HK1130051A - Substituted 2-amino-4-phenyl-dihydroquinolines, method for the production thereof, use thereof as medicaments, and medicaments containing them - Google Patents

Description

Substituted 2-amino-4-phenyl-dihydroquinolines, method for the production thereof, use thereof as medicaments and medicaments containing the same

The invention relates to substituted 2-amino-4-phenyldihydroquinolines. Medicaments containing such compounds for the prevention or treatment of various disorders. Thus, the compounds are particularly useful in renal disorders, such as acute or chronic renal failure; biliary dysfunction; respiratory disorders such as snoring or sleep apnea; or a stroke.

The present invention relates to compounds of formula I and pharmaceutically acceptable salts and trifluoroacetates thereof:

wherein the radicals have the following meanings:

r1, R2, R3 and R4

Independently of one another, hydrogen, F, Cl, Br, I, CN, NO₂、CF₃、CH₃-SO₂Alkyl having 1, 2, 3 or 4C atoms, NH₂、NH-CH₃Or N (CH)₃)₂；

R5 and R6

Independently of one another, hydrogen, alkyl having 1, 2, 3, 4, 5 or 6C atoms, CF₃-CH₂-, cycloalkyl having 3, 4, 5 or 6C atoms or cyclopropyl-CH₂-，

Or

R5 and R6

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring in which one or both CH' s₂The radicals being independently of one another substituted by NR12, sulfur, oxygen, C (O) or SO₂Replacement;

r12 hydrogen, alkyl having 1, 2, 3 or 4C atoms or cycloalkyl having 3, 4, 5 or 6C atoms;

r7 hydrogen or alkyl having 1, 2, 3 or 4C atoms;

r8 and R9

Independently of one another, hydrogen, F, Cl, Br, OH, alkyl having 1, 2, 3 or 4C atoms, CH₃O、CF₃Or CH₃SO₂；

R10 and R11

Independently of one another R13- (CmH2m) -B_nWherein

m is zero, 1, 2, 3 or 4;

n is zero or 1;

B-CO-, -CONR 14-or-SO₂-；

R14 hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

r13 hydrogen, alkyl having 1, 2, 3 OR 4C atoms, cycloalkyl having 3, 4, 5 OR 6C atoms, 1-pyrrolidinyl, 1-piperidinyl, 1- (4-methylpiperazinyl), 1-morpholinyl, -COOR15, OR16, NR17R18 OR phenyl which, independently of one another, has 1 OR 2 substituents selected from chlorine, fluorine, methyl and methoxy;

r15, R16, R17 and R18

Independently of one another, hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

or

R10 and R11

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring in which one, two or three CH₂The radicals being independently of one another bound by NR19, sulfur, oxygen, C (O) or SO₂Replacement;

r19 hydrogen, alkyl having 1, 2, 3 or 4C atoms or cycloalkyl having 3, 4, 5 or 6C atoms.

Preference is given to compounds of the formula I in which the radicals have the following meanings and their pharmaceutically acceptable salts and trifluoroacetates

R1, R2, R3 and R4

Independently of one another, hydrogen, F, Cl, Br, CN, CF₃、CH₃-SO₂Alkyl having 1, 2, 3 or 4C atoms, NH₂、NH-CH₃Or N (CH)₃)₂；

R5 and R6

Independently of one another, hydrogen, alkyl having 1, 2, 3, 4, 5 or 6C atoms, CF₃-CH₂-, cycloalkyl having 3, 4, 5 or 6C atoms or cyclopropyl-CH₂-，

Or

R5 and R6

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring;

r7 hydrogen;

r8 and R9

Independently of one another, hydrogen, F, Cl, OH, alkyl having 1, 2, 3 or 4C atoms, CH₃O、CF₃Or CH₃SO₂；

R10 and 11

Independently of one another R13- (C)_mH_2m)-B_nWherein

m is zero, 1, 2, 3 or 4;

n is zero or 1;

B-CO-, -CONR 14-or-SO₂-；

R14 hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

r13 hydrogen, alkyl having 1, 2, 3 OR 4C atoms, cycloalkyl having 3, 4, 5 OR 6C atoms, 1-pyrrolidinyl, 1-piperidinyl, 1- (4-methylpiperazinyl), 1-morpholinyl, -COOR15, OR16, NR17R18 OR phenyl which, independently of one another, has 1 OR 2 substituents selected from chlorine, fluorine, methyl and methoxy;

r15, R16, R17 and R18

Independently of one another, hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

or

R10 and R11

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring, one CH of which₂The group may be replaced by oxygen or NR 19;

r19 hydrogen or alkyl having 1, 2, 3 or 4C atoms.

Particular preference is given to compounds of the formula I in which the radicals have the following meanings and the pharmaceutically acceptable salts and trifluoroacetates thereof

R1, R2, R3 and R4

Independently of one another, hydrogen, F, Cl, Br, CN, CF₃、CH₃-SO₂Methyl, ethyl, NH₂、NH-CH₃Or N (CH)₃)₂；

R5 and R6

Independently of one another, hydrogen, methyl, ethyl, isopropyl, CF₃-CH₂-or cycloalkyl having 3, 4, 5 or 6C atoms;

r7 hydrogen;

r8 and R9

Independently of one another, hydrogen, Cl or methyl;

r10 and 11

Independently of one another R13- (C)_mH_2m)-B_nWherein

m is zero, 1, 2, 3 or 4;

n is zero or 1;

B-CO-, -CONR 14-or-SO₂-；

R14 hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

r13 hydrogen, methyl, cycloalkyl having 3, 4, 5 OR 6C atoms, 1-pyrrolidinyl, 1-piperidinyl, 1- (4-methylpiperazinyl), -COOR15, OR16 OR NR17R 18; r15, R16, R17 and R18

Independently of one another, hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

or

R10 and R11

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring, one CH of which₂The group may be replaced by oxygen or NR 19;

r19 hydrogen or methyl.

Particular preference is given to compounds of the formula I in which the radicals have the following meanings and the pharmaceutically acceptable salts and trifluoroacetates thereof

R1 and R3

Hydrogen;

r2 and R4

Independently of one another, hydrogen or Cl;

r5 and R6

Independently of one another, hydrogen, methyl or ethyl;

r7 hydrogen;

r8 and R9

Independently of one another, hydrogen or Cl;

r10 and 11

Independently of one another R13- (C)_mH_2m)-B_nWherein

m is zero, 1, 2, 3 or 4;

n is zero or 1;

B -CONR14-；

r14 hydrogen or methyl;

r13 hydrogen, methyl, cycloalkyl having 3, 4, 5 OR 6C atoms, 1-pyrrolidinyl, 1-piperidinyl, 1- (4-methylpiperazinyl), -COOR15, OR16 OR NR17R 18; r15, R16, R17 and R18

Independently of one another, hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

or

R10 and R11

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring, one CH of which₂The group may be replaced by NR 19;

r19 hydrogen or methyl.

Very particular preference is given to compounds of the formula I in which the radicals have the following meanings and the pharmaceutically acceptable salts and trifluoroacetates thereof

R1 and R3

Hydrogen;

r2 and R4

Independently of one another, hydrogen or Cl;

r5 and R6

Independently of one another, hydrogen, methyl or ethyl;

r7 hydrogen;

r8 and R9

Independently of one another, hydrogen or Cl;

r10 and 11

Independently of one another R13- (C)_mH_2m)-B_nWherein

m is zero, 1, 2, 3 or 4;

n is zero or 1;

B -CONR14-；

r14 hydrogen or methyl;

r13 hydrogen, methyl or NR17R 18;

r17 and R18

Independently of one another, hydrogen, methyl or ethyl.

Particular preference is given to compounds of the formula I selected from the following, and pharmaceutically acceptable salts and trifluoroacetates

2-amino-4- (4-aminophenyl) -6-chloro-3, 4-dihydroquinoline,

4- (4-aminophenyl) -6-chloro-2-ethylamino-3, 4-dihydroquinoline,

4- (4-aminophenyl) -6-chloro-2-diethylamino-3, 4-dihydroquinoline,

and

n- (2-dimethylaminoethyl) -N' -4- [ (6-chloro-3, 4-dihydro-2-diethylaminoquinolin-4-yl) phenyl ] urea.

In one embodiment, preferred compounds of formula I are those wherein the radicals R1, R2, R3 and R4 are described independently of one another as hydrogen, F, Cl, Br, CN, CF3, CH₃-SO₂Alkyl having 1, 2, 3 or 4C atoms, e.g. methyl or ethyl, NH₂、NH-CH₃Or N (CH)₃)₂Those of (a); particularly preferred compounds of the formula I are those in which R1 and R3 are hydrogen and R2 and R4 are, independently of one another, hydrogen, F, C, Br, CN, CF₃、CH₃-SO₂Methyl, ethyl, NH₂、NH-CH₃Or N (CH)₃)₂Such as hydrogen or Cl; in yet another embodiment, preferred compounds of formula I are those wherein R1, R3 or R4 are hydrogen, and R2 is F, Cl, Br, CN, CF₃、CH₃-SO₂Methyl, ethyl, NH₂、NH-CH₃Or N (CH)₃)₂Such as Cl.

In one embodiment, preferred compounds of formula I are those wherein R5 and R6 are described independently of each other as hydrogen, alkyl having 1, 2, 3, 4, 5 or 6C atoms, CF₃-CH₂Or having 3, 4, 5 or 6C atomsOr R5 and R6 together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring; in another embodiment, preferred compounds of formula I are those wherein R5 and R6 are independently from each other hydrogen, methyl, ethyl, isopropyl, CF₃-CH₂Or cycloalkyl having 3, 4, 5 or 6C atoms, in particular hydrogen, methyl or ethyl, for example hydrogen or ethyl.

In another embodiment, preferred compounds of formula I are those wherein R7 is described as hydrogen or methyl, for example hydrogen.

In one embodiment, preferred compounds of the formula I are those in which the radicals R8 and R9 are described, independently of one another, as hydrogen, F, Cl, OH, alkyl having 1, 2, 3 or 4C atoms, CH₃O、CF₃Or CH₃SO₂Those compounds of (a); particularly preferred compounds of the formula I are those in which R8 and R9 independently of one another are hydrogen, Cl or methyl, in particular hydrogen or Cl, for example hydrogen.

The group NR10R11 on the phenyl ring may be bonded in the ortho, meta or para position, for example in the ortho or para position, in particular in the para position, of the dihydroisoquinoline group.

In one embodiment, preferred compounds of formula I are those wherein the groups R10 and R11 are described as R13- (C) independently of each other_mH_2m)-B_nOr R10 and R11, together with the nitrogen atom to which they are bound, form a 4, 5, 6, 7, 8, 9 or 10 membered ring in which one CH is₂The group may be replaced by oxygen or NR19, wherein R19 is hydrogen or alkyl having 1, 2, 3 or 4C atoms, in particular hydrogen or methyl; in another embodiment, preferred compounds of formula I are those wherein the groups R10 and R11 are described as R13- (C) independently of each other_mH_2m)-B_nThose compounds of (1).

In one embodiment, preferred compounds of formula I are those wherein m is zero, 1 or 2, e.g. zero or 2.

In one embodiment, preferred compounds of formula I are those wherein n is zero; in another embodiment, preferred compounds of formula I are those wherein n is 1.

In one embodiment, preferred compounds of formula I are those wherein B is-CONR 14, wherein R14 is hydrogen or has 1, 2, 3, 4, 5 or 6C atoms, in particular hydrogen or methyl, for example hydrogen.

In one embodiment, preferred compounds of formula I are those wherein R13 is described as hydrogen, methyl, ethyl, isopropyl, cycloalkyl having 3, 4, 5 OR 6C atoms, 1-pyrrolidinyl, 1-piperidinyl, 1- (4-methylpiperazinyl), -COOR15, OR16 OR NR17R18, wherein R15, R16, R17 and R18 are independently from each other hydrogen OR alkyl having 1, 2, 3, 4, 5 OR 6C atoms; in another embodiment, preferred compounds of formula I are those wherein R13 is described as hydrogen, methyl or NR17R18, wherein R17 and R18 are independently of each other hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms, in particular hydrogen, methyl or ethyl, for example methyl, particularly preferred compounds of formula I are those wherein R13 is hydrogen or dimethylamino.

If the compounds of the formula I contain one or more asymmetric centers, they may, independently of one another, have the S or R configuration. The compounds may be present as optical isomers, diastereomers, racemates or mixtures thereof in all ratios. Furthermore, the compounds of the formula I may also exist in the form of internal rotamers.

The present invention includes all tautomeric forms of the compounds of formula I.

The invention additionally includes derivatives of the compounds of formula I, for example solvates such as hydrates and alcohol adducts, esters, prodrugs and other physiologically acceptable derivatives of the compounds of formula I, and active metabolites of the compounds of formula I. The invention likewise encompasses all crystal modifications of the compounds of the formula I.

The alkyl group may be linear or branched. This also applies when they have substituents or substituents which are other groups, for example in fluoroalkyl groups or alkoxy groups. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl (═ 1-methylethyl), n-butyl, isobutyl (═ 2-methylpropyl), sec-butyl (═ 1-methylpropyl), tert-butyl (═ 1, 1-dimethylethyl), n-pentyl, isopentyl, tert-pentyl, neopentyl or hexyl. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl.

Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. One or more CH in cycloalkyl radicals₂The radicals being O, NH or N-alkyl, e.g. NCH₃And (6) replacing. This also applies to cycloalkylmethyl groups.

Examples of NR5R6 rings are morpholine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, pyrrolidin-2-one, pyrrolidine-2, 5-dione, imidazolidine, 3-methyl-imidazolidine, imidazolidin-2-one, 3-methylimidazolidin-2-one, imidazolidine-2, 4-dione and 1-methylimidazolidin-2, 4-dione, in particular pyrrolidine and piperidine, for example pyrrolidine.

Examples of NR10R11 rings are morpholine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, pyrrolidin-2-one, pyrrolidine-2, 5-dione, imidazolidine, 3-methyl-imidazolidine, imidazolidin-2-one, 3-methylimidazolidin-2-one, imidazolidine-2, 4-dione and 1-methylimidazolidin-2, 4-dione, in particular pyrrolidine-2, 5-dione and imidazolidine-2, 4-dione, for example imidazolidine-2, 4-dione.

Terminal CH in alkyl radicals₃The radical is also considered to be CH₂Units, for which reason CH is to be understood₂-a H group.

If a variable, such as cycloalkyl or R1, occurs more than one time as a constituent, the definitions of the variables are independent of each other at each occurrence.

If the compounds of the formula I contain one or more acidic or basic groups or one or more basic heterocyclic groups, the invention also encompasses the corresponding physiologically or toxicologically acceptable salts, in particular the pharmaceutically usable salts. Thus, the compounds of the formula I can be deprotonated on the acidic group and used, for example, as alkali metal salts, preferably sodium or potassium salts, or ammonium salts, for example with ammonium or organic amines or amino acids. Since the compounds of the formula I always contain at least one basic group, they can also be prepared in the form of their physiologically tolerated acid addition salts, for example with the following acids: inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid or from organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, malonic acid, methanesulfonic acid, fumaric acid. Suitable acid addition salts are therefore all the salts of pharmacologically acceptable acids (which also correspond to physiologically acceptable anions), for example halides, in particular the hydrochloride, lactate, sulfate, citrate, tartrate, acetate, phosphate, methanesulfonate, p-toluenesulfonate, adipate, fumarate, gluconate, glutamate, glycerophosphate, maleate and pamoate, but also trifluoroacetate.

The invention also relates to the process described below for the preparation of the compounds of formula I.

Compounds of formula I, wherein R10 and R11 are hydrogen and which are described herein, can be prepared, for example, starting from quinoline derivatives of formula II by reduction to the corresponding 3, 4-dihydroquinoline of formula Ia.

Wherein the substituents R1, R2, R3, R4, R5, R6, R8 and R9 are as defined above. The reduction of quinoline derivatives of formula II to the corresponding 3, 4-dihydroquinolines of formula Ia can be carried out, for example, using sodium amalgam (US3,538,101).

Further compounds of the formula I according to the invention can be prepared from the compounds of the formula Ia) according to the invention, for example by derivatization of the amino group on the phenyl radical, by methods known to the skilled worker. In these cases, for example, the amino group of the compound Ia) is reacted with an alkylating, acylating or sulfonylating agent of the formula R10-L and/or R11-L, preferably in the presence of an auxiliary base such as pyridine, triethylamine or Hunig's base, in a manner known to the skilled worker. It is likewise suitable to use isocyanates of the formula R10-N ═ C ═ O and/or R11-N ═ C ═ O in a manner known to the skilled worker for the preparation of the corresponding urea derivatives of the formula Ib or Ic.

Wherein the substituents R1, R2, R3, R4, R5, R6, R8, R9, R10 and R11 have the meanings indicated above, but when B is-C (O) -R10 and R11 are not hydrogen and L is F, Cl, Br, I, -OR, -OC (O) R OR-SR, wherein R is an alkyl group having 1, 2, 3, 4, 5 OR 6C atoms, for example methyl OR ethyl, and L may be-SR. It is possible to obtain the mono-substituted compounds of the invention of formula Ib stepwise by reaction and isolation and/or subsequent reaction to give the di-substituted compounds of formula Ic.

The compounds of the formula II can be converted analogously to the compounds of the formula IIIa or IIIb by derivatization of the amino group on the phenyl radical by methods known to the skilled worker.

Wherein the substituents R1, R2, R3, R4, R5, R6, R8, R9, R10 and R11 have the meanings indicated above, but R10 and R11 are not hydrogen.

The quinoline derivatives of the formula IIIa or IIIb obtained in this way and in which R10 and R11 do not have the meaning of hydrogen can then be reduced in a known manner, for example with sodium amalgam, to the corresponding 3, 4-dihydroquinoline derivatives of the formula Ib or Ic of the invention,

wherein the substituents R1, R2, R3, R4, R5, R6, R8, R9, R10 and R11 have the meanings indicated above, but R10 and R11 are not hydrogen.

The anilines of the formula II used above are preferably obtained by reduction of the corresponding nitro compounds of the formula IVa

Wherein the substituents R1, R2, R3, R4, R5, R6, R8, R9 have the indicated meanings. The reduction can be carried out by methods known to the skilled worker, for example by catalytic hydrogenation or inorganic reducing agents such as, for example, iron powder and hydrochloric acid in glacial acetic acid.

Compounds of formula IVa in which R5 and R6 are hydrogen can be obtained, for example, by reaction of compounds of formula V with acetonitrile in basic condensation (I.A. Nicolls et al Life Sciences 53, 343-347(1993)) to give compounds of formula IVb,

wherein R1, R2, R3, R4, R8 and R9 have the meanings indicated above, and Y is hydrogen or NO₂。

Compounds of formula IVb wherein Y is hydrogen may be converted by nitration to nitro substituted compounds of formula IVa wherein R5 and R6 are hydrogen.

Compounds of formula IVa in which R5 and R6 are not both exclusively hydrogen are obtainable, for example, by nucleophilic exchange reaction of quinoline derivatives of formula VI with amines of formula VII

Wherein R1, R2, R3, R4, R5, R6, R8, R9 and Y have the meanings indicated above, but R5 and R6 are not both hydrogen, X represents a leaving group capable of undergoing nucleophilic substitution, such as for example chlorine, bromine, tosylate, mesylate, triflate, alkoxy having 1, 2, 3, 4, 5 or 6C atoms, for example ethoxy, aryloxy, for example phenoxy, or RS (O)_n-wherein n is 0 or 2 and R' is an alkyl group, preferably having 1, 2, 3 or 4C atoms, such as methyl, and M is hydrogen or a metal, in particular an alkali metal or an equivalent alkaline earth metal, such as lithium, or compound VII is a grignard compound. Preferably with amines>Temperatures of 100 c, it being possible to recommend the use of autoclaves or microwaves.

The corresponding compounds of formula IVb, wherein R5 and R6 are hydrogen, can be prepared by reacting NH₃The reaction was similarly prepared under pressure.

Compounds of formula IVc wherein Y is hydrogen can be converted by nitration to nitro substituted compounds of formula IVa wherein R5 and R6 are not both hydrogen.

The compounds of the formula VI can be prepared in a manner known to the skilled worker, for example from compounds of the formula VIII by the action of inorganic acid chlorides such as phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride, for example to prepare compounds of the formula VI in which X is Cl,

wherein R1, R2, R3, R4, R8, R9, Y and X have the indicated meanings and Z is an OH group.

Compounds of formula I wherein R7 is other than hydrogen can be prepared by known methods starting from compounds known to the skilled person, for example such as in helv.

The compounds R10-Hal, R11-Hal, R10-N ═ C ═ O, R11-N ═ C ═ O and the compounds of formulae V, VII and VIII can be obtained commercially or prepared analogously to the methods described in the literature and known to the skilled worker.

Work-up and, if desired, purification of the products and/or intermediates is carried out by customary methods, for example extraction, chromatography or crystallization and customary drying.

It has been possible to demonstrate that the compounds of the formula I are excellent inhibitors of the sodium-hydrogen exchanger (NHE), in particular of the sodium-hydrogen exchanger subtype 3(NHE 3).

The NHE3 inhibitors disclosed to date are derived from, for example, the following compounds: acylguanidines (EP825178), norbornylamines (WO0144164), 2-guanidinoquinazolines (WO0179186) or benzamidines (WO0121582, WO 017242). According to the current state of knowledge, squalamine (M.Donowitz et al, am.J.Physiol.276 (Cell Physiol.45): C136-C144), which is also an NHE3 inhibitor, does not act as immediately as the compound of formula I, but acts by an indirect mechanism, and thus reaches its maximum strength of action after 1 hour.

Tetrahydroisoquinolines as inhibitors of the sodium-hydrogen exchanger subtype 3(NHE3) have been described in the patent applications WO03048129, WO2004085404 and german applications 102004046492.8 and 102005001411.9. Patent application WO03055880 describes related types of tetrahydroisoquinolinium salt compounds as NHE3 inhibitors.

It has now surprisingly been found that the compounds of formula I as described herein are also potent NHE3 inhibitors and have better pharmacological and pharmacokinetic properties.

NHE3 was found in vivo in several species, especially in the gallbladder, intestine and kidney (Larry Fliegel et al, biochem. cell. biol. 76: 735-741, 1998), but was also detected in the brain (E. Ma et al, Neuroscience 79: 591-603).

Due to their NHE-inhibiting properties, the compounds of formula I and their pharmaceutically acceptable salts are suitable for the prevention and treatment of diseases caused by activated or activated NHE as well as secondary diseases caused by NHE-related injuries.

The compounds of formula I may also be used, for example, to treat or prevent diseases in which NHE is only partially inhibited, by using lower doses.

The use of the compounds of the invention relates to the prevention and treatment of acute and chronic diseases in veterinary and human medicine.

The importance of the pharmacological action of the compounds of the formula I is that they are particularly suitable for improving respiratory drive. They may therefore be used to treat impaired respiratory conditions which may occur, for example, in the following clinical conditions and diseases: impaired central respiratory drive (e.g., central sleep apnea, sudden infant death, post-operative hypoxia), muscle-related respiratory damage, respiratory damage after prolonged ventilation, respiratory damage associated with high altitude adaptation, obstructive and mixed sleep apnea, acute and chronic lung disease with hypoxia and hypercapnia.

In addition, the compounds can increase the tone of upper airway muscles, thus can inhibit snoring. Therefore, the compounds can be advantageously used for the preparation of medicaments for the prevention and treatment of sleep apnea and muscle-related respiratory impairment and for the preparation of medicaments for the prevention and treatment of snoring.

The combination of the NHE inhibitor of formula I with a carbonic anhydrase inhibitor (e.g. acetazolamide) may prove to be advantageous, the latter being able to induce metabolic acidosis and thus being able to increase respiratory activity itself, thus enabling the effect of enhancing the active ingredient and reducing its dosage.

Due to its NHE3 inhibitory effect, the compounds of the invention are able to maintain a reserve of cellular energy which is rapidly consumed during intoxication and morbidity leading to cellular damage or cell death. In this regard, under the influence of NHE3 inhibitors, the energy-intensive ATP-consuming sodium uptake temporarily ceases at the proximal tubule, and thus the cells are able to survive in acute onset, ischemic or toxic states. The compounds are therefore suitable, for example, as medicaments for the treatment of ischemic lesions, such as acute renal failure. The compounds are also suitable for the treatment of all chronic renal disorders and nephritis classes which can lead to chronic renal failure (as a consequence of increased protein excretion). Accordingly, the compounds of formula I are suitable for the preparation of medicaments for the treatment of the following diseases: late damage from diabetes, diabetic nephropathy and chronic kidney disorders, in particular all kidney inflammation associated with increased protein/albumin excretion (nephritis).

It has been determined that the compounds used in the present invention have mild laxative effects and can therefore also be used as laxatives if there is a risk of constipation.

The compounds of the present invention may also be advantageously used in the prevention and treatment of acute and chronic intestinal disorders, which are caused for example by ischemic states and/or subsequent reperfusion or inflammatory states and events in the intestinal region. Such complications may be due to e.g. defects in intestinal peristalsis, which are often observed after e.g. surgical intervention, which are associated with constipation or a drastic reduction in intestinal activity.

The compounds of the present invention are also capable of preventing the formation of gallstones.

The NHE inhibitors of the invention are generally useful in the treatment of diseases caused by ischemia and reperfusion.

Due to their pharmacological properties, the compounds of the invention are suitable as antiarrhythmic drugs. Due to their cardioprotective component, NHE inhibitors are notably useful in the prevention and treatment of infarcts and in the treatment of angina pectoris, in which case they inhibit or prophylactically greatly reduce the pathophysiological processes associated with the development of ischemia-induced damage, in particular the triggering of ischemia-induced arrhythmias. Due to cellular Na⁺/H⁺Inhibition of the exchange mechanism, which has a protective effect on pathological hypoxic and ischemic conditions, the compounds of the formula I for use according to the invention can therefore be used as medicaments for the treatment of all acute or chronic injuries induced by ischemia or of primary or secondary diseases induced thereby.

The invention also relates to a medicament for use as a surgical intervention. Thus, the compounds of the invention can be used in organ transplantation, in which case they can be used to protect donor organs before and during transplantation, to protect transplanted organs, for example during handling or storage in physiological baths, or also to pretreat them with compounds of formula I during transfer into the recipient organism.

The compounds of the invention are also valuable pharmaceuticals which have a protective effect, for example in the heart and in the case of interventions for angioplasty on peripheral organs and blood vessels.

The compounds of the invention may also be used when bypass grafting is performed, for example in coronary bypass surgery and in Coronary Artery Bypass Grafting (CABG).

The compounds of the invention of formula I can also be used in resuscitation after cardiac arrest due to their action against ischemia-induced damage.

Due to their protective effect against ischemia-induced damage, the compounds are also suitable as medicaments for the treatment of ischemia of the nervous system, in particular of the CNS, for example for the treatment of strokes or cerebral edemas.

Since NHE inhibitors of human tissues and organs are not only effective against ischemia and reperfusion-induced damage but also against the cytotoxic effects of drugs, such as those used in particular in cancer therapy and in the treatment of autoimmune diseases, the administration of such drugs in combination with compounds of formula I is suitable for reducing or inhibiting the cytotoxic effects of the therapy. The reduction in cytotoxic effects (particularly cardiotoxicity) due to co-administration with NHE inhibitors makes it possible to increase the dose of cytotoxic therapeutic agents and/or to prolong the treatment time of such drugs. The therapeutic benefit of such cytotoxic therapies is significantly increased by combination with NHE inhibitors.

The compounds of formula I are particularly useful for improving therapy with drugs containing undesirable cardiotoxic components.

In general, the NHE inhibitors described herein may advantageously be combined with other compounds that also modulate intracellular pH, suitable combinations being formulated as carbonic anhydrase-based inhibitors, inhibitors of systemically transported bicarbonate ions (e.g., sodium bicarbonate cotransporter (NBC) or sodium-dependent chloride-bicarbonate exchanger (NCBE)), as well as NHE inhibitors having inhibitory effects on other NHE subtypes, since the pharmacologically relevant pH-modulating effects of the NHE inhibitors described herein may thus be potentiated or modulated.

Owing to their protective effect on ischemia-induced damage, the compounds are also suitable as medicaments for the treatment of ischemia of the nervous system, in particular of the central nervous system, for example for the treatment of strokes or cerebral edemas.

The compounds of the formula I are also suitable for the treatment and prophylaxis of disorders and injuries induced by excessive excitation of the central nervous system, in particular for the treatment of epileptiform disorders, centrally induced clonic and tonic spasms, dysthymic states, anxiety disorders and psychoses. In this connection, the NHE inhibitors of the invention may be used alone or in combination with other substances having antiepileptic activity or antipsychotic active ingredients, or in combination with carbonic anhydrase inhibitors (e.g. acetazolamide) and further NHE inhibitors or sodium-dependent chloride-bicarbonate exchanger (NCBE) inhibitors.

In addition, the compounds of formula I of the present invention are also useful in the treatment of various shock types such as anaphylactic shock, cardiogenic shock, hypovolemic shock and bacterial shock.

The compounds of formula I are also useful in the prevention and treatment of thrombotic disorders, since they are capable of inhibiting platelet aggregation as NHE inhibitors per se. In addition, they are able to inhibit or prevent the excessive release of inflammatory and coagulation mediators, in particular of von willebrand factor and thromboselectin, after ischemia and reperfusion. Therefore, it is possible to reduce and alleviate the pathogenic effects of the thrombotic and inflammation-related factors. Thus, the NHE inhibitors of the invention may be combined with other anticoagulant and/or thrombolytic active ingredients such as recombinant or native tissue plasminogen activator, streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, drugs with fibrinolytic activity, thromboxane receptor antagonists, phosphodiesterase inhibitors, factor VIIa antagonists, clopidogrel, ticlopidine, and the like. The use of the NHE inhibitors of the invention in combination with NCBE inhibitors and/or with carbonic anhydrase inhibitors, for example with acetazolamide, is particularly advantageous.

In addition, the strong inhibitory effect of the NHE inhibitors of the present invention on cell proliferation (e.g., on fibroblast proliferation and proliferation of smooth vascular muscle cells) is of interest. The compounds of formula I are therefore suitable as valuable therapeutic agents for diseases in which cell proliferation is a primary or secondary cause and can therefore be used as anti-atherosclerotic agents, anti-chronic renal failure agents, anti-cancer agents. They may be used to treat organ hypertrophy and hyperplasia, such as of the heart and prostate. The compounds of the formula I are therefore suitable for the prophylaxis and therapy of heart failure (congestive heart failure ═ CHF) and for the treatment and prophylaxis of prostatic hyperplasia or prostatic hypertrophy.

In addition, NHE inhibitors are of interest for the delay or prevention of fibrotic disorders. They are therefore suitable as prominent drugs for the treatment of myocardial and pulmonary fibrosis, liver fibrosis, kidney fibrosis and other fibrotic disorders.

Since NHE is significantly elevated in essential hypertension, the compounds of formula I are suitable for the prevention and treatment of hypertension and cardiovascular disorders. In this regard, they may be used alone or in combination with suitable combinations for the treatment of hypertension and for the treatment of cardiovascular disorders. Thus, for example, one or more diuretics having thiazide-like activity, loop diuretics, aldosterone and pseudoaldosterone antagonists (e.g., hydrochlorothiazide, indapamide, polythiazide, furoanilide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone, or eplerenone (eplerone)) can be combined with a compound of formula I. In addition, the NHE inhibitors of the present invention may be used in combination with calcium antagonists (e.g., verapamil, diltiazem, amlodipine or nifedipine) and with ACE inhibitors (e.g., ramipril, enalapril, lisinopril, fosinopril or captopril). Other useful co-formulations may also be beta blockers (e.g. metoprolol, salbutamol, etc.), antagonists of the angiotensin receptor and its receptor subtypes (e.g. losartan, irbesartan, valsartan, omatra, gernopatrilat), endothelin antagonists, renin inhibitors, adenosine receptor agonists, potassium channel inhibitors and activators (e.g. glibenclamide, glimepiride, diazoxide, chromancarbine, clonidine and derivatives thereof), activators of the mitochondrial ATP-sensitive ATP channel (mitoK channel), potassium channel inhibitors (e.g. kv1.5 inhibitors), etc.

Due to its anti-inflammatory effect, the NHE inhibitor of the present invention may be used as an anti-inflammatory agent. In this regard, their inhibition of inflammatory mediator release is of concern. The compounds can therefore be used for the prevention or treatment of chronic and acute inflammatory disorders, either alone or in combination with anti-inflammatory agents. Advantageously, a combination of steroidal and non-steroidal anti-inflammatory drugs is used.

In addition, it has been found that NHE inhibitors show a beneficial effect on serum lipoproteins. They can therefore be used to prevent and resolve atherosclerotic lesions by eliminating the incidental risk factors. They include not only primary hyperlipidemia but also certain secondary hyperlipidemia, such as secondary hyperlipidemia associated with diabetes. In addition, NHE inhibitors cause a significant reduction in metabolic abnormality-induced infarctions, and in particular, a significant reduction in the size and severity of the induced infarctions. Therefore, the NHE inhibitors of formula I are advantageously used for the preparation of a medicament for the treatment of hypercholesterolemia, for the preparation of a medicament for the prevention of atherogenesis, for the preparation of a medicament for the prevention and treatment of atherosclerosis, for the preparation of a medicament for the prevention and treatment of diseases induced by elevated cholesterol levels, for the preparation of a medicament for the prevention and treatment of diseases induced by endothelial dysfunction, for the preparation of a medicament for the prevention and treatment of atherosclerosis-induced hypertension, for the preparation of a medicament for the prevention and treatment of atherosclerosis-induced thrombosis, for the preparation of a medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced ischemic injury and post-ischemic reperfusion injury, for the preparation of a medicament for the prevention and treatment of cardiac hypertrophy and cardiomyopathy and Congestive Heart Failure (CHF), for the preparation of a medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced coronary vasospasm and myocardial infarction For the manufacture of a medicament for the treatment of said disorders in combination with a hypertensive agent, preferably with an Angiotensin Converting Enzyme (ACE) inhibitor and an angiotensin receptor antagonist. The combination of the NHE inhibitor of formula I with a lipid-lowering active ingredient, preferably with an HMG-CoA reductase inhibitor (e.g. lovastatin or pravastatin), the latter causing hypolipidemic effect and thus increasing the hypolipidemic properties of the NHE inhibitor of formula I, represents an advantageous combination thereof for the purpose of potentiating the effect of the active ingredient and reducing the use of the active ingredient.

Therefore, NHE inhibitors have potent protective effects against endothelial injury of various origins. Due to vascular protection against endothelial dysfunction syndrome, NHE inhibitors are valuable drugs for the prevention and treatment of coronary vasospasm, peripheral vascular disease (especially intermittent claudication), atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy, and thrombotic disorders.

In addition, NHE inhibitors are suitable for the treatment of non-insulin dependent diabetes mellitus (NIDDM) in which insulin resistance is inhibited. In this connection, it may be advantageous to reinforce the antidiabetic efficacy and the quality of action of the compounds of the invention, it being advantageous to combine them with: biguanides (e.g., metformin), antidiabetic sulfonylureas (e.g., glibenclamide, glimepiride, tolbutamide, etc.), glucosidase inhibitors, PPAR agonists (e.g., rosiglitazone, pioglitazone, etc.), insulin products in various administration forms, DB4 inhibitors, insulin sensitizers or meglitinide.

In addition to acute antidiabetic effects, NHE inhibitors impede the development of diabetic late complications and thus may be used as medicaments for the prevention and treatment of diabetic late damage (e.g., diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and other disorders occurring as a result of diabetes). In this connection, they can advantageously be combined with antidiabetic drugs as described in the treatment of NIDDM above. In this connection, the combination with a beneficial dosage form of insulin is of particular importance.

In addition to the protective effect against acute ischemic problems and subsequently also acute stress reperfusion problems, NHE inhibitors also have a direct therapeutic effect on disorders and injuries of the whole mammalian body which are associated with the manifestation of a chronic progressive aging process and which are independent of the acute state of a deficiency in blood supply and which occur under normal, non-ischemic conditions. These pathological, age-related manifestations (induced by long-term aging, such as disease, inactivity and death, which can now respond to treatment with NHE inhibitors) are disorders and injuries essentially caused by age-related changes (in vital organs and their functions) and are increasingly important in the aging body.

Age-related functional impairment, age-related impairment of organ wear performance-related disorders are e.g. inappropriate responses and responses of blood vessels to contraction and relaxation responses. This age-related reduction in the response of blood vessels to contraction and relaxation stimuli, which is an important process of the cardiovascular system and thus of life and health, can be significantly eliminated or reduced by NHE inhibitors. An important function and method of maintaining vascular response is to prevent or delay the age-related progression of endothelial dysfunction, which can be very significantly abrogated by NHE inhibitors. Therefore, NHE inhibitors are significantly useful in the treatment and prevention of age-related progression of endothelial dysfunction, in particular intermittent claudication. In addition, NHE inhibitors are notably useful in the treatment and prevention of heart failure, Congestive Heart Failure (CHF), and in the treatment and in particular prevention of various age-related cancers.

In this connection, hypotensive agents such as ACE inhibitors, vasoconstrictive agents and the like are contemplatedZhangin receptor antagonist, diuretic, Ca²⁺Antagonists, etc. or in combination with agents that normalize metabolism, such as cholesterol-lowering agents. Thus, the compounds of formula I are useful for preventing age-related tissue damage and for maintaining health and prolonging life while maintaining a high level of quality of life.

The compounds of the invention are potent inhibitors of cellular sodium-proton antiporters (Na/H exchangers), which transport is also increased in cells that are susceptible to response to measurements (e.g. erythrocytes, platelets or leukocytes) in a large number of disorders (essential hypertension, atherosclerosis, diabetes, etc.). The compounds used in the present invention are therefore suitable as a remarkable and simple scientific tool, for example for their use as diagnostic reagents to determine and differentiate between different types of hypertension, as well as atherosclerosis, diabetes and diabetic late complications, proliferative disorders, etc.

NHE inhibitors are also useful in the treatment of diseases induced by bacteria and protozoa (human and veterinary). Among the diseases caused by protozoa, particular mention may be made of malaria diseases in humans and coccidiosis in poultry.

The compounds according to the invention are also suitable as medicaments for controlling trematodes in human and veterinary medicine and in plant protection. In this connection, it is preferably used as a medicament against schistosomes in human and veterinary medicine.

The compounds are therefore advantageously used, alone or in combination with other drugs or active ingredients, for the preparation of a medicament for the treatment or prevention of the following diseases: respiratory power injury, respiratory disorders, sleep-related respiratory disorders, sleep apnea, snoring, acute or chronic renal disorders, acute renal failure and chronic renal failure, intestinal dysfunction, hypertension, essential hypertension, central nervous system disorders, disorders resulting from CNS hyperexcitability, epilepsy and centrally induced spasticity or anxiety states, depression and psychosis, ischemic states or strokes of the peripheral or central nervous system, acute and chronic injuries and disorders of peripheral organs or limbs resulting from ischemic or reperfusion events, atherosclerosis, impairment of lipid metabolism, thrombosis, impairment of biliary function, ectoparasitic infection, disorders resulting from endothelial dysfunction, protozoal diseases, malaria, protection and storage of grafts during surgery, for surgery and organ transplantation, or for the treatment of shock states or diabetes and late-stage injuries of diabetes or diseases in which cell proliferation is of primary or secondary origin, and to maintain health and prolong life.

The invention further relates to compounds of formula I and pharmaceutically acceptable salts thereof for use as medicaments.

The invention also relates to medical/pharmaceutical preparations for human, veterinary or plant-protective use which comprise an effective amount of a compound of the formula I and/or a pharmaceutically acceptable salt thereof, and to pharmaceutical preparations for human, veterinary or plant-protective use which comprise an effective amount of a compound of the formula I and/or a pharmaceutically acceptable salt thereof, alone or in combination with one or more other pharmacologically active ingredients or medicaments.

Thus, medicaments comprising a compound of formula I or a pharmaceutically acceptable salt thereof may be administered, for example, orally, parenterally, intramuscularly, intravenously, rectally, nasally, by inhalation, subcutaneously or via a suitable transdermal dosage form, the preferred mode of administration depending on the respective manifestation of the disorder. In addition, the compounds of the formula I can be used, alone or together with pharmaceutical excipients, in particular in veterinary and human medicine and in plant protection. The medicament typically comprises the active ingredient of formula I and/or a pharmaceutically acceptable salt thereof in an amount of 0.01mg to 1g per dosage unit.

Excipients suitable for the intended pharmaceutical formulation are well known to the skilled person on the basis of his expert knowledge. In addition to solvents, gel formers, suppository bases, tablet excipients, and carriers for other active ingredients, it is also possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, taste masking agents, preservatives, solubilizers, or colorants.

For oral administration, the active compounds are mixed with additives suitable for the purpose, for example carriers, stabilizers or inert diluents, and converted by customary methods into suitable dosage forms, for example tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert carriers which may be used are gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. Alternatively, the preparation may be carried out by dry granulation and wet granulation. Examples of suitable oily carriers or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous, transdermal or intravenous administration, the active compounds employed are converted, if desired together with customary substances for this purpose, such as solubilizers, emulsifiers or other excipients, into solutions, suspensions or emulsions. Examples of suitable solubilizers are: water, physiological saline or alcohols (e.g., ethanol, propanol, glycerol), and sugar solutions (e.g., glucose or mannitol solutions), or mixtures of the above solvents.

Pharmaceutical preparations suitable for administration as aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or mixtures of such solvents. The formulation may also contain other pharmaceutically acceptable excipients such as surfactants, emulsifiers and stabilizers, and a propellant gas, if desired. The formulations generally comprise the active ingredient in a concentration of about 0.1% to 10%, especially about 0.3% to 3%, by weight.

The dose of the active ingredient of formula I to be administered and the frequency of administration depend on the intensity and duration of action of the compounds used; and also on the nature and severity of the disease to be treated and on the sex, age, weight and individual response of the mammal to be treated.

For a patient weighing about 75kg, the average daily dose of the compound of formula I is at least 0.001mg/kg (body weight), preferably 0.1mg/kg (body weight), and at most 30mg/kg (body weight), preferably 1mg/kg (body weight). Higher doses may also be required in acute situations, such as in the case of apnea at high altitude. For example in intensive care patients with infarctions, in particular for intravenous administration, daily doses of up to 300mg/kg per day are required. The daily dose may be divided into one or more, e.g. up to four, single doses.

Description of the experiments and examples

Abbreviation list:

m.p. melting Point

min, min

MPRC column L-026-30; SI 6040-63 μm; super Vario Flash; maximum pressure 3barGtec-Labortechnik GmbH

MPLC Medium pressure liquid chromatography

Example 1: 2-amino-4- (4-aminophenyl) -6-chloro-3, 4-dihydroquinoline hydrochloride

a) 2-amino-6-chloro-4-phenylquinoline

A stirred suspension of 1.4g of powdered KOH in 25ml of anhydrous acetonitrile is heated to boiling under reflux for 30 minutes under argon, and a solution of 1.15g of 2-amino-5-chlorobenzophenone in 5ml of anhydrous acetonitrile is then added. The mixture was boiled for 12 hours with a reflux condenser. The mixture was cooled by pouring into ice, extracted with ethyl acetate, washed with water, and the solvent was removed by distillation.

m.p.：123-125℃。

b) 2-acetylamino-6-chloro-4-phenylquinoline

A mixture of 0.1g of 2-amino-6-chloro-4-phenylquinoline and 8ml of acetic anhydride is stirred at 70 ℃ for 1 hour, the solvent is distilled off, the solid residue is stirred with water and the crystalline material is filtered off.

m.p.：178-182℃。

c) 2-acetylamino-6-chloro-4- (4-nitrophenyl) quinoline

200mg of 2-acetylamino-6-chloro-4-phenylquinoline are added portionwise to 4ml of 100% HNO at 0 ℃ to 5 ℃ over a period of 30min₃The reaction mixture was poured into ice-water. Neutralized with 2n naoh, then extracted with ethyl acetate and the solvent was distilled off. The solid residue was boiled several times with diisopropyl ether and the solvent of the filtrate was evaporated until the crystalline material was isolated.

m.p.: decomposing at a temperature higher than 180 deg.C.

d) 2-amino-6-chloro-4- (4-aminophenyl) quinoline

1.8ml of concentrated hydrochloric acid are added dropwise to a suspension of 0.59g of 2-acetylamino-6-chloro-4- (4-nitrophenyl) quinoline and 0.29g of iron powder, and the reaction mixture is then heated under reflux for 4 hours and filtered while hot. The solvent was distilled off and MPLC was performed on MPRC column with 10 volumes of dichloromethane and 1 volume of methanol to give the material as a yellow viscous oil.

e) 2-amino-4- (4-aminophenyl) -6-chloro-3, 4-dihydroquinoline

6.76g of sodium amalgam are added over the course of one hour with stirring to a solution of 255mg of 2-amino-6-chloro-4- (4-aminophenyl) quinoline in 3.4ml of water and 22ml of ethanol. The mixture was stirred overnight and the Hg precipitate was filtered off and the solvent was distilled off under reduced pressure. After MPLC column chromatography in a mixture of 10 parts by volume of ethyl acetate and 5 parts by volume of methanol, 5 parts by volume of n-heptane and 1 part by volume of ammonia (concentrated), acidification is carried out with a small amount of concentrated hydrochloric acid, the solvent is removed by distillation and the residue is induced to crystallize with a small amount of ethyl acetate.

m.p.: decomposing at a temperature higher than 300 deg.C.

Example 2: 4- (4-aminophenyl) -6-chloro-2-ethylamino-3, 4-dihydroquinoline hydrochloride

a) 6-chloro-2-ethylamino 4- (4-nitrophenyl) quinoline

500mg of 2-acetylamino-6-chloro-4- (4-nitrophenyl) quinoline (compound 1c) are suspended in 10ml of THF and added portionwise under argon to 2.9ml of borane-THF complex. A foam was generated and then a yellow solution was formed. After stirring at room temperature for 12 hours, the solution was mixed with 5ml of ethanol and 2ml of concentrated HCl and heated on a water bath, cooled and water was distilled off. The residue was mixed with water, made alkaline with 2N NaOH, extracted with ethyl acetate and washed with water. The product was purified by MPLC chromatography using MPRC column with 1 volume of ethyl acetate, 2 volumes of toluene. The product was isolated as a yellow solid.

m.p.：145-150℃。

b)4- (4-aminophenyl) -6-chloro-2-ethylaminoquinoline

254mg of 6-chloro-2-ethylamino-4- (4-nitrophenyl) quinoline are suspended in 1.6ml of diglyme, and 9mg of iron phthalocyanine and 97mg of 2-bromoethanol are added. The mixture was stirred at room temperature for 3 minutes and then 3.1ml of NaBH was injected₄Solution (0.5M in diglyme). An exothermic reaction occurred and was kept at room temperature with a water bath. The greenish black mixture was stirred at room temperature for 4 hours. The mixture was mixed with water and extracted with ethyl acetate. The product was purified by MPLC chromatography using MPRC column with a mixture of 1 part by volume of ethyl acetate and 1 part by volume of toluene. The product was dissolved in a small amount of ethyl acetate, acidified with etherified HCl, stirred at room temperature and filtered off with suction.

m.p.：308-314℃

c)4- (4-aminophenyl) -6-chloro-2-ethylamino-3, 4-dihydroquinoline

148mg of 4- (4-aminophenyl) -6-chloro-2-ethylaminoquinoline are dissolved in 10.3ml of ethanol and 1.6ml of water, and 3.6g of sodium/amalgam are added over a period of one hour. The mixture was stirred overnight and filtered to remove the Hg precipitate and the solvent was evaporated under reduced pressure. Acidification with a small amount of concentrated hydrochloric acid, removal of the solvent by distillation, and induction of crystallization of the residue with a small amount of ethyl acetate.

m.p.: decomposing at a temperature higher than 310 deg.C.

Example 3: 4- (4-aminophenyl) -6-chloro-2-diethylamino-3, 4-dihydroquinoline hydrochloride

a) 6-chloro-2- (N-acetyl-N-ethylamino) -4- (4-nitrophenyl) quinoline

600mg of 6-chloro-2-ethylamino-4- (4-nitrophenyl) quinoline (mixture 2a) are added to 0.19g of acetic anhydride. The mixture is boiled at 70 ℃ for 4 hours and cooled and the acetic anhydride is distilled off. The residue was mixed with water, extracted with ethyl acetate and washed with water, and the product was obtained as a yellow oil. b) 6-chloro-2-diethylamino-4- (4-nitrophenyl) quinoline

570mg of 6-chloro-2- (N-acetyl-N-ethylamino) -4- (4-nitrophenyl) quinoline are suspended in 11.4ml of THF and added portionwise to 3.1ml of borane-THF complex under argon. The temperature was increased to 30 ℃. After stirring at room temperature for 3 hours, the solvent was distilled off and the residue was mixed with 50ml of ethanol and 20ml of concentrated HCl and heated on a water bath, cooled and distilled to remove water. The residue was mixed with water, made alkaline with 2N NaOH, extracted with ethyl acetate and washed with water. The product was purified by MPLC chromatography using a MPRC column with a mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane, 5 parts by volume of methanol and 1 part by volume of concentrated aqueous ammonia solution. The product was isolated as a yellow solid.

m.p.：133-138℃。

c)4- (4-aminophenyl) -6-chloro-2-diethylaminoquinoline

179mg of iron powder are added to a solution of 380mg of 6-chloro-2-diethylamino-4- (4-nitrophenyl) quinoline in 12.7ml of glacial acetic acid, 3.0ml of concentrated hydrochloric acid are then added dropwise and the mixture is boiled for 2 hours at 70 ℃. The solvent was distilled off, and the residue was mixed with water and made alkaline with 2N NaOH. The aqueous phase was extracted with ethyl acetate. The product was a dark brown viscous oil.

d)4- (4-aminophenyl) -6-chloro-2-diethylamino-3, 4-dihydroquinoline

5.49g of sodium/amalgam are added over 5 hours with stirring to a solution of 250mg of 4- (4-aminophenyl) -6-chloro-2-diethylaminoquinoline in 2.5ml of water and 16ml of ethanol. The mixture was stirred overnight and filtered to remove the Hg precipitate and the solvent was distilled off under reduced pressure. The residue was mixed with water and extracted with ethyl acetate. The solid product of the light-colored residue was dissolved in a small amount of ethyl acetate, acidified with diethylether HCl, stirred at room temperature and filtered off with suction.

m.p.：128-134℃。

Example 4: n- (2-dimethylaminoethyl) -N' -4- [ (6-chloro-3, 4-dihydro-2-diethylaminoquinolin-4-yl) phenyl ] urea hydrochloride

a) O- (2-nitrophenyl) -N-4- [ (6-chloro-3, 4-dihydro-2-diethylaminoquinolin-4-yl) phenyl ] carbamate

62mg of 4- (4-aminophenyl) -6-chloro-2-diethylamino-3, 4-dihydroquinoline (example 3) are dissolved in 5ml of dichloromethane and 46mg of 4-nitrophenyl chloroformate are added. After a short time a solid precipitated out. After stirring at room temperature for 3 hours, methylene chloride was distilled off. The product was isolated as a pale solid.

b) N- (2-dimethylaminoethyl) -N' -4- [ (6-chloro-3, 4-dihydro-2-diethylaminoquinolin-4-yl) phenyl ] urea

105mg of o- (2-nitrophenyl) -N-4- [ (6-chloro-3, 4-dihydro-2-diethylaminoquinolin-4-yl) phenyl ] carbamate are dissolved in 5ml of THF. Then, 21mg of N, N-dimethylethylenediamine was added dropwise thereto, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off, and the residue was extracted with water and ethyl acetate. The product was purified by MPLC chromatography using a MPRC column with a mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane, 5 parts by volume of methanol and 1 part by volume of concentrated aqueous ammonia solution. The resulting product was mixed with water, 2N HCl and 20% HCl, and the clear solution was freeze-dried overnight. The product was obtained as a hygroscopic solid, which was dissolved in a small amount of ethyl acetate, acidified with diethylether HCl, stirred at room temperature and filtered off with suction.

Rf 0.57 (silica gel, ethyl acetate/methanol/heptane/dichloromethane/ammonia 10:5:5:5:1)

1H-NMR(DMSO-d6)：δ＝1.07(t，2H)，1.17(t，2H)，2.50(s，6H)，2.80(d，2H)，3.13(q，2H)，3.30(m，1H)，3.57(m，1H)，3.70(m，1H)，3.83(q，2H)，4.39(m，1H)，6.66(t，1H)，6.99(d，1H)，7.04(d，2H)，7.43(m，3H)，7.70(d，1H)，9.11(s，1H)。

MS：m/z＝441(m)+。

Pharmacological data:

description of the test: measurement of NHE inhibition

In this assay, intracellular pH (pH) after acidification is determined_j) The acidification is performed with functional NHE in the absence of bicarbonate. For this purpose, the pH is determined using the pH-sensitive fluorescent dye BCECF (Calbeiochem, using the precursor BCECF-AM)_j. Cells were initially loaded with BCECF. Fluorescence of BCECF was measured in a ratiometric (ratio) fluorescence spectrometer (Photon technology International, South Brunswick, N.J., USA) using excitation wavelengths of 505 and 440nm and emission wavelengths of 535nm, using a calibrationThe quasi graph converts this to pHj. Cells were plated on NH for BCECF loading₄Cl buffer (pH 7.4) (NH)₄Cl buffer solution: 115mM NaCl, 20mM NH₄Cl、5mM KCl、1mM CaCl₂、1mM MgSO₄20mM Hepes, 5mM glucose, 1mg/mL BSA, adjusted to pH 7.4 with 1M NaOH). Intracellular acidification is via reaction to NH₄975. mu.L of NH-free aliquots were added to 25. mu.L aliquots of cells cultured in Cl buffer₄Cl buffer (see below). The recovery of pH was then recorded for the following cases: NHE1, 2 min; NHE2, 5 min; NHE3, 3 min. To calculate the inhibitory capacity of the test substances, cells were initially studied in buffer, and the results showed that there was no or complete pH recovery. To determine complete pH recovery (100%), cells were incubated in the presence of Na⁺In (5) (133.8mM NaCl, 4.7mM KCl, 1.25mM CaCl)₂、1.25mMMgCl₂、0.97mM Na₂HPO₄、0.23mM NaH₂PO₄5mM Hepes, 5mM glucose, adjusted to pH 7.0 with 1M NaOH). To determine the value of 0%, cells were incubated in the absence of Na⁺In (5) (133.8mM choline chloride, 4.7mM KCl, 1.25mM CaCl)₂、1.25mM MgCl₂、0.97mM K₂HPO₄、0.23mM KH₂PO₄5mM Hepes, 5mM glucose, adjusted to pH 7.0 with 1M NaOH). Subjecting the test substance to Na-containing reaction⁺Prepared in the buffer of (1). The recovery rate of intracellular pH for each tested concentration of substance is expressed as the maximum recovery percentage. The IC of each substance for each NHE subtype was calculated from the percentage recovery from pH using the Sigma Plot program₅₀。

Inhibition of NHE3 (IC) by various exemplary compounds₅₀Values) are detailed in the following table:

examples	IC50[μM]
		1	4.39
2	10.87
		3	9.19
4	13.85

Claims (14)

1. A compound of formula I:

wherein the radicals have the following meanings:

r1, R2, R3 and R4

Independently of one another, hydrogen, F, Cl, Br, I, CN, NO₂、CF₃、CH₃-SO₂An alkane having 1, 2, 3 or 4C atomsRadical, NH₂、NH-CH₃Or N (CH)₃)₂；

R5 and R6

Independently of one another, hydrogen, alkyl having 1, 2, 3, 4, 5 or 6C atoms, CF₃-CH₂-, cycloalkyl having 3, 4, 5 or 6C atoms or cyclopropyl-CH₂-，

Or

R5 and R6

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring in which one or both CH' s₂The radicals being independently of one another substituted by NR12, sulfur, oxygen, C (O) or SO₂Replacement;

r12 hydrogen, alkyl having 1, 2, 3 or 4C atoms or cycloalkyl having 3, 4, 5 or 6C atoms;

r7 hydrogen or alkyl having 1, 2, 3 or 4C atoms;

r8 and R9

Independently of one another, hydrogen, F, Cl, Br, OH, alkyl having 1, 2, 3 or 4C atoms, CH₃O、CF₃Or CH₃SO₂；

R10 and R11

Independently of one another R13- (C)_mH_2m)-B_nWherein

m is zero, 1, 2, 3 or 4;

n is zero or 1;

B-CO-, -CONR 14-or-SO₂-；

R14 hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

r13 hydrogen, alkyl having 1, 2, 3 OR 4C atoms, cycloalkyl having 3, 4, 5 OR 6C atoms, 1-pyrrolidinyl, 1-piperidinyl, 1- (4-methylpiperazinyl), 1-morpholinyl, -COOR15, OR16, NR17R18 OR phenyl which, independently of one another, has 1 OR 2 substituents selected from chlorine, fluorine, methyl and methoxy;

r15, R16, R17 and R18

Independently of one another, hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

or

R10 and R11

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring in which one, two or three CH₂The radicals being independently of one another bound by NR19, sulfur, oxygen, C (O) or SO₂Replacement;

r19 hydrogen, alkyl having 1, 2, 3 or 4C atoms or cycloalkyl having 3, 4, 5 or 6C atoms.

2. Compounds of the formula I as claimed in claim 1, in which the radicals have the following meanings:

r1, R2, R3 and R4

Independently of one another, hydrogen, F, Cl, Br, CN, CF₃、CH₃-SO₂Alkyl having 1, 2, 3 or 4C atoms, NH₂、NH-CH₃Or N (CH)₃)₂；

R5 and R6

Independently of one another, hydrogen, alkyl having 1, 2, 3, 4, 5 or 6C atoms, CF₃-CH₂-, cycloalkyl having 3, 4, 5 or 6C atoms or cyclopropyl-CH₂-，

Or

R5 and R6

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring;

r7 hydrogen;

r8 and R9

Independently of one another, hydrogen, F, Cl, OH, alkyl having 1, 2, 3 or 4C atoms, CH₃O、CF₃Or CH₃SO₂；

R10 and 11

Independently of one another R13- (C)_mH_2m)-B_nWherein

m is zero, 1, 2, 3 or 4;

n is zero or 1;

B-CO-, -CONR 14-or-SO₂-；

R14 hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

r13 hydrogen, alkyl having 1, 2, 3 OR 4C atoms, cycloalkyl having 3, 4, 5 OR 6C atoms, 1-pyrrolidinyl, 1-piperidinyl, 1- (4-methylpiperazinyl), 1-morpholinyl, -COOR15, OR16, NR17R18 OR phenyl which, independently of one another, has 1 OR 2 substituents selected from chlorine, fluorine, methyl and methoxy;

r15, R16, R17 and R18

Independently of one another, hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

or

R10 and R11

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring, one CH of which₂The group may be replaced by oxygen or NR 19;

r19 hydrogen or alkyl having 1, 2, 3 or 4C atoms.

3. Compounds of the formula I as claimed in claim 1 or 2, in which the radicals have the following meanings:

r1, R2, R3 and R4

Independently of one another, hydrogen, F, Cl, Br, CN, CF₃、CH₃-SO₂Methyl, ethyl, NH₂、NH-CH₃Or N (CH)₃)₂；

R5 and R6

Independently of one another, hydrogen, methyl, ethyl, isopropyl, CF₃-CH₂-or cycloalkyl having 3, 4, 5 or 6C atoms;

r7 hydrogen;

r8 and R9

Independently of one another, hydrogen, Cl or methyl;

r10 and 11

Independently of one another R13- (C)_mH_2m)-B_nWherein

m is zero, 1, 2, 3 or 4;

n is zero or 1;

B-CO-, -CONR 14-or-SO₂-；

R14 hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

r13 hydrogen, methyl, cycloalkyl having 3, 4, 5 OR 6C atoms, 1-pyrrolidinyl, 1-piperidinyl, 1- (4-methylpiperazinyl), -COOR15, OR16 OR NR17R 18; r15, R16, R17 and R18

Independently of one another, hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

or

R10 and R11

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring, one CH of which₂The group may be replaced by oxygen or NR 19;

r19 hydrogen or methyl.

4. A compound of the formula I as claimed in one or more of claims 1 to 3, in which the radicals have the following meanings:

r1 and R3

Hydrogen;

r2 and R4

Independently of one another, hydrogen or Cl;

r5 and R6

Independently of one another, hydrogen, methyl or ethyl;

r7 hydrogen;

r8 and R9

Independently of one another, hydrogen or Cl;

r10 and 11

Independently of one another R13- (C)_mH_2m)-B_nWherein

m is zero, 1, 2, 3 or 4;

n is zero or 1;

B -CONR14-；

r14 hydrogen or methyl;

r13 hydrogen, methyl, cycloalkyl having 3, 4, 5 OR 6C atoms, 1-pyrrolidinyl, 1-piperidinyl, 1- (4-methylpiperazinyl), -COOR15, OR16 OR NR17R 18; r15, R16, R17 and R18

Independently of one another, hydrogen or alkyl having 1, 2, 3, 4, 5 or 6C atoms;

or

R10 and R11

Together with the nitrogen atom to which they are bound form a 4, 5, 6, 7, 8, 9 or 10 membered ring, one CH of which₂The group can beAn NR19 substitution;

r19 hydrogen or methyl.

5. Compounds of the formula I as claimed in one or more of claims 1 to 4, and the pharmaceutically acceptable salts and trifluoroacetates thereof, are selected from:

2-amino-4- (4-aminophenyl) -6-chloro-3, 4-dihydroquinoline,

4- (4-aminophenyl) -6-chloro-2-ethylamino-3, 4-dihydroquinoline,

4- (4-aminophenyl) -6-chloro-2-diethylamino-3, 4-dihydroquinoline,

and

n- (2-dimethylaminoethyl) -N' -4- [ (6-chloro-3, 4-dihydro-2-diethylaminoquinolin-4-yl) phenyl ] urea.

6. A compound of the formula I as claimed in one or more of claims 1 to 5 and the pharmaceutically acceptable salts thereof for use as a medicament.

7. The use of a compound of the formula I as claimed in one or more of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof for producing a medicament for the treatment or prophylaxis of the following diseases: respiratory power injury, respiratory disorders, sleep-related respiratory disorders, sleep apnea, snoring, acute or chronic renal disorders, acute renal failure and chronic renal failure, intestinal dysfunction, hypertension, essential hypertension, central nervous system disorders, disorders resulting from CNS hyperexcitability, epilepsy and centrally induced spasticity or anxiety states, depression and psychosis, ischemic states or strokes of the peripheral or central nervous system, acute and chronic injuries and disorders of peripheral organs or limbs resulting from ischemic or reperfusion events, atherosclerosis, impairment of lipid metabolism, thrombosis, impairment of biliary function, ectoparasitic infection, disorders resulting from endothelial dysfunction, protozoal diseases, malaria, shock states or diabetes and late-stage injuries of diabetes or diseases in which cellular proliferation is a primary or secondary cause, protection and storage of grafts during surgery, for use in surgery and organ transplantation, as well as for maintaining health and prolonging life.

8. The use of a compound of the formula I as claimed in one or more of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof in combination with a further medicament or active ingredient for the preparation of a medicament for the treatment or prophylaxis of the following diseases: respiratory power injury, respiratory disorders, sleep-related respiratory disorders, sleep apnea, snoring, acute or chronic renal disorders, acute renal failure and chronic renal failure, intestinal dysfunction, hypertension, essential hypertension, central nervous system disorders, disorders resulting from CNS hyperexcitability, epilepsy and centrally induced spasticity or anxiety states, depression and psychosis, ischemic states or strokes of the peripheral or central nervous system, acute and chronic injuries and disorders of peripheral organs or limbs resulting from ischemic or reperfusion events, atherosclerosis, impairment of lipid metabolism, thrombosis, impairment of biliary function, ectoparasitic infection, disorders resulting from endothelial dysfunction, protozoal diseases, malaria, states of shock or diabetes and late-stage injuries of diabetes or diseases in which cellular proliferation is a primary or secondary cause, protection and storage of grafts during surgery, for use in surgery and organ transplantation, as well as for maintaining health and prolonging life.

9. Use of a compound of the formula I as claimed in one or more of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof alone or in combination with other medicaments or active ingredients for the preparation of a medicament for the treatment or prophylaxis of impairment of respiratory drive and/or sleep-related respiratory impairment, such as sleep apnea.

10. Use of a compound of the formula I as claimed in one or more of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof alone or in combination with other medicaments or active ingredients for the preparation of a medicament for the treatment or prophylaxis of snoring.

11. The use of a compound of the formula I as claimed in one or more of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof, alone or in combination with other medicaments or active ingredients, for the preparation of a medicament for the treatment or prophylaxis of acute or chronic renal disorders, acute renal failure and chronic renal failure.

12. The use of a compound of the formula I as claimed in one or more of claims 1 to 5 and/or of a pharmaceutically acceptable salt thereof alone or in combination with other medicaments or active ingredients for the preparation of a medicament for the treatment or prevention of impaired intestinal function.

13. Pharmaceutical preparations for human, veterinary or plant protection use, which contain an effective amount of a compound of the formula I as claimed in one or more of claims 1 to 5 and/or a pharmaceutically acceptable salt thereof.

14. Pharmaceutical preparations for human, veterinary or plant protection use, which contain an effective amount of a compound of the formula I as claimed in one or more of claims 1 to 5 and/or a pharmaceutically acceptable salt thereof, in combination with other pharmacologically active ingredients or medicaments.