EP1315704A1 - 2-guanidino-4-aryl-quinazoline - Google Patents

Abstract

The invention relates to compounds of formula (I), wherein Y represents (II) or (III) and Ar, R<1>, R<2>, R<5>, R<6>, R<7> and R<8> have the above-mentioned meaning, in addition to the salts and solvates thereof and the use thereof as NHE-3-inhibitors.

Description

 2-guanidino-4-aryl-quinazolines

The invention relates to compounds of the formula I.

wherein

Ar is phenyl or naphthyl which is unsubstituted or simply substituted by R and / or R,

R ¹ , R ² , R ³ , R ⁴ each independently of one another H, A, OA, Hai, CF ₃ , OH, N0 ₂ , NH ₂ , NHA, NA ₂ , NH-CO-A, NH-CO-Ph, SA, SO-A, S0 ₂ -A, S0 ₂ - Ph, CN, OCF ₃ , CO-A, C0 ₂ H, C0 ₂ A, CO-NH ₂ , CO-NHA, CO-NA ₂ , S0 ₂ NH ₂ , S0 ₂ NHA, S0 ₂ NA ₂ or unsubstituted or mono- or polysubstituted by A, OA, shark or CF ₃

A alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

Shark F, Cl, Br or l

R ⁵ , R ⁶ , R ⁷ , R ⁸ each independently of one another are H, A, unsubstituted or mono- or polysubstituted by A, OA, shark, CF ₃ means, where R ⁵ and R ⁷ , R ⁵ and R ⁶ , R ⁷ and R ⁸ can form 5-7-membered rings,

and their salts and solvates, with the proviso that compounds in which R ⁵ , R ⁶ , R ⁷ and R ^{8 are} simultaneously H and none of the radicals R ¹ , R ² , R ³ , R ⁴ OH, N0 ₂ , NH ₂ , NHA, NA ₂ , NH-CO-A, NH-CO-Ph, SA, SO-A, S0 ₂ -A, S0 ₂ -Ph, CN, OCF ₃ , CO-A, C0 ₂ H, C0 ₂ A, CO-NH ₂ , CO-NHA, CO-NA ₂ , S0 ₂ NH ₂ , S0 ₂ NHA, S0 NA ₂ or unsubstituted or mono- or polysubstituted by A, OA, shark or CF _{3 are} phenyl, excepted ,

The invention also relates to the use of the compounds of the formula I and their salts and solvates as NHE-3 inhibitors.

Other inhibitors of the subtype 3 sodium / proton exchanger are e.g. in EP 0 825 178.

The compounds exempted from the stipulation have already been described in US Pat. No. 3,131,187, and their use for other purposes. Quinazdlinyl guanidine derivatives are described by V.I. Shvedov et al. in

Pharm. Chem. J. (Engl. Transl.) 1980, 14, 532-538 or in Khim. Farm. Zh. 1980, 14, 38-43, and by S.C. Bell et al. in J. Med. Pharm. Chem. 1962, 5, 63-69.

The invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.

Surprisingly, it has been found that the compounds of the formula I and their salts inhibit the sodium / proton exchanger subtype 3 with good tolerability.

The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine.

It is known that the Na ⁺ / H ⁺ exchanger is a family with at least 6 different isoforms (NHE-1 to NHE-6), all of them are cloned. While the NHE-1 subtype is ubiquitously distributed throughout the body in all tissues, the remaining NHE subtypes are selectively expressed in specific organs such as the kidney or in the lumen wall and contraluminal wall of the small intestine. This distribution reflects the specific functions that the various isoforms serve, namely on the one hand the regulation of the intracellular pH and cell volume by the subtype NHE-1 and on the other hand the Na ⁺ uptake and reuptake in the intestine and kidney by the Isoforms NHE-2 or NHE-3. The NHE-4 isoform was found mainly in the stomach. The expression of NHE-5 is limited to brain and neuronal tissue. NHE-6 represents the isoform that forms the sodium proton exchanger in the mitochondria.

The NHE-3 isoform is particularly expressed in the apical membrane of the proximal renal tubules; an NHE-3 inhibitor therefore exercises a kidney protection effect.

The therapeutic use of a selective inhibitor for NHE-3 isoforms is versatile. NHE-3 inhibitors inhibit or reduce tissue damage and cell necrosis following pathophysiological hypoxic and ischemic events that lead to activation of NHE activity, such as during renal ischemia or during kidney transplant removal, transport, and reperfusion during kidney transplantation , The compounds of the formula I have a cytoprotective effect by preventing the excessive absorption of sodium and water into the cells of organs which are under-supplied with oxygen.

The compounds of formula I lower blood pressure and are suitable as active pharmaceutical ingredients for the treatment of hypertension. They are also suitable as diuretics.

The compounds of the formula I, alone or in conjunction with NHE inhibitors of other subtype specificity, have anti-ischemic effects and can be used for thromboses, atherosclerosis, vascular spasms, for protecting organs, for example kidney and liver, before and during operations, and for chronic or acute kidney failure. They can also be used to treat stroke, himedema, ischemia of the nervous system, various forms of shock, e.g. allergic, cardiological, hypovolaean or bacterial shock, and to improve respiratory drive in the following conditions, for example: central sleep apneas, sudden

Child death, postoperative hypoxia and other breathing disorders. Combination with a carbonic anhydrase inhibitor can further improve breathing. The compounds of formula I have an inhibitory effect on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of vascular smooth muscle cells and can therefore be used for the treatment of diseases in which cell proliferation is a primary or secondary cause. The compounds of formula I can be used against late diabetic complications, cancer, fibrotic diseases, endothelial dysfunction, organ hypertrophy and hyperplasia, especially in prostatic hyperplasia or prostate hypertrophy. They are also suitable as diagnostics for the determination and differentiation of certain forms of hypertension, atherosclerosis, diabetes and proliferative diseases.

Since the compounds of the formula I also have an advantageous effect on the level of the serum lipoproteins, they can be used for the treatment of an increased blood lipid level alone or in combination with other medicaments.

The invention relates to the use of compounds of the formula I as claimed in claim 1 and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of thromboses, ischemic conditions of the heart, peripheral and central nervous system and stroke, ischemic conditions of peripheral organs and limbs and for the treatment of shock conditions.

The invention further relates to the use of compounds of the formula I according to claim 1 and their physiologically acceptable Salts and / or solvates for the manufacture of a medicament for use in surgical operations and organ transplants and for the preservation and storage of grafts for surgical measures.

The invention also relates to the use of compounds of the formula I according to claim 1 and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of diseases in which cell proliferation is a primary or secondary cause, for the treatment or prophylaxis of disorders of

Fat metabolism or disturbed respiratory drive.

The invention further relates to the use of compounds of the formula I according to claim 1 and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of ischemic kidney, ischemic bowel disease or for the prophylaxis of acute or chronic kidney disease.

Methods for identifying substances which inhibit the sodium / proton exchanger ^• type 3 are described, for example, in US Pat. No. 5,871,919.

The compounds of formula I are also suitable for the treatment of bacterial and parasitic diseases.

For all residues in the compounds of formula I which occur several times, e.g. A, the meanings are independent of each other.

Hydrates and solvates are e.g. the hemi, mono- or dihydrates, among solvates e.g. Alcohol addition compounds such as with methanol or ethanol.

In the above formulas, A means alkyl, is linear or branched, and has 1, 2, 3, 4, 5 or 6 carbon atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2 , 2-

Dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyi, 1 , 1, 2- or 1, 2,2-trimethylpropyl.

OA preferably means methoxy, ethoxy, propoxy, isopropoxy or butoxy.

Shark is preferably F, Cl or Br, but also I, in particular F, Cl or Br.

Above and below, Ph denotes an unsubstituted phenyl radical, unless stated otherwise.

Ar preferably denotes unsubstituted phenyl or naphthyl, further preferably monosubstituted phenyl or naphthyl, for example by A, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, 5 propoxy, butoxy or CF ₃ .

Particularly preferably, Ar is unsubstituted or substituted by A, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, butoxy or CF ₃ phenyl monosubstituted.

R ⁵ , R ⁶ , R ⁷ and R ^{8 are} preferably H at the same time or, independently of one another, H or A, which is defined as indicated above.

If R ⁵ and R ⁷ together form a ring, Y preferably adopts one of the following structures

R

° wherein R ⁶ and R ^{8 have} the meaning given above and n is 1, 2 or 3, preferably 1 or 2.

If R ⁷ and R ⁸ together form a ring, Y preferably adopts one of the following structures: 5

wherein R ⁵ and R ^{6 have} the meaning given above and n is 1, 2 or 3, preferably 1 or 2.

If R ⁵ and R ⁶ together form a ring, Y preferably adopts one of the following structures:

wherein R ⁷ and R ^{8 have} the meaning given above and n is 1, 2 or 3, preferably 1 or 2.

The invention relates in particular to the compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above and the use thereof. Some preferred groups of compounds can be expressed by the following sub-formulas la to le, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which

in la R ¹ denotes H, OH, OA, SA or shark, in particular H, OH, OCH ₃ or CH ₃ ;

in Ib R ¹ H, OH, OA, SA or shark, in particular H, OH, OCH ₃ or CH ₃ R ² H, shark, OH, A, NH ₂ , N0 ₂ or CN, in particular H, Cl, OH, CH ₃ or NH ₂ . mean; in le R ¹ H, OH, OA, SA or shark, in particular H, OH, OCH ₃ or CH ₃ R ² H, shark, OH, A, NH ₂ , N0 ₂ or CN, in particular H, Cl, OH, CH ₃ or NH ₂ .

Ar is phenyl;

in Id R ¹ H, OH, OA, SA or shark, in particular H, OH, OCH ₃ or CH ₃ R ² H, shark, OH, A, NH ₂ , N0 ₂ or CN, in particular H,

Cl, OH, CH ₃ or NH ₂ . Ar phenyl

R ^{3 is} H, A, NH ₂ or SA, in particular H or CH ₃

mean;

in le R ¹ H, OH, OA, SA or shark, in particular H, OH, OCH ₃ or CH ₃ R ² H, shark, OH, A, NH ₂ , N0 ₂ or CN, in particular H,

Cl, OH, CH ₃ or NH ₂ . Ar phenyl

R ^{3 is} H, A, NH ₂ or SA, in particular H or CH ₃

R ⁴ H, shark, NH ₂ , or N0 _2, in particular H or NH ₂

Also preferred are those compounds of the formula I and their salts and solvates in which R simultaneously denotes H, Ar phenyl and at least one of the radicals R ¹ , R ² , R ³ , R ^{4 has} one of the following meanings: OH, N0 ₂ , NH ₂ , NHA, NA ₂ , NH-CO-A, NH-CO-Ph, SA, SO-A, S0 ₂ -A, S0 ₂ - Ph, CN, OCF ₃ , CO-A, C0 ₂ H, C0 ₂ A , CO-NH ₂ , CO-NHA, CO-NA ₂ , S0 ₂ NH ₂ , S0 ₂ NHA, S0 ₂ NA ₂ or unsubstituted or mono- or polysubstituted by A, OA, shark, CF ₃ . Of these connections are those particularly preferred whose radical R is Cl, in particular in position 6, and those compounds whose radical R ^{3 is} methyl, in particular in position 4 '.

Such compounds of the formula I and their are also preferred

Salts and solvates, in which the radicals R ⁵ , R ⁶ , R ⁷ , R ⁸ also have the meaning H. Of these compounds, those are particularly preferred whose radical R ^{1 is} Cl, in particular in position 6, and those compounds whose radical R ^{3 is} methyl, in particular in position 4 ', and those compounds whose radical R ^{4 is} NH ₂ , especially in position 2 '.

Compounds of the formula I, the radical R ^{3 of which is} methyl, in particular in the 4 'position, have a particularly pronounced selectivity of the binding to the NHE-3 receptor.

Compounds of the formula I, the radical R ^{4 of which is} NH ₂ , in particular in the 2 'position, show particularly good solubility in aqueous solutions.

Compounds of the formula I in which R ^{1 is} H, R ² Cl in the 6-position and R ^{3 is} methyl in the 4'-position are preferred. Compounds of the formula I are very particularly preferred, the radical R ^{4 of which} additionally denotes NH ₂ in the 2'-position.

The compounds of the formulas If to Ik are particularly preferred:

wherein R ¹ , R ² , R ³ , R ⁴ and Y have the meaning given above and R ^{1 is} preferably H, OH, OA, SA, or F, in particular H, OH, OCH ₃ or CH ₃ . R ¹ in the formulas If to lk H very particularly preferably. R ² preferably denotes H, Cl, A, NH ₂ , N0 ₂ , SCH ₃ , SOCH ₃ , S0 ₂ CH ₃ , OCH ₃ , OH, CN, CF ₃ , OCF ₃ or F, in particular H, Cl, F, Br , OH, CH ₃ , N0 ₂ or NH ₂ , R ² in the formulas If to lk Cl very particularly preferably.

R ³ preferably denotes H, Cl, A, NH ₂ , N0 ₂ , SCH ₃ , CN, C ₂ H ₅ , OCF ₃ or

C ₆ H ₅ , in particular H, A or CH ₃ . R ³ in the formulas If to lk is very particularly preferably CH ₃ .

R ⁴ preferably denotes H, F, NH ₂ or N0 ₂ , in particular H or NH ₂ . R ⁴ in the formulas If to lk is NH ₂ very particularly preferably.

Y has the meaning given above in the formulas If to lk. Y preferably assumes one of the following meanings:

Y particularly preferably has one of the following meanings:

The following compounds 11 to 110 and their salts and solvates are furthermore particularly preferred:

N- (6-chloro-4-phenyl-quinazolin-2-yl) -N'-methyl-guanidine 11

N- (6-chloro-4-p-tolyl-quinazolin-2-yl) -N'-methyl-guanidine 12

N- [6-chloro-4- (2-nitro-phenyl) -quinazolin-2-yl] -N'-methyl-13 guanidine

N- [4- (2-Amino-phenyl) -6-chloro-quinazolin-2-yl] -N'-methyl-14 guanidine

N- [6-chloro-4- (4-methyl-2-nitro-phenyl) -quinazolin-2-yl] -N'- 15 methyl-guanidine

N- [4- (2-Amino-4-methylphenyl) -6-chloroquinazolin-2-yl] -N'- 16 methyl guanidine

N- [6-chloro-4- (2-nitro-phenyl) -quinazolin-2-yl] guanidine 17

N- [4- (2-aminophenyl) -6-chloro-quinazolin-2-yl] guanidine 18

N- [6-chloro-4- (4-methyl-2-nitro-phenyl) -quinazolin-2-yl] - 19 guanidine

N- [4- (2-Amino-4-methylphenyi) -6-chloroquinazolin-2-yl] - 110 guanidine

The hydrochlorides and p-toluenesulfonates of the compounds of the formulas 11 to 110 are very particularly preferred.

The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions that are mentioned implementations are known and suitable. Use can also be made of variants which are known per se and are not mentioned here in detail.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.

The 2-guanidino-4-aryl-quinazolines of the formula I are preferably prepared by using o-aminophenyl ketones or o-aminonaphthyl ketones of the formula II

wherein R ¹ , R ² and Ar have the meanings given in claim 1, with 1-cyanguanidine or a correspondingly N-alkylated or N-arylated 1-cyanguanidine of the formula NC-Y, where Y has the meaning given above.

The reaction can be carried out in an inert solvent.

Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether,

Tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

DMF, water or an alcohol is preferably used. The reaction is very particularly preferred without a solvent, i.e. in the melt, carried out at temperatures between 100 and 200 ° C.

The presence of an acidic catalyst such as AICI ₃ , TiCI, p-toluenesulfonic acid, BF ₃ , acetic acid, sulfuric acid, oxalic acid, POCI ₃ or phosphorus pentoxide is advantageous.

A preferred variant is that one of the reactants is already in the form of a salt, e.g. is used as the hydrochloride.

Another valuable method for preparing the compounds of formula I is that instead of a compound of formula NC-Y, a compound of formula III

HN = CX-Y III

wherein

X -S-alkyl, -S-aryl, -O-alkyl or -OAryl and alkyl, preferably the meaning of A and aryl given above has the meaning of Ar given above, with a compound of formula II.

Finally, the compounds of the formula I can be reacted with 2-chloro-4-arylquinazolines of the formula IV

wherein Ar, R ¹ and R ^{2 have} the meanings given above, be prepared with a compound of formula HY, wherein Y has the meaning given above. HY particularly preferably means guanidine.

A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, especially aliphatic, alicyclic, araiiphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.

Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ^• 2-ethanesulfonic acid, ^• ethanesulfonic acid, Benzenesulfonic acid, p-

Toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.

The invention further relates to the use of the compounds of the formula I as NHE-3 inhibitors and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more further active ingredients. The invention further relates to pharmaceutical preparations containing at least one NHE-3 inhibitor of the formula I and / or one of its physiologically acceptable salts and solvates.

These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions for parenteral use, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for which topical application ointments, creams or powders, or transdermally in patches.

The new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables. ^■ The stated preparations can be sterilized and / or

Excipients such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active ingredients, e.g. one or more vitamins. As a pharmaceutical preparation for administration in the form of

Aerosols or sprays are suitable e.g. Solutions, suspensions or emulsions of the active ingredient of formula I in a pharmaceutically acceptable solvent.

The compounds of formula I and their physiologically acceptable

Salts and solvates can be used to treat and / or prevent the diseases or conditions described above.

The substances according to the invention are generally preferably administered in doses between about 0.1 and 100 mg, in particular between 1 and 10 mg, per dosage unit. The daily Dosage is preferably between about 0.001 and 10 mg / kg body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion and combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.

Examples:

Example 1 :

A mixture of 1.00 g of 2-amino-5-chloro-2'-nitrobenzophenone, 0.60 g of 1-

Cyanguanidine and 2.00 g of p-toluenesulfonic acid monohydrate were melted at 150 ° C for 2 h. The cooled melt was mixed with methanol and for 30 min. stirred at 65 ° C. The residue obtained after filtration was discarded and water was added to the filtrate. The solution was then made alkaline and extracted with ethyl acetate. The extract was concentrated and crystallized from acetonitrile, whereby the free base N- [6-chloro-4- (2-nitro-phenyl) -quinazolin-2-yl] guanidine was obtained.

To form the acid addition salt, the base was dissolved in methanol, the mixture was acidified with HCI-containing isopropanol and the solvent was then removed. Crystals of N- [6-chloro-4- (2-nitro-phenyl) -quinazolin-2-yl] guanidinium chloride could be obtained from acetonitrile.

Example 2: 1.20 g of N- (5-methoxy-4-phenyl-quinazolin-2-yl) guanidinium chloride were stirred with 8.00 g of pyridinium chloride at 170 ° C. for 6 h. The cooled melt was then treated with 20 ml of a Na ₂ S ₂ 0 ₄ solution. The precipitate obtained was isolated, dissolved in methanol and the solution acidified with HCI-containing isopropanol. After removal of the solvent, the residue was crystallized from acetonitrile, whereby N- (5-Hydroxy-4-phenyl-quinazolin-2-yl) guanidinium chloride was obtained (mp. 310 ° C).

Example 3: A mixture of 3.01 g of 2-amino-5-chlorobenzophenone, 2.55 g of N-cyano

N'-methylguanidine and 7.42 g of p-toluenesulfonic acid monohydrate were stirred in the melt at 150 to 160 ° C. for 2 h. The cooled melt was mixed with methanol and for 30 min. stirred at 65 ° C. The residue obtained after filtration was discarded, the filtrate was mixed with water and ethyl acetate and again for 30 min. stirred at 65 ° C. The mixture was then left to crystallize in an ice bath with stirring, giving N- (6-chloro-4-phenyl-quinazolin-2-yl) -N'-methyl-guanidinium-p-toluenesulfonate (mp. 268-269 ° C.).

Example 4:

300 mg of N- [6-chloro-4- (2-nitro-phenyl) -quinazolin-2-yl] guanidinium p-toluenesulfonate were dissolved in 50 ml of methanol and in the presence of 300 mg of Raney nickel at RT within Hydrogenated under normal pressure for 21 h. After filtration and removal of the solvent, N- [6-chloro-4- (2-aminophenyl) -quinazolin-2-yl] guanidinium p-toluenesulfonate was obtained from the filtrate. (Mp 250 ° C).

Example 5:

A mixture of 0.350 g of N- (6-methylsulfanyl-4-phenyl-quinazolin-2-yl) guanidinium chloride and 0.140 g of sodium perborate trihydrate in 5 ml

Acetic acid was left for 30 min. stirred at 80 ° C. The solution was then concentrated and water was added. The aqueous solution was adjusted to pH 12 and extracted with ethyl acetate. Concentration of the extract gave N- (6-methanesulfinyl-4-phenyl-quinazolin-2-yl) guanidine in crystalline form (mp. 175-180 ° C.).

Example 6:

A mixture of 1,200 g of N- (6-methylsulfanyl-4-phenyl-quinazolin-2-yl) guanidinium chloride and 0.154 g of sodium perborate trihydrate in 5 ml of acetic acid was stirred at 80 ° C. for 1 h. The reaction mixture was then concentrated and water was added. The received The solution was adjusted to pH 12 and extracted with ethyl acetate. Concentration of the extract gave N- (6-methanesulfonyl-4-phenyl-quinazolin-2-yl) guanidine in crystalline form (mp. 180-185 ° C.). To form the acid addition salt, 0.80 g of N- (6-methanesulfonyl-4-phenyl-quinazolin-2-yl) guanidine were treated with an aqueous 1 N HCl solution and the crystals obtained were recrystallized from ethanol.

Example 7:

2.70 g of the hydrochloride of 2-amino-5-chlorobenzophenone and 1.70 g of N-cyano-N ', N "-dimethyl-guanidine were mixed and heated at 150 ° C. for 3 h. The reaction product was taken up in methanol and filtered. The The filtrate was concentrated and the residue was recrystallized from a mixture of isopropanol and diethyl ether to give N- (6-chloro-4-phenyl-quinazolin-2-yl) -N ', N "-dimethyl-guanidinium chloride (mp. 264-267 ° C).

Example 8:

A mixture of 500 mg of 2-amino-5-chloro-2'-nitrobenzophenone, 406 mg of N-cyano-N'-ethylguanidine and 1.03 g of p-toluenesulfonic acid monohydrate was stirred in the melt at 150 to 160 ° C. for 2 h and as in

Example 3 worked up, whereby N- [6-chloro-4- (2-nitro-phenyl) -quinazolin-2-yl] -N'-ethyl-guanidinium-p-toluenesulfonate was obtained (mp. 298-300 ° C.) ,

Example 9:

A mixture of 500 mg of 2-amino-5-chloro-2'-nitrobenzophenone, 580 mg of N-cyano-N-phenylguanidine and 1.03 g of p-toluenesulfonic acid monohydrate was stirred in the melt at 150 to 160 ° C. for 2 h and worked up as in Example 3, whereby N- [6-chloro-4- (2-nitro-phenyl) -quinazolin-2-yl] -N'-phenyl-guanidinium-p-toluenesulfonate was obtained (mp. 261-263 ° C). The following acid addition salts which are preferred as NHE-3 inhibitors were obtained analogously to the processes given above using the corresponding precursors:

In the following, pTsOH means p-toluenesulfonic acid.

R ¹ R ² R ^J R ⁴ HX

(10) H Cl H S0 ₂ CH ₃ pTsOH

(11) H Cl CH ₃ S0 ₂ CH ₃ HCl

(12) H Cl C ₂ H _Ö S0 ₂ CH ₃ HCl

(13) H Cl OCH ₃ S0 ₂ CH ₃ HCl

(14) H Cl N0 ₂ H pTsOH

(15) H Cl NH ₂ H pTsOH (mp 260-266 ° C)

(16) H Cl N (CH ₃ ) ₂ H pTsOH

(17) H Cl H NH ₂ HCl

(18) H Cl CH ₃ NH ₂ pTsOH (mp 211-214 ° C)

(19) H Cl C ₂ H _δ NH ₂ HCl

(20) H Cl OCH ₃ NH ₂ HCl

(21) H Cl N0 ₂ NH ₂ HCl

(22) H Cl NH ₂ NH ₂ HCl

(23) H Cl N (CH ₃ ) ₂ NH ₂ HCl

(24) H Cl H NHCH ₃ HCl

(25) H Cl CH ₃ NHCH ₃ HCl

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(63) H OCH ₃ H OCF3 pTsOH

(64) H OH H H HCl (mp 333 ° C)

(65) H NH ₂ HH HCl (mp. 290-296 ° C)

(66) H SCH ₃ HH HCI (mp. 234-238 ° C)

(67) H CH ₃ CN CO-NH ₂ pTsOH

(68) HC _ß Hs HH pTsOH (mp. 188 ° C)

(70) H OCF ₃ HH HCI (mp. 255-259 ° C)

(71) H CN H H HCI (mp 330 ° C)

(72) HFH SOC ₂ H ₅ pTsOH

(73) H SOCH ₃ HH pTsOH

(74) H SO ₂ CH ₃ HH pTsOH

(75) H Cl CN H HCl (mp 344 ° C)

(76) NH ₂ Cl Cl Cl HCl

(77) H Cl H OCF3 pTsOH (mp 274-277 ° C)

(78) H Cl OCF3 H HCl (mp. 310-315 ° C)

(79) Cl Cl CH ₃ OH HCl

(80) Cl H NH ₂ H HCl

(81) Cl H NH ₂ CH ₃ HCl

(82) CH ₃ Cl CH ₃ CO ₂ H HCl

(83) C _δ Hs Cl CH ₃ F HCl

(84) OH CO-NH2 H H pTsOH

(85) Cl HH SCH ₃ pTsOH

(86) H Cl Cl SCH ₃ pTsOH

(87) SCH ₃ HHH HCI (mp. 303-306 ° C)

(88) HF CH ₃ CN HCl

(89) H Cl SCH ₃ H HCl (mp 324-327 ° C)

(90) CH ₃ H CN H HCl

(91) H Cl CeHs H HCl (mp 200 ° C)

(92) H Cl CH ₃ N0 ₂ pTsOH (mp 210-214 ° C)

(93) HH Br S0 ₂ CH ₃ pTsOH

(94) HH OCH ₃ OCF ₃ pTsOH

(95) H Cl H CN HCl. (Mp> 350 ° C, decomposition)

(96) H Cl C ₂ H _δ NH ₂ pTsOH (mp> 257 ° C, decomposition)

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(266) H OCF ₃ HF HCI

(267) H CN HF HCI

(269) H SOCH ₃ HF HCI

(271) H Cl CN F HCI

(273) H Cl H OCF ₃ pTSOH (mp 260-264 ° C)

(274) H Cl OCF3 F HCI

(275) Cl Cl SO2NH2 F HCI

(276) Cl H NH ₂ F HCI

(277) Cl H NH ₂ CH ₃ HCl

(278) CH ₃ Cl NHCH ₃ F HCl

(279) F Cl CH ₃ NHCH ₃ HCl

(281) Cl NH ₂ FF HCI

(282) NH ₂ Cl Cl F HCI

(283) SCH ₃ HHF HCI *

(284) HFN (CH ₃ ) ₂ F HCl

(285) H Cl SCH ₃ F HCI

(286) HH OCF ₃ CH ₃ HCl

(287) H Cl SOCH ₃ H HCl (mp 240 ° C)

(288) H Cl CH ₃ NH ₂ pTsOH (mp. 217-218 ° C)

(289) H Cl H OCF3 HCI (mp 260-264 ° C)

(290) H Cl H CO2CH3 HCI (mp. 275-277 ° C)

(291) H Cl CH ₃ N0 ₂ pTsOH (mp 218-220 ° C)

(292) H Cl H NHCOCH ₃ HCl (mp. 317-320 ° C) co co ro ro cn on o cn o cn o

(316) H Cl C ₂ H ₅ N (CH ₃ ) ₂ HCl

(317) H Cl OCH ₃ N (CH ₃ ) ₂ HCl

(318) H Cl N0 ₂ N (CH ₃ ) ₂ HCl

(319) H Cl NH ₂ N (CH ₃ ) ₂ HCl (320) H Cl N (CH ₃ ) ₂ N (CH ₃ ) ₂ HCl

(321) H Cl H OH HCl

(322) H Cl CH ₃ OH HCl

(323) H Cl C ₂ H ₅ OH HCl

(324) H Cl OCH ₃ OH HCl (325) H Cl N0 ₂ OH HCl

(326) H Cl NH ₂ OH HCl

(327) H Cl ^' N (CH ₃ ) ₂ OH HCl

(328) H Cl H CH ₃ HCl

(329) H Cl CH ₃ CH ₃ HCl (330) H Cl C ₂ H ₅ CH ₃ HCl

(331) H Cl OCH ₃ CH ₃ HCl

(332) H Cl NO ₂ CH ₃ HCl

(333) H Cl NH ₂ CH ₃ HCl

(334) H Cl N (CH ₃ ) ₂ CH ₃ HCl (335) H Cl H N0 ₂ pTsOH (mp. 278-279 ° C)

(336) H Cl N0 ₂ H HCl

(337) HH NH ₂ H HCl

(338) HH NH ₂ CH ₃ HCl

(339) H Cl CH ₃ Cl HCl (340) HH CH ₃ H HCl

(341) H Cl H F HCI

(342) H Cl F H HCl

(343) H Br H H HCI

(344) H Br HF HCI (345) H N0 ₂ HH HCI

(346) H OCH ₃ HH HCl

(347) H OH H H HCl

(348) H NH ₂ HH HCl

(349) H SCH ₃ HH HCl (350) H CH ₃ HH HCl

(351) HC ₆ H ₅ HH HCI (352) H CF ₃ HH HCl

(353) H OCF ₃ H ^• H HCl

(354) H CN H H HCl

(355) H F H H HCl

(356) H SOCH ₃ HH HCl

(358) H Cl CN H HCl

(359) H Cl H Cl HCl

(362) Cl Cl H H HCI

(363) Cl H ⁴ NH ₂ H HCl

(364) Cl H NH ₂ CH ₃ HCl

(365) CH ₃ Cl CH ₃ H HCl

(366) F Cl CH ₃ H HCl

(367) H H H H pTsOH (mp 225-226 ° C)

(368) Cl H H H HCI

(369) H Cl Cl H HCl

(370) SCH ₃ HHH HCI

(371) HF CH ₃ H HCl

(372) H Cl SCH ₃ H HCl

(373) CH ₃ HHH HCl

(374) H Cl C _δ H _δ H HCl

(375) H Cl CH ₃ N0 ₂ HCl

(376) HH Br H HCI

(378) HHH NH ₂ HCI

(379) H Cl H NH ₂ pTsOH (mp 252-254 ° C) 00 co cn cn o ro ro cn o cn

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(438) H CεHs H H HCl

(439) H CF ₃ HH HCl

(440) H OCF ₃ HH HCl

(441) H CN H H HCl

(442) HFHH HCI

(444) H SO ₂ CH ₃ HH HCl

(445) H Cl CN H HCl

(446) H Cl H Cl HCl

(447) H Cl H OCF3 HCl

(449) Cl Cl ^> HH HCl

(450) Cl H NH ₂ H HCl

(451) Cl H NH ₂ CH ₃ HCl

(452) CH ₃ Cl CH ₃ H HCl

(453) F Cl CH ₃ H HCl

(454) H H H H HCl

(455) Cl H H H HCI

(456) H Cl Cl H HCl

(457) SCH ₃ HHH HCI

(458) HF CH ₃ H HCl

(459) H Cl SCH ₃ H HCl

(460) CH ₃ HHH HCl

(461) H Cl C _Ö H _Ö H HCI

(462) H Cl CH ₃ N0 ₂ HCl

(463) HH Br H HCI

(465) HHH NH ₂ HCI oo oo ro ro n cn o cn co cn

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(663) H Cl C2H ₅ N (CH ₃ ) ₂ HCl

(664) H Cl OCH3 N (CH ₃ ) ₂ HCl

(665) H Cl N0 ₂ N (CH ₃ ) ₂ HCl

(666) H Cl NH ₂ N (CH ₃ ) ₂ HCl

(667) H Cl N (CH ₃ ) ₂ N (CH ₃ ) ₂ HCl

(668) H Cl H OH HCl

(669) H Cl CH ₃ OH HCl

(670) H Cl C ₂ H _δ OH HCl

(672) H Cl N0 ₂ OH HCl

(673) H Cl NH ₂ OH HCl

(674) H Cl ^% N (CH ₃ ) ₂ OH HCl

(675) H Cl H CH ₃ HCl

(676) H Cl CH ₃ CH ₃ HCl

(677) H Cl C ₂ H _δ CH ₃ HCl

(679) H Cl N0 ₂ CH ₃ HCl

(680) H Cl NH ₂ CH ₃ HCl

(681) H Cl N (CH ₃ ) ₂ CH ₃ HCl

(682) H Cl H N0 ₂ HCI

(683) H Cl N0 ₂ H HCl

(684) HH NH ₂ H HCl

(685) HH NH ₂ CH ₃ HCl

(686) H Cl CH ₃ Cl HCl

(687) HH CH ₃ H HCl

(688) H Cl H F HCI

(689) H Cl F H HCl

(690) H Br H H HCI

(691) H Br H F HCI

(692) H N0 ₂ HH HCl

(693) H OCH ₃ HH HCl

(694) H OH H H HCl

(695) H NH ₂ HH HCl

(696) H SCH ₃ HH HCl

(697) H CH ₃ HH HCl (699) H CF ₃ HH HCl

(700) H OCF ₃ HH HCl

(701) H CN H H HCl

(702) HFHH HCI

(704) H SO ₂ CH ₃ HH HCl

(705) H Cl CN H HCl

(706) H Cl H Cl HCl

(709) Cl Cl H H HCI

(710) Cl H ^% NH ₂ H HCl

(711) Cl H NH ₂ CH ₃ HCl

(712) CH ₃ Cl CH ₃ H HCl

(713) F Cl CH ₃ H HCl

(714) H H H H HCl

(715) Cl H H H HCI

(716) H Cl Cl H HCl

(717) SCH ₃ HHH HCI

(718) HF CH ₃ H HCl

(719) H Cl SCH ₃ H HCl

(720) CH ₃ HHH HCl

(722) H Cl CH ₃ N0 ₂ HCl

(723) HH Br H HCI

(725) H Cl H NH ₂ pTsOH (mp 178-180 ° C)

(726) H Cl HH pTsOH (mp 219-220 ° C) 00 oo ro ro cn cn o cn o cn

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(786) H CF ₃ HH HCl

(787) H OCF ₃ HH HCl

(788) H CN H H HCl

(789) HFHH HCI

(791) H SO ₂ CH ₃ HH HCl

(792) H Cl CN H HCl

(793) H Cl H Cl HCl

(794) H Cl H OCF3 HCl

(795) H Cl OCF ₃ H HCl

(796) Cl Cl H H HCI

(797) Cl H ^% NH ₂ H HCl

(798) Cl H NH ₂ CH ₃ HCl

(799) CH ₃ Cl CH ₃ H HCl

(800) F Cl CH ₃ H HCl

(801) H H H H HCl

(802) Cl H H H HCI

(803) H Cl Cl H HCl

(804) SCH ₃ HHH HCl

(805) HF CH ₃ H HCl

(806) H Cl SCH ₃ H HCl

(807) CH ₃ HHH HCl

(808) H Cl CeHs H HCl

(809) H Cl CH ₃ N0 ₂ HCl

(810) HH Br H HCI

(812) H Cl H N0 ₂ HCI

(813) H Cl HH pTsOH

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(923) H Cl N (CH ₃ ) ₂ NHCH3 HCl

(924) H Cl N (CH ₃ ) ₂ NHCH ₃ HCl

(925) H Cl HN (CH ₃ ) ₂ HCl

(926) H Cl CH ₃ N (CH ₃ ) ₂ HCl

(927) H Cl C ₂ H ₅ N (CH ₃ ) ₂ HCl

(928) H Cl OCH3 N (CH ₃ ) ₂ HCl

(929) H Cl N0 ₂ N (CH ₃ ) ₂ HCl

(930) H Cl NH ₂ N (CH ₃ ) ₂ HCl

(931) H Cl N (CH ₃ ) ₂ N (CH ₃ ) ₂ HCl

(932) H Cl H OH HCl

(933) H Cl ^* CH ₃ OH HCl

(934) H Cl C ₂ H ₅ OH HCl

(935) H Cl OCH ₃ OH HCl

(936) H Cl N0 ₂ OH HCl

(937) H Cl NH ₂ OH HCl

(938) H Cl N (CH ₃ ) ₂ OH HCl

(940) H Cl H CN HCl

(941) H Cl C ₂ H ₅ SO2NH2 HCl

(943) H Cl NO ₂ CH ₃ HCl

(944) H Cl NH ₂ CH ₃ HCl

(945) H Cl N (CH ₃ ) ₂ CH ₃ HCl

(946) H Cl H N0 ₂ pTsOH

(947) H Cl N0 ₂ H HCl

(948) HH NH ₂ H HCl

(949) HH NH ₂ CH ₃ HCl

(950) H Cl CH ₃ CO-NH ₂ HCl

(951) HH CH ₃ S0 ₂ CH ₃ pTsOH

(952) H Cl OH F pTsOH

(953) H Cl F SCH ₃ HCI

(954) H Br H CONH ₂ pTsOH

(955) H Br CO-NH ₂ F pTsOH

(956) H N0 ₂ HH pTsOH

(957) H OCH ₃ H OCF3 pTsOH (958) H OH HH HCl

(959) H NH ₂ HH HCl

(960) H SCH ₃ HH HCl

(961) H CH ₃ CN CO-NH ₂ pTsOH

Pharmacological tests

The methodology used to characterize the compounds of the formula I as NHE-3 inhibitors is shown below.

The compounds of the formula I were characterized with regard to their selectivity towards the isoforms NHE- to NHE-3. The three isoforms were stably expressed in mouse fibroblast cell lines. The inhibitory effect of the compounds was assessed by determining the EIPA-sensitive ²² Na ⁺ uptake into the cells after intracellular acidosis.

material and methods

LAP1 cell lines that express the different NHE isoforms

The LAP1 cell lines expressing the isoforms NHE-1, -2 and -3 (a mouse fibroblast cell line) were developed by Prof. J. Pouyssegur (Nice,

France). The transfections were carried out according to the method of Franchi et al. (1986). The cells were cultured in Dulbecco's modified Eagle medium (DMEM) with 10% inactivated fetal calf serum (FCS). For the selection of the NHE-expressing cells, the so-called "acid killing method" by Sardet et al. (1989) used. The cells were first incubated for 30 minutes in a NHCl-containing bicarbonate and sodium free buffer. The extracellular NH CI was then removed by washing with a buffer free of bicarbonate, NH ₄ CI and sodium. The cells were then incubated in a bicarbonate-free, NaCl-containing buffer. Only those Cells that functionally express NHE could survive in the intracellular acidification to which they were exposed.

Characterization of NHE inhibitors in terms of their isoform selectivity

With the above mouse fibroblast cell lines expressing the isoforms NHE-1, NHE-2 and NHE-3, compounds according to the method described by Counillon et al. (1993) and Scholz et al. (1995) described procedure for selectivity compared to the isoforms. The cells were acidified intracellularly using the NH CI prepulse method and then by incubation in a bicarbonate-free ²² Na ⁺ -containing buffer. Due to the intracellular acidification, NHE was activated and sodium was absorbed into the cells. The effect of the test compound was expressed as an inhibition of the ²² Na ⁺ uptake sensitive to EIPA (ethyl isopropylamiloride). The cells expressing NHE-1, NHE-2 and NHE-3 were seeded at a density of 5-7.5 x 10 ⁴ cells / well in microtiter plates with 24 wells and grown to confluence for 24 to 48 hours. The medium was aspirated and the cells were incubated for 60 minutes at 37 ° C. in the NH ₄ CI buffer (50 mM NH ₄ CI, 70 mM choline chloride, 15 mM MOPS, pH 7.0). The buffer was then removed and the cells were quickly overlaid twice with the choline chloride washing buffer (120 mM choline chloride, 15 mM PIPES / Tris, 0.1 mM ouabain, 1 mM MgCl ₂ , 2 mM CaCl ₂ , pH 7.4) The cells were then aspirated with the choline chloride loading buffer (120 mM choline chloride, 15 mM PIPES / Tris, 0.1 mM PIPES / Tris, 0.1 mM Quabain, 1mM MgCl ₂ , 2mM CaCl ₂ , pH 7.4, ²² Overlaid Na * (0.925 kBg / 100 ml loading buffer)) and incubated therein for 6 minutes. After the incubation period had elapsed, the incubation buffer was aspirated. For the purpose of

After removing extracellular radioactivity, the cells were quickly washed four times with ice-cold phosphate-buffered saline (PBS). The cells were then solubilized by adding 0.3 ml of 0.1 N NaOH per well. The cell fragment-containing solutions were transferred to scintillation tubes. Each well was washed twice more with 0.3 ml of 0.1 N NaOH and the washing solutions were also placed in the appropriate scintillation tubes. Scintillation cocktail was added to the tubes containing the cell lysate and the radioactivity absorbed into the cells was determined by determining the β radiation.

Literature:

Counillon et al. (1993) Mol. Pharmacol. 44: 1041-1045 J. Membrane Biol. 120, 41-49 Franchi et al. (1986) Proc. Natl. Acad. Be. USA 83: 9388-9392 J. Membrane Biol. 118, 193-214 Sardet et al. (1989) Cell 56: 271-280 Scholz et al. (1995) Cardiovasc. Res. 29: 260-268

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an NHE-3 inhibitor of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized and sterile sealed under sterile conditions , Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an NHE-3 inhibitor of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution of 1 g is prepared of an NHE-3 inhibitor of the formula I, 9.38 g of NaH ₂ P0 ₄ ^■ 2 H ₂ 0, 28.48 g Na ₂ HP0 ₄ ^• 12 H ₂ 0 and 0.1 g of

Benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of an NHE-3 inhibitor of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of an NHE-3 inhibitor of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a customary manner such that each tablet 10 mg contains active ingredient. Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsules

2 kg of an NHE-3 inhibitor of the formula I are conventionally filled into hard gelatin capsules so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of NHE-3 inhibitor of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Claims

claims

1. Compounds of formula I.

wherein

Ar unsubstituted or simply substituted by R ³ and / or R ⁴ phenyl or naphthyl,

R ¹ , R ² ,

R ³ , R ⁴ each independently of one another H, A, OA, Hai, CF ₃ , OH,

N0 ₂ , NH ₂ , NHA, NA ₂ , NH-CO-A, NH-CO-Ph, SA, SO-A, S0 ₂ - A, S0 ₂ -Ph, CN, OCF ₃ , CO-A, C0 ₂ H, C0 ₂ A, CO-NH ₂ , CO-NHA, CO-NA ₂ , S0 ₂ NH ₂ , SO ₂ NHA, SO2NA2 or unsubstituted or mono- or polysubstituted by A, OA, shark, CF ₃

A alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

Shark F, Cl, Br or I

R ⁵ , R ⁶ ,

R ⁷ , R ⁸ each independently of one another H, A, unsubstituted or mono- or polysubstituted by A, OA, Hai, CF ₃ Is phenyl, where R ⁵ and R ⁷ , R ⁵ and R ⁶ , R ⁷ and R ⁸ can form 5-7-membered rings,

and their salts and solvates, with the proviso that compounds in which R ⁵ , R ⁶ , R ⁷ and R ^{8 are} simultaneously H and none of the radicals R ¹ , R ² , R ³ , R ⁴ OH, N0 ₂ , NH ₂ , NHA, NA ₂ , NH-CO-A, NH-CO-Ph, SA, SO-A, S0 ₂ -A, S0 ₂ -Ph, CN, OCF ₃ , CO-A, C0 ₂ H, C0 ₂ A, CO-NH ₂ , CO-NHA, CO-NA ₂ , S0 ₂ NH ₂ , S0 ₂ NHA, S0 ₂ NA ₂ or unsubstituted or mono- or polysubstituted by A, OA, shark or CF ₃ , except are.

2. Compounds deY formula I according to claim 1 and their salts and solvates as NHE 3 inhibitors.

3. Compounds of formula I according to claim 1 and their physiologically acceptable salts or solvates for use in combating diseases.

Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts or solvates for the manufacture of a medicament.

5. Use of compounds of formula I according to claim 1 and their physiologically acceptable salts and / or solvates for

Manufacture of a medicament for the treatment of hypertension, thrombosis, ischemic conditions of the heart, peripheral and central nervous system and stroke, ischemic conditions of peripheral organs and limbs and for the treatment of shock conditions.

6. Use of compounds of formula I according to claim 1 and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for use in surgical operations and organ transplants and for preservation and

Storage of grafts for surgical measures.

7. Use of compounds of formula I according to claim 1 and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of diseases in which cell proliferation is a primary or secondary cause, for the treatment or prophylaxis of disorders of the fat metabolism or disturbed respiratory drive.

8. Use of compounds of formula I according to claim 1 and their physiologically acceptable salts and / or solvates for

Production of a medicament for the treatment of ischemic kidney, ischemic bowel disease or for the prophylaxis of acute or chronic kidney disease.

9. Use of compounds of formula I according to claim 1 and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of bacterial and parasitic diseases.

10. Pharmaceutical preparation, characterized by a content of at least one NHE-3 inhibitor according to claim 1 and / or one of its physiologically acceptable salts and / or solvates.

11. Compounds selected from the group of compounds 11 to HO N- (6-chloro-4-phenyl-quinazolin-2-yl) -N'-methyl-guanidine 11

N- (6-chloro-4-p-tolyl-quinazolin-2-yl) -N'-methyl-guanidine 12

N- [6-chloro-4- (2-nitro-phenyl) -quinazolin-2-yl] -N'-methyl-13 guanidine

N- [4- (2-Amino-phenyl) -6-chloro-quinazolin-2-yl] -N'-methyl-14 guanidine

N- [6-chloro-4- (4-methyl-2-nitro-phenyl) -quinazolin-2-yl] -N ^, -15 methyl-guanidine

N- [4- (2-Amino-4-methylphenyl) -6-chloroquinazolin-2-yl] -N ^, - 16 methyl guanidine N- [6-chloro-4- (2-nitro-phenyl ) -quinazolin-2-yl] guanidine 17

N- [4- (2-aminophenyl) -6-chloro-quinazolin-2-yl] guanidine 18 N- [6-chloro-4- (4-methyl-2-nitro-phenyl) -quinazolin-2-yl] - 19 guanidine

N- [4- (2-Amino-4-methylphenyl) -6-chloroquinazolin-2-yl] - 110 guanidine

and their salts and solvates.

12. Compounds according to claim 1 as active pharmaceutical ingredients.

13. Process for the preparation of the 2-guanidino-4-aryl-quinazolines

Formula I and their salts and solvates, characterized in that either

(A)

Compounds of formula II

wherein R ¹ , R ² and Ar have the meanings given above, with 1-cyanguanidine or a correspondingly N-alkylated or N-arylated cyanguanidine of the formula NC-Y, where Y has the meaning given in claim 1

or

(b) instead of a compound of the formula NC-Y, a compound of

Formula III

HN = CX-Y III

wherein X is -S-alkyl, -S-aryl, -O-alkyl or -OAryl, reacted with a compound of formula II

or

(C) 2-chloro-4-arylquinazolines of the formula IV

wherein Ar, R ¹ and R ^{2 have} the meanings given in Claim 1 with a compound of the formula HY, wherein Y has the meaning given in Claim 1 and, if appropriate, following steps (a), (b) or (c) converts a basic or acidic compound of the formula I into one of its salts or solvates by treatment with an acid or base.