1-C5)-alkyl-phenyl)- or -NH-;


n    a number from 0 to 4;


Cyc1 a 3 to 7 membered saturated, partially saturated or unsaturated ring, where 1 C atom may be replaced by 0, Nor

S;


R7, RS, R9 hydrogen, F, Cl, Br, I, OH, CF3, NOz, CN, COOH, COO(C1-C5)-alkyl, CO(C1-C4)-alkyl, CONHz, CONH(C1-C6)-alkyl, CON[(C1-C5)-alkyl]z, (C1-C5)-alkyl, (Cz-C6)-alkenyl,

(Cz-C6)-alkynyl, (C•1-Cs)-alkoxy, HO-(C1-C5)-alkyl, (C1-C6)-alkyi-O-(C1-C6)-alkyl, •it being possible for one, more than one or all hydrogen(s) in the alkyl, alkoxy, alkenyl or alkynyf radicals to be replaced by fluorine~

SOz-NHz, SOzNH(C1-C5)-alkyl, SOzN[(C1-C6)-alkyl]z, S-(C1-C5)-alkyl, S-(CHz)0 -phenyl, SCF3, SO-(C1-C6)-alkyl, SO-(CHz)o-phenyl, SOz-(C1-C6)-alkyl, SOz-(CHz)0 -phenyl, where o can be 0-6, and the phenyl radical may be substituted up to twice by F, Cl, Br, OH, CF3, NOz, CN, OCF3, O-(C1-C5)-alkyl, (C1-C5)-alkyl, NHz;

•NHz, NH-(C1-C5)-alkyl, N((C1-C5)-alkyl)z, NH(C1-C7)-acyl, phenyl, O-(CHz) 0 -phenyl, where o can be 0-6, where the phenyl ring may be substituted one to 3 times by F, Cl, Br, I, OH, CF3, NOz, CN, OCF3, (C1-Cs)-alkoxy, (C1-C5)-alkyl, NHz, NH(C1-C6)-alkyl, N((C1-C5)-alkyl)z, S02-CH3, COOH, COO(C1-C5)-alkyl, CONHz;

or

R8 and R9   together  with  the  C atoms  carrying  them  a  5  to

7 membered,  saturated,  partially or completely  unsaturated

. ring Cyc2, it being possible for 1 or 2 C atom(s) in the ring also to be replaced by N, 0 or S, and Cyc2 may optionally be substituted by (C1-C5)-alkyl, (Cz-Cs)-alkenyl, (Cz-Cs)-alkynyl, where in each case one CHz group may be replaced by 0, or substituted by H, !=, Cl, OH, CF3; NOz, CN, COO(C1-C4)-alkyl, CONHz, CONH(C1-C4)-alkyl, OCF3;

and the pharmaceutically acceptable salts thereof.


2.    A compound of the formula I as claimed  in claim 1, in which the
 

30    meanings are


R1 and R2 independently of one another F or H and one of the radicals R1 or R2 = OH, where one of the radicals R1 or R2 must be F;

35
A    0 or NH;


X    C, 0 or N, where X must be C when Y is S;

y    S orN;


m    a number 1 or 2;


R5 hydrogen, F, Cl, Br, I, OH, CF3, N02, CN, COOH, CO(C1-C5)-alkyl, COO(C1-C6)-alkyl, CONH2, CONH(C1-C5)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl; (C1-C5)-alkoxy, HO-(C1-C5)-alkyl, (C1-C6)-alkyi-O-(C1-C6)-alkyl, phenyl, benzyl, (C1-C4)-alkylcarboxyl, SO-(C1-C5)-alkyl, it being possible for one, more than one or all hydrogen(s) in the alkyl or alkoxy radicals to be replaced by fluorine; or

when Y is S, R5 and R6 together with the C atoms carrying them phenyl;

R6 optionally H, (C1-C5)-alkyl, (C1-C5)-alkenyl, (C3-C5)-cycloalkyl, or phenyl that may optionally be substituted by halogen or (C1-C4)-a•lkyl;

8    (Co-C15)-alkanediyl, where one or more C atom(s) in the alkanediyl radical may be replaced independently of one another by -0-, -(C=O)-, -CH=CH-, -C=C-, -S-, -:CH(OH)-, -CHF-, -CF2-, -(S=O)-, -(S02)-, -N((C1-C5)-alkyl)~, -N((C1-C5)-alkyl-phenyl)- or -NH-;

n    a number from 0 to 4;


Cyc1 a 3 to 7 membered saturated, partially saturated or unsaturated ring, where 1 C atom may be replaced by .Q or S;

R7, R8, R9 hydrogen, F, Cl, Br, 1', OH, CF3, N02, CN, COOH, COO(C1-C6)-alkyl, CO(C1-C4)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (~1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C1-Ca)-alkoxy, HO-(C1-C5)-alkyl, (C1-C5)-a!kyi-O-(C1-C6)-alkyl,
 

54

SO-(C1-C5)-alkyl, it being possible for one, more than one or

. -all hydrogen(s)--in the alkyl or alkoxy radicals to be replaced by fluorine;

or

5 RB and R9 together with the C atoms carrying them a 5 to 7 membered, saturated, partially or completely unsaturated ring Cyc2, where 1 or 2 C atom(s) in the ring may also be replaced by N, 0 or S, and Cyc2 may optionally be substituted by (C1-C5)-alkyl, (C2-C5)-alkenyl, •(C2-Cs)-alkynyl,

10 where in each case one CH2 group may be replaced by 0, or substituted by H, F, Cl, OH, CF3, N02, CN, COO(C1-C4)-alkyl, CONH2, CONH(C1-C4)-alkyl, OCF3.

3.    A compound of the formula I as claimed in claim 1 or 2, in which the

15    sugar residues are beta(B).-Iinked and the stereochemistry in the 2-, 3- and 5-position of the sugar residue has the D-gluco configuration.

4.    A compound of the formula I as claimed in claims 1 to 3, in which


20 R1 and R2 are independently of one another F, H or one of the radicals R1 or R2=0H, where at least one of the radicals R1 or R2 must be F;



R3    is OH;

25

R4    is  OH;

A    isO;


30    X is C, 0 or N, where X must be C when Y is S;


Y isS or N;


m    is a number 1;

35

R5 is hydrogen, (C1-C5)-alkyl, (C1-C4)-alkoxy, HO-(C1-C4)-alkyl, (C1-C4)-alkyi-O-(C1-C4)-alkyl, F, Cl, CF3, OCF3, OCH2CF3, (C1-C4)-alkyi-CF2-, phenyl, benzyl, (C1-C4)-alkylcarboxyl, (C?-C4)-alkenvl, (C2-C4)-alkynyl, COO(C1~C4)-alkyl;
 

        55
        or
        when Y is S, R5 and R6 together with the C atoms carryin~
        • th~m are phenyl;
5    R6    is  optionally  H,  (C1-C5)-alkyl,  (C1-C5)-alkenyl,  (C3-C5)
        cycloalkyl,  or phenyl that may optionally . be substituted  b:
        halogen oi- (C1-C4)-al~yl;
    B    •is (C1-C4)-alkanediyl,  where one  CH2 group may also  bE
•1 0        replaced by -(C=O)-, -CH(OH)-, -CO-NH-, -CHF-, -CF2-, -0-;•
    n    is a number 2 or 3;
    Cyc1  is an unsaturated 5- or 6-membered. ring, where 1 C aton
15        may be replaced•by 0 or S;


R7, R8, R9 are hydrogen, (C1-C4)-alkyl, (C1-Cs)-alkoxy, S-(C1 C4)-alkyl, SCF3, F, Cl, Br, I, OCF3, OCH2CF3, OH, HO (C1-C4)-alkyl, (C1-C4)-alkyi-O-(C1-C4)-alkyl, or

20

R8 and R9 together are -CH=CH-0-, -CH=CH-S-, -CH=CH CH=CH-, which is optionally substituted by (C1-C4)-alkoxy, c -O-(CH2)p-O-, with p = 1 or 2 and

25    R7 is hydrogen.


5.    A compound of the formula I as claimed in claims 1 to 4, in which


R1, R2 are H or F, where one of the radicals R1, R2 must be F;

30

R3    isOH;


R4    isOH;


35    A    isO;

X    is C and Y is S, or

X    is 0 andY is N, or
 

56

X    is Nand Y is N;


m    is a number 1;.


5 R5 is hydrogen, CF3, (C1-C5)-alkyl, or when Y is S R5 and R6 together with the C atoms carrying them are phenyl;

R6    is optionally H, (C1-C4)-alkyl or phenyl;


10    B       
    n    is a number 2 or 3;
    Cyc1  is an unsaturated    5 to 6 membered ring, where 1 C atom can
. 15        be replaced by S;   


R7, R8, R9 are hydrogen, (C1-C5)~alkyl, •(C1-C4)-alkoxy, S-(C1-C4)-alkyl, SCF3,. F, Cl, Br, I, OCF3, or

20 R8 and R9 together are -CH=CH-0-, -CH=CH-CH=CH-, which is • optionally substituted by (C1-C4)-alkoxy, and

R7    is hydrogen.


25    6. A compound of the formula I as Claimed in claims 1 to 5, in which R1, R2 are H or F, where one of the radicals R1 or R2 is F;
R3 is OH;


R4 is OH; A isO;
35    X    is C and Y is S or


X    is Nand Y is N;
 


m    is a number 1;
 

57


R5    is hydrogen, (C1-C4)-alk.yl-or-GF.s or-when Y is-S R5 and RE together with the carbon atoms carrying them are phenyl;

5    • R6    is optionally H or (C1-C4)-alkyl;


B    is -CH2- or -CO-NH-CH2-;


n    is a number 2 or 3;

10

Cyc1  is phenyl or thiophene;


R7    is hydrogen, methoxy, F, Cl, Br, I; (C1-C4)-alkyl, OCF3;


15    R8, R9  are hydrogen or Cl or


R8 and R9 together with the carbon atoms carrying them are phenyl which may optionally be substituted by methoxy, o

• furan and

20

R7    is hydrogen.


7.    A medicament comprising one or more of the compounds as claimed in one or more of claims 1 to 6.
25

8.    A medicament comprising one or more of the compounds as claimed in one or more of claims 1 to 6 and one or more blood glucose-lowering active ingredients.

30    9.    •The use of the compounds as claimed in one or more of claims 1 to

6 for producing a medicament for the treatment of type 1 and type 2 diabetes.

10.    The use of the compounds as claimed in one or more of claims 1

35    to 6 for producing a medicament for lowering blood glucose.


11.    The use of the compounds as claimed in one or more of claims 1 to 6 in combination with at least one other blood glucose-lowering active ingredient for producing a medicament for the treatment of

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