WO2006002983A1

WO2006002983A1 - Combination of organic compounds

Info

Publication number: WO2006002983A1
Application number: PCT/EP2005/007252
Authority: WO
Inventors: Victor Hartmann
Original assignee: Novartis Ag; Novartis Pharma Gmbh
Priority date: 2004-07-06
Filing date: 2005-07-05
Publication date: 2006-01-12

Abstract

The invention relates to a pharmaceutical combination comprising an AT1 receptor blocker or pharmaceutically acceptable salts thereof and a compound which exhibits advanced glycosylation end product (AGE) breaking activity (also called AGE breaker)or a pharmaceutically effective salts thereof, optionally in the presence of a pharmaceutically acceptable carrier.

Description

Combination of Organic Compounds

The present invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising an AT1 receptor blocker or pharmaceutically acceptable salts thereof and a compound which exhibits advanced glycosylation end product (AGE) breaking activity (also called AGE breaker), optionally in the presence of a pharmaceutically acceptable carrier for simultaneous, separate or sequential use, especially in the prevention, delay of progression or treatment of cardiac and renal related conditions and in the prevention, delay of progression or treatment of diabetes and aging-related vascular complications; the use of such combination for the preparation of a pharmaceutical preparation for the prevention, delay of progression or treatment of such conditions.

The present invention relates to pharmaceutical compositions comprising an AT1 receptor blocker or pharmaceutically acceptable salts thereof a,nd a compound which exhibits advanced glycosylation end product (AGE) breaking activity or a pharmaceutically effective salt thereof, optionally in the presence of a pharmaceutically acceptable carrier.

The present invention furthermore relates to pharmaceutical compositions which comprise in combination an AT 1- receptor blocker and a compound which exhibits advanced glycosylation end product (AGE) breaking activity selected from the group of :

a) Pyridinium, 3-((2-(methylslufonyl) hydrazino) carbonyI)-1-(2-oxo-2-(2-thienyl)ethyl)-, bromide of general formula 1

b) compounds of general formula 2

wherein

R 1 is -R 4 -R 5 or -N(R 7 )N (R 7 )R 9 ;

R 4 is selected from the group consisting of -N(R 7 )R 6 O--, -N(R 7 )R 6 N(R 7 )-, OR 6 O, and -OR 6 N(R 7 )-,

where R 6 is alkyl;

R 5 is selected from the group consisting of alkyl, aryl including heteroaryl, —COR 7 , SO 2 R 7 , -C(S)NHR 7 , -C(NH)NHR 7 , -COR 10 ,

where R 7 is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R 7 might be different for R 1 and R 3 in the same compound; R 2 is selected from the group consisting of F, Cl, Br, I, OR 7 , NO 2 , alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR 7 R 10 , C(O)OR 7 , NR 7 R 10 , N&oxH;C(R 7 )(R 10 ), SR 7 , SO 2 NH 2 , SO 2 alkyl and SO 2 aryl,

and m is 0, 1 or 2;

R 3 is selected from the group consisting of R 7 , OR 7 , N(R 7 )(R 10 ), N&oxH;C(R 7 )(R 10 ), N(R 7 )N(R 7 )(R 10 ), N(R 7 ) N&oxH;C(R 7 )(R 10 ) and CH(R 7 )C(O)R 8

where R 8 is selected from the group consisting of R 7 , OR 7 and NR 7 R 10 ;

R 9 is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, C(O)R 10 , -SO 2 R 10 , -C(S)NHR 10 , -C(NH)NH(R 10 ) and -C(O)NHR 10 ,

R 10 is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case optionally different from substituent R 10 , provided R 10 might be different for R 1 and R 3 in the same compound;

X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF 4 ^"and PF 6 ^" ;

with proviso that,

(i) when two alkyl groups are present on the same carbon or nitrogen, they are optionally linked together to form a cyclic structure and

(ii) the nitrogen of heteroaryl ring of R 10 , when present, is optionally quaternized with compound such as X-CH 2 C(O)-R 3

c) compounds of general formula 3

wherein

R 1 is -R 4 -R 5 or -N(R 7 ) N (R 7 ) R 9 ;

R 4 is selected from the group consisting of -N(R 7 )R 6 O-, -N(R 7 )R 6 N(R 7 )-, -OR 6 O-, and -OR 6 N(R 7 )--, where R 6 is alkyl with C 2 to C 8 carbon atoms;

R 5 is selected from the group consisting of alkyl, aryl including heteroaryl, —COR 7 , —SO 2 R 7 , -Q(S)NHR 7 , -C(NH)NHR 7 , -COR 10 ,

where R 7 is selected from the group consisting of H, alkyl and aryl including heteroaryl ^'. provided R 7 may be the same or different for R 1 and R 3 in the same compound;

R 2 is selected from the group consisting of F, Cl, Br, I, OR 7 , NO 2 , alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR 7 R 10 , C(O)OR 7 , NR 7 R 10 , N&oxH;C(R 7 )(R 10 ), SR 7 , SO 2 NH 2 , SO 2 alkyl and SO 2 aryl, and m is 0, 1 or 2;

R 3 is selected from the group consisting of R 7 , OR 7 , N(R 7 )(R 10 ), N&oxH;C(R 7 )(R 10 ), N(R 7 )N(R 7 )(R 10 ), N(R 7 )N&oxH;C(R 7 )(R 10 ) and CH(R 7 )C(O)R 8 where R 8 is selected from the group consisting of R 7 , OR 7 and NR 7 R 10 ;

R 9 is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, — C(O)R 10 , -SO 2 R 10 , -C(S)NHR 10 , -C(NH) NH(R 10 ) and -C(O)NHR 10 ;

R 10 is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case may be the same or different from substituent R 7 , provided R 10 may be the same or different for R 1 and R 3 in the same compound; X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF 4 ^"and PF 6 ^"; with proviso that,

(i) when two alkyl groups are present on the same carbon or nitrogen, they may be linked together to form a cyclic structure and

(ii) the nitrogen of heteroaryl ring of R 10 , when present, may be quatemized with compound such as X-CH 2 C(O)-R 3 .

In a preferred embodiment, (iii) R 3 is OR 7 and R 1 is -NHNH 2 then R 7 is not alkyl, and (iv) when R 3 is OR 7 , R 1 is N(R 7 )(NR 7 )R 9 and R 9 is C(O)R 10 where R 10 is alkyl, then R 7 is not hydrogen.

d) compounds of general formula 4

wherein

R 1 is -R 4 -R 5 or -N(R 7 )N(R 7 )R 9 ;

R 4 is selected from the group consisting of -N(R 7 )R 6 O-, -N(R 7 )R 6 N(R 7 )--, OR 6 O, and -OR 6 N(R 7 )--, where R 6 is alkyl;

where R 7 is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R 7 might be different for R 1 and R 3 in the same compound; R 2 is selected from the group consisting of F, Cl, Br, I, OR 7 , NO 2 , alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR 7 R 10 , C(O)OR 7 , NR 7 R 10 , N&oxH;C(R 7 )(R 10 ), SR 7 , SO 2 NH 2 , SO 2 alkyl and SO 2 aryl, and m is 0, 1 or 2;

R 3 is selected from the group consisting of R 7 , OR 7 , N(R 7 )(R 10 ), N&oxH;C(R 7 )(R 10 ), N(R 7 )N(R 7 )(R 10 ), N(R 7 )N&oxH;C( 7 )(R 10 ) and CH(R 7 )C(O)R 8 where R 8 is selected from the group consisting of R 7 , OR 7 and NR 7 R 10 ;

with proviso that,

(ii) the nitrogen of heteroaryl ring of R 10 , when present, is optionally quatemized with compound such as X-CH 2 C(O)-R 3 e) compounds of general formula 5

wherein

R₁ is -R₄-R₅Or -N(R₇) N(R₇) R₉;

R₄ Js selected from the group consisting of - N(R₇)R₆O-, -N(R₇)R₆N(R₇)-, OR₆O, and - OR₆N(R₇)-,

where R₆ is alkyl;

[0020] R₅ is selected from the group consisting of alkyl, aryl including heteroaryl, -COR₇, SO₂R₇, -C(S)NHR₇, -C(NH)NHR₇, -COR₁₀, -C(O) NHR₇ and 3

where

R₇ is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R₇ might be different for R₁ and R₃ in the same compound;

R₂ is selected from the group consisting of F, Cl, Br, I, OR₇, NO₂, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR₇R₁₀, C(O)OR₇, NR₇R₁₀, N&oxH;C(R₇)(R₁₀), SR₇, SO₂NH₂, SO₂ alky! and S0₂alyl,

and m is 0, 1 or 2;

R₃ is selected from the group consisting of R₇, OR₇, N(R₇) (R₁₀), N&oxH; C(R₇) (R₁₀), N(R₇) N(R₇) (R₁₀), N(R₇) N&oxH;C(R₇) (R₁₀ ) and CH(R₇)C(O)R₈

where R₈is selected from the group consisting of R₇, OR₇ and NR₇R₁₀;

Rg is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, C(O)R₁₀, -SO₂ R₁₀, -C(S)NHR₁₀, -C(NH)NH(R₁₀) and - C(O)NHR₁₀,

R₁₀ is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case optionally different from substituent R₁₀, provided R₁₀ might be different for R₁ and R₃ in the same compound;

X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF₄ ^" and PF₆ ^";

with proviso that,

(ii) the nitrogen of heteroaryl ring of R₁₀, when present, is optionally quatemized with compound such as X-CH₂ C(O)-R₃ f) compounds of general formula 6

wherein

R₁ is -R₄-R₅Or -N(R₇)N(R₇)R₉;

R₄ is selected from the group consisting of — N(R₇)R₆O-, -N(R₇)R₆N(R₇)-, OR₆O, and OR₆N(R₇)-, where R₆ is alkyl with C₂ to C₈ carbon atoms; R₅ is selected from the group consisting of alkyl, aryl including heteroaryl, -COR₇, SO₂R₇, — C(S) NHR₇, -C(NH)NHR₇, -COR₁₀, 3

where R₇ is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R₇ may be the same or different for R₁ and R₃ in the same compound;

R₂is selected from the group consisting of F, Cl, Br, I, OR₇, NO₂, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR₇R₁₀, C(O)OR₇, NR₇R₁₀, N&oxH;C(R₇)(R₁₀), SR₇, SO₂NH₂, SO₂ alkyl and S0₂aryl, and m is 0, 1 or 2;

R₃is selected from the group consisting of R₇, OR₇, N(R₇) (R₁₀), N&oxH; C(R₇) (R₁₀), N(R₇) N(R₇) (R₁₀), N(R₇) N&oxH;C(R₇) (R₁₀ ) and CH(R₇)C(O)R₈ where R₈ is selected from the group consisting of R₇, OR₇ and NR₇R₁₀;

R₉ is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, C(O)R₁₀, --SO₂ R₁₀, -C(S)NHR₁₀, -C(NH) NH (R₁₀) and - C(O) NHR₁₀,

R₁₀ is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case may be the same or different from substituent R₇, provided R₁₀ may be the same or different for R₁ and R₃ in the same compound;

X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF₄ ^" and PF₆ ^"; with proviso that,

(ii) the nitrogen of heteroaryl ring of R₁₀, when present, may be quaternized.

In a preferred embodiment, (iii) R₃ is OR₇ and R₁ is -NHNH₂ then R₇ is not alkyl, and (iv) when R₃ is OR₇, R₁ is N(R₇)(NR₇)R₉ and R₉ is C(O) Ri₀ where R₁₀ is alkyl, then R₇ is not hydrogen. g) compounds of general formula 7

wherein

R1 is alkyl or aryl group;

Y is selected from the group consisting of sulfur, oxygen, nitrogen or alkyl;

A and B are independently selected from nitrogen, sulfur, oxygen or carbon to form heteroaromatic ring system;

R2, R3 and R4 are independently selected from the group consisting of F, Cl, Br, I, OR₇, NO₂, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR₆R₇, C(O) OR₆, NR₆R₇, N&oxH;C(R₆) (R₇), SR₆, SO₂NH₂, SO₂ alkyl, S0₂aryl; R₂, R₃ and R₄ might be optionally joined together to form a ring system;

If quatemized, R₅ is independently selected for the group consisting of alkyl or aryl; if not quatemized, R₅ is null, and X is null;

R₆ is independently selected from the group consisting of H, alkyl and aryl including heteroaryl provided R₆ might be different for R₂, R₃ and R₄ in the same compound;

R₇ is independently selected from the group consisting of H, alkyl and aryl including heteroaryl and in each case optionally different from substituent R₆, provided R₇ might be different for R₂, R₃ and R₄ in the same compound;

If quatemized, X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF₄ ^" and PF₆ with proviso that when two alkyl groups are present on the same carbon or nitrogen, they are optionally linked together to form a cyclic structure, h) compounds of general formula 8

or its cosmetically acceptable salts contained in a cosmetically acceptable carrier wherein

R₁ is selected from -R₄-R₅, - -N(R₇)N(R₇)R₉ and Y-R 11

R₄Js selected from the group consisting of - N(R₇)R₆O-, -N(R₇)R₆N(R₇)-, OR₆O, and - OR₆N(R₇)-,

where R₆ is alkyl;

R₅ is selected from the group consisting of alkyl, aryl including heteroaryl, -COR₇, SO₂R₇, - C(S)NHR₇, -C(NH)NHR₇, -COR₁₀, 2

R₂ is selected from the group consisting of F, Cl, Br, I, OR₇, NO₂, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR₇R₁₀, C(O)OR₇, NR₇R₁₀, N&oxH;C(R₇)(R₁₀), SR₇, SO₂NH₂, SO₂ alkyl and S0₂aryl, and m is O, 1 or 2;

R₃ is selected from the group consisting of R₇, OR₇, N(R₇)(R₁₀), N&oxH;C(R₇)(R₁₀), N(R₇)N(R₇)(R₁₀) , N(R₇)N&oxH;C(R₇)(R₁₀) and CH(R₇) C(O)R₈

Where R₈ is selected from the group consisting of R₇, OR₇ and NR₇R₁₀; R₉ is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, C(O)R₁₀, -SO₂R₁₀, - C(S)NHR₁₀, -C(NH)NH(R₁₀) and -C(O)NHR₁₀ R₁₀ is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case may be the same or different from substituent R₇, provided R₁₀ may be the same or different for R-i and R₃ in the same compound;

Y is selected from oxygen, NH, NR₂ and null

R₁₁ and R₁₂ are independently selected from hydrogen, alkyl and aryl.

X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF₄ ^" and PF₆ ^" with proviso that,

1. when alkyl groups are present on the same carbon or nitrogen they may be linked together to form a cyclic structure and

2. the nitrogen of heteroaryl ring of R₁₀, when present, may be quarternized

3. when R₃ is OR₇ and R₁ is NHNH₂ then R₇ is not alkyl and

4. when R₃ is OR₇, R₁ is N(R₇)N(R₇)R₉ and R₉ is C(O) R₁₀ where R₁₀ is alkyl then R₇ is not hydrogen or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

By "general formula" it is understood the formula itself .

By "formula" it is understood the general formula itself together with the characteristics of the functionals group related to said formula.

In a preferred embodiment, the present invention relates to pharmaceutical compositions which comprise in combination the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 1. In another preferred embodiment, the present invention relates to pharmaceutical compositions which comprise in combination the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 2.

In another preferred embodiment, the present invention relates to pharmaceutical compositions which comprise in combination the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 3.

In another preferred embodiment, the present invention relates to pharmaceutical compositions which comprise in combination the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 4.

In another preferred embodiment, the present invention relates to pharmaceutical compositions which comprise in combination the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 5.

In another preferred embodiment, the present invention relates to pharmaceutical compositions which comprise in combination the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 6.

In another preferred embodiment, the present invention relates to pharmaceutical compositions which comprise in combination the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 7.

In another preferred embodiment, the present invention relates to pharmaceutical compositions which comprise in combination the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 8.

In one aspect the present invention relates to pharmaceutical compositions according to the invention for the treatment or prevention of cardiac and renal related conditions and for treatment or prevention of diabetes and aging-related vascular complications, which comprise in combination the AT 1- receptor blocker, especially valsartan or a pharmaceutically acceptable salt thereof and a compound which exhibits advanced glycosylation end product (AGE) breaking activity or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

A further aspect of the present invention provides a pharmaceutical composition according to the invention , e.g, for the treatment or prevention of cardiac and renal related condition or disease ,i e, selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, cognitive dysfunction (such as Alzheimer's), glaucoma , stroke, and for the management of diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth, comprising administering a therapeutically effective amount of combination of (i) the AT 1 - receptor blocker or a pharmaceutically acceptable salt thereof and (ii) an AGE breaker compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a mammal in need of such treatment.

In this composition, components (i) and (ii) can be obtained and administered together, one after the other or separately in one combined unit dose form or in two separate unit dose forms. The unit dose form may also be a fixed combination.

Furthermore the invention provides the use of a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment of cardiac and renal related conditions and for the management of diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.

In another embodiment, the invention provides the use of a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment or prevention of cardiac and renal related condition or disease wherein the condition is selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, cognitive dysfunction (such as Alzheimer's), glaucoma , stroke, and for treatment or prevention of diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.

In another embodiment, the invention provides the use of a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment or prevention of cardiac and renal related condition or disease wherein the condition is selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy. In another embodiment, the invention provides the use of of a pharmaceutical composition according to. the invention for the preparation of a medicament for use in combination with a . compound; which exhibit advanced, glycosylation end product (AGE) breaking activity or a pharmaceutically effective salts thereof and a pharmaceutically acceptable carrier wherein the condition is selected from the group consisting of supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodelling and myocardial infarction and its sequelae.

In another embodiment, the invention provides the use of a pharmaceutical composition according to the invention for the treatment or prevention of cardiac and renal related condition or disease wherein the condition is selected from the group consisting of diabetes,diabetic cardiac myopathy, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), renal failure conditions, such as diabetic nephropathy and angina pectoris.

In another embodiment, the invention provides the use of a pharmaceutical composition according to the invention for the treatment or prevention of aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.

The present invention provides a kit comprising in separate containers in a single package pharmaceutical compositions comprising in one container a pharmaceutical composition comprising a compound which exhibits advanced glycosylation end product (AGE) breaking activity and in a second container a pharmaceutical composition comprising an AT 1- receptor blocker.

The present invention provides a kit comprising in separate containers in a single package pharmaceutical compositions comprising in one container a pharmaceutical composition comprising a compound which exhibits advanced glycosylation end product (AGE) breaking activity and in a second container a pharmaceutical composition comprising the AT 1- receptor blocker valsartan.

The kit form is particularly advantageous when the separate components must be administered in different dosage forms or are administered at different dosage intervals.

The present invention relates to a package comprising an AT 1- receptor blocker (especially valsartan) together with instructions for use in combination with a compound which exhibits advanced glycosylation end product (AGE) breaking activity for the treatment or prevention of cardiac and renal related conditions and for the management of diabetes and aging- ^: . . related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth. ..

In yet further aspects the invention provides a package comprising the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof together with instructions for use in combination with a compound which exhibits advanced glycosylation end product (AGE) breaking activity or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, cognitive dysfunction (such as Alzheimer's), glaucoma , stroke, diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth. In a preferred embodiment, the package according to the invention comprises in combination the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 1.

In another preferred embodiment, the package according to the invention comprises in combination the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 2.

In another preferred embodiment, the package according to the invention comprises AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 3.

In another preferred embodiment, the package according to the invention comprises the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 4.

In another preferred embodiment, the package according to the invention comprises the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 5.

In another preferred embodiment, the package according to the invention comprises the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 6.

In another preferred embodiment, the package according to the invention comprises the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 7.

In another preferred embodiment, the package according to the invention comprises the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof and a AGE breaker compound of formula 8. In another embodiment the present invention relates to methods of prevention or treatment of cardiac and renal related conditions and for the management of diabetes and aging- related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth by administration of a therapeutically effective amount of any preferred pharmaceutical composition according to the invention comprising an AT1 receptor blocker valsartan plus a compound which exhibits advanced glycosylation end product (AGE) breaking activity or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a mammal in need thereof.

AT-) -receptor antagonists (also called angiotensin Il receptor antagonists) are understood to be those active ingredients that bind to the ATi -receptor subtype of angiotensin Il receptor but do not result in activation of the receptor. As a consequence of the inhibition of the AT₁ receptor, these antagonists can, for example, be employed as antihypertensives or for treating congestive heart failure.

The class of AT₁ receptor antagonists comprises compounds having differing structural features, essentially preferred are the non-peptidic ones. For example, mention may be made of the compounds that are selected from the group consisting of valsartan (cf. EP 443983), losartan (cf. EP253310), candesartan (cf. 459136), eprosartan (cf. EP 403159), irbesartan (cf. EP454511), olmesartan (cf. EP 503785), tasosartan (cf. EP539086), telmisartan (cf. EP 522314), the compound with the designation E-1477 of the following formula

the compound with the designation SC-52458 of the following formula

and the compound with the designation the compound ZD-8731 of the following formula

or, in each case, a pharmaceutically acceptable salt thereof.

Preferred ATVreceptor antagonist are those agents that have been marketed, most preferred is valsartan or a pharmaceutically acceptable salt thereof.

Valsartan is the AT 1 -receptor blocker (S)-N-(I -carboxy-2-methyl-prop-i -yl)-N-pentanoyl-N- [2;(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]amine of formula (I)

and is disclosed in EP 0443983 A and U.S. Patent No. 5,399,578, the disclosures of which are incorporated herein in their entirety as if set forth herein.

The compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds having at least one acid group (for example COOH) can also form salts with bases. Corresponding internal salts may furthermore be formed, if a compound comprises, e.g., both a carboxy and an amino group. The corresponding active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization. Pharmacologically acceptable salts of the AT1 receptor blocker valsartan and AGE breaker are preferably salts with bases, conveniently metal salts derived from groups Ia, Ib, Ha and Hb of the Periodic Table of the Elements, including alkali metal salts, e.g. potassium and especially sodium salts, or alkaline earth metal salts, preferably calcium or magnesium salts, and also ammonium salts with ammonia or organic amines.

Salts and salt hydrates of valsartan are selected from the group of earth alkalimetals consisting of the magnesium salt and the calcium salt, as well as salt mixtures, or respectively, an amorphous form, a solvate, especially hydrate, as well as a polymorphous form thereof.

Salt mixtures are (i) single salt forms from different cations selected from the above group or (ii) mixtures of those single salt forms which exist for example in the form of conglomerates or (III) mixtures of a single salt or a salt hydrate consisting of different physical phases such as several polymorphic forms, of different hydrates or also the anhydrate, of different amorphous forms or (IV) mixtures of any form listed under (I), (II), and (III) with each other.

Preferred salts are for example selected from the calcium salt of valsartan in crystalline and amorphous forms, especially in hydrate form, primarily the tetrahydrates, the trihydrates, the monohydrate, the di-(calcium salt of valsartan) pentahydrate, the anhydrate, the amorphous forms thereof; magnesium salt of valsartan in crystalline form, especially in hydrate form, primarily the hexahydrates, the trihydrates, the monohydrate, the anhydrate, the amorphous forms thereof.

The salts of valsartan preferably exist in isolated and essentially pure form, for example in a degree of chemical purity of >95%, preferably >98%, primarily >99%. The enantiomer purity of the salts according to the invention is >98%, preferably >99%. .

Compared with the free acid, the salts according to the invention, or the amorphous forms, solvates. such as salt hydrates, and also the corresponding polymorphous forms thereof, have unexpectedly advantageous properties. Under given conditions, the crystalline salts and crystalline salt hydrates have a clear melting point which is linked with a marked, endothermic melting enthalpy. The crystalline salts, salt hydrates, amorphous forms and mixtures thereof according to the invention have limited stability, i.e. as the solid, they have a restricted stability range. To be stabilised, they require certain measures which can be achieved for example by galenic formulations.

In addition, both the crystalline and the amorphous salts and salt hydrates according to the invention have a high degree of dissociation in water and thus substantially improved water solubility. These properties are of advantage, since on the one hand the dissolving process is quicker and on the other hand a smaller amount of water is required for such solutions. Furthermore, the higher water solubility can, under certain conditions, also lead to increased biological availability of the salts or salt hydrates in the case of solid dosage forms. Improved properties are beneficial especially to the patients. The high crystallinity of certain salt hydrates allows the use of a choice of analytical methods, especially the various X-ray methods and/or the infrared spectrum preferably by means of ATR-IR (Attenuated Total Reflection-Infrared Spectroscopy), the usage of both methods permit a clear and simple analysis of their release to be made. This factor is also of great importance to the quality of the active substance and its galenic forms during production, storage and administration to the patients.

Valsartan can be used in form of a crystalline, also partly crystalline and amorphous salts or salt hydrates.

Valsartan can also be used in form of solvates, such as hydrates, or in form of polymorphous forms of the salts.

Advanced glycosylation end product. (AGE) breaking activity (also called AGE breaker) Are essential for the treatment of diabetic and aging- related complications including kidney disease, nerve damage, atherosclerosis, retinopathy and dermatological conditions. A. preferred AGE breaker class is the class of compounds of the pyridinium series which exhibit advanced glycosylation end product (AGE) breaking activity and comprise compounds having differing structural features.

Mention is made of the compound of the chemical name Pyridinium, 3-((2-(methylslufonyl) hydrazino) carbonyl)-1-(2-oxo-2-(2-thienyl)ethyl)-, bromide and of the formula 1 :

, and the compounds that are cited in the compound claims and examples of United State Patents number US6,624,178; US6,608,094, US6,462,057; United State Patents Application having the publication number US 2003/0092744A1;US2003/0032660A1;US 2003/0045554A1;US2002/0103228A1. Said compounds are incorporated by reference in this application.

United State Patents number US6,624,178 discloses compounds having AGE-breaking and AGE-inhibiting activity of general formula 2,

wherein

R1 is-R4-R5or-N(R7)N(R7)R9;

R 4 is selected from the group consisting of -N(R 7 )R 6 O-, --N(R 7 )R 6 N(R 7 )--, OR 6 O, and -OR 6 N(R 7 )-, where R 6 is alkyl;

where R 7 is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R 7 might be different for R 1 and R 3 in the same compound;

R 2 is selected from the group consisting of F, Cl₁ Br, I, OR 7 , NO 2 , alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR 7 R 10 , C(O)OR 7 , NR 7 R 10 , N&oxH;C(R 7 )(R 10 ), SR 7 , SO 2 NH 2 , SO 2 alkyl and SO 2 aryl,

and m is 0, 1 or 2;

where R 8 is selected from the group consisting of R 7 , OR 7 and NR 7 R 10 ;

X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF 4 ^"and PF 6 ^";

with proviso that,

(i) when two alkyl groups are present on the same carbon or nitrogen, they are optionally linked together to form a cyclic structure and (ii) the nitrogen of heteroaryl ring of R 10 , when present, is optionally quaternized with compound such as X-CH 2 C(O)-R 3

United State Patents number US 6,608,094 B2 discloses compounds having AGE-breaking and AGE-inhibitinq activity of general formula 3

wherein

R 1 is -R 4 -R 5 or -N(R 7 ) N (R 7 ) R 9 ;

R 4 is selected from the group consisting of -N(R 7 )R 6 O-, -N(R 7 )R 6 N(R 7 )-, -OR 6 O-, and -OR 6 N(R 7 )-, where R 6 is alkyl with C 2 to C 8 carbon atoms;

R 5 is selected from the group consisting of alkyl, aryl including heteroaryl, —COR 7 , -SO 2 R 7 , -C(S)NHR 7 , -C(NH)NHR 7 , -COR 10 ,

where R 7 is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R 7 may be the same or different for R 1 and R 3 in the same compound;

R 3 is selected from the group consisting of R 7 , OR 7 , N(R 7 )(R 10 ), N&oxH;C(R 7 )(R 10 ), N(R 7 )N(R 7 )(R 10 ), N(R 7 )N&oxH;C(R 7 )(R 10 ) and CH(R 7 )C(O)R 8 where R 8 is selected from the group consisting of R 7 , OR 7 and NR 7 R 10 ; R 9 is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, — C(O)R 10 , -SO 2 R 10 , -C(S)NHR 10 , -C(NH) NH(R 10 ) and -C(O)NHR 10 ;

R 10 is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case may be the same or different from substituent R 7 , provided R 10 may be the same or different for R 1 and R 3 in the same compound;

X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF 4 ^"and PF 6 ^' ; with proviso that,

United State Patents number US6,462,057 discloses compounds having AGE-breaking and AGE-inhibiting activity of general formula 4

wherein

R 1 is -R 4 -R 5 or -N(R 7 )N(R 7 )R 9 ; R 4 is selected from the group consisting of -N(R 7 )R 6 O-, -N(R 7 )R 6 N(R 7 )-, OR 6 O, and -OR 6 N(R 7 )--, where R 6 is alkyl;

R 5 is selected from the group consisting of alkyl, aryl including heteroaryl, -COR 7 , SO 2 R 7 , -C(S)NHR 7 , -C(NH)NHR 7 , -COR 10 ,

where

R 7 is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R 7 might be different for R 1 and R 3 in the same compound; R 2 is selected from the group consisting of F, Cl, Br, I, OR 7 , NO 2 , alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR 7 R 10 , C(O)OR 7 , NR 7 R 10 , N&oxH;C(R 7 )(R 10 ), SR 7 , SO 2 NH 2 , SO 2 alkyl and SO 2 aryl, and m is 0, 1 or 2;

R 9 is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, C(O)R 10 , --SO 2 R 10 , -C(S)NHR 10 , -C(NH)NH(R 10 ) and -C(O)NHR 10 ,

X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF 4 ^"and PF 6 ^' ;

with proviso that,

(i) when two alkyl groups are present on the same carbon or nitrogen, they are optionally linked together to form a cyclic structure and (ii) the nitrogen of heteroaryl ring of R 10 , when present, is optionally quatemized with compound such as X-CH 2 C(O)-R 3

United State Patents Application having the publication number 2003/0092744A1 discloses compounds having AGE-breaking and AGE-inhibiting activity of general formula 5,

wherein

R₁ is --R₁-R₅Or -N(R₇) N(R₇) R₉;

R₄Js selected from the group consisting of - N(R₇)R₆O-, -N(R₇)R₆N(R₇)-, OR₆O, and — OR₆N(R₇)-,

where R₆ is alkyl;

where

R₂ is selected from the group consisting of F, Cl, Br, I, OR₇, NO₂, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR₇R₁₀, C(O)OR₇, NR₇R₁₀, N&oxH;C(R₇)(R₁₀), SR₇, SO₂NH₂, SO₂ alkyl and S0₂alyl,

and m is 0, 1 or 2; R₃ is selected from the group consisting of R₇, OR₇, N(R₇) (R₁₀), N&oxH; C(R₇) (R₁₀), N(R₇) N(R₇) (R₁₀), N(R₇) N&oxH;C(R₇) (R₁₀ ) and CH(R₇)C(O)R₈

where

R₈ is selected from the group consisting of R₇, OR₇ and NR₇R₁₀;

X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate' ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF₄ ^" and PF₆ ^';

with proviso that,

(ii) the nitrogen of heteroaryl ring of R₁₀, when present, is optionally quatemized with compound such as X-CH₂ C(O)-R₃

United State Patents Application having the publication number US2003/0032660A1 discloses compounds having AGE-breaking and AGE-inhibiting activity of general formula 6

wherein

R₁ is -R₄-R₅Or -N(R₇)N(R₇)R₉;

R₄ is selected from the group consisting of - N(R₇)R₆O-, -N(R₇)R₆N(R₇)--, OR₆O, and - OR₆N(R₇)-, where R₆ is alkyl with C₂ to C₈ carbon atoms;

R₅ is selected from the group consisting of alkyl, aryl including heteroaryl, -COR₇, SO₂R₇, - C(S) NHR₇, -C(NH)NHR₇, -COR₁₀, 3

R₂ is selected from the group consisting of F, Cl, Br, I, OR₇, NO₂, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR₇R₁₀, C(O)OR₇, NR₇R₁₀, N&oxH;C(R₇)(R₁₀), SR₇, SO₂NH₂, SO₂ alkyl and S0₂aryl, and m is 0, 1 or 2;

R₉ is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, C(O)R₁₀, -SO₂ R₁₀, -C(S)NHR₁₀, -C(NH) NH (R₁₀) and - C(O) NHR₁₀,

R-io is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case may be the same or different from substituent R₇, provided R₁₀ may be the same or different for R₁ and R₃ in the same compound; X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF₄ ^" and PF₆ ^"; with proviso that,

In a preferred embodiment, (iii) R₃ is OR₇ and R₁ is -NHNH₂ then R₇ is not alkyl, and (iv) when R₃ is OR₇, R₁ is N(R₇)(NR₇)R₉ and R₉ is C(O) R₁₀ where R₁₀ is alkyl, then R₇ is not hydrogen.

United State Patents Application having the publication number US 2003/0045554A1 discloses compounds having AGE-breaking and AGE-inhibitirig activity of general formula 7

R1 is alkyl or aryl group;

Y is selected from the group consisting of sulfur, oxygen, nitrogen or alkyl;

R2, R3 and R4 are independently selected from the group consisting of F, Cl, Br, I, OR₇, NO₂, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR₆R₇, C(O) OR₆, NR₆R₇, N&oxH;C(R₆) (R₇), SR₆, SO₂NH₂, SO₂ alkyl, S0₂aryl; R₂, R₃ and R₄ might be optionally joined together to form a ring system; If quatemized, R₅ is independently selected for the group consisting of alkyl or aryl; if not quaternized, R₅ is null, and X is null;

R₆ is independently selected from the group consisting of H, alkyl and aryl including heteroaryl provided R₆ might be different for R₂, Rβand R₄Jn the same compound;

R₇ is independently selected from the group consisting of H, alkyl and aryl including heteroaryl and in each case optionally different from substituent R₆, provided R₇ might be different for R₂, R₃ and R₄Jn the same compound;

If quaternized, X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF₄ ^' and PF₆

with proviso that when two alkyl groups are present on the same carbon or nitrogen, they are optionally linked together to form a cyclic structure.

United State Patents Application having the publication number US2002/0103228A1 discloses compounds having AGE-breaking and AGE-inhibiting activity of general formula 8

R₁ is selected from -R₄-R₅, - -N(R₇)N(R₇)R₉ and Y-R₁₁

R₄ is selected from the group consisting of — N(R₇)R₆O-, -N(R₇)R₆N(R₇)-, OR₆O, and — OR₆N(R₇)-,

where R₆ is alkyl; R₅ is selected from the group consisting of alkyl, aryl including heteroaryl, -COR₇, SO₂R₇, -- C(S)NHR₇, -C(NH)NHR₇, -COR₁₀, 2

R₃ is selected from the group consisting of R₇, OR₇, N(R₇)(R₁₀), N&oxH;C(R₇)(Ri₀), N(R₇)N(R₇)(R₁₀) , N(R₇)N&oxH.;C(R₇)(R₁₀) and CH(R₇) C(O)R₈

Where R₈ is selected from the group consisting of R₇, OR₇ and NR₇R₁₀; R₉ is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, C(O)R₁₀, -SO₂R₁₀, — C(S)NHR₁₀, -C(NH)NH(R₁₀) and -C(O)NHR₁₀ . .

R₁₀ is.selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case may be the same or different from substituent R₇, provided R₁₀ may be the same or different for R₁ and R₃ in the same compound;

Y is selected from oxygen, NH, NR₂ and null

R₁₁ and R₁₂ are independently selected from hydrogen, alkyl and aryl.

[0056] 1. when alkyl groups are present on the same carbon or nitrogen they may be linked together to form a cyclic structure and

2. the nitrogen of heteroaryl ring of R₁₀, when present, may be quartemized 3. when R₃ is OR₇ and R₁ is NHNH₂ then R₇ is not alkyl and

4. when R₃ is OR₇, R₁ is N(R₇)N(R₇)R₉ and R₉ is C(O) R₁₀ where R₁₀ is alkyl then R₇ is not hydrogen.

It has surprisingly been found that the pharmaceutical compositions according to the invention can be used for the prevention or the treatment of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, cognitive dysfunction (such as Alzheimer's), glaucoma , stroke, diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.

It has surprisingly been found that, a combination of an AT1 receptor blocker, especially valsartan, and an AGE breaker achieves greater therapeutic effect ( a potentiation) than the administration of valsartan or the AGE breaker alone. The combination surprisingly elicits an increased antihypertensive effect in rodent models of hypertension. The combination also surprisingly ameliorates symptoms and improves mortality rates in animal models of heart failure.

The combination also unexpectedly improves renal function in an animal model of renal dysfunction.

The combination also unexpectedly ameliorates symptoms related to diabetes and aging- related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.

Greater efficacy can also be documented as a prolonged duration of action. The duration of action can be monitored as either the time to return to baseline prior to the next dose or as the area under the curve (AUC) and is expressed as the product of the change in blood pressure in millimeters of mercury (change in mmHg) and the duration of the effect (minutes, hours or days). Further benefits are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used to diminish the incidence of side effects. Preferred are low dose combination of valsartan and AGE breaker. The combined administration of an AT1 receptor blocker, especially valsartan, or a pharmaceutically acceptable salt thereof and AGE breaker or a pharmaceutically acceptable salt thereof results in a significant response in a greater percentage of treated patients, that is, a greater responder rate results, regardless of the underlying etiology of the condition. This is in accordance with the desires and requirements of the patients to be treated. It can be shown that combination therapy with an AT1 receptor blocker, especially valsartan, and AGE breaker results in a more effective antihypertensive therapy through improved efficacy as well as a greater responder rate. The combination is also useful in the treatment or prevention of heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter or detrimental vascular remodeling. It can further be shown that a an AT1 receptor blocker, especially valsartan, and AGE breaker therapy proves to be beneficial in the treatment and prevention of myocardial infarction and its sequelae. A valsartan plus AGE breaker combination is also useful in treating atherosclerosis, angina (whether stable or unstable), and renal insufficiency (diabetic and non-diabetic). Furthermore, combination therapy using an AT1 receptor blocker, especially valsartan, and AGE breaker can improve endothelial dysfunction, thereby providing benefit in diseases in which normal endothelial function is disrupted such as heart failure, angina pectoris and diabetes. Furthermore, the combination of the present invention may be used for the treatment or prevention of renal failure conditions, such as diabetic nephropathy, cognitive dysfunction (such as Alzheimer's), glaucoma , stroke, diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.

Thus in the present description the terms "treatment" or "treat" refer to both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of patients at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition. The Agents of the Invention, i.e. the AGE breaker and an AT1 receptor blocker, especially valsartan, are preferably used in the form of pharmaceutical preparations that contain the relevant therapeutically effective amount of each active ingredient (either separately or in combination) optionally together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for administration. The Agents of the Invention may be present in the same pharmaceutical compositions, though are preferably in separate pharmaceutical compositions. Thus the active ingredients may be administered at the same time (e.g. simultaneously) or at different times (e.g. sequentially) and over different periods of time, which may be separate from one another or overlapping.The unit dose form may also be a fixed combination.

Preferably, the pharmaceutical compositions are adapted for oral or parenteral (especially oral) administration. Intravenous and oral, first and foremost oral, administration is considered to be of particular importance.

The pharmaceutical compositions according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral, rectal, aerosol inhalation or = nasal administration, and parenteral such as intravenous or subcutaneous administration, or compositions for transdermal administration (e.g. passive or iontσphoretic) to mammals . (warm-blooded animals), including man. Such compositions comprise a therapeutically effective amount of the pharmacologically active compound, alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application. Typical oral formulations include tablets, capsules, syrups, elixirs and suspensions. Typical injectable formulations include solutions and suspensions. Tablets may be either film coated or enteric coated according to methods known in the art. Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 85%, preferably about 1 to 70%, of the active ingredient.

The typical pharmaceutically acceptable carriers for use in the formulations described above are exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as cornstarch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; ethylene glycol polymers; betacyclodextrin; fatty alcohols; and hydrolyzed cereal solids, as well as other non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavoring agents, and the like commonly used in pharmaceutical formulations.. ■ , . . -

Pharmaceutical preparations for enteral and parenteral administration are, for example, those in dosage unit forms, such as dragees, tablets or capsules and also ampoules. They are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, where appropriate granulating a resulting mixture, and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, into tablets or dragee cores.

Other orally administrable pharmaceutical preparations are dry-filled capsules made of gelatin, and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, where appropriate, stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilisers to be added. Parenteral formulations are especially injectable fluids that are effective in various manners, such as intravenously, intramuscularly, intraperitoneally, intranasally, intradermally or subcutaneously. Such fluids are preferably isotonic aqueous solutions or suspensions which can be prepared before use, for example from lyophilised preparations which contain the active ingredient alone or together with a pharmaceutically acceptable carrier. The pharmaceutical preparations may be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.

Suitable formulations for transdermal application include an effective amount of a compound of the invention with carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Suitable formulations for topical application, e.g. to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, for example, for delivery by aerosol or the like.

For example, the pharmaceutical preparations consist of from about 0.1-90%, preferably of from about 1 % to about 80 %, of the active compounds. Pharmaceutical preparations for enteral or parenteral administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner which is known per se, for example using conventional mixing, granulation, coating, solubulizing or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances. The dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition. Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutically effective dosages, especially those which are commercially available. Valsartan is supplied in the form of suitable dosage unit form, for example, a capsule or tablet, and comprising a therapeutically effective amount, e.g. from about 20 to about

320 mg, of valsartan which may be applied to patients. The application of the active ingredient may occur up to three times a day, starting, e.g., with a daily dose of 20 mg or

40 mg of valsartan, increasing via 80 mg daily and further to 160 mg daily up to 320 mg daily. Preferably, valsartan is applied once a day or twice a day in heart failure patients with a dose of 80 mg or 160 mg, respectively, each. Corresponding doses may be taken, for example, in the morning, at mid-day or in the evening. Preferred is q.d. or b.i.d. administration in heart failure.

The person skilled in the pertinent art is fully enabled to select a relevant test model to prove the efficacy of a combination of the present invention in the hereinbefore and hereinafter indicated therapeutic indications.

For example, representative studies are carried out with a combination of valsartan andAGE breaker , e.g., applying the following methodology:

Drug efficacy is assessed in various animal models including the spontaneously hypertensive rat (SHR) maintained on a normal, high or low salt diet.

Blood, pressure will be monitored in the chronic study procedure by means of a radiotransmitter. The radiotransmitter is surgically implanted into the abdominal aorta of ^■ rats. Blood pressure is chronically monitored for periods of up 6 weeks.

Blood pressure, heart rate and activity are determined at various pre-selected time points before, during, and after drug administration. All measurements are performed in unrestrained and undisturbed animals. The maximum study time, determined by battery life, could be as long as nine months. For studies of this duration, rats are dosed orally

(1-3 mL/kg vehicle), no more than twice daily or drug is administered via the drinking water or mixed with food. For studies of a longer duration, that is, up to 8 weeks, drugs are given via subcutaneously implanted osmotic minipumps. Osmotic minipumps are selected based on drug delivery rate and time. Valsartan dosages range from 1- 50 mg/kg/day.

The hypertensive background of the SHR is modified either by chronic salt loading in an effort to suppress the renin angiotensin system (RAS) or chronic salt depletion to activate the RAS in the SHR. These manipulations will be carried out to more extensively evaluate the efficacy of the various test substances. Experiments performed in SHR are supplied by

Taconic Farms, Germantown, New York (Tac:N(SHR)fBR). A radiotelemetric device (Data

Sciences International, Inc., St. Paul, Minnesota) is implanted into the lower abdominal aorta of all test animals between the ages of 14 to 16 weeks of age. All SHR are allowed to recover from the surgical implantation procedure for at least 2 weeks prior to the initiation of the experiments. Cardiovascular parameters are continuously monitored via the radiotransmitter and transmitted to a receiver where the digitized signal is then collected and stored using a computerized data acquisition system. Blood pressure (mean arterial, systolic and diastolic pressure) and heart rate are monitored in conscious, freely moving and undisturbed SHR in their home cages. The arterial blood pressure and heart rate are measured every 10 minutes for 10 seconds and recorded. Data reported for each rat represent the mean values averaged over a 24-hour period and are made up of the 144-10 minute samples collected each day. The baseline values for blood pressure and heart rate consist of the average of three consecutive 24-hour readings taken prior to initiating the drug treatments. All rats are individually housed in a temperature and humidity controlled room and are maintained on a 12-hour light dark cycle.

Upon completion of the chronic studies, rats are anesthetized and the heart rapidly removed. After separation and removal of the atrial appendages, left ventricle and left plus right ventricle (total) are weighed and recorded. Left ventricular and total ventricular mass are then normalized to body weight and reported. All values reported for blood pressure and cardiac mass represent the group mean ± sem. . •

Vascular function and structure are evaluated after treatment to assess the beneficial effects of the combination. SHR are studied according to the methods described by lntengan et al., Circulation, Vol. 100, No. 22, pp. 2267-2275 (1999).

Myocardial infarction (Ml) is produced in Sprague-Dawley rats by ligation of the left coronary artery. At four weeks after surgery, animals are treated with the combination of valsartan and cox-2 inhibitor. At 16 weeks after surgery, the animals are examined for hemodynamic function, euthanized and the hearts weighed. For assessments of hemodynamic function, rats are anesthetized with sodium pentobarbital (50 mg/kg i.p.). A miniature pressure transducer catheter (Millar Micro-Tip) is inserted into the right carotid artery and then advanced into the left ventricle. Left ventricular end-diastolic and left ventricular peak systolic pressures are recorded. After these assessments, the rats are sacrificed and the heart excised for weighing.

The available results indicate an unexpected therapeutic effect of a combination according to the invention.

The following examples illustrate the above-described invention; however, it is not intended to restrict the scope of this invention in any manner. EXAMPLES

A) AGE breaker inhibitor formulation examples

Preparation of oral dosage form:

A typical tablet can have the following composition: an effective

Active ingredient of general formula 1 to 8 amount

Lactose 100 mg

Microcrystaline Cellulose 51 mg

Starch 60 mg

Polyvinyl pyrolidone (K-30) 2 mg

Talc 1.5 mg

Magnesium Stearate 1.0 mg

OR an effective

Active ingredient of general formula I amount

Lactose 130 mg

Starch 75 mg

Polyvinyl pyrolidone (K-30) 2 mg

Talc 1.5 mg

Magnesium Stearate 1.0 mg

Preparation of oral dosage form:

A typical tablet has the following composition: Active ingredient of formula 1 to 8 an effective amount

Lactose 135 mg

Starch 76 mg

Polyvinyl pyrolidone (K-30) 2 mg

Talc 1.5 mg

Magnesium Stearate 1.0 mg

Preparation suitable for parenteral administration has the following composition:

Active ingredient of formula an effective

1 to 8 amount

Polethylene glycol (400) 0.75 ml

Sodium metabisulphite 0.01%

Isotonic saline/WFI q.s

B) Examples of valsartan formulation Formulation Example 1 : Film-Coated Tablets:

*)Removed during processing.

The film-coated tablet is manufactured, e.g., as follows:

A mixture of valsartan, microcrystalline cellulose, crospovidone, part of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200, silicon dioxide and magnesium stearate is premixed in a diffusion mixer and then sieve through a screening mill. The resulting mixture is again pre-mixed in a diffusion mixer, compacted in a roller compactor and then sieve through a screening mill. To the resulting mixture, the rest of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200 are added and the final blend is made in a diffusion mixer. The whole mixture is compressed in a rotary tabletting machine and the tablets are coated with a film by using Diolack pale red in a perforated pan.

Formulation Example 2: Film-coated tablets:

The film-coated tablet is manufactured, e.g., as described in Formulation Example 1. Formulation Example 3: Film-Coated Tablets:

*) The composition of the Opadry® brown OOF16711 coloring agent is tabulated below. **) Removed during processing

Opadry® Composition:

The film-coated tablet is manufactured, e.g., as described in Formulation Example 1.

Formulation Example 4: Capsules:

The tablet is manufactured, e.g., as follows:

Granulation/Drying

Valsartan and microcrystallin cellulose are spray-granulated in a fluidized bed granulator with a granulating solution consisting of povidone and sodium lauryl sulphate dissolved in purified water. The granulate obtained is dried in a fluidized bed dryer.

Milling/Blending The dried granulate is milled together with crospovidone and magnesium stearate. The mass is then blended in a conical srew type mixer for approximately 10 minutes.

Encapsulation

The empty hard gelatin capsules are filled with the blended bulk granules under controlled temperature and humidity conditions. The filed capsules are dedusted, visually inspected, weightchecked and quarantined until by Quality assurance department.

Formulation Example 5:

Capsules:

The formulation is manufactured, e.g., as described in Formulation Example 4. Formulation Example 6: Hard Gelatine Capsule:

Formulation Example 7:

A hard gelatin capsule, comprising as active ingredient, e.g., (S)-N-(I -carboxy-2-methylprop-

1-yl)-N-pentanoyl-N-[2'(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]amine, can be formulated, for example, as follows:

Composition:

(1 ) valsartan 80.0 mg

(2) microcrystalline cellulose 110.0 mg

(3) polyvidone K30 45.2 mg

(4) sodium lauryl sulfate 1.2 mg

(5) crospovidone 26.0 mg

(6) magnesium stearate 2.6 mg

Components (1) and (2) are granulated with a solution of components (3) and (4) in water. ^• The components- (5) and (6) are added to the dry granulate and the mixture is filled into size

1- hard gelatin capsules.

All. publications and patents mentioned herein arejncorporate by. reference in their entirety as if set forth in full herein.

What is claimed is:

1. A pharmaceutical combination comprising an AT1 receptor blocker, especially valsartan, or pharmaceutically acceptable salts thereof and a compound which exhibits advanced glycosylation end product (AGE) breaking activity or a pharmaceutically effective salts thereof, and optionally a pharmaceutically acceptable carrier.

2. Pharmaceutical combination according to claimi which comprise in combination the AT 1- receptor blocker valsartan and a compound which exhibits advanced glycosylation end product (AGE) breaking activity selected from the group of

a) Pyridinium, 3-((2-(methylslufonyl) hydrazino) carbonyl)-1-(2-oxo-2-(2-thienyl)ethyl)-, bromide of general formula 1

b) compounds of general formula 2

wherein

R 1 is -R 4 -R 5 or -N(R 7 )N (R 7 )R 9 ;

R 4 is selected from the group consisting of -N(R 7 )R 6 O-, -N(R 7 )R 6 N(R 7 )-, OR 6 O, and -OR 6 N(R 7 )-,

where R 6 is alkyl;

R 2 is selected from the group consisting of F, Cl, Br, I, OR 7 , NO 2 , alkyl, aryi including heteroaryl, formyl, acyl, C(O)NR 7 R 10 , C(O)OR 7 , NR 7 R 10 , N&oxH;C(R 7 )(R 10 ), SR 7 , SO 2 NH 2 , SO 2 alkyl and SO 2 aryl,

and m is 0, 1 or 2;

where R 8 is selected from the group consisting of R 7 , OR 7 and NR 7 R 10 ;

R 10 is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case optionally different from substituent R 10 , provided R 10 might be different for R 1 and R 3 in the same compound; X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF 4 ^'and PF 6 ^~ ;

with proviso that,

(ii) the nitrogen of heteroaryl ring of R 10 , when present, is optionally quaternized with compound such as X--CH 2 C(O)-R 3

c) compounds of general formula 3

(R₂)m

wherein

R 1 is -R 4 -R 5 or --N(R 7 ) N (R 7 ) R 9 ;

R 5 is selected from the group consisting of alkyl, aryl including heteroaryl, —COR 7 , —SO 2 R 7 , -C(S)NHR 7 , -C(NH)NHR 7 , -COR 10 ,

where R 7 is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R 7 may be the same or different for R 1 and R 3 in the same compound; R 2 is selected from the group consisting of F, Cl, Br, I, OR 7 , NO 2 , alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR 7 R 10 , C(O)OR 7 , NR 7 R 10 , N&oxH;C(R 7 )(R 10 ), SR 7 , SO 2 NH 2 , SO 2 alkyl and SO 2 aryl, and m is 0, 1 or 2;

X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maieate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF 4 ^"and PF 6 ^"; with proviso that,

(ii) the nitrogen of heteroaryl ring of R 10 , when present, may be quaternized with compound such as X-CH 2 C(O)-R 3 .

d) compounds of general formula 4

R 1 is -R 4 -R 5 or -N(R 7 )N(R 7 )R 9 ;

R 4 is selected from the group consisting of -N(R 7 )R 6 O-, -N(R 7 )R 6 N(R 7 )--, OR 6 O, and -OR 6 N(R 7 )-, where R 6 is alkyl;

where

R 10 is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case optionally different from substituent R 10 , provided R 10 might be different for R 1 and R 3 in the same compound; X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF 4 ^"and PF 6 ^';

with proviso that,

(ii) the nitrogen of heteroaryl ring of R 10 , when present, is optionally quaternized with compound such as X-CH 2 C(O)-R 3 e) compounds of general formula 5

wherein

R₁ is -R₄-R₅Or -N(R₇) N(R₇) R₉;

where R₆ is alkyl;

where R₇ is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R₇ might be different for R₁ and R₃ in the same compound;

R₂ is selected from the group consisting of F, Cl, Br, I, OR₇, NO₂, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR₇R₁₀, C(O)OR₇, NR₇R₁₀, N&oxH;C(R₇)(R₁₀), SR₇, SO₂NH₂, SO₂ alkyl and SO₂alyl,

and m is 0, 1 or 2;

where

R₈ is selected from the group consisting of R ₇, OR₇ and NR₇Ri₀;

R₉ is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryf, C(O)R₁₀, --SO₂ R₁₀, --C(S)NHR₁₀, -C(NH)NH(R₁₀) and - C(O)NHR₁₀,

(ii) the nitrogen of heteroaryl ring of R₁₀, when present, is optionally quaternized with compound such as X-CH₂ C(O)-R₃ f) compounds of general formula 6

wherein

R₁ is -R₄-R₅Or -N(R₇)N(R₇)R₉;

R₄ is selected from the group consisting of — N(R₇)R₆O-, -N(R₇)R₆N(R₇)-, OR₆O, and - OR₆N(R₇)-, where R₆ is alkyl with C₂ to C₈ carbon atoms;

R₁₀ is selected for the group consisting of H, alkyl or aryl including heteroaryl and in each case may be the same or different from substituent R₇, provided R₁₀ may be the same or different for R₁ and R₃ in the same compound; X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF₄ ^" and PF₆ ^"; with proviso that,

(ii) the nitrogen of heteroaryl ring of R₁₀, when present, may be quatemized.

In a preferred embodiment, (iii) R₃ is OR₇ and R₁ is -NHNH₂ then R₇ is not alkyl, and (iv) when R₃ is OR₇, R₁ is N(R₇)(NR₇)R₉ and R₉ is C(O) R₁₀ where R₁₀ is alkyl, then R₇ is not hydrogen. g) compounds of general formula 7

wherein

R1 is alkyl or aryl group;

Y is selected from the group consisting of sulfur, oxygen, nitrogen or alkyl;

R2, R3 and R4 are independently selected from the group consisting of F, Cl, Br, I, OR₇, NO₂, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR₆R₇, C(O) OR₆, NR₆R₇, N&oxH;C(R₆) (R₇), SR₆, SO₂NH₂, SO₂ alkyl, S0₂aryl; R₂, R₃ and R₄ might be optionally joined together to form a ring system; If quaternized, R₅ is independently selected for the group consisting of alkyl or aryl; if not quatemized, R₅ is null, and X is null;

R₇ is independently selected from the group consisting of H, alkyl and aryl including heteroaryl and in each case optionally different from substituent R₆, provided R₇ might be different for R₂, Rsand R₄In the same compound;

If quaternized, X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF₄ ^" and PF₆

with proviso that when two alkyl groups are present on the same carbon or nitrogen, they are optionally linked together to form a cyclic structure, h) compounds of general formula 8

R₁ is selected from -R₄-R₅, - -N(R₇)N(R₇)R₉ and Y-Rn

where R₆ is alkyl;

R₅ is selected from the group consisting of alkyl, aryl including heteroaryl, -COR₇, SO₂R₇, ^■ C(S)NHR₇, -C(NH)NHR₇, -COR₁₀, 2 where R₇ is selected from the group consisting of H, alkyl and aryl including heteroaryl provided R₇ may be the same or different for R₁ and R₃ in the same compound;

R₂ is selected from the group consisting of F, Cl, Br, I, OR₇, NO₂, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR₇R₁₀, C(O)OR₇, NR₇R₁₀, N&oxH;C(R₇)(R₁₀), SR₇, SO₂NH₂, SO₂ alkyl and SO₂aryl, and m is 0, 1 or 2;

Where R₈ is selected from the group consisting of R₇, OR₇ and NR₇R₁₀; R₉ is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl, C(O)R₁₀, -SO₂Ri₀, — C(S)NHR₁₀, -C(NH)NH(R₁₀) and -C(O)NHR₁₀

R₁₀ is selected for the group consisting of H, alkyl or aryl including heteroaryi and in each case may be the same or different from substituent R₇, provided R₁₀ may be the same or different for R₁ and R₃ in the same compound;

Y is selected from oxygen, NH, NR₂ and null

R₁₁ and R₁₂ are independently selected from hydrogen, alkyl and aryl.

Claims

2. the nitrogen of heteroaryl ring of R₁₀, when present, may be quartemized

3. when R₃ is OR₇ and R₁ is NHNH₂ then R₇ is not alkyl and 4. when R₃ is OR₇, Ri is N(R₇)N(R₇)R₉ and R₉ is C(O) R₁₀ where R₁₀ is alkyl then R₇ is not hydrogen or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

3. Pharmaceutical combination according to claims'! -2 for the treatment or prevention of cardiac and renal related conditions and for treatment or prevention of diabetes and aging- related vascular complications, which comprises in combination an AT 1- receptor blocker , especially valsartan or a pharmaceutically acceptable salt thereof and a compound which exhibits advanced glycosylation end product (AGE) breaking activity or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for simultaneous, sequential or separate use.

4. Pharmaceutical combination according to claim 3, for

(i) the treatment or prevention of cardiac and renal related condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, cognitive dysfunction (such as Alzheimer's), glaucoma , stroke, or,

(II) for the management of diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth, comprising administering a therapeutically effective amount of combination of

An AT 1- receptor blocker (especially valsartan) or a pharmaceutically acceptable salt thereof and an AGE breaker compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a mammal in need of such treatment.

5. Use of a pharmaceutical combination according to claims 1-4 for the preparation of a medicament for treatment of cardiac and renal related conditions or for the management of diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.

6. Use according to claim 6 wherein the condition is selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, cognitive dysfunction (such as Alzheimer's), glaucoma , stroke, diabetes , aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.

7. A kit comprising in separate containers in a single package a pharmaceutical compositions comprising in one container a pharmaceutical composition comprising a compound which exhibits advanced glycosylation end product (AGE) breaking activity and in a second container a pharmaceutical composition comprising an AT 1- receptor blocker.

8. Kit according to claim 7 comprising the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof together with instructions for use in combination with a compound which exhibits advanced glycosylation end product (AGE) breaking activity or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, cognitive dysfunction (such as Alzheimer's), glaucoma , stroke, diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.

9. A package comprising an AT 1- receptor blocker (especially valsartan) together with instructions for use in combination with a compound which exhibits advanced glycosylation end product (AGE) breaking activity for the treatment or prevention of cardiac and renal related conditions and for the management of diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.

10. A package comprising the AT 1- receptor blocker valsartan or a pharmaceutically acceptable salt thereof together with instructions for use in combination with a compound which exhibits advanced glycosylation end product (AGE) breaking activity or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, cognitive dysfunction (such as Alzheimer's), glaucoma , stroke, diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.

11. A Method of prevention or treatment of cardiac and renal related conditions and for the management of diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth comprising the administration of the combination according to claimsi- 4 and optionally a pharmaceutically acceptable carrier to a mammal in need thereof.

12. Method according to claim 11 wherein the condition or disease is selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, cognitive dysfunction (such as Alzheimer's), glaucoma , stroke, diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth.