Arylglycinamide derivatives, method of producing said derivatives and pharmaceutical compositions containing these compounds

This application is a continuation of application Ser. No. 09/703,758, filed Nov. 1, 2000, which is a continuation of application Ser. No. 09/142,271, filed Nov. 30, 1998, now abandoned, which is a national stage entry under 35 U.S.C. § 371 of PCT/EP97/01038, filed Mar. 3, 1997.

The invention relates to new arylglycinamide derivatives of general formula

and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin) antagonists.

The abbreviations used in this specification and claims are explained as follows:

The formulae are shown in simplified form. In representing the compounds, for example, all the CH 3 -substituents are represented by a hyphen and CH is represented by, thus, for example:

The invention relates to new arylglycinamide derivatives of general formula I

or the pharmaceutically acceptable salts thereof, wherein

Ar denotes unsubstituted or mono- to penta-substituted phenyl, or unsubstituted or mono- or disubstituted naphthyl [wherein the substituents of the phenyl and naphthyl independently of one another denote halogen (F, Cl, Br, I), (C 1-4 )alkyl, O—(C 1-4 )alkyl, CF 3 , OCF 3 or NR 12 R 13 (wherein R 12 and R 13 independently of one another denote H, methyl or acetyl)] or Ar is phenyl substituted by —O—CH 2 —O— or —O—(CH 2 ) 2 —O—; R 1 and R 2 together with the N to which they are bound denote a ring of the formula

wherein

r, s and t are 2 or 3; R 6 denotes H, (C 1-5 )alkyl, (C 3-5 )alkenyl, propynyl, hydroxy(C 2-4 )alkyl, methoxy(C 2-4 )alkyl, di(C 1-3 )alkylamino(C 2-4 )alkyl, amino(C 2-4 )alkyl, amino, di(C 1-3 )alkylamino, monofluoro- to perfluoro(C 1-2 )alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or the group —CH 2 —C(O)NR 14 R 15 ,

wherein

R 14 is H or (C 1-4 )alkyl and R 15 is H, (C 1-4 )alkyl, (C 3-6 )cycloalkyl, hydroxy(C 2-4 )alkyl, alkoxy(C 2-3 )alkyl, phenyl(C 1-4 )alkyl, or R 14 and R 15 together with the N to which they are bound form a ring (1-pyrrolidinyl, piperidino, morpholino or 1-methylpiperazin-4-yl); R 7 has one of the definitions (a) to (d), (a) hydroxy (b) 4-piperidinopiperidyl,

wherein R 16 and R 17 independently of one another denote

H, (C 1-4 )alkyl, (C 3-6 )cycloalkyl, hydroxy(C 2-4 )alkyl, (C 1-3 )alkoxy(C 2-4 )alkyl, phenyl(C 1-4 )alkyl or di(C 1-3 )alkylamino(C 2-4 )alkyl, or if R 16 is H or (C 1-4 )alkyl, R 17 may also be —CH 2 C(O)NR 18 R 19 , wherein R 18 and R 19 are defined as R 14 and R 15 hereinbefore;

wherein R 20 denotes

H,

(C 1-4 )alkyl,

(C 4-6 )cycloalkyl or

—CH 2 C(O)NR 21 R 22 ,

wherein R 21 and R 22 are defined as R 14 and R 15 hereinbefore;

R 8 is H

R 9 and R 10 independently of each other denote (C 1-4 )alkyl;

R 11 denotes

H,

(C 1-5 )alkyl,

(C 3-5 )alkenyl,

propynyl,

hydroxy(C 2-4 )alkyl,

methoxy(C 2-3 )alkyl,

di(C 1-3 )alkylamino(C 2-3 )alkyl,

amino(C 2-3 )alkyl,

amino,

di(C 1-3 )alkylamino,

monofluoro- to perfluoro(C 1-2 )alkyl,

N-methylpiperidinyl,

pyridyl,

pyrimidinyl,

pyrazinyl,

pyridazinyl

or the group —CH 2 —C(O)NR 23 R 24 ,

wherein R 23 and R 24 are defined as R 14 and R 15 hereinbefore;

R 3 denotes H, (C 1-4 )alkyl, unsubstituted or mono- to trisubstituted phenyl, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C 1-4 )alkyl, O—(C 1-4 )alkyl, CF 3 , OCF 3 or NR 25 R 26 (wherein R 25 and R 26 independently of one another denote H, methyl or acetyl); R 4 denotes phenyl(C 1-4 )alkyl or naphthyl(C 1-4 )alkyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C 1-4 )alkyl, O—(C 1-4 )alkyl, CF 3 , OCF 3 or NR 27 R 28 (wherein R 27 and R 28 independently of one another denote H, methyl or acetyl);

and

R 5 denotes H, (C 1-4 )alkyl, (C 3-6 )cycloalkyl, CH 2 COOH, CH 2 C(O)NH 2 , OH or phenyl(C 1-4 )alkyl.

Preferred compounds of general formula I are those wherein

Ar denotes unsubstituted or mono- or disubstituted phenyl, or unsubstituted naphthyl, or Ar is phenyl substituted by —O—CH 2 —O— or —O—(CH 2 ) 2 —O—; R 1 and R 2 together with the N to which they are bound denote a ring of the formula

wherein

r is 2 or 3 and s and t are 2; R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as hereinbefore defined;

R 3 is H or (C 1-4 )alkyl, R 4 denotes phenyl(C 1-4 )alkyl or naphthyl(C 1-4 )alkyl, wherein phenyl may be substituted by 1 or 2 substituents, wherein the substituents independently of one another are halogen (F, Cl, Br, I), (C 1-4 )alkyl, O—(C 1-4 )alkyl, CF 3 or OCF 3 ;

and

R 5 denotes H, (C 1-4 )alkyl, (C 3-6 )cycloalkyl, OH or (C 1-4 )alkylphenyl.

Particular mention should be made of compounds of formula I wherein

Ar is unsubstituted or mono- or disubstituted phenyl, or unsubstituted naphthyl [wherein the substituents of the phenyl independently of one another are halogen (F, Cl, Br, I), methyl, methoxy, CF 3 or OCF 3 ] or Ar is phenyl substituted by —O—CH 2 —O— or —O—(CH 2 ) 2 —O—;

particularly those wherein Ar is phenyl, naphthyl, phenyl substituted in position 3 and/or 4 by methoxy or halogen, or phenyl in which positions 2 and 3 or 3 and 4 are linked by —O—CH 2 —O—, preferably those compounds wherein

Ar is phenyl, phenyl substituted by methoxy in positions 3 and 4 or phenyl wherein positions 3 and 4 or 2 and 3 are linked by —O—CH 2 —O—.

Of the compounds defined above, special mention should be made of those wherein, in the ring

r is 2 or 3 and

R 6 denotes

H,

(C 1-5 )alkyl,

(C 3-5 )alkenyl,

propynyl,

hydroxy(C 2-4 )alkyl,

methoxy(C 2-4 )alkyl,

di(C 1-3 )alkylamino(C 2-4 )alkyl,

amino(C 2-4 )alkyl,

amino,

di(C 1-3 )alkylamino,

monofluoro- to perfluoro(C 1-2 )alkyl,

N-methylpiperidinyl,

pyridyl,

pyrimidinyl,

or

particularly those wherein

r is 3 and R 6 is methyl;

and those wherein

r is 2 and R 6 is H, (C 1-4 )alkyl, propenyl, propynyl, hydroxy(C 2-3 )alkyl, methoxyethyl, di(C 1-2 )alkylamino(C 2-3 )alkyl, aminoethyl, amino, dimethylamino, CH 2 CF 3 , N-methylpiperidinyl, pyridyl, pyrimidinyl,

or

preferably those wherein

r is 2 and R 6 is H, (C 1-3 )alkyl, allyl, 2-propynyl, —CH 2 CH 2 OCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , N-methylpiperidinyl, 2-pyrimidinyl

or

particularly those wherein

r is 2 and R 6 is H, CH 3 , C 3 H 7 , CH(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 CH 2 OCH 3 or CH 2 C 2 N(CH 3 ) 2 .

Of the compounds defined above, mention should also be made of those wherein

R 1 and R 2 together with the N to which they are bound form the ring

wherein R 8 is H and

R 7 is OH

wherein R 16 and R 17 independently of one another denote:

H (C 1-3 )alkyl,

(CH 2 ) n OH wherein n is 2, 3 or 4

(CH 2 ) 2 OCH 3

—(CH 2 ) n Ph wherein n is 2 or 4

(CH 2 ) 2 N(CH 3 ) 2

particularly those wherein

R 16 and R 17 are both CH 3 or C 2 H 5 or R 16 is H or CH 3 and R 17 is (C 1-3 )alkyl,

(CH 2 ) 2 OH,

(CH 2 ) 4 OH or

and those wherein

R 7 denotes

N(CH 3 ) 2

or

especially those wherein

R 1 and R 2 together with the N to which they are bound form the ring

wherein

(a) R 8 is H and

R 7 is

wherein R 16 and R 17 both represent CH 3 , C 2 H 5 l or CH 2 CH 2 OH or

R 16 is H or CH 3 and R 17 is (C 1-3 )alkyl,

(CH 2 ) 2 OH or

(CH 2 ) 4 OH or

(b) R 8 is H and

R 7 denotes

Of the compounds defined above, mention should also be made of those wherein

R 1 and R 2 together with the N to which they are bound form the ring

Of the compounds defined above, special mention should also be made of those wherein

R 1 and R 2 together with the N to which they are bound form the ring

wherein R 11 is H or (C 1-3 )alkyl, particularly those wherein

R 11 is —CH(CH 3 ) 2 .

Of the compounds defined above, the ones of particular interest are those wherein R 3 is H;

and/or

R 4 denotes phenyl(C 1-4 )alkyl, wherein phenyl may be substituted by 1 or 2 substituents, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C 1-4 )alkyl, O—(C 1-4 )alkyl, CF 3 or OCF 3 ;

and/or

R 5 denotes H, (C 1-4 )alkyl, (C 3-6 )cycloalkyl, —OH or phenyl(C 1-4 )alkyl,

particularly those wherein

R 4 denotes phenyl(C 2-4 )alkyl, wherein the substituents are in positions 3 and/or 5 of the phenyl ring and/or

R 5 is H, methyl, OH or phenethyl,

preferably those wherein

and R 5 is methyl.

Compounds of general formula I may have acid groups, chiefly carboxyl groups, and/or basic groups such as amino functions, for example. Compounds of general formula I may therefore be present either as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as dimethylamine, triethylamine, triethanolamine, etc.

The compounds according to the invention may occur as racemates but may also be obtained as pure enantiomers, i.e. in the (R)- or (S)-form.

The term naphthyl used hereinbefore includes both 1-naphthyl and 2-naphthyl.

Test results for compounds according to the invention:

The receptor affinity for the NK 1 -receptor (substance P-receptor) is determined on human lymphoblastoma cells (IM-9) with cloned NK 1 -receptors, by measuring the displacement of 125 I-labelled substance P. The K 1 -values thus obtained show the efficacy of the compounds:

The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P antagonism and also neurokinin A and neurokinin B antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases:

for the treatment or prevention of inflammatory and allergic diseases of the respiratory tract, such as asthma, chronic bronchitis, hyperreactive respiratory tract, emphysema, rhinitis and cough, and of the eyes, such as conjunctivitis and iritis, of the skin, such as dermatitis in contact eczema, urticaria, psoriasis, sunburn, insect bites and stings, itching, sensitive or hypersensitive skin, of the gastrointestinal tract, such as gastric and duodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel and Hirschsprung's disease, of the joints, such as rheumatoid arthritis, reactive arthritis and Reiter syndrome; for treating diseases of the central nervous system such as dementia, Alzheimer's disease, schizophrenia, psychoses, depression, headache (e.g. migraine or tension headaches), epilepsy, Parkinson's disease and stroke; for treating herpes zoster and postherpetic pain, tumours, collagenoses, dysfunction of the deferent urinary tract, haemorrhoids, nausea and vomiting, caused for example by radiation or cytostatic therapy or motion and pain of all kinds.

The invention therefore also relates to the use of the compounds according to the invention as therapeutic agents and pharmaceutical preparations which contain these compounds. They are preferably used in humans. The compounds according to the invention may be administered by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation, by transdermal route, optionally aided by iontophoresis or enhancers known from the literature, and by oral route.

For parenteral administration the compounds of formula I or the physiologically acceptable salts thereof, possibly with the conventional substances such as solubilisers, emulsifiers or other adjuvants, are dissolved, suspended or emulsified. Solvents which may be used include: water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of several solvents.

In addition, the compounds may be administered by means of implants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or intranasal preparations.

The oral efficacy of compounds of general formula I can be demonstrated by the following standard test:

Inhibition of lowering of blood pressure caused by NK 1 in anaesthetised guinea pigs.

Guinea pigs weighing 300–500 grams were anaesthetised with pentobarbital (50 mg/kg i.p.), intubated and artificially ventilated. They were ventilated with 10 ml/kg of air at a frequency of 60 breaths per minute. The carotid artery was canulated and the arterial blood pressure was recorded. A polyethylene tube was inserted into the jugular vein for the intravenous supply of substances.

A temporary reduction in blood pressure was brought about at intervals of 10 minutes by intravenous administration of the NK 1 -agonist [βAla 4 , Sar 9 , Met (O 2 ) 11 ]Sp(4-11)

in a dose of 0.2 μmol/kg. After the blood pressure thus produced had been measured, the test compound was introduced into the duodenum and the NK 1 -agonist was again injected every 10 minutes.

The results were expressed as a % inhibition of the reduction in blood pressure caused by the NK 1 -agonist specified.

In a dosage of 1 mg/kg (administered into the duodenum) the compound of Example 1 inhibited the lowering of blood pressure caused by the NK 1 -agonist by 80%.

The compounds according to the invention can be produced using generally known methods.

The compounds may be prepared in various ways. The two most common procedures are represented by the following diagram:

Method A. The carboxylic acid may be linked to the amine HN(R 5 )R 4 by various methods. Conventional methods are coupling processes such as those used in peptide chemistry. A coupling reagent such as TBTU, DCCI/HOBt, CDI, etc., is added to the coupling partners in substantially equivalent quantities. Suitable solvents are DMF, THF, CH 2 Cl 2 , CHCl 3 , acetonitrile or other inert solvents or mixtures thereof. The suitable temperature range is between −50° C. and +120° C., preferably between 0° C. and 40° C.

The carboxylic acid may also initially be converted into the corresponding acid halide by known methods using SOCl 2 , SO 2 Cl 2 , PCl 3 , PCl 5 or PBr 3 or mixtures thereof, and the acid halide is then reacted with the amine HN(R 5 )R 4 in an inert solvent such as CH 2 Cl 2 , THF or dioxane at temperatures between −50° C. and +100° C., typically at 0° to 20° C.

Another alternative is to convert the carboxylic acid initially into the alkylester, usually the methylester, by known methods and this ester is then reacted with the amine HN(R 5 )R 4 in an inert solvent such as DMF, dioxane or THF. The reaction temperatures are between 20° C. and 150° C., typically between 50° C. and 120° C. The reaction may also be carried out in a pressurized container.

Method B. Here, the α-halo-arylacetamide derivative obtained by known methods is reacted with the amine R 1 (R 2 )NH, thereby cleaving hydrogen halide. Inorganic bases such as K 2 CO 3 , NaHCO 3 or CaCO 3 or organic bases such as triethylamine, Hünig base, pyridine or DMAP are used to mop up the cleaved (or excess) hydrogen halide, or an excess of the amine R 1 (R 2 )NH may be used. DMF, THF, dioxane or other inert solvents are used. The temperature range for the reaction is from 0 to 100° C., typically between 10 and 80° C.

Method C. The compounds according to the invention wherein R 5 is not H may also be prepared as follows: first of all, the corresponding compound in which R 5 is H is synthesised using method A or B. Then, N-alkylation is carried out as follows in order to introduce alkyl, cycloalkyl or CH 2 COOH. The compounds according to the invention wherein R 5 is H are deprotonated with an equivalent quantity of NaH, NaNH 2 , KOH, NaOCH 3 or another strong base. Anhydrous inert solvents such as THF, dioxane or diethylether are used for this. Then the corresponding alkylating agent is added slowly in the form of the corresponding halide, tosylate or mesylate. The reaction is carried out at a temperature within the range from −50° C. to +100° C., typically between 0° C. and +50° C.