US3879541A - Antihyperglycemic methods and compositions - Google Patents

Antihyperglycemic methods and compositions Download PDF

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US3879541A
US3879541A US32421873A US3879541A US 3879541 A US3879541 A US 3879541A US 32421873 A US32421873 A US 32421873A US 3879541 A US3879541 A US 3879541A
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blood sugar
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Hans-Joachim Kabbe
Harald Horstmann
Hans Plumpe
Walter Puls
Siegfried Petersen
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Bayer AG
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24Y being a hetero atom
    • C07C279/26X and Y being nitrogen atoms, i.e. biguanides

Abstract

The blood sugar level of hyperglycemic animals can be reduced through administration of an N1-phenylbiguanide which is substituted in the N5-position by the group CH2R2 in which R2 is hydrogen, alkyl of 1 to 7 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms, cyclohexyl or vinyl, and optionally substituted by one or two groups in the phenyl ring. Solid, orally administered pharmaceutical compositions are also described. A typical embodiment is the use of N1-(4-chlorophenyl)-N5-(npropyl)biguanide hydrochloride which can be administered in a tablet, capsule or dragee.

Description

United States Patent Kabbe et al.

1*Apr. 22, 1975 ANTIIIYPERGLYCEMIC METHODS AND COMPOSITIONS Inventors: Hans-Joachim Kabbe, Leverkusen;

Harald I-Iorstmann, Wuppertal-Elberfeld; Hans Plumpe, Wuppertal-Elberfeld; Walter Puls, Wuppertal-Elberfeld; Siegfried Petersen, Leverkusen, all of Germany Notice: The portion of the term of I this patent subsequent to Sept. 19, 1989, has been disclaimed.

Assignee: Bayer Aktiengesellschaft,

Leverkusen, Germany Filed: Jan. 16, 1973 Appl. No.: 324,218

Related US. Application Data Continuation-in-part of Ser. No. 118,958, Feb. 25, 1971, abandoned, and Ser. No. 120,332, March 2, 1971, abandoned.

Foreign Application Priority Data Mar. 3, 1970 Germany 2009738 Mar. 3. 1970 Germany 2009743 U.S. Cl. 424/326 Int. Cl. A6lk 27/00 Field of Search 118/958; 120/332; 426/326 56] References Cited UNITED STATES PATENTS 2,961,377 1 1/1960 Shapiro et a1 424/326 3.689.674 9/1972 Kabbe et al 424/326 FOREIGN PATENTS OR APPLICATIONS 581.346 10/1946 United Kingdom 424/326 649,692 1/1951 United Kingdom 426/326 OTHER PUBLICATIONS Chemical Abstracts, Vol. 41, (1947), 16264628; Vol. 43, (1949), 5868; Vol. 44, (1950) 6032.

Primary E.raminer-Frederick E. Waddel] [57] ABSTRACT 14 Claims, No Drawings ANTIHYPERGLYCEMIC METHODS AND COMPOSITIONS CROSS-REFERENCE This is a continuation-in-part of Ser. No. 118,958, filed Feb. 25, 1971, and Ser. No. 120,332, filed Mar. 2, 1971 now abandoned.

DETAILED DESCRIPTION The present invention pertains to a method of treating hyperglycemia and to solid, orally administerable pharmaceutical compositions for use in this treatment.

As a result of the extensive work of Curd and coworkers, a wide variety of biguanides were prepared as potential antimalarial agents; see for example British patent specification Nos. 577,843; 599,714; 603,069; 603,070; 607,720; 618,613; 624,540; and 667,094. This extensive program led to the development of compound No. 4888 which is N-(4-chlorophenyl)-N isopropylbiguanide or proguanil. This compound possessed unique action on the preerythrocytic and erythrocytic forms of a number of species of avian malaria parasites and has been used since that time in the treat ment of malaria. Curiously there is substantial evidence that the compound itself has little effect on the malaria parasite and Hawkins et al., Brit. J. PharmacoL, 3, 320 (1948) have suggested that it is transformed by the body into a different active species. At present, it is believed that this active species may be cycloguanide which is l(4-chlorophenyl)-2,2-dimethyl-4,6-diamino* 1,2-dihydro-l,3,5-triazine. In actual use, proguanil is administered to humans for therapeutic purposes at doses in the range of 300 mg per day, generally through the administration of 100 mg tid. In an examination of the toxicity and general pharmacology of proguanil, Chen et al. noted a slight blood sugar depressing effect. J. Pharmacol. Exp. Therap., 91, 157 1947). The slight hypoglycemic effect of the compound was not considered remarkable by Chen et al. and occurred only at a dose approaching the toxic dose and well above the therapeutic dose of the compound when utilized for the treatment of malaria. The poor antidiabetic effect of N'-ary1-N -alkylbiguanide has also been observed by Elpern, Ann. N.Y. Acad. Sci., 148,577 (1968).

The present invention is based upon the discovery that a specific class of N -phenyl-N -substituted biguanides possess remarkable anti-hyperglycemic action at doses far lower than would have been expected from the work of Chen et al. and indeed far lower than the doses contemplated for such compounds as proguanil when utilized in the treatment of malaria. In particular, the present invention pertains to the method of achieving a hypoglycemic effect, in particular a antihyperglycemic effect, through administration of an effective amount of a biguanide of the formula:

NH NH R 1| 1 uu-c-mr-c-mtcl -a wherein each of R and R, independent of the selection of the other, is selected from the group consisting of hydrogen,

alkyl of 1 to 6 carbon atoms, alkoxy of l to 6 carbon atoms, chloro, fluoro and bromo, and

R is hydrogen, alkyl of 1 to 7 carbon atoms, alkoxyalkyl having a total of 2 to 5 carbon atoms, cyclohexyl or vinyl, or an equivalent amount of nontoxic acid addition salt thereof.

In addition, the present invention provides a solid, orally administerable composition adapted for use in the foregoing method of treating hyperglycemia, which composition comprises a pharmaceutical carrier in admixture with a unit dosage amount of from about 5 to about 55 mg of the above specified biguanide or an equivalent amount of a non-toxic acid addition salt thereof.

In view of the findings of Chen et al., supra, concerning proguanil, the most active of the N -phenyl-N substituted biguanides in terms of antimalarial effect, it is totally unexpected that compounds of the above formula should demonstrate such outstanding antihyperglycemic effects and do so at extremely low and non-toxic levels. Moreover, in comparison with known biguanides which are commercially available as antidiabetic agents, such as n-butylbiguanide and N,N- dimethylbiguanide, the compounds utilized in the present invention can be administered for therapeutical purposes at lower doses and superior therapeutic ratios.

The compounds utilized in the present invention can be prepared for example through the reaction of an appropriately substituted aniline with a dicyanodiamide. Alternatively, an amine of the formula R Nl-l can be reacted with a phenyl dicyanodiamide. Finally, it is possible to prepare the compounds utilized in the present invention through the reaction of a thio or dithiobiuret, or an S-alkyl derivative thereof with an appropriately substituted aniline, amine or ammonia.

1n the method of the present invention, a biguanide as herein defined is administered to effect an antihyperglycemic response. As with any hypoglycemic agent, the specific dosage and dosage regimen must in each case be carefully adjusted to the recipient, utilizing sound professional judgement and taking into consideration the age, weight and conditions of the recipient, the nature and gravity of the illness and the response observed in the specific individual. in general, a hypoglycemic effect can be observed utilizing a daily dose of from 2.5 to 10 mg/kg. In some instances, a hypoglycemic effect can be obtained at a lower dose while in others, a larger dose may be required. Preferably, the biguanide is administered in a single daily dose although it can also be divided into two, three or more doses per day. The route of administration is oral and such administration can be effected utilizing solid dosage unit forms such as powders, tablets, dragees, capsules and the like. These can be formulated so as to provide a sustained release pattern. These solid dosage unit forms intended for oral administration will comprise the biguanide in an amount of from 0.5 to of the total composition together with a pharmaceutical carrier which is non-toxic, inert and pharmaceutically acceptable. Other therapeutic agents can also be present but in general no advantage is observed in administering two therapeutic agents in a single dose over individual administration of the two agents.

Powders are prepared by comminuting the biguanide to a suitably fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible car bohydrate, as for example starch, lactose, sucrose, glucose or mannitol. Sweetening, flavoring, preservative and/or coloring agents can also be present Capsules are prepared by filling formed gelatin sheaths with a powder mixture, prepared as above. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate and/or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can be added to improve the availability of the medicament when the capsule is ingested.

Tablets are formulated by preparing a powder mixture, granulating or slugging, adding a lubricant, optionally with a disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound with a solid diluent, as described above, and optionally with a binder such as carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidine. In addition, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or absorption agent such as bentonite, kaolin or dibasic dicalcium phosphate can be included. The powder mixture is granulated by wetting with a binder such as syrup, a starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing the mass through a screen. Alternatively, the powder mixture can be run through a tablet machine and the resulting imperfectly formed slugs broken into granules. These granules can be lubricated to prevent sticking by means of the addition of stearic acid, a stearate salt, talc or mineral oil and the lubricated mixture is then compressed into tablets. In some instances, the medicament can be combined with a free flowing inert carrier and compressed directly into tablets without going through a granulating or slugging step. The biguanide can also be mixed ,with a low melting solid such as a mixture of hydrogenated castor oil and glycerin monostearate in a melt to form a matrix which may then be pressed into tablets or coated with an outside layer of active material. A protective coating, which may be clear or opaque, such as shellac, sugar or a polymeric material may also be provided and a final polish coating of wax can then be applied. Dyestuffs can also be added to these coatings to distinguish different dosage unit forms or origin of manufacture.

As noted above, prolonged or sustained release formulations are also included in these compositions and can be'achieved through microencapsulation, or by coating or embedding particulate material in polymers, wax or the like.

Although these solid oral dosage unit forms can contain from 5 to as much as 100 mg of biguanide, generally the amount will be from about 5 to about 55 mg and most preferably about 30 mg of biguanide per single dosage unit form.

The desired anti-hyperglycemic effect of the compounds utilized in these compositions can be conveniently observed in well known and conventional animal models. Thus for example the test compound is administered orally to fasting rats at several dosage levels. After several administrations, a solution of glucose in physiological saline is administered per s. The blood glucose level of the animal is measured 30 to 60 minutes after administration of the glucose and the dose which causes a significant (P 0.05) reduction in byperglycemia is recorded. Typical results are as follows (for the hydrochlorides except as otherwise noted).

" naphthalcncl .S-disulfonalc The toxicity of the compounds utilized in the present method and composition is also favorable.

N Substitucnt N Substitucnt LD (Rat mg/kg) 4-methylphcnyl n-propyl 198 n-butyl 87 isobutyl 302 3-methylphcnyl n-butyl 57 3 3,4-dimcthylphenyl n-butyl 600 isobutyl 28 8 4-ethylphenyl n-propyl 208 n-butyl 204 isobutyl 23 3 B-methoxycthyl 420 4-n-butylphenyl n-pentyl 1000 phenyl n-butyl 25 6 isobutyl 636 4-mcthnxyphenyl isobutyl 808 3-mcthoxyphcnyl n-butyl 45 2 isobutyl 55 2' 4-chlorophenyl n-propyl I20 I n-butyl 320 isobutyl 38 2 n-pentyl 45 2 n-propyl 7l 4-fluorophcnyl isobutyl 367 naphthalene-l.5-disulfonatc in mouse In contrast to the above, proguanil as the hydrochloride demonstrates anti-hyperglycemic activity at 10 mg/kg but has an LD of 114 mg/kg in the rat. The known n-butyl biguanide demonstrates antihyperglycemic activity at 16 mg/kg with an LD of 220 mg/kg in the rat.

The following examples will serve to further typify the nature of this invention but should not be construed as a limitation thereof, the invention being defined solely by the appended claims.

EXAMPLE I A mixture of 18.8 g 4-ethylphenyldicyanodiamide and 8.2 g ethylamine hydrochloride is heated at C.

for 1 hour. The resultant oil is dissolved hot in I00 ml isopropanol and upon'coolin'g, there are obtained 15.6

1 5 g (58%) N -(4-ethylphenyl)-N -ethylbiguanide hydro- Continued chloride, m.p. 165 167C.

EXAMPLE 2 N Substituent N5 Substituent Melting Point (HCl) A mixture of 17.4 g 5-methylphenyldicyanodiamide 5 any] lgmgfioc and 16.6 g n-octylamine hydrochloride is reacted as den-butyl 21 1-212C scribed in Example 1. There are thus obtained 16.2 g isobutyl 239-2403: (48%) N -(4-methylphenyl)-N -n-octylbiguanide as 21333 "$338 C the hydrochloride, m.p. 183 185C. n-octyl 190-l91C 1O B-methoxycthyl 165- 1 67C EXAMPLE 3 3-chlorophenyl isobutyl 212-214C 4-bromo hen l nent'l l99-20lC A mixture of 16 g p-anisidine hydrochloride and 14 p y p y g n-butyldicyanodiamide is stirred at 160C for 2 hours. Upon dissolving the product in isopropanol and cooling there are obtained 11.3 g (34%) of the hydrochloride 15 EXAMPLE 6 l 5 Salt of o N YP Y Y Conversion of the hydrochloride salt of N -(4- 186 chlorophenyl)-N -propy1biguanide to the free base and treatment with naphthalene-l,S-disulfonic acid ields EXAMPLE 4 h d h h l 5 d If y l t e corres on in na t a ene-l isu onate sa t, A mixture of 13.9 g N-p-tolyl-N -n-pentylguanyl thio- 0 o p o g p mp 169 -171 C.

urea, 12 g mercury oxide and 100 ml of 17% ammonia in methanol is stirred in a pressure vessel at 50C for 6 EXAMPLE 7 hours' Insoluble mimer removed by filtrallon The following formulations are specific embodiments under suction and the filtrate is concentrated, mixed of pharmaceutical compositions in which the biguanide with ml of 2N hydrochloric acid and concentrated 25 s can be any of those set forth above: again. The residue is recrystallized from isopropanol to yield 6 g (38%) N -(4-methylphenyl)-N -n-pentyl biguanide (compound 6) in the form of the hydrochloride, m.p. 215C. A Tablet Ingredient Amount/Tablet EXAMPLE 5 Biguanidc 30 mg. [n a similar fashion to that described in Examples Lactose 99 mg, 1-3, disubstituted biguanides, which are described by Starch 60 I Talcum 10 mg. analogous chemical terminology, are obtained. Magnesium stearate 1 mg 200 mgv N Substitucnt N5 Substitucnt Melting Point (HCl) The biguanide, lactose and half the quantity of maize phcnyl mpmpyl ZOLZOQOC 40 starch are mixed, kneaded together with a paste of one n-butyl 206208C quarter of the quantity of maize starch. This mass is i pressed through a sieve with 3 5 mm. mesh size, and Z1 4 methy|phcny| ethyyl 303 204C dried at 60 80C. The dry granulate is forced through -g p y a sieve with 0.8 mm. mesh width, and the remaining figgjl 227:2396C maize starch, talcum and magnesium stearate are p y mixed in. The composition is pressed mto round tablets g fjg 21 8 220C of 8 mm. diameter and total weight of 200 mg. with tab- 'y-ethoxypropyl 185-187C let press, 3-mcthylphcnyl n-hutyl 188C 3.4-dimcthylphcnyl n'hutyl 207209C isobutyl l94l95C 5O 4-cthylphcnyl n-propyl 160C n.butyl 196-198C B Tablet isobutyl 22 l-222C y l 96C Ingredient Amountfl'ablet cyclohexylmethyl 205-207C 4'(n-butyl)phcnyl n-butyl 193C Bi 7 30 I, o guani 0 mg.

f [86488; Dibasic calcium phosphate 97 mg. 4-tcrtbutylphcnyl isobutyl 217-219 C G 7 m 4-fluorophcnyl isobutyl 238C I h 6 isopemyl 2| 15C agncsium stearate mg 4-methox hen l ethyl 162-164C 150 mg.

" yp y n-propyl 169-171C isobutyl 207-209c 6Q S-mcthoxyphenyl n-butyl 168l70C I I isobuty {$1225 The biguanide and calcium phosphate are mixed, 4'e.ihoxyphcnyl kneaded with an aqueous solution of gelatin, sieved Y- p y y ggi-ggfg through a 3 to 5 mm mesh and dried at to C. The

isobuty 3-chloro-4-meth0Xyp enyl isobutyl 20140; 65 dry granulate is resieved through 0.8 mm mesh. The 3-methoxy-4-methylphcnyl isigbutyl 133-13 wheat starch and magnesium stearate are mixed in and 3-chloro-4-meth l henyl nutyl z g 4mm 180C the resultant composition formed into round tablets of 213-214C mg having a diameter of 7 mm.

4chlorophenyl ri-propyl C Delayed Release Two-layer Dragee lngredicnt Amount/Dragee Nucleus Biguanidc mg.

Dibasic calcium phosphate 82 mg.

Gelatin 2 mg.

Wheat starch mg.

Magnesium stearate l mg 10 I20 mg.

40% l7( 0. l I1 I07: ad 100% Biguanide Sugar Gum arabic Gelatin Talcum Water When the applied layer contains 15 mg biguanide per dragee. the dragee is sealed with several layers ofa suspension of:

Sugar 607: Gum arabic l)? Gelatin 0.1% Talcum 10% Water ad 100% to the required final weight. Edible dye can be added to the syrup at this point and the dragees glazed or polished with glazing wax. These dragees release the first half of the the biguanide dose (15 mg) immediately in the stomach and the second half only in the intestine.

D Delayed Release Wax-matrix Tablets lngredient Amount/Tablet 5O Biguanide 30 mg. Hydrogenated castor oil 60 mg. Glycerin monostcarate 10 mg I00 mg.

E Capsules Ingredient Amount/Capsule Biguanide 30 mg. Dibasic calcium phosphate 1 16 mg. Magnesium stcarate 3 mg. Colloidal silicic acid l mg The ingredients are mixed and filled into hard gelatin capsules.

F Capsules lngredient Amount/Capsule Biguanide 30 mg. Lactose 60 mg. Polyvinylpyrrolidonc 3 mg. Stearic acid 1 mg. Colloidal silicic acid I mg. Talcum 5 mg The biguanide and lactose are mixed, kneaded with a solution of polyvinylpyrrolidone and stearic acid in methylene chloride, sieved (3 5 mm) and dried (50 60C). The dry granulate is forced through a sieve with mesh width of 0.5 0.6 mm. Colloidal silicic acid and talcum are mixed in, and the resultant composition is filled with a suitable apparatus into hard gelatin capsules.

Alternatively, the wax granulate described in Example 7!), instead of being tabletted, can be introduced into hard gelatin capsules to provide capsules with delayed release of the biguanide.

What is claimed is:

l. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a. blood sugar lowering amount of a component of the formula 11a in 2 NE- mt NHCHZ a or a pharmaceutically acceptable non-toxic acid addior a pharmaceutically acceptable non-toxic acid addition salt thereof wherein one of R and R is hydrogen and the other is 4-methyl, and R is isobutyl.

3. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula I l NE- --NH "NECK R or a pharmaceutically acceptable non-toxic acid addition salt thereof wherein one of R and R is hydrogen and the other is 3-methyl, and R is n-butyl.

4. A method of reducing the blood sugar level in a hy perglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula flu Ha un- -mrmicu R2 or a pharmaceutically acceptable non-toxic acid addition salt thereof wherein one of R and R is hydrogen and the other is 4 ethyl, and R is n-propyl.

5. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula I E NH== ==NH=. unen R2 or a pharmaceutically acceptable non-toxic acid addition salt thereof wherein one of R and R is hydrogen and the other is 4ethyl, and R is n-butyl.

6. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula or a pharmaceutically acceptable non-toxic acid addition salt thereof wherein one of R and R is hydrogen and the other is 4-ethyl, and R is isobutyl.

7. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula Ha NH- c-uauucu R2 or a pharmaceutically acceptable non-toxic acid addition salt thereof wherein R and R are both hydrogen, and R is isobutyl.

9. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula or a pharmaceutically acceptable non-toxic acid addition salt thereof wherein one of R and R is hydrogen and the other is 3-methoxy, and R is n-butyl.

10. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula i i NH' NH- -uuca R2 or a pharmaceutically acceptable non-toxic acid addition salt thereof wherein one of R and R is hydrogen and the other is 3-methoxy, and R is isobutyl.

11. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula i i NH- -NH NHCH2- R2 or a pharmaceutically acceptable non-toxic acid addition salt thereof wherein one of R and R is hydrogen and the other is 4-chloro, and R is n-butyl.

12. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula or a pharmaceutically acceptable non-toxic acid addition salt thereof wherein one of R and R is hydrogen and the other is 4-chloro, and R is isobutyl.

13. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula 3" l Nil- -NH --Nl'lCH R or a pharmaceutically acceptable non-toxic acid addition salt thereof wherein one of R and R is hydrogen and the other is 4-fluoro, and R is isobutyl.

Claims (14)

1. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a component of the formula
1. A METHOD OF REDUCING THE BLOOD SUGAR LEVEL IN A HYPERGLYCEMIC HUMAN OR ANIMAL WHICH COMPRISES ORALLY ADMINISTERING TO SUCH HUMAN OR ANIMAL A BLOOD SUGAR LOWERING AMOUNT OF A COMPONENT OF THE FORMULA
2. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
3. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
4. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
5. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
6. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
7. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
8. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
9. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
10. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
11. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
12. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
13. A method of reducing the blood sugar level in a hyperglycemic human or animal which comprises orally administering to such human or animal a blood sugar lowering amount of a compound of the formula
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US6548481B1 (en) 1998-05-28 2003-04-15 Probiodrug Ag Effectors of dipeptidyl peptidase IV
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US20030148961A1 (en) * 2001-10-12 2003-08-07 Ulrich Heiser Peptidyl ketones as inhibitors of DPIV
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US20040033051A1 (en) * 2002-08-16 2004-02-19 Ip Kiril Kun Wan Method and system for producing and displaying visual presentations which inhibit off-screen duplication
US20040043919A1 (en) * 2000-10-27 2004-03-04 Stephan Von Horsten Method for the treatment of neurological and neuropsychological disorders
US20040058876A1 (en) * 2002-09-18 2004-03-25 Torsten Hoffmann Secondary binding site of dipeptidyl peptidase IV (DP IV)
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US20040171555A1 (en) * 1998-06-24 2004-09-02 Hans-Ulrich Demuth Prodrugs of DP IV-inhibitors
US20040214762A1 (en) * 2001-08-16 2004-10-28 Hans-Ulrich Demuth Use of inhibitors of proline endopeptidase to modulate inositol (1,4,5) triphosphate concentration dependent on intracellular signal cascades
US20040224875A1 (en) * 2003-05-05 2004-11-11 Stephan Schilling Inhibitors of glutaminyl cyclase
US20050058635A1 (en) * 2003-05-05 2005-03-17 Hans-Ulrich Demuth Use of effectors of glutaminyl and glutamate cyclases
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US20050171112A1 (en) * 2003-11-03 2005-08-04 Probiodrug Ag Combinations useful for the treatment of neuronal disorders
US20050176622A1 (en) * 2002-09-18 2005-08-11 Kerstin Kuhn-Wache Secondary binding site of dipeptidyl peptidase IV (DPIV)
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US7368421B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
US20100099721A1 (en) * 2003-11-03 2010-04-22 Probiodrug Ag Novel compounds for the treatment of neurological disorders
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US20030134802A1 (en) * 1998-05-28 2003-07-17 Hans-Ulrich Demuth Novel effectors of dipepetidyl peptidase IV
US20050203030A1 (en) * 1998-05-28 2005-09-15 Hans-Ulrich Demuth Novel effectors of dipeptidyl peptidase IV
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US7166579B2 (en) 1998-06-24 2007-01-23 Prosidion Limited Prodrugs of DP IV-inhibitors
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US20030176357A1 (en) * 1998-10-06 2003-09-18 Pospisilik Andrew J. Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels
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US20030092630A2 (en) * 1999-08-24 2003-05-15 Probiodrug Ag New effectors of dipeptidyl peptidase iv for topical use
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US20030008905A1 (en) * 2000-03-31 2003-01-09 Hans-Ulrich Demuth Method for the improvement of islet signaling in diabetes mellitus and for its prevention
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US20040043919A1 (en) * 2000-10-27 2004-03-04 Stephan Von Horsten Method for the treatment of neurological and neuropsychological disorders
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US20040092495A1 (en) * 2001-03-21 2004-05-13 Gerard Moinet Biguanide derivatives
US7285681B2 (en) 2001-03-21 2007-10-23 Merck Patent Gesellschaft Biguanide derivatives
US6890905B2 (en) 2001-04-02 2005-05-10 Prosidion Limited Methods for improving islet signaling in diabetes mellitus and for its prevention
US20030130199A1 (en) * 2001-06-27 2003-07-10 Von Hoersten Stephan Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
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US7368421B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
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US20040214762A1 (en) * 2001-08-16 2004-10-28 Hans-Ulrich Demuth Use of inhibitors of proline endopeptidase to modulate inositol (1,4,5) triphosphate concentration dependent on intracellular signal cascades
US20050107308A1 (en) * 2001-08-17 2005-05-19 Pospisilik Andrew J. Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels
US7144856B2 (en) 2001-09-06 2006-12-05 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US6844316B2 (en) 2001-09-06 2005-01-18 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US20050233978A1 (en) * 2001-09-06 2005-10-20 Andre Niestroj Novel inhibitors of dipeptidyl peptidase I
US20030119738A1 (en) * 2001-09-06 2003-06-26 Andre Niestroj Novel inhibitors of dipeptidyl peptidase I
US20030148961A1 (en) * 2001-10-12 2003-08-07 Ulrich Heiser Peptidyl ketones as inhibitors of DPIV
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US20040033051A1 (en) * 2002-08-16 2004-02-19 Ip Kiril Kun Wan Method and system for producing and displaying visual presentations which inhibit off-screen duplication
US20040058876A1 (en) * 2002-09-18 2004-03-25 Torsten Hoffmann Secondary binding site of dipeptidyl peptidase IV (DP IV)
US20050176622A1 (en) * 2002-09-18 2005-08-11 Kerstin Kuhn-Wache Secondary binding site of dipeptidyl peptidase IV (DPIV)
US20050058635A1 (en) * 2003-05-05 2005-03-17 Hans-Ulrich Demuth Use of effectors of glutaminyl and glutamate cyclases
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US7381537B2 (en) 2003-05-05 2008-06-03 Probiodrug Ag Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease
US20040224875A1 (en) * 2003-05-05 2004-11-11 Stephan Schilling Inhibitors of glutaminyl cyclase
US7462599B2 (en) 2003-10-15 2008-12-09 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
US20060189523A1 (en) * 2003-10-15 2006-08-24 Stephan Schilling Use of effectors of glutaminyl and glutamate cyclases
US20050171112A1 (en) * 2003-11-03 2005-08-04 Probiodrug Ag Combinations useful for the treatment of neuronal disorders
US20100099721A1 (en) * 2003-11-03 2010-04-22 Probiodrug Ag Novel compounds for the treatment of neurological disorders
US20100159032A1 (en) * 2003-11-03 2010-06-24 Probiodrug Ag Combinations useful for the treatment of neuronal disorders
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