OA16324A

OA16324A - Disubstituted tetrahydrofuranyl compounds as antagonists of the bradykinin B1 receptor.

Info

Publication number: OA16324A
Application number: OA1201300060
Authority: OA
Inventors: Angelo Ceci; Norbert Hauel; Henri Doods; Birgit Jung; Raimund Kuelzer
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2010-08-20
Filing date: 2011-08-19
Publication date: 2015-05-11

Abstract

The invention relates to disubstituted tetrahydrofuranyl compounds of general formula I

Description

BACKGROUND TO THE INVENTION

TECHNICAL FIELD

The présent invention relates to disubstituted tetrahydrofuranyl compounds and the use thereof as B1-receptor antagonists, pharmaceutical compositions contaîning these compounds and methods for using them for the prévention or treatment of acute pain, viscéral pain, neuropathie pain, inflammatory and pain receptor-mediated pain, tumour pain and headaches.

PRIOR ART

Compounds with a B1-antagonistic activîty hâve already been described in the patent applications WO 2009/027450 and WO 2010/057899.

One aim ofthe présent invention was to provide new compounds which are particularly suitable as pharmacological active substances in médicaments that can be used for the 30 treatment of diseases which are at least partially mediated by the B1 receptor.

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DETAILED DESCRIPTION OF THE INVENTION

In the above general formula I, in an embodiment 1_

R¹ dénotés a group selected from

R² dénotés H, Cl or F and

X dénotés CH or N, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.

An embodiment 2 of the présent invention consists in the compounds of general formula la

CF , (la) wherein

R² dénotés H, Cl or F and

X dénotés CH or N, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases. Y

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An embodîment 3 of the présent invention consists in the compounds of générai formula

Ib

cf₃ . (Ib) wherein

R² dénotés H, Cl or F and

An embodîment 4 of the présent invention consists in the compounds of general formula le

CF₃

.(IC) wherein dénotés H, Cl or F and dénotés CH or N,

-416324 the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.

An embodiment 5 of the présent invention consiste in the compounds of general formula Id

wherein

R² dénotés H, Cl or F and

The following are mentioned as examples of most particularly preferred compounds of the above general formula I:

-516324

-616324

No.	Structure
(7)	.N. fi H 9 îYV°'^ch3 ο O ^H LA JU '-o ^H CF₃
(8)	,hk fi h 9 ^ΝΑ^Νχ V°'^CH:! ο Ο^H ΛΛ JU '-o CL^ n Y ^H cf₃
(9)	/N. fi H 9 ^ΝΆτ^Νχ HÀY ÀT°'^ch’ θ Q _F W ^H CF,
(10)	IÎ *1 H 9 ^ν·Ατ’Υ¹ν-χ% zy°'ch_s» O^H LÀ AJ ^v-o n r ^H À
(11)	A H 9 »YY_N-/ îV-ûh. O \AÀ xà ^-0 cr n Y ^H L
(12)	,N. ii 5 h 9 Ν^Ζ_γΝ_>Α_Ν^_γ ^Ν y ’ O ^H eÀÀ AJ ί-O F N Y ^H cf₃
(13)	^H3°Y% h 9 ⁿUæhYY îTY°'^CH3o Q ^H LA_NJ^ ^H cf₃

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No.	Structure
	h₃c^n.	H	0
		k A/		ΑΧ		AJ-
(14)		τίΑ		AYch,
	0 \	7 ^H			i ³
			-0 CA		~Ά
					H	cf₃
	AX	H	0
	n...X	x^N,,
(15)			<A		rV CH,
	o V	/ ^H	î		) 1 ³
	-o Y	XX	''N''	xx

					H	cf₃
	h₃c^n.	H	O
	k..,X	V^N/'	ΧΐΆ / ^H			îTV°'^CH3
(16)		O \	ü
			0		V
					H	cf₃
	ί-ΧγΧ	H	o
(17)		X^N?'	< N'^^X'	ri A		Αγ^ο'ΟΗ._
	Ô	/ ^H	U		O
			-o cA		V
					H	cf₃
	H₃C^bL	H	o
(18)	N^X	V^N/'	Ν'^Λχ	Ti A		\|kX^/0'CH
	⁰ i.	/ ^H	U		1 3
			-o Y		'''N''
					H	cf₃
	HN'%	H	0
(19)			; nA;	-Ά		'^A°'ch₃
	° C	> H [I	^A	Jj	^χ
			O		N
					H	C^F ₃
	hn'ⁿA	H	o
(20)		^Ν,,_χ		'X		^Y°'ch₃
	o V	7 h JJ	'^ίΧ'	J	^X
			o cr		‘N
					H	cf₃

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No.	Structure
	HN'%		H	O
	-A..A		-N,						,0.
(21)					H	i J		ΓΤ	CH₃
	0		-o	A	o	Y	Y

							H	cf₃
	HN-%		H	o
			.N,		nY	,N.			o
(22)	0						AA	CH,
				H	1
	0		-o		o	-J	Y

							H	Y
	... .-hx
	HN X		H
(23)		V	Y	Λ	nY	A		Y	°'CH₃
	II o	f		H	LJ.		L J
			*o	cr	+A	Y
							H	o^; -n
	HN'%		H	o
						.N.			o. _,,
(24)					N A	f A		i Az	CH,
	0			^H J	Q		U
				o	F		1
							H	Y

the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.

TERMS AND DEFINITIONS USED

The subject-matter of this invention encompasses the novel compounds of general formula I as mentioned hereinbefore, including the salts thereof, wherein one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced io by deuterium.

Unless stated otherwise, a chemical formula or a name specified in the description or in a claim encompasses not only ail the structurally possible and thermodynamically stable tautomers but also ail the stereoisomers, optical isomers, géométrie isomers (eg-wA

-916324 enantiomers, diastereomers, E/Z isomers, etc.), racemates and mixtures of different proportions of the individual enantiomers, mixtures of diastereomers or mixtures of each form mentioned hereinbefore in which isomers and enantiomers exist.

Also covered by the subject-matter of the invention are solvatés of the compounds of general formula I, for example the hydrates thereof.

Also included in the subject-matter of the invention are the salts of the compounds mentioned in each case, including the physiologically acceptable salts, as well as the solvatés thereof, such as the hydrates, for example.

Compounds of general formula I, if they contain suitable basic functions, for example amino groups, may be converted into the physiologically acceptable salts thereof with inorganic or organic acids, particularly for pharmaceutical applications.

The term physiologically acceptable sait as used in the présent invention is preferably taken to mean salts of the compounds according to the invention which are physiologically acceptable, i.e. which are particularly suitable for use in humans and/or mammals.

The term physiologically acceptable is used in the présent invention to refer to those compounds, ingrédients, compositions and/or préparations which are deemed suitable for use in contact with human or animal tissue within the scope of a reasonable medical judgment, without excessive toxicity, irritation, allergie reactions or other problems or complications, and which correspond to a proportionate risk/benefit ratio.

Examples of inorganic acids for this purpose include for example hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid or sulphuric acid, while examples of organic acids include formic acid, malic acid, ascorbic acid, benzoic acid, succinic acid, acetic acid, ethylenediaminetetraacetic acid, fumaric acid, glutamic acid, hexane-1-sulphonic acid, carbonic acid, maleic acid, mandelic acid, lactic acid, monomethylsebacic acid, nicotinic acid, oxalic acid, 5-oxoproline, saccharinic acid, sulphonic acids, such as for example methanesulphonic acid, camphorsulphonie acid, ethanesulphonic acid, ethane-

1,2-disulphonic acid, benzenesulphonic acid or p-toluenesulphonic acid, tartaric acid or citricacid (cf. Pharmaceutical salts”, Birge, S.M. étal., J. Pharm. Sci., (1977), 66,1-19).

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Moreover, the compounds of general formula I, if they contain suitable carboxylic acid functions, may be converted into the physiologically acceptable salts thereof with inorganîc or organic bases, particularly for pharmaceutical applications. Examples of inorganîc bases include for example alkali métal or alkaline earth métal hydroxides, for example sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxides; examples of organic amines include diethylamine, triethylamine, ethanolamine, diethanoiamine, triethanolamine, cyclohexylamine or dicyclohexylamine.

The physiologically acceptable salts according to the présent invention may be synthesised starting from the compounds according to the invention which contain a suitable basic or acid unit, using conventional chemical methods. Generally, salts of this kind may be prepared by reacting the free acid or base group with the required amount of base or acid in water or an organic solvent, such as for example diethyl ether, ethyl acetate, éthanol, isopropanol, acetonitrile or a mixture of these solvents.

The compounds according to the invention may occur as racemates if they hâve only one chiral element, but they may also be obtained as pure enantiomers, i.e. in the (R) or (S) form.

However, the application also encompasses the individual diastereomeric pairs of antipodes or the mixtures thereof which are présent when there is more than one chiral element in the compounds of general formula I, as well as the individual optically active enantiomers of which the above-mentioned racemates are made up.

Compounds with a carbon double bond may be présent in both the Eand Z form.

If a compound may be présent in different tautomeric forms, the compound prepared is not restricted to one tautomeric form but includes ail tautomeric forms. This also applies particularly to nitrogen-containing heteroaryls:

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METHODS OF PREPARATION

According to the invention the compounds of general formula I are obtained using methods known per se, for example by the following methods:

(A) amide coupling:

(il) (I) (III)

The illustrated linking of carboxylic acids of general formula II, wherein R¹ is as hereinbefore defined, with amines of general formula III, wherein R² and X are as hereinbefore defined, to form carboxylic acid amides of general formula I wherein R¹, R²and X are as hereinbefore defined, may be carried out by conventional methods of amide formation.

The coupling is preferably carried out using methods known from peptide chemistry (cf. for example Houben-Weyl, Methoden der Organîschen Chemie, vol. 15/2), using for example carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl-(3-dimethylamino-propyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-/V,/V-/V,/\/'-tetramethyluronium-hexafluorophosphate (HBTU) or -tetrafluoroborate (TBTU) or 1H-benzotriazoi-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). The speed of the reaction may be increased by the addition of 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-di-hydro-1,2,3-benzotriazine (HOObt). The couplings are normally carried out with equimolar amounts of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), /V-methylpyrrolidone (NMP) or mixtures thereof. If necessary, an auxiliary base such as, for example, diisopropylethylamine (DIPEA, Hünig base) is additionally used.

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It is also possible to convert the carboxylic acids of general formula II, wherein R¹ is as hereinbefore defined, into the corresponding carboxylic acid chlorides and then react the latter with amines of general formula III, wherein R² and X are as hereinbefore defined. Carboxylic acid chlorides are synthesised by methods known from the literature (cf. for example Houben-Weyl, Methoden der Organischen Chemie, vol. E5/1).

(B) Réduction of the nitrile group:

CH₃

The réduction of a nitrile of general formula IV, wherein R² and X are as hereinbefore defined, to obtain an amine of general formula III, wherein R² and X are as hereinbefore defined, may be carried out under standard conditions of catalytic hydrogenolysis with a catalyst, such as for example Raney nickel, in a solvent, such as for example ammoniacal 15 methanol or éthanol, or with a reducing agent, such as for example lithium aluminium hydride or sodium borohydride, in a solvent, such as for example tetrahydrofuran, optionally in the presence of a Lewis acid such as aluminium chloride.

(C) Nucleophilic aromatic substitution or transition metal-catalysed coupling:

(IV)

The reaction of the aniline VI with a nitrile of general formula V, wherein R² and X are as hereinbefore defined and Hal dénotés a fluorine, chlorine or bromine atom, is carried out w

-1316324 by known methods, for example without solvent or in a solvent such as tetra hydrofuran, dimethylformamide or drmethylsulphoxide and conveniently in the presence of a base, such as for example triethylamine, sodium hydroxide solution or potassium carbonate, at a température of 20’C to 160°C.

An alternative method of preparing compounds of general formula IV is the palladiumcatalysed reaction of a nitrile of general formula V, wherein Hal dénotés chlorine, bromine or iodine, with the aniline VI. Reaction conditions for this reaction, also known as the Buchwald-Hartwig réaction, are known from the literature.

Description of the method of binding the cvnoBKI-receptor

CHO cells that express the cynomolgus B1 receptor are cultivated in HAM’S F-12

Medium. The medium is removed from confluent cultures, the cells are washed with PBS buffer, scraped off or detached using Versene and isolated by centrifuging. Then the cells 15 are homogenised in suspension, the homogenate is centrifuged and resuspended. After the protein content has been determined 200 yl of the homogenate (50 to 250 pg protein/assay) are incubated for 60-180 minutes at ambient température with 0.5 to 5.0 nM kallidîne (DesArg10,Leu9), [3,4-Prolyl-3,43H(N)] and increasing concentrations of the test substance in a total volume of 250 pl. The incubation is stopped by rapid filtration 20 through GF/B glass fibre filters that hâve been pre-treated with polyethyleneimine (0.3%).

The radioactivity bound to the protein is measured with a TopCount NXT. The radioactivity bound in the presence of 1.0 pM kallidîne (DesArglO) is defîned as nonspecific binding. The concentration binding curve may be analysed using computer-aided non-linear curve fitting to détermine the corresponding K| value for the test substance.

Test results of the cynoBK! -receptor binding assay;

Example No.	K, [nM]
(1)	1.0
(3)	4.7
(4)	3.6
(6)	18

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Example No.	K_s[nM]
(21)	1,6

INDICATIONS | In view of their pharmacological properties, the novel compounds and their physiologically

I 5 acceptable salts are suitable for treating diseases and symptoms of diseases caused at least to some extent by stimulation of bradykinin-B1 receptors, or in which antagonisation of the of bradykînin-B1 receptor can bring about an improvement in symptoms.

In a further aspect the présent invention encompasses the compounds of the aboveio mentioned general formula I according to the invention for use as médicaments.

In view of their pharmacological effect the substances are suitable for the treatment of (a) acute pain such as for example toothache, péri- and post-operative pain, traumatic pain, muscle pain, the pain caused by bums, sunburn, trigeminal neuralgia, pain caused

I 15 by colic, as well as spasms of the gastro-intestinal tract or utérus;

(b) viscéral pain such as for example chronic pelvic pain, gynaecological pain, pain before and during menstruation, pain caused by pancreatitis, peptic ulcers, interstitial cystitis, rénal colic, cholecystitis, prostatitis, angina pectoris, pain caused by irritable bowel, non-ulcerative dyspepsia and gastritis, prostatitis, ποη-cardiac thoracic pain and pain caused by myocardial ischaemia and cardiac infarct;

(c) neuropathie pain such as for example painful polyneuropathies, pain of diabetic neuropathy, AIDS-associated neuropathie pain, non-herpes-associated neuralgia, post- zoster neuralgia, nerve damage, cerebro-cranial trauma, pain of nerve damage caused by toxins or chemotherapy, phantom pain, pain of multiple sclerosis, nerve root tears and painful traumatically-caused damage to individual nerves, and central pain such as for example pain after stroke, spinal injuries or tumours;

d) inflammatory / pain receptor-mediated pain in connection with diseases such as for example osteoarthritis, rheumatoid arthritis, rheumatic fever, tendo-synovitis, bursitis, \j/~

-1516324 tendonitis, goût and gout-arthritis, traumatic arthritis, vulvodynia, damage to and diseases of the muscles and fascia, juvénile arthritis, spondylitis, psoriasis-arthritis, myositides, dental disease, influenza and other viral infections such as colds, systemic lupus erythematodes or pain caused by burns, (e) tumour pain associated with cancers such as for example lymphatic or myeloid leukaemia, Hodgkin's disease, non-Hodgkin's lymphomas, lymphogranulomatosis, lymphosarcomas, solid malignant tumours and extensive métastasés;

(f) headache diseases of various origins, such as for example cluster headaches, migraine (with or without aura) and tension headaches.

(g) painful conditions of mixed origin, such as for example chronic back pain including lumbago, orfibromyalgia.

The compounds are also suitable for treating (h) inflammatory and/or oedematous diseases of the skin and mucous membranes, such as for example allergie and non-allergic dermatitis, atopie dermatitis, psoriasis, burns, sunburn, bacterial inflammations, irritations and inflammations triggered by chemical or naturel substances (plants, insects, insect bites), itching; inflammation of the gums, oedema following trauma caused by burns, angiooedema or uveitis;

(i) inflammatory changes connected with diseases of the airways and lungs such as bronchial asthma, including allergie asthma (atopie and non-atopic) as well as bronchospasm on exertion, occupationslly induced asthma, viral or bacterial exacerbation of an existing asthma and other non-aîlergically induced asthmatic diseases; chronic bronchitis and chronic obstructive pulmonary disease (COPD) including pulmonary emphysema, viral or bacterial exacerbation of chronic bronchitis or chronic obstructive bronchitis, acute adult respiratory distress syndrome (ARDS), bronchitis, lung inflammation, allergie rhinitis (seasonal and ail year round) vasomotor rhinitis and diseases caused by dust in the lungs such as aluminosis, anthracosis, asbestosis, chalicosis, siderosis, silicosis, tabacosis and byssînosis, exogenous allergie alveolitis, pulmonary fibrosis, bronchiectasis, pulmonary diseases in alphal-antitrypsin deficiency and cough; Ά

-1616324 (j) inflammatory diseases ofthe gastrointestinal tract including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis;

(k) diabètes mellitus and its effects (such as e.g. dîabetic vasculopathy, diabetic neuropathy, diabetic retinopathy) and diabetic symptoms in insulitis (for example hyperglycaemia, diu resis, proteînuria and increased rénal excrétion of nitrite and kallikrein);

(l) sepsis and septic shock after bacterial infections or after trauma;

(m) inflammatory diseases of the joints and connective tissue such as vascular diseases of the connective tissue, sprains and fractures, and musculoskeletal diseases with inflammatory symptoms such as acute rheumatic fever, polymyalgia rheumatica, reactive arthritis, rheumatoîd arthritis, spondylarthritis, and also osteoarthritis, and inflammation of the connective tissue of other origins, and collagénoses of ail origins such as systemic lupus erythematodes, scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, Still's disease or Felty syndrome; as well as vascular diseases such as panarteriitis nodosa, polyarthritis nodosa, periarteriitis nodosa, arteriitis temporalis, Wegner’s granulomatosis, giant cell arteriitis, arteriosclerosis and erythema nodosum;

(n) diseases of and damage to the central nervous System such as for example cérébral oedema and the treatment and prévention of psychiatrie diseases such as dépréssion, for example, and for the treatment and prévention of epilepsy;

(o) disorders of the motility or spasms of respiratory, genito-urinary, gastro-intestinal including biliary or vascular structures and organs;

(p) post-operative fever;

(q) for the treatment and prévention of cardiovascular diseases such as for example high blood pressure and related corn plaints;

(r) for the treatment and prévention of arteriosclerosis and related complaints;

(s) for the treatment and prévention of cancer and related complaints;

(t) for the treatment and prévention of diseases of the genito-urinary tract such as for example urinary incontinence and related complaints, benign prostatic hyperplasia and hyperactive bladder, nephritis, cystitis (interstîtial cystitis);

(u) for the treatment and prévention of morbid obesity and related complaints.

The substances are suitable for causal treatment in the sense of slowing down or stopping the progress of chrontcally progressive diseases, particularly osteoarthritis, rheumatoîd arthritis and spondylarthritis. yA “17•l •i ln another aspect the présent invention encompasses the use of the compounds of the above-mentioned general formula I according to the invention for preparing a médicament for therapeutic use in the above-mentioned indications.

ί 5 l Preferably, the compounds of general formula I according to the invention are used for the j treatment of osteoarthritis, rheumatoid arthritis or COPD.

H i

Preferably the novel compounds of general formula 1 are also used for the treatment of w inflammatory diseases of the skin, such as for example allergie and non-allergie dermatitis, atopie dermatitis, psoriasis, bums, sunburn, bacterial inflammations, irritations and inflammations triggered by chemical or natural substances (plants, insects, insect bites) or itching.

The term treatment or therapy refers to a therapeutic treatment of patients with a manifest, acute or chronic indication, including on the one hand symptomatic (palliative) treatment to relieve the symptoms of the disease and on the other hand causal or curative

J ί treatment of the indication with the aim of ending the pathological condition, reducing the severity of the pathological condition or delaying the progression of the pathological condition, depending on the nature or gravity of the indication.

The présent invention further relates to the use of a compound of general formula I for preparing a médicament for the acute and prophylactic treatment of acute pain, viscéral pain, neuropathie pain, inflammatory / pain receptor-mediated pain, tumour pain, headache pain and pain of mixed causes and other diseases as mentioned above. This use is characterised in that it comprises administering an effective amount of a compound of general formula I or a physiologically acceptable sait thereof to a patient requiring such treatment.

The term patient preferably refers to a human being.

ln addition to their suitability as therapeutic drugs for humans, these substances are also useful in the veterinary medical treatment of domestic pets, exotic animais and farmed animais.

ί !

i ?

t

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The présent invention further relates to médicaments containing at least one novel compound of general formula I and optionally suitable additives and/or adjuvants and/or optionally other active substances.

The dosage required to achieve a pain-relieving effect varies depending on the weight of the patient, the method of administration, the indication and severity of the complaint. Normally, the amount of active substance to be given is 0.01 to 3 mg/kg body weight, preferably 0.1 to 1 mg/kg, when administered intravenously, and 0.1 to 8 mg/kg body weight, preferably 0.5 to 3 mg/kg, when administered orally, in each case once to three times a day.

The médicaments according to the invention optionally contain, in addition to at least one compound of general formula I according to the invention, suitable inert additives and/or adjuvants, such as for example carrier materials, fillers, solvents, dîluents, colourings and/or binders. They may be given as liquid medicines in the form of injectable solutions, drops or syrups, as semi-solid préparations in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aérosols.

The compounds prepared according to the invention may be administered by intravenous, subcutaneous, intramuscular, intrarectal or intranasal route, by inhalation, by transdermal or oral route, perorally, parenterally, intradermaîly, by mouth, rectally or topically, for example to the skin, mucous membranes or into the eyes, while aérosol formulations are particularly suitable for inhalation. They may optionally be incorporated, together with one or more inert conventional carriers and/or dîluents, e.g. with maize starch, lactose, glucose, microcrystalline cellulose, magnésium stéarate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearylalcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic préparations such as tablets, coated tablets, capsules, granules, drops, élixirs, syrups, powders, suspensions, solutions, metered-dose aérosols or suppositories. W

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COMBINATIONS ί^! [ For treating pain, it may be advantageous to combine the compounds according to the

I invention with stimulating substances such as caffeine or other pain-alleviating active ; 5 compounds. If active compounds suitable for treating the cause of the pain are available, : these can be combined with the compounds according to the invention.

ï

The following compounds may be used for combination therapy, for example:

ΐ io Non-steroidal antirheumatics (NSAR) such as for example propionic acid dérivatives î' which may be selected from among alminoprofen, bucloxic acid, carprofen, fenoprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, pirprofen, pranoprofen and tiaprofenic acid; acetic acid dérivatives which may be selected from among indomethacin, acemetacin, alclofenac, isoxepac, sulindac and tolmetin; fenamic dérivatives which may be selected from among meclofenamic acid, mefenamic acid and tolfenamic acid; biphenyl-carboxylic acid dérivatives; oxicams which may be selected from among meloxicam, piroxicam and tenoxicam; salicylic acid dérivatives which may be selected from among acetylsalicylic and sulphasalazine; pyrazolones which may be selected from among apazone and feprazone; and coxibs which may be selected from among celecoxib and etoricoxib.

Opiate receptor agonists which may for example be selected from among morphine, ί Darvon, tramadol and buprénorphine;

;

Cannabinoid agonists such as for example GW-1000;

Sodium channel blockers which may for example be selected from among carbamazepine, mexiletin, pregabalin, tectin and ralfinamide.

N-type calcium channel blockers such as for example ziconotide.

Serotonergic and noradrenergic modulators which may be selected from among for example duloxetine and amitriptyline

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Corticosteroids which may be selected from among for example betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, méthylprednisolone, prednisolone, prednisone and triamcinolone.

Histamine H1-receptor antagonïsts which may for example be selected from among bromopheniramine, chloropheniramine, dexchloropheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, promethazlne, trimeprazine azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine.

Leukotrrene antagoniste and 5-iipoxygenase inhibitors which may for example be selected from among zafirlukast, montelukast, pranlukast and zileuton.

Local anaesthetics which may for example be selected from among ambroxol and lidocaine.

TRVP1 antagonïsts which may for example be selected from among AZD-1386, JTS-653 and PHE-377.

Nicotine receptor agonists such as for example A-366833.

P2X3-receptor antagoniste such as e.g. A-317491.

anti-NGF antibodies and NGF antagonïsts which may for example be selected from among JNJ-42160443 and PPH 207.

NK1 and NK2 antagonïsts such as e.g. CP-728663.

NMDA antagoniste which may for example be selected from among CNS-5161, A2-756 and V-3381.

Potassium channel modulators such as e.g. CL-888.

GABA modulators such as e.g. baclofen.

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Anti-migraine drugs such as e.g. sumatriptan, zolmitriptan, naratriptan and eietriptan.

For treating one or more of the above-mentioned respîratory complaints it may be advantageous to combine the compounds of general formula I according to the invention with other active substances for treating respîratory complaints. If suitable active substances for treating the cause of the respîratory complaints are available, these may be combined with the compounds according to the invention.

The compounds of general formula hmay optionally also be used in conjunction with other pharmacologically active substances. It is préférable to use active substances of the type selected from among the betamimetîcs, antîcholinergics, corticosteroids, PDE4-inhibitors, LTD4-receptor antagoniste, inhibîtors of MAP kinases, EGFR-inhibitors, H1-receptor antagoniste, H4-receptor antagonîsts, PAF-antagonists, PI3-kînase inhibîtors, CXCR1 and/or CXCR2 receptor antagonîsts and anti-tussives.

Betamimetîcs used according to the invention are preferably compounds selected from among arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenaline, ibuterol, isoetharin, isoprénaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, milveterol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, soterenol, sulphonterol, terbutalin, tîaramide, tolubuterol and zinterol or • 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}4H-benzo[1,4]oxazin-3-one, • 8-{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylaniino]-1-hydroxy-ethyl}-6-hydroxy4H-benzo[1,4]oxazin-3-one, • 8-{2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy4H-benzo[1,4]oxazin-3-one, • 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy4H-benzo[1,4]oxazin-3-one, • 8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy4H-benzo[1,4]oxazin-3-one, • N-(5-{2-[3-(4,4-diethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1 -dimethyl-propylaminoj1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide, s\/

-2216324 • N-(5-{2-[3-(4,4-diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1_I1-dimethylpropylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide, • N-(5-{2-[3-(4,4-diethyl-6-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethylpropylam ino]-1 -hyd roxy-ethyl}-2-hydroxy-pheny I )-metha nesulphonam ide, • N-(5-{2-[1J-dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-yl)-propylamino]1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide, • 8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1 -hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, • 8-{2-[1, 1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1 -yl)-propylamino]-

1- hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, • 8-{2-[1,1 -d imethyl-3-(2-oxo-5-trifl uoromethyl-2,3-d ihydro-benzi mid azol-1 -yl )propy(amino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, • 8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-pfopylamino]-

-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, • N-[2-hydroxy-5-(( 1 R)-1 -hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]ethylamino}-ethyl)-phenyl]-formamide, • 8-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-y!amino)-phenylJethylamino}-eth yl )-1 H-q ui nolin-2-one, • 8-hydroxy-5-[(1 R)-1-hydroxy-2-(6-phenethy!amino-hexylamino)-ethyl]-1 H-quinolin-2one, • 5-[(1R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-

-hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one, • [3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}butyl)-5-methyl-phenyl]-urea, • 4-((1 R)-2-[6-[2-(2,6-dich[oro-benzyloxy)-ethQxy]-hexylamino}-1 -hydroxy-ethyl)-

2- hydroxymethyl-phenol, • 3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethyiamino]-hexyloxy}butyl)-benzenesulphonamide, • 3-(3-{7-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylaniino]-heptyloxy}propyl)-benzenesulphonamide, • 4-((1 R)-2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylami no}-1 -hydroxyethyl)-2-hydroxymethyl-phenol,

-2316324 • N-1-Adamantanyl-2-(3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide, • (1R)-5-{2-[6-(2,2-difluoro-2-phenyl-ethoxy)-hexylannino]-1-hydroxy-ethyl}-8-hydroxy1H-quinolin-2-one • ( R, S )-4-(2-((6-(2,2-d ifluoro-4-phenylbutoxy )hexyl]amino}-1 -hyd roxy-ethyl )-2-(hydroxylmethyl)phenol, • (R,S)-4-(2-([6-(2_J2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxylmethyl)phenol, • (R,S)-4-(2-([4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxylmethyl)phenol, • (R, S )-4-(2-((6-(4,4-d if luoro-4-phenylbutoxy )hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxylmethyl)phenol, • (R,S)-5-(2-([6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8hydroxyquinolin-2(1 H)-one, • (R,S)-[2-((6-[2,2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1- hydroxyethyl]-

2-(hydroxymethyl)phenoi, • 4-(1R)-2-([6-(2,2-difluoro-2-phenylethoxy)hexy]]amino}-1-hydroxyethyî)-2-(hydroxylmethyl)phenol, • (R,S)-2-(hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5l5-tetrafluoro-6-(3-phenylpropoxy)hexyl]amino}ethyl)phenol, • (R,S)-[5-(2-([6-(2,2-difluoro-2-phenylethoxy)hexyl]annino}-1-hydroxy-ethyl)-2-hydroxyphenyljformamide, • (R,S)-4-[2-((6-[2-(3-bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-

2-(hyd roxymeth yl Jphenol, • (R, S)-N-[3-( 1,1 -difluoro-2-([6-((2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl)ethyl}a m ino)hexyl]oxy}ethyl )phenyl]-urea, • 3-(3-(1,1-difluoro-2-{[6-((2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyljethyl}am îno )hexyl]oxy}ethyl )phenyl]im idazol id in-2,4-d ione, • (R,S)-4-[2-((6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-

2-(hydroxymethyl)phenol, • 5-((1R)-2-([6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydrDxyethyl)-8hydroxyquinolin-2(1H)-one,

-2416324 • 4-((1 R)-2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxyl- methyl)phenol, • (R,S)-4-(2-{[6-(3,3-difluoro-3-phenylpropoxy)hexyl]amino}-1 -hydroxy-ethyl)-2(hydroxyl methyl )phenol, î 5 · (R,SX2-{[6-(2,2-difluoro-2-phenyIethoxy)-4,4-difluorohexyl]amîno}-1-hydroxyethyl)| 2-(hydroxymethyl)phenol,

O · (R,S)-4-(2-{[6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxyl| methyl)phenoi, ί · 3-[2-(3-chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2“[2-(4-hydroxy-2-oxo-2,3io dih yd ro-benzoth iazole-7-yl)-ethylam ino]-ethyl}-propiona m ide, | · N-(2-d iethylami no-ethyl )-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazole-7-yl )i ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide, • 7-[2-(2-{3-[2-(2-chloro-phenyl)-ethylamino]-propylsulphanyl}-ethylamino)-1-hydroxyethyl]-4-hydroxy-3H-benzothiazol-2-one, optionally in the form of their racemates, enantiomers, dîastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvatés or hydrates thereof. Preferably, according to the invention, the acid addition salts of the betamimetics are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate ! and hydro-p-toluenesulphonate.

Anticholinergics used according to the invention are preferably compounds selected from among the tiotropium salts, preferably the bromide sait, oxitropium salts, preferably the bromide sait, flutropium salts, preferably the bromide sait, Ipratropiumsalzen, preferably the bromide sait, aclidinium salts, preferably the bromide sait, glycopyrronium salts, preferably the bromide sait, trospium salts, preferably the chloride sait, tolterodine, (3 R)-1 -phenethyl-3-(9H-xanthene-9-carbonyloxy)-1 -azoniabicyclo [2.2.2]octane salts. In the above-mentioned salts the cations are the pharmacologically active constituents. As anions X the above-mentioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while the chloride, bromide,

-2516324 iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counterîons. Of ail the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.

Other anticholinergics may be selected from among • tropenol 2,2-diphenylpropionate-methobromide, scopine 2,2-diphenylpropionate-methobromide, scopîne 2-fluoro-2,2-diphenylacetate methobromide, tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol 3,3',4,4‘-tetrafluorobenzilate methobromide, scopine 3,3',4,4'-tetrafluorobenzilate methobromide, tropenol 4,4'-difluorobenzilate methobromide, scopine 4,4'-difluorobenzilate methobromide, tropenol 3,3-difluorobenzilate methobromide, scopine 3,3'-difluorobenzilate methobromide, tropenol 9-hydroxy-fluorene-9-carboxylate methobromide, tropenol 9-fluoro-fluorene-9-carboxylate methobromide, scopine 9-hydroxy-fluorene-9-carboxyiate methobromide, scopine 9-fluoro-fluorene-9-carboxylate methobromide, tropenol 9-methyl-fluorene-9-carboxylate methobromide, scopine 9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropine benzilate methobromide, cyclopropyltropine 2,2-diphenylpropionate methobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropine 9-methyl-xanthene-9- carboxylate methobromide, cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide, cyclopropyltropine methyl 4,4'-difluorobenzilate methobromide, tropenol 9-hydroxy-xanthene-9-carboxylate methobromide, scopine 9-hydroxy-xanthene-9-carboxylate methobromide, tropenol 9-methyl-xanthene-9-carboxylate methobromide, scopine 9-methyl-xanthene-9-carboxylate methobromide, tropenol 9-ethyl-xanthene-9-carboxylate methobromide, tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide, and <|\Λ~

-2616324 i

• scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide.

Corticosteroids used according to the invention are preferably compounds selected from among beciomethasone betamethasone, budesonide, butixocort, ciclesonide, deflazacort, 5 dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone and tipredane orpregna-1,4-diene3,20-dione, 6-f luoro-11-hydroxy-16,17-[(1-methylethylidene)-bis(oxy)]-21-[[4[(nitroxy)methyl]benzoyl]oxy], (6-alpha,11-beta,16-alpha)-(9CI) (NCX-1024) • 16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-ene-3-one (RPR-106541), • (S)-fluoromethyl 6,9^ίΑυοΓθ-17-[(2-ίυΓ3ηνΙθ3^οηνΙ)οχν]-11-ίΊνάΓθχν-16-ηπβίΐΊνΙ-3-οχοandrosta-1,4-diene-17-carbothionate, • (S)-(2-oxo-tetrahydrofuran-3S-yl) 6,9-difluoro-11 -hydroxy-16-methyl-3-oxo-17propionyloxy-androsta-1,4-diene-17-carbothionate, and · cyanomethyl 6-alpha,9-a!pha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha(2,2,3,3-tetramethylcyciopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxylate, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of the salts and dérivatives thereof, the solvatés and/or hydrates thereof. Every so reference to steroids includes a reference to any salts or dérivatives, hydrates or solvatés thereof which may exist. Examples of possible salts and dérivatives of the steroids may be: alkali métal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acétates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates orfuroates.

PDE4-inhibitors used according to the invention are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, apremilast, arofyllin, atizoram, oglemilast and tetomilast or • 5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-quinoiine (D-4418), · N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)quinoline (D-4396 (Sch-351591 )),N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5hydroxy-indol-3-yl]glyoxylic acid amide (AWD-12-281 (GW-842470)), 9-[(2fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purin-6-amine (NCS-613),

-2716324 • 4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine (CDP-840), • N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepin-

3-yi]-4-pyridinecarboxamide (PD-168787), • 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H)pyridinone (T-440), • 2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)1(2H)-phthalazinone (T-2585), • (3-(3-cyclopentyloxy-4-nnethoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine (V-11294A), • beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole2-propanamide (CDC-801 ), • imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one, 9-ethyl-2-methoxy-7-methyl-5-propyl(D-22888) • 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl], (3S,5S)-2-piperidinone (HT-0712), • 4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyndinyl)ethyl]alpha,alpha-bis(trifluoromethyl)-benzenemethanol (L-826141 ), • N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difliJoromethoxy-3cyclopropylmethoxybenzamide, • (-)p-[(4aR*,10dS*)-9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo[s]- [1,6]naphthyndin-6-yl]-N,N-diisopropylbenzamide, • (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone, • 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N4N-2-cyano-S-methyl-isQthioureido]benzyl )-2-pyrrolidone, • cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1 -carboxylic acid], • 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, • cis[4-cyano-4-(3-cyclopropylmethoxy-4-d ifluoromethoxy phenyl )cyclohexan-1-ol], • (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, • (S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, • 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine and • 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(fert-butyl)-9H-pyrazQlQ[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvatés or hydrates thereof. Preferably, according to the invention, acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-ptoluenesulphonate.

LTD4-receptor antagoniste used according to the invention are preferably compounds selected from among montelukast, pranlukast and zafirlukast, or(E)-8-[2-[4-[4-(4fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one (MEN-91507), • 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid (MN-001), • 1-(((R)-(3-(2-(6,7-difluoro-2-quînolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2propyl)phenyl)thio)methylcyclopropane-acetic acid, • 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yf)-(E)-ethenyl)phenyl)-3-(2-(1hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid and • [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvatés or hydrates thereof. Preferably, according to the invention, acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-ptoluenesulphonate. By salts or dérivatives which the LTD4-receptor antagonists may optionally be capable of forming are meant, for example: alkali métal salts, such as for example sodium or potassium salts, alkaline earth salts, sulphobenzoates, phosphates, isonicotinates, acétates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. A

-2916324

MAP Kinase inhibitors used according to the invention are preferably compounds selected from among:

• Bentamapimod (AS-602801) • Doramapimod, • 5-carbamoylindole (SD-169), • 6-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3pyridinecarboxamide (VX-702), • alpha-[2“H2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl]-2-benzothiazoleacetonitrile (AS601245), • 9,12-epoxy-1H-dîindolo[1,2,3-fg:3’.2'.1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10carboxylic acid (CEP-1347), and • 4-[3-(4-ch lorophenyl)-5-( 1 -methyl-4-pi peridinyl )-1 H-pyrazol-4-yl]-pyri m idine (SC-409), optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvatés or hydrates thereof.

EGFR-inhibitors used according to the invention are preferably compounds selected from among cetuximab, trastuzumab, panitumumab (- ABX-EGF), Mab ICR-62, gefitinib, canertinib and erlotinib or • 4-[(3-ch loro-4-fluorophenyl )amino]-6-([4-(morpholi n-4-yl )-1 -oxo-2-b uten-1 -yl]am i no}-

7-cyclopropylmethoxy-q uinazoli ne, • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1 -oxo-2-buten-1 -yl]amino}-

7-cyclopropylmethoxy-quînazoline, • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1yl]amino}-7-cyclopropylmethoxy-quînazoline, • 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-

7-cyclopentyloxy-quinazoltne, • 4-[( 3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo2-buten-1 -y I ]a m ino}-7-cyclopropylmethoxy-q ui nazoli ne, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-

2-buten-1-yl]amîno}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, xjxX

-3016324 • 4-[(3-chioro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-

-oxo-2-buten-1 -yi]amino}-7-cyclopropylmethoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yI)-ethoxy]-

7-methoxy-quinazoline, · 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-arnino]-1 -oxo2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1yl]amino}-7-cyclopentyloxy-quinazoline, “ 4-[( R)-( 1 -phenyl-ethyl )a mino]-6-{[4-(N, N-bis-(2-methoxy-ethyl )-am ino)-1 -oxo-2-butenio 1-yl]amino}-7-cyclopropylmethoxy-quinazoline, • 4-[(R)-( 1 -phenyl-ethyl )am ino]-6-({4-[N-(2-methoxy-ethyl )-N-ethyl-a m i no]-1 -oxo2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, • 4-[( R)-( 1 -phen yl-ethyl )amino]-6-({4-[N-(2-methoxy-ethyl)-N-rri ethyl-a m i no]-1 -oxo2-buten-1 -y l}a m ino )-7-cyclopropylmethoxy-q uinazoli ne, · 4-[( R)-( 1 -phenyl-ethyl )amino]-6-((4-[N-(tetrahyd ropyra n-4-yl)~N-methyl-a m i no]-1 -oxo2-buten-1 -yl}amino)-7-cyclopr opylmethoxy-q ui nazo Ii ne.

• 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylaniino)-1 -oxo-2-buten-1 yl]amino)-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline, • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dinnethylamino)-1 -oxo-2-buten-1 - yl]amino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, • 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, • 4-[(3-chloro-4-f I uoro phenyl )a mino]-6-{[4-(N-cyclopropyl-N-methyl-a m ino)-1 -oxo-2buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, · 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, • 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, · 4-[(3-chloro-4-fluorophenyi)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbQnyl)amino]-quinazoline, • 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, ιψΖ

-31 16324 • 3-cyano-4-[( 3-chloro-4-fluorophenyl)am ino]-6-{[4-( N, N-di m ethylamino)-1 -oxo-2-b uten1-yl]amino}-7-ethoxy-quinoline, • 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino)-6-(5-{[(2-methanesulphonylethyl)amino]methyt}-furan-2-yl)quinazoline, s · 4-[(R)-(1 -phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1 -oxo-2-buten1-yl]amino}-7-methoxy-quinazoline, • 4-[(3-ch loro-4-f luorophenyl )am ino]-6-{[4-(morpholi π-4-yl )-1 -oxo-2-buten-1 -y l]a m ino}7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, • 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo- io 2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, • 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten1-yl]amino}-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]7-methoxy-quinazoline, · 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-

6- [(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, • 4-[(3-chioro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]- ethoxy}-7-methoxy-quinazoiine, • 4-[(3-chloro-4-fluoro-phenyl)aminoj-6-[1-(/ert-butyloxycarbonyf)-piperidin-4-yloxy]-

7- methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxyquinazoline, * 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan1-yloxy)-7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxyquinazoline, • 4-[(3-chloro-4-fluoro-phenyÎ)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy- quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}7-methoxy-quinazoline, -Ά

-3216324 • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-pheny!)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]7-methoxy-qulnazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-qu)nazoline, • 4-[(3-chloro-4-fluoro-pheny[)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxyquinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amïno]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamirio]cyclohexan-1-yloxy}-7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyi)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]cyclohexan-1-yloxy}-7-methoxy-quinazoline, • 4-[(3-ch]oro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]cyclohexan-1-yloxy}-7-methoxy-quinazoline, • 4-[(3-chloro-4-fIuoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylarninoethoxy)-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2methanesulphonylamino-ethoxy)-quinazoline, • 4-[(3-chloro-4-fluoro-phenyt)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}7-methoxy-quînazoline, • 4-[(3-chloro-4-fluoro-phenyl)amÎno]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amlno]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]N-methyl-amino}-cyclohexan-1-yîoxy)-7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cÎs-4-{N-[(morpholin-4-yl)carbonyl]-N-ni ethylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-pheny[)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-rnethyla m i no}-cyclohexa n-1 -yloxy)-7-methoxy-q u inazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1yloxy)-7-methoxy-quinazoline, £

-3316324 • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7ethoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2methoxy-ethoxy)-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]7-(2-methoxy-ethoxy)-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7methoxy-quinazoline, • 4-[(3-ethynyl-phenyl)amino]-6-[1-( tert-butyloxycarbonyl )-piperidin-4-yloxy]-7-methoxyquinazoline, • 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, • 4-[(3-chlo ro-4-f luoro-phenyl )a mino]-6-( cis-4-{N-[(pipe rid in-1 -yl )carbonyl]-N-methylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoljne, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, • 4-[( 3-chloro-4-f luoro-phenyl )amino]-6-{cis-4-[(morpholin-4-yl)carbonyla mi no]cyclohexan-1-yloxy}-7-methoxy-quinazoline, • 4-[(3-chloro-4-f!uoro-phenyÎ)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4yloxy}-7-methoxy-quinazoline, • 4-[(3-chloro-4-f[uoro-phenyl)amino]-6-{1-[(morpholîn-4-yl)carbonyl]-piperïdin-4-yloxy}-

7-(2-methoxy-ethoxy)-q uinazol ine, • 4-[(3-ethynyl-phenyl)amino]-6-(1-acety[-piperidin-4-yloxy)-7-methoxy-quinazoline, • 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-q uinazol ine, • 4-[(3-ethynyl-phen yl )a m ino]-6-( 1 -methanesu I phonyl-piperid i n-4-yloxy)-7-m ethoxyquinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxyethoxy)-q uinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]cyclohexan-1 -yloxy}-7-methoxy-quinazoline, ar/’”'

-3416324 • 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, • 4-[(3-ethynyl-pheny[)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxyquinazoline, • 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperïdin-4-yloxy)-

7-methoxy-quinazolîne, • 4-[(3-chloro-4-fluoro-phenyi)aniino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]piperidin-4-yloxy]-7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-pheny[)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-

4-yloxy}-7-rnethoxy-quinazoline, io · 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]’pipe rid in-4-yloxy}-7-methoxy-q uinazoli ne, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-[(N-rriethyl-N-2-rriethoxyethyl- amino )carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, • 4-[(3-ch)oro-4-fluoro-phenyl)amino]-6-( 1 -ethyl-piperidin-4-yloxy)-7-methoxy- quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)aminoj-6’{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-

4-yloxy}-7-methoxy-quinazoline, · ^[(S-chloro-A-fluoro-phenylJaminol-ericis-A-ÎN-methanesulphonyl-N-methyl-amino)cyclohexan-1-yloxy]’7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-rnethyl-amino)-cyclohexan1-yloxy]-7-methoxy-quinazoline, • 4-[(3-chloro-4“f[uoro-phenyl)amino]-6-(trans-4-rnethylamino-cyclohexan-1-yloxy)-

7-methoxy-quinazoline, • 4-[(3-chloro-4-f(uoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)cyclohexan-1-yloxy]-7-methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)7-methoxy-quinazoline, · 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methylamîno}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, • 4-[(3-chloro-4-fiuoro-phenyl)aminoj-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]7-[(S)-(telrahydrofuran-2-yl)methoxy]-quinazoline,

-3516324 • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7methoxy-quinazoline, • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxyquinazoline, · 3-cyano-4-[(3-chloro-4-fluorophenyl)arnino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten1 -yl]a m ino}-7-ethoxy-quinoline;

• [4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, • 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]w piperazin-1 -yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline, • 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]6-[(vinylcarbonyl)amino]-quinazoline, • 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]6-[(vinylcarbonyl)amino]-quinazoline, · 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]6-[(vinylcarbonyl)amino]-quînazoline, and • 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N-[(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form ofthe pharmacologicallyacceptable acid addition salts, solvatés and/or hydrates thereof. Preferably, according to the invention, acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-ptoluenesulphonate.

Histamine H1 receptor antagonists used according to the invention are preferably compounds selected from among epinastin, cetirizin, azelastin, fexofenadin, levocabastin, 30 loratadine, mizolastin, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, olopatadine, desloratldine and meclozine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the

-3616324 form of the pharmacologically acceptable acid addition salts, solvatés or hydrates thereof. Preferably, according to the invention, the acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosuIphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-ptoluenesulphonate.

Histamine H4 receptor antagonists used according to the invention are preferably compounds such as for example (5-chloro-1H-indol-2-yl)-(4-methyl-1-piperazinyl)methanone (JNJ-7777120), optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvatés or hydrates thereof. Preferably, according to the invention, acid addition salts selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate are used.

PAF-antagonists used according to the invention are preferably compounds selected from among lexipafantand the compounds • 4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]- [1,2,4]triazolo[4,3-a][1,4]diazepine and • 6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclopenta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazeptne, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvatés or hydrates thereof. Preferably, according to the invention, the acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-ptoluenesulphonate.

PI3-Kinase inhibitors used according to the invention are preferably compounds selected from among • 5-(quinoxalin-6-ylmethylene)thiazolidine-2,4-dione (AS-605240), x/

-3716324 • 2-[(6-amino-9H-purin-9-yl)methyî]-5-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone (C-87114)and • 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1yl]phenyl]propîonitrile (BEZ-235), optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvatés or hydrates thereof.

CXCR1 or CXCR2 antagonists used according to the invention are preferably compounds selected from among 3-[[3-[(dimethylamino)carbonyl]-2hydroxyphenyl]amino]-4-[[(R)-1-(5-methylfuran-2-yl)propyl]amino]cyclobut-3-ene-1,2-dione (SCH-527123), optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvatés or hydrates thereof.

Antitussive substances used according to the invention are preferably compounds selected from among hydrocodone, caramiphen, carbetapentane and dextramethorphane, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvatés or hydrates thereof.

For treating inflammatory and/or oedematous diseases of the skin and mucous membranes the compounds of general formula I according to the invention may be combined for example with substances selected from among méthotrexate, cyclosporin, topical steroids, topical calcineurin inhibitors, vitamin D analogues, fumurates, PDE4inhibitors and TNF-antagonists, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvatés or hydrates thereof.

Calcineurin inhibitors used according to the invention are preferably compounds selected from among tacrolimus and pimecrolimus.

A vitamin D analogue preferably used according to the invention is calcipotriol

-3816324

A fumurate preferably used according to the invention is BG 12 (oral fumurate).

TNF-antagonists used according to the invention are preferably compounds selected from among etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira).

The dosage necessary for obtaîning a pain-alteviating effect is, in the case of intravenous administration, expediently from 0.01 to 3 mg/kg of body weight, preferably from 0.1 to 1 mg/kg, and, in the case of oral administration, from 0.1 to 8 mg/kg of body weight, preferably from 0.5 to 3 mg/kg, in each case once, twice or three times per day. The compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, aérosol formulations being particularly suitable for inhalation. They can be incorporated into customary pharmaceutical préparations, such as tablets, coated tablets, capsules, powders, suspensions, solutions, metered-dose aérosols or suppositories, if appropriate together with one or more customary inert carriers and/or dîluents, for example with maize starch, lactose, cane sugar, microcrystalline cellulose, magnésium stéarate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/giycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances, such as hardened fat, or suitable mixtures thereof.

EXPERIMENTAL SECTION

Generally, there are mass spectra and/or ¹H NMR spectre for the compounds that hâve been prepared. The ratios given for the eluants are in volume units of the solvents in question. For ammonia, the given volume units are based on a concentrated solution of ammonia in water. Unless indicated otherwise, the acid, base and sait solutions used for working up the reaction solutions are aqueous Systems having the stated concentrations.

For chromatographie purification, silica gel from Millipore (MATREX™, 35 to 70 pm) or Alox (E. Merck, Darmstadt, Aiumina 90 standardized, 63 to 200 pm, article No. 1.01097.9050) is used.

In the descriptions of the experiments, the following abbreviations are used:

-3916324

TLC	thin layer chromatograph
DIPEA	dîisopropylethylamine
DMA	N./V-dimethylacetamide
DMAP	4-di m ethyla minopyridine
DMF	Ν,Λί-dimethylformamide
DMSO	dimethylsulphoxide
HATU	O-(7-azabenzotriazol-1-yl)-A/,/V,/V',A/'-tetramethyluronium hexafluorophosphate
Pd₂(dba)₃ RP	tris(dibenzylideneacetone)-dipalladium(0) reverse phase
Rt	rétention time
tert	tertiary
TBTU	2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate
TEA	triethylamine
THF	tetra hydrofuran
XPhos	2-dicyclohexyl-phosphino-2’.4’.6’-tri-isopropyl-1, T-biphenyl

The following analytical HPLC methods were used:

Method 1 : Column:

Eluant A:

Eluant B:

Merck Cromolith Flash RP18e, 4.6 x 25 mm water / 0.1% formîc acid acetonitrile / 0.1 % formîc acid

Gradient:

time în min	%A	%B	flow rate in mL/min
0.0	90.0	10.0	1.6
2.7	10.0	90.0	1.6
3.0	10.0	90.0	1.6
3.3	90.0	10.0	1.6

-40Method 2: Column:

Eluant A:

Eluant B:

Waters, Sunfire C18, 4.6 x 30 mm; 3.5 pm water /0.1 % trifluoroacetic acid methanol / 0.1% trifluoroacetic acid

Température: 60°C

Gradient

time in min	%A	%B	flow rate in mL/min
0.0	95	5	4.0
0.15	95	5	4.0
1.7	0	100	4.0
2.25	0	100	4.0

Method 3: Column:

Eluant A:

Eluant B:

Waters, Xbridge, C18, 4.6 x 30 mm; 3.5 pm water /0.1% trifluoroacetic acid methanol / 0.1% trifluoroacetic acid

Température; 60°C

Gradient:

Method 4: Column:

Agilent, StableBond, C18, 3 x 30 mm; 1.8 pm

Eluant A: water / 0.1 % trifluoroacetic acid

Eluant B: acetonitrile

Température; 60°C

Gradient:

time in min	%A	%B	flow rate in mL/min
0.0	95	5	2.2
0.05	95	5	2.2
1.40	0	100	2.2
1.80	0	100	2.2

-41 16324

Préparation of the end compounds

Example 1 (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid- {3-[2-fluoro-4-(4-methoxy-2trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide

CF₃

1a) 2-fluoro-4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzonitrile

2-Amino-5-methoxy-benzotrifluoride (10.46 mmol), K,_;PO₄ (15.7 mmol), Xphos (1.05 mmol) and Pd₄(dba)₃ (0.314 mmol) were added under nitrogen to a solution of 4bromo-2-fluoro-benzonitrile (10.46 mmol) in 50 mL toluene and the mixture was stirred for 20 hours at a bath température of 110°C. Then the mixture was filtered through a glass fibre filter, then the filtrate was extracted with 150 mL water. The organic phase was dried on sodium sulphate and evaporated down. In this way the product was obtained in a yield of 87% of theory.

C₁₅H_1QF₄N₂O (310.2)

Mass spectrum (ESI): [M+HJ+ = 311 [M-H]- = 309

Thin layer chromatograph (silica gel; petroleum ether / ethyl acetate 7 : 3):

R_f = 0.48

1b) 2-fluoro-4-(4-methoxy-2-trifluoromethyl-phenylamino)-l

J	0			Cl.	ex
A			T			T
		H	cf₃			cf₃

2-fluoro-4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzonitrile (2.85 g, 9.19 mmol) was hydrogenated in 40 mL saturated methanolic ammonia solution after the addition of 300 mg of Raney nickel at ambient température. After the catalyst had been filtered off and the mixture evaporated down the product was obtained in a yield of 99% of theory. C₁₅H₁₄F₄N₂O ¢314.3)

Thin layer chromatograph (silica gel; dichloromethane / éthanol 19 ; 1):

R_f = 0.21

c) n-butyl (S)-3-[(6-oxo-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydrofuran-3carboxylate

A solution of 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid (10.5 g, 74.9 mmol), TBTU (25.3 g, 78.7 mmol), triethylamine (20.9 mL) and 40 mL DMF in 200 mL THF was stirred for 30 minutes at ambient température. Then π-butyl (S)-3-amino-tetrahydrofuran-3carboxylate (14.0 g, 74.9 mmol) was added and the mixture was stirred further overnight. For working up the mixture was evaporated to dryness in vacuo and the residue was stirred with 200 mL ethyl acetate. This solution was washed twice with 5% sodium hydrogen carbonate solution, then dried and evaporated down.

The product was thus obtained in a yield of 90% of theory.

C14H19N3O5 (309.3)

Thin layer chromatograph (silica gel; dichloromethane/ethanol 19:1): R_f = 0.16

1d) (S)-3-[(6-oxo-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydro-furan-325 carboxylic acid \j\X

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η-Butyl (S)-3-[(6-oxo-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydrofuran-3carboxylate (21.0 g, 67.9 mmol) was stirred vigorously in 200 mL of 1N sodium hydroxide solution for 1 hour. The mixture was then extracted twice with 100 mL of diethyl ether, the alkaline aqueous phase was then combined with 50 mL of 4N hydrochloric acid. The mixture was then evaporated to dryness and the residue was stirred with 150 mL éthanol. Undissolved ingrédients were then filtered off and the filtrate was evaporated down. In this way the product was obtained in a yield of 71% of theory. The product thus obtained was further processed without purification.

CwHnNaOs (253.2) ¹H-NMR (dg-DMSO): δ = 2.32 (m, 2H); 3.84 (t, 2H); 3.95 (d, 1H); 4.12 (d, 1H); 7.28 (s, 1H); 8.10 (s, 1H); 9.21 (broad S; 1H).

e) (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid- {3-[2-fluoro-4-(4-methoxy-2-trif I uoro methyl-phenylam ino )-benzylcarba moyl]-tetrahyd rofuran-3-yl}-a m ide

(S)-3-[(6-oxo-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (0.55 mmol) was dissolved in a mixture of 30 mL tetrahydrofuran, 4 mL DMF and 0.15 mL triethylamine, then TBTU (0.19 g, 0.58 mmol) was added and the mixture was stirred for 30 minutes at ambient température. Then 2-fluoro-4-(4-methoxy-2-trifluoromethylphenylamino)-benzylamine (0.17 g, 0.55 mMol, from 1b) was added and the mixture was stirred for a further two hours. As there was still some unreacted amine présent, another 10 mg of the acid and 20 mg TBTU were added and the mixture was stirred further ovemight. Then the solvents were evaporated off and the residue was chromatographed on silica gel (eluant: dichloromethane/methanol/ammonia: 95/510.5). In this way the product was obtained in a yield of 19% of theory. tyA”

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C₂,H_2iF₄N₅O₅ (549.5)

Mass spectrum (ESI): [M+H]+ = 550 [M-H]- = 548

Thin layer chromatograph (silica gel; dichloromethane ! methanol ! ammonia: 9/1 /0.1): R_f = 0.46

Example 2 (S)-5-amino-N-(3-[2-fluoro-4-(4-methoxy-2-trifluoroniethyl-phenylamino)benzylcarbamoyl]-tetrahydro-furan-3-yl)-nicotinamide

2a) n-Butyl (S)-3-[(5-amîno-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylate

Analogously to Example 1c), 5-aminopyridine-3-carboxylic acid (72.4 mmol) was reacted with n-butyl (S)-3-amino-tetrahydrofuran-3-carboxylate (72.4 mmol). The product was obtained in a yield of 96% of theory.

Ci₅H₂₁N₃O₄ (307.3)

Mass spectrum (ESI): [M+H]+ = 308 [M-H]- = 306

Thin layer chromatograph (silica gel; ethyl acetate / éthanol 9:1):

Rf = 0.58

2b) (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid yM

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Analogously to Example 1d), n-butyl (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]tetrahydrofuran-3-carboxylate (69.9 mmol) was saponified with sodium hydroxide solution. The product was obtained in a yield of 86% of theory.

C₁iH₁₃N₃O4 (251.2)

Mass spectrum (ESI): [M+H]+ = 252 ¹H-NMR (d₆-DMSO): δ = 2.33 (m, 2H); 3.82 (m, 2H); 5.48 (broad s, 2H); 7.27 (s, 1H); 8.03 (s, 1 H); 8.18 (s, 1H); 8.85 (s, 1H); 12.60 (broad s, 1H) ppm.

2c) (S)-5-amino-N-{3-[2-fluoro-4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-nicotinamide

Analogously to Example 1e), (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-

3-carboxylic acid (0.55 mmol) was reacted with 2-fluoro-4-(4-methoxy-2-trifluoromethylphenylamino)-benzylamine (0.55 mMol, from 1b). The product was obtained in a yield of 27% of theory.

C26H25F4N5O4 (547.5)

Mass spectrum (ESI); [M+H]+ - 548 [M-H]- = 546

HPLC: Rt= 2.44 min (method 1)

Exampïe 3 (S)-5-amino-N-( 3-{[3-fluoro-5-(4-methoxy-2-trifluoromethyl-phenyla m i no )-py rid in-2ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide

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3a) tert-butyl (5-bromo-3-fluoro-pyridin-2-ylmethyl)-carbamate

A solution of 2-aminomethyl-3-fluoro-5-bromopyridine (185 mg, 0.77 mmol) in 8 mL dichloromethane was combined with 0.32 mL triethylamine and di-terf-butyl-dicarbonate (167.2 mg, 0.77 mmol) while cooling with an ice bath and then stirred overnight at ambient température. After standard working up of the réaction mixture the product was obtaîned in a yield of 72% of theory.

C _iH₁„BrFN_?O₂ (305.14)

MS(ESI); [M+H]+= 305/7

HPLC: R,= 2.31 min (method 1)

3b) tert-butyl [3-fluoro-5-(4-methoxy-2-trifluoromethyl-phenylamjno)-pyridin-2ylmethyl]-carbamate

Analogously to Example 1a), tert-butyl (5-bromo-3-fluoro-pyridin-2-ylmethyl)-carbamate (0.55 mmol) was reacted with 4-methoxy-2-trifluoromethyl-aniline. The crude product was purified by chromatography (column: Varian PursuitXRS C18; 10 μΜ; 41.4 x 250 mm, gradient: acetonitrile / water/CF₃COOH: 10/90/0.1 -> 100/0/0.1). The product was thus obtained in a yield of 26% of theory.

C₁₉H₂₁F₄N₃O₃ (415.4) v/

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MS (ESI): [M+HJ+ = 416

HPLC: R_t= 2.77 min (method 1)

3c) (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-methoxy-2-trifluoromethyl-phenyl)-amine

cf₃ cf₃

Tert-butyl [3-fluoro-5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]carbamate (0.13 mmol) was stirred for two hours at 60°C in a mixture of 2 mL semiconcentrated hydrochloric acid and 3 mL dioxane. The mixture was then evaporated to dryness, then the residue was stirred with 3 mL toluene and evaporated down agaîn. The crude product thus obtained (89% of theory) was used further without purification. C₁₄H₁₃F₄N₃O (315.3)

MS (ESI): [M+HJ+ = 316

3d) (S)-5-amino-N-(3-{[3-fIuoro-5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridin-2ylmethyi]-carbamoyl}-tetrahydro-furan-3-y!)-nicotinamide

Analogously to Example 1e), (S]-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-

3-carboxylic acid (from 2b) was reacted with (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4methoxy-2-trîfluoromethyl-phenyl)-amine. The product was obtained in a yield of 34% of theory.

C₂₅H₂₄F₄N₆O₄ ¢548.5)

MS (ESI): [M+H]+ = 549

HPLC: R_t= 2.55 min (method 1)

Example 4

-4816324 (S)-5-amino-A/-{3-[4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]tetrahydrofuran-3-yl}-nicotinamide

Analogously to Example 1a), 4-bromobenzonitrile was reacted with 2-trifluoromethyl-4methoxy-aniline. After chromatographie purification through silica gel (petroleum ether io with 10 to 30% ethyl acetate) the 4-(4-methoxy-2-trifluoromethyi-phenylamino)benzonitrile was obtained in a yield of 60.5% of theory.

CfgHnFsNzO (292.3)

Mass spectrum (ESI): [M+H]⁺ = 293 [M-H]' = 291

4b) (4-aminomethyi-phenyl)-(4-methoxy-2-trifluoromethyl-phenyÎ)-amine

3.7 g (12.7 mmol)of 4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzonitrile were hydrogenated in a 7N solution of ammonia in methanol (100 mL)with the addition of

2o Raney nickel at ambient température. After the catalyst had been filtered off and the solvent distilled off, the crude product thus obtained was reacted further without purification,

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CîsH.sFsNjO (296 3)

4c) (S)-5-amino-/V-{3-[4-(4-methoxy-2-trifluoromethyl-phenylamjno)-benzylcarbamoyl]tetra hydrofuran-3-yl}-nicotinamide

3-carboxylic acid (1.00 mmol) was reacted with (4-aminomethyl-phenyl)-(4-methoxy-2trifluoromethyl-phenyl)-amine (1.00 mMol, from Example 4b)). The product was obtained in a yield of 32% of theory.

C₂₆H₂₆F₃N₅O₄ (529.5)

Mass spectrum (ESI): [M+H]+ = 530 [M-H]- = 528

HPLC: R_t= 0.842 min (method 4)

Thin layer chromatograph (silica gel; dichloromethane ! éthanol 9:1 + 1% NH₄OH):

R_f - 0.25

Example 5 (S)-5-amino-N-(3-{[5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]carbamoyl}-tetrahydrofuran-3-yl)-nîcotinamide

cf₃

5a) 5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile

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Analogously to Example 1a) 5-bromo-pyridine-2-carbonitrile was reacted with 2trifluoromethyl~4-methoxy-aniline. After chromatographie purification through silica gel (petroleum ether with 10 to 30% ethyl acetate) the 4-(4-ΓηβίΐΊθχν-24ηΑυοΓοηηβϋΊνΙ-ρΐΊθπνΙamino)-benzonitrile was obtained in a yield of 97.4% of theory.

Ci₄H₁₀F₃N₃O (293.2)

Mass spectrum (ESI): [M+H]⁺ = 294 [M-H]' - 292 ¹H-NMR (d_e-DMSO): δ = 3.87 (s, 3H); 6.88 (dd, 1H); 7.31 (m, 2H); 7.47 (d, 1H); (7.67 (d, 1H); 8.11 (s, 1H); 8.62 (s, 1H)ppm.

5b) (6-aminomethyl-pyridin-3-yl)-(4-methoxy-2-trifluoromethyl-phenyl)-amine

Analogously to Example 4b, 5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridine-2carbonitrile (1.71 mmol) was hydrogenated in a 7N solution of ammonia in methanol (30 mL) with the addition of Raney nickel at ambient température. After the catalyst had been filtered off and the solvent distilled off, the crude product thus obtained was further reacted without purification.

C_UH₁₄F₃N₃O (297.3)

Thin layer chromatograph (silica gel; dichloromethane ! éthanol 9 :1):

Rf = 0.11

5c) n-butyl (S)-3-[(5-fert-butoxycarbonylamino-pyridine-3-carbonyl)-amino]tetrahydrofuran-3-carboxylate

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A suspension of 5-tert-butoxycarbonylamino-pyrïdine-3-carboxylic acid (2.5 mmol) in 20 mL tetrahydrofuran was combined with N,/V-carbodiimidazole (2.75 mmol) and stirred for 15 minutes at ambient température. Then a solution of π-butyl (S)-3-aminotetrahydrofuran-3-carboxylate (2.5 mmol) in 4 mL tetrahydrofuran was added and the reaction mixture was stirred further overnight. Then the solvent was distilled off and the crude product thus obtained was purifîed by chromatography (silica gel; dichloromethane with 1-25% éthanol).

Yield: 31% of theory

CzoHzgNaOg (407.5)

Mass spectrum (ESI): [M+H]* = 408 [M-H]' = 406

5d) (S)-3-[(5-tert-butoxycarbonylamino-pyridin-3-carbonyl)-amino]-tetrahydrofuran-

3-carboxylic acid

A solution of n-butyl (S)-3-[(5-fert-butoxycarbonylamino-pyridin-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylate (29.7 mmol) in 150 mL méthanol was combined with 60 mL of 1N sodium hydroxide solution and stirred for three hours at ambient température. Then the méthanol was distilied off, the solution was then washed with 50 mL tertbutylmethylether and then adjusted to pH 3 with 4N hydrochloric acid. The product that then precipitated was filtered off and further reacted without purification.

Yield: 94% of theory

C₁₆H₂₁N₃O₆ (351.4)

Mass spectrum (ESI): [M+H]* = 352 [M-H]’ = 350

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5e) tert-butyl ($)-[5-(3-{[5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridin-2ylmethyl]-carbamoyl}-tetrahydrofuran-3-ylcarbamoyl)-pyridin-3-yl]-carbamate

CF.

Analogously to Example 1e), (S)-3-[(5-iert-butoxycarbonylamino-pyridine-3-carbonyl)amino]-tetrahydrofuran-3-carboxylic acid (product from Example 5d, 1.7 mmol) was reacted with (6-aminomethyl-pyridin-3-yl)-(4-methoxy-2-trifluoromethyl-phenyl)-amine (product from Example 5b, 1.7 mmol). The product was purified by chromatography (silica gel, dichloromethane with 0-10% methanol).

Yield: 69%oftheory

C₃₀H₃₃F₃N₆O₆ ¢630.6)

Thin layer chromatograph (silica gel; dichloromethane / éthanol 9 ; 1 ):

R_f = 0.46

5f) (S)-5-amino-A/-(3-{[5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridin-2ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide

5e tert-Butyl (S)-[5-(3-[[5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]carbamoyl}-tetrahydrofuran-3-ylcarbamoyl)-pyridin-3-yl]-carbamate (product from Example 5e, 1.2 mmol) was stirred with a 4N HCl solution in dioxane (20 mL) for two hours at ambient température. Then the mixture was evaporated to dryness, the residue was triturated with approx. 20 mL diethyl ether and suction filtered.

Yield: 82% of theory

C^H^NsCti (530.5)

Mass spectrum (ESI): [M+H]⁺ == 531

HPLC:

[M-H]’ = 529

R_t= 1.014 min (method 3)

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Example 6 (S)-5-amino-A/-(3-{[3-chloro-5-(4-methoxy-2-trifiuoromethyl-phenylamîno)-pyridin-2-yl5 methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide

6a) 3-chloro-5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridin-2-carbonitrile i i I I

5-bromo-3-chloro-pyridine-2-carbonitrîie (2.3 mmol) was reacted analogously to Example

1a) with 4-methoxy-2-trifluoroanîline (2.3 mmol). After chromatographie purification through silica gel (petroleum ether with 15 to 30% ethyl acetate) the product was obtained în a yield of 27% of theory.

C₁₄H₉CIF₃N₃O (327.7)

Mass spectrum (ESI): [M+H]⁺ = 328 [Μ-H]' = 326

HPLC; R_t= 1.558 min (method 2)

6b) (6-aminomethyl-5-chloro-pyridin-3-yl)-(4-methoxy-2-trîfluoromethyl-phenyl)-amine

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A solution of 3-chloro-5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile (0.64 mmol) în 10 mL éthanol and 0.1 mL hydrochloric acid (37%) was combined with 30 mg of Pd/charcoal (10%) and hydrogenated with stirring at ambient température. Then the catalyst was filtered off and the solution was evaporated down. The product thus obtained was reacted further without purification.

Yield: 99% of theory

C_UH₁₃CIF₃N₃O (331.7)

HPLC: R_t= 1.167 min (method 2)

6c) (S)-5-amino-/V-(3-{[3-chloro-5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridin2-ylmethyl]-carbamoyl)-tetrahydrofuran-3-yl)-nicotinamide

H,N'

CH.

CF.

Analogousiy to Example 1e), (6-aminomethyl-5-chloro-pyridîn-3-yl)-(4-methoxy-2trifluoromethyl-phenyl)-amine (1.3 mmol) was reacted with (S)-3-[(5-amino-pyridin-3carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (product from Example 2b, 1.3 mmol). After chromatographie purification (silica gel, dichloromethane/methanol 9:1 with 3-8% ammonia) the product was obtained in a yield of 13% of theory.

C_2SH₂₄CIF₃N₆O₄ (564.9) ¹H-NMR (dg-DMSO): δ = 2.27-2.46 (m, 2H); 3.78 - 3.88 (m, 2H); 3.85 (s, 3H); 3.94 (m, 1H); 4.23 (m, 1H); 4.24-4.38 (m, 2H); 5.49 (m 2H); 6.97 (d, 1H); 7.27-7.31(m, 3H); 7.35-7.41 (m, 1H); 7.85 (d, 2H); 7.95 (m, 1H); 8.04 (d, 1H); 8.23 (s, 1H); 8.80 (s, 1H) ppm.

The following Examples describe pharmaceutical formulations which contain as active substance any desired compound of general formula I, without however restricting the scope of the présent invention thereto:

-5516324

Example I

Dry ampoule with 75 mg of active compound per 10 ml

Composition:

Active compound Mannitol	75.0 mg 500 mg
Water for injection	ad 10.0 ml

Production:

Active compound and mannitol are dissolved in water. The charged ampoules are freeze dried. Water for injection is used to dissolve to give the solution ready for use.

Example II

Tablet with 50 mg of active compound

Composition:

(1) Active compound	50.0 mg
(2) Lactose	98.0 mg
(3) Maize starch	50.0 mg
(4) Polyvinylpyrrolidone	15.0 mg
(5) Magnésium stéarate	2.0 mg
	215.0 mg

Production:

(1 ), (2) and (3) are mixed and granulaîed with an aqueous solution of (4). (5) is admixed to the dry granules. Tablets are compressed from this mixture, biplanar with a bevel on both sides and dividing groove on one side.

Diameter of the tablets: 9 mm.

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Example III

Tablet with 350 mg of active compound

Composition:

(1) Active compound (2) Lactose (3) Maize starch (4) Polyvinylpyrrolidone

350.0 mg

136.0 mg

80.0 mg

30.0 mg (5) Magnésium stéarate______________4.0 mg

600.0 mg

Production:

(1 ), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is admixed to the dry granules. Tablets are compressed from this mixture, biplanar with a bevel on both sides and dividing groove on one side.

Diameter of the tablets: 12 mm.

Example IV

Capsule with 50 mg of active compound

Composition:

(1) Active compound 50.0mg (2) Maize starch dried 58.0mg (3) Lactose powdered 50.0mg (4) Magnésium stéarate 2.0mg

160.0 mg

Production:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.

This powder mixture is packed into hard gélatine two-piece capsules of size 3 in a capsule-fillîng machine. xjA”

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Example V

Capsules with 350 mg of active compound

Composition; (1) Active compound (2) Maize starch dried (3) Lactose powdered (4) Magnésium stéarate

350.0 mg 46.0 mg 30.0 mg 4.0 mg 430.0 mg

Production:

(1 ) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous stirring.

This powder mixture is packed into hard gélatine two-piece capsules of size 0 in a capsule-filiing machine.

Example VI

Suppositories with 100 mg of active compound suppository comprises:

Active compound

Polyethylene glycol (M.W. 1500)

Polyethylene glycol (M.W. 6000)

Polyethylene sorbitan monostearate

100.0 mg

600.0 mg

460.0 mg

840.0 mg

2000.0 mg

Claims

Patent Claims

1. Compounds of general formula I

R² dénotés H, Cl or F and

X dénotés CH or N, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
2. Compounds of general formula la cf₃ , (la) wherein dénotés H, Cl or F and

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X dénotés CH or N, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
3. Compounds of general formula Ib , (Ib) wherein

R² dénotés H, Cl or F and

X dénotés CH or N, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
4. Compounds of general formula le

CF₃ .(IC) wherein

R² dénotés H, Cl or F and

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X dénotés CH or N, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganîc acids or bases.
5. Compounds of general formula Id wherein

R² dénotés H, Cl or F and

X dénotés CH or N, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganîc acids or bases.

6. The following compounds of general formula I according to claim 1 ;

No. Structure (1) o ΥΥχι._ΝχΤ“· ^H cf₃

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No. Structure .N. ί X H 0 XZN (9) O \ 7 ^H 1 J A —0 4' H cf₃ ) .Nk il U H O ,N X7 n Y <> Y CH, (W) ⁰ \ / ^H [1 Jl A —0 ^N' H cf₃ ï .N. ίί X H O xS .N. A°'CH₂ (11) ⁰ \ / ^H Y j( A —0 cr N H cf₃ 1 fi X H O XXN 'S? A°'CH₃ (12) O \ / ^H Jl ^ÿ- J[ A —O F Ή H cf₃ f ^Η3°Ύ^ΝΧ H î N_vAz N^ |4V°'^CH3 (13) 0 H Y .^A, JU X-O 'N' H cf₃ > h₃c^n H S N^ X (f^T⁰'^CH3 (14) 0 H Y AJ '-O Ci N H cf₃ ) h₃c^n H § X Y^Y°'ch₃ (15) O H Y ^A AJ O F' 'N' H cf₃ 1

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No. Structure h₃c^n H 9 n-X Ti % rX ' CH, (16) o C2 H U KJ '“O 'n H cf₃ 9 h₃c^n H ί X^N/>< N'''’'''' /X Ύ k ^x°'ch₃ (17) θ X2 H U O '—O ck X H cf₃ 9 h₃c^i< H f ^-X \.N-, A /L· Ίι k XX UHrJ (18) Ô \_z? H 1 . X ^L0 Y H cf₃ 1 «A H ? N'X' °'CH₃ (19) ô X2 ^H L AL J A 'N H cf₃ 1 HN'% H î X °'ch₃ (20) ô Ç 2 H J· A J X '—o cX 'N H cf₃ f hA H î 0 νΆ -A/ °'ch₃ (21) o \ 2 h J AL X 0 c N H cf₃ HN-% H 2 qXX'' nX k °'CH₃ (22) ο X2 h L AL J —o 'N X H cf₃ 1

7. Physiologically acceptable salts of the compounds according to one of ciaims 1, 2,

3, 4, 5 or 6 with inorganic or organic acids or bases.
8. Médicaments containing a compound according to at least one of ciaims 1,2, 3, 4, 5 or 6 or a physiologically acceptable sait according to claim 7 optionally together with one or more inert carriers and/or diluents.
9. Compound of general formula I according to one of ciaims 1, 2, 3, 4, 5, 6 or 7 for use as médicaments.
10. Compound of general formula I according to one of ciaims 1, 2, 3, 4, 5, 6, or 7 for the acute and prophylactic treatment of acute pain, viscéral pain, neuropathie pain, inflammatory / pain-receptor-mediated pain, tumour pain and headache diseases.
11. Compound of general formula I according to at least one of ciaims 1,2, 3, 4, 5, 6 or 7 for the acute and prophylactic treatment of osteoarthritis.
12. Compound of general formula 1 according to at least one of ciaims 1,2, 3, 4, 5, 6 or 7 for the acute and prophylactic treatment of asthma or chronic bronchitis or COPD.<m

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J
13. Compound of general formula f according to at least one of claims 1, 2, 3, 4, 5, 6 or 7 for the treatment of allergie and non-allergic dermatitis, atopie dermatitis, psoriasis, i burns, sunburn, bacterial inflammations, irritations and inflammations triggered by i

5 chemicals or natural substances (plants, insects, insect bites), and itching.
14. Process for preparing a médicament according to claim 8, characterised in that a compound according to at least one of claims 1, 2, 3, 4, 5, 6 or 7 is incorporated in one or more inert carriers and/or diluents by a non-chemical method. νΎ