CZ289930B6 - Aryl and heteroaryl peptide derivatives and pharmaceutical preparations in which they are comprised - Google Patents

Abstract

Disclosed are derivatives of the general formula I, in which all the substituents have specific meanings. Pharmaceutical preparations, in which these derivatives are comprised as active substances are intended for treating inflammatory diseases in mammals, caused by insufficient immunity, particularly for prevention and treatment of respiratory tract diseases.

Description

Technical field

The invention relates to aryl and heteroaryl peptide derivatives and pharmaceutical compositions containing them. Said derivatives have anti-inflammatory effects and are suitable for the treatment and prevention of diseases in mammals caused by immunodeficiency. More specifically, they are novel tryptase inhibitors useful for the prevention and treatment of inflammatory diseases of the respiratory tract, such as asthma and allergic rhinitis, advanced bronchoconstriction and airway hypersensitivity associated with chronic asthma.

BACKGROUND OF THE INVENTION

Asthma is a complex disease caused by an increase in the level of biochemical mediators. His symptoms are both acute and chronic. Asthma is often manifested by the progressive development of trachea and bronchial hypersensitivity to both immunospecific allergens and various chemical and physical stimuli. Hypersensitivity of asthmatic bronchial tissue is considered to be the result of chronic inflammatory reactions that irritate and damage the airway surface epithelium and promote pathological thickening of subsurface tissues. Bronchial biopsy studies have shown that stable patients with mild asthma have signs of inflammation on the airway walls.

One of the initiators of the inflammatory process is an allergic response to inhaled allergens. Leukocytes that carry IgE receptors, predominantly mast cells and basophils, but also monocytes, macrophages and eosinophils, are present in the epithelium and subsurface tissues of bronchial smooth muscle. There, they are activated by the binding of specific inhaled antigens to IgE receptors. Activated mast cells release a number of active or primary chemical mediators of the inflammatory response and enzymes. In addition, many secondary inflammatory mediators are produced in situ by the enzymatic reaction of activated mast cells, particularly superoxides and lipid-derived mediators. Degranulation of mast cells also produces some large molecules: proteoglycans, peroxidase, arylsulfatase B and proteases - tryptase and chymotryptic proteinase (chymase). See "Drug Therapy of Asthma", Chap. 62, 1054-54.

This release of chemicals from mast cells is probably the cause of early bronchocostriction. This reaction occurs in hypersensitive individuals after exposure to airborne allergens. Early asthmatic response is maximal 15 minutes after allergen exposure, improvement occurs in one to two hours. In 25 to 35% of cases, an early asthmatic reaction is followed by a further decrease in respiratory function, which begins within a few hours and is maximal between 6 and 12 hours after exposure. This late asthmatic reaction is accompanied by a noticeable increase in the number of inflammatory cells that penetrate the bronchial smooth muscle and epithelial tissues and emerge into the airways. These cells include eosinophils, neutrophils and lymphocytes. Cells are attracted by chemitactic agents released from mast cells. Penetrating cells are activated during the late phase of the reaction. The late asthmatic response is considered to be a secondary inflammatory response partly due to the secretory activity of macrophages.

A corresponding set of inflammatory reactions also occurs in the upper mucosa, usually in response to airborne allergens. As with asthma, mast cells are activated by cross-linking IgE molecules and specific antigens. In allergic persistent or vasomotor rhinitis, mast cells are activated even without exposure to particulate antigens. In this case too, mast cells release the primary and secondary mediators of inflammation by degranulation. Eosinophils and macrophages are attracted to the site of these processes and develop an inflammatory response. In the late phase of the reaction, destruction of nasal epithelial tissue often occurs.

Tryptase is the most important protease produced by human mast cells. It participates in the preparation of neuropeptides and tissue inflammation. Human tryptase is a glycosylated, heparin-linked tetramer. It consists of 4 heterogeneous catalytic subunits. The amino acid sequence of the tryptase monomer, as well as its gene structure, do not resemble any of the many proteases whose structure has been characterized. See Vanderslice et al. (1990) Proc. Nati. Acad. Sci. USA 87: 3811-3815; Miller et al. (1990) J. Clin. Invest. 86: 864-870; Miller et al. (1989) J. Clin. Invest. 84: 11881195; and Vanderslice et al. (1989) Biochemistry 28: 4148-4155; and Katunuma et al. (1990) Monographs in Allergy 27: 51-66.

Tryptase is stored in secretory granules of mast cells. After mast cell activation, tryptase can be easily measured in various biological fluids. For example, after anaphylaxis, tryptase appears in the bloodstream where it remains for several hours. See Schwartz et al. (1987) N. Engl. J. Med. 316: 1622-1626. Its presence was detected in fluid samples after nasal and lung lavage after exposure to a specific antigen. See Castells and Schwartz (1988) J, Allerg. Clin. Immunol. 82: 348-355 and Wenzel et al. (1988) Am. Roar. Resp. Dis. 141: 563-568. Tryptase levels in the lung lavage of atopic asthmatic are increased after endobronchial allergen stimulation. Some cigarette smokers have significantly elevated tryptase levels in the lung flush compared to the non-smoking group. This supports the hypothesis that protease release from activated mast cells may contribute to lung destruction in smoking emphysema. See Kalenderian et al. (1988) Chest 94: 119-123. In addition, tryptase has been shown to be a potential mitogen for fibroblasts, suggesting its involvement in pulmonary fibrosis and intestinal lung diseases. See Ruoss et al. (1991) J. Clin. Invest. 88: 493-499.

Tryptase is involved in various biological processes, including degradation of vasodilatory and bronchorelaxant neuropeptides, (see Caughey et al. (1988) J. Pharmacol. Exp. Ther. 244: 133-137; Franconi et al. (1988) J. Pharmacol. Exp. Ther. 248: 947-951 and Tam et al (1990) Am J. Respir. Cell Mol .. Biol. 3: 27-32) and inhibition of bronchial sensitivity to histamine (see Sekizawa et al (1989) J). Clin Invest Invest 83: 175-179). These studies show that tryptase appears to increase bronchocostriction in asthma by destroying bronchodilator peptides.

Furthermore, tryptase has been shown to cleave fibrinogen α-chains, as well as high molecular weight kininogens, to form kinins, and thus, together with heparin, act as a local anticoagulant. The ability of tryptase to activate prostomelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3 suggests that tryptase is also involved in the tissue inflammation and transformation process. It has also been found in this observation that tryptase plays a role in joint destruction in rheumatoid arthritis. In addition, tryptase cleaves peptides genetically similar to calcitonin. Because this peptide is involved in the process of neurogenic inflammation, tryptase is a factor in the regulation of cutaneous neurogenic inflammation. See, Caughey (1991) Am. J. Respir. Cell Mol. Biol. 4: 387-394. Recently, various forms of tryptase that cleave prothrombin into thrombin have been published and mediate recognition of the HIV gp 120 surface protein by CD4 + T lymphocytes (see Katunuma et al. (1990) Monographs in Allergy 27: 51-66).

Asthma has become the most common chronic disease in industrialized countries. In the treatment of asthma or other immune-related diseases, conventional methods and therapeutic agents have proved to be ineffective. For this reason, it has been desirable to provide improved means and methods that overcome the disadvantages of these conventional means and methods and allow effective treatment of these diseases.

These drawbacks are largely eliminated with the derivatives and pharmaceutical compositions of the present invention.

-2GB 289930 B6

SUMMARY OF THE INVENTION

The present invention provides aryl and heteroaryl peptide derivatives of formula (I)

in which

Ar is C 10-10 aryl or C 1-4 heteroaryl having 1 or 2 ring nitrogen atoms, each of said aryl groups being substituted with hydroxyl at the ortho position relative to the amide side chain and optionally having additional substituents selected from the group consisting of halogen, C 1-4 alkyl , C _M alkoxy, Ci ^ alkylthio, trifluoromethyl, C] _4acyloxyl C-ioaryl, C ioheteroaryl defined above, and hydroxy, with the proviso that the aromatic ring bearing the amide side chain is further substituted by halogen, with the further proviso that the aromatic ring bearing the amide side chain does not have a C 1-4 alkyl ortho to the hydroxyl,

R ¹ is hydrogen, C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl or C 6-10earyl-C 1-4 alkyl, in which C 1-4 heteroaryl is as defined above,

R ² is hydrogen or C ^ alkyl,

R ³ is selected from the group consisting of radicals of formulas II to IX • (CH ₂ ) _b -X

NH

nh ₂ (II)

(III)

(IV)

-3GB 289930 B6 (VI)

(VII) / --- \ NH ~ '(w _CHjJp-CH2) ^ X' -t NH ₂ (VIII) "An ^ICH ₂ ^H _(IX) in which m and W are integers, where m is 3 to 6, n is 0 to 3, p is 0 to 2, q is 0 to 2, r is 0 to 5, s is 0 to 2, t is 1 to 3, u is 1 or 2, v is 3 to 6 aw is 0 to 3, A is-CH = CH- or-CsC- and X is -NH- or-CH ₂ -,

R ⁴ is C 1-4 alkyl, hydroxy-substituted C 6-10 aryl-C 1-4 -alkyl or hydroxy-substituted C 6-10 heteroaryl-C 1-4 -alkyl in which C 1-4 -alkyl-C 1-4 alkyl is as defined above, and

R ⁵ and R ^{6 are} each independently hydrogen, C 1-4 alkyl, hydroxy substituted C 1-4 aryl-C 1-4 alkyl or hydroxy substituted C 1-4 heteroaryl-C 1-4 alkyl, in which C 1-4 heteroaryl is as defined above, or

R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxy substituted 4-, 5 or 6-membered N-heterocycle and R ⁶ is hydrogen, or

R ⁴ and R ⁶ together with the nitrogen and carbon to which they are attached form a hydroxy substituted 4-, 5 or 6-membered N-heterocycle and R ⁵ is hydrogen, and

R ⁷ is OR ⁸ or -NR ⁸ R ⁹ , wherein R ⁸ and R ^{9 are} each independently hydrogen, C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-4 alkyl or C 1-4 heteroaryl C 1-4 alkyl, in which C 1-4 heteroaryl has as defined above, or

R ⁸ and R ⁹ together with the nitrogen to which they are attached form a hydroxyl and / or carbamoyl substituted 5- or 6-membered N-heterocycle, and pharmaceutically acceptable salts thereof.

One preferred group is represented by the derivatives of the invention of formula (I) in which:

Ar is 1-hydroxy-2-naphthyl, 2-hydroxy-1-naphthyl, 3-hydroxy-2-pyridyl, 2-hydroxy-3-pyridyl, 2-hydroxy-3-quinoxalyl, 2-hydroxy-4-methylphenyl, 4-hydroxy-7-methyl-3- (1,8) naphthyridin-3-yl, 2-hydroxyphenyl, 2 ', 5'-dihydroxyphenyl or 4-hydroxy-3-biphenyl,

R ^1, R ^2, R ⁵ and R ⁶ are individually hydrogen,

-4GB 289930 B6

R ³ is selected from the group consisting of the radicals of formulas II-IX above wherein m to w are integers wherein m is 3 to 6, n is 0 to 3, p is 0 to 2, q is 0 to 2, r is 0 to 5, s is 0 to 2, t is 1 to 3, u is 1 or 2, v is 3 to 6 and w is 0 to 3, A is -CH = CH- or-C = C and X is -NH -or-CH ₂ -,

R ⁴ is methyl, or

R ⁴ and R ⁵ form with the nitrogen and carbon to which they are attached a hydroxyl-substituted 5-membered heterocycle, and

R ⁷ is -OH, -OCH ₃ , -NH ₂ , -3'-carbamoyl-1'-piperidyl, -4'-carbamoyl-1'-piperidyl, -carbamoyl-2-phenylamino or -N (CH ₃ ) ₂ , and pharmaceutically acceptable salts thereof.

A second preferred group of compounds of the present invention are derivatives of Formula I wherein:

Ar is 1-hydroxy-2-naphthyl, 2-hydroxy-1-naphthyl, 3-hydroxy-2-pyridyl or 2-hydroxy-3-quinoxalyl,

R ¹ and R ² is hydrogen,

R ³ is selected from the group consisting of radicals of formulas II to V wherein m to w are integers wherein m is 3 to 6, n is 0 to 3, p is 0 to 2, q is 0 to 2, and v is 0 to 3, A is -CH = CH- or -C = C- and X is -NH- or -CH 4, and the other substituents have the above meanings.

A preferred derivative of the invention within the scope of Formula I wherein:

A is 1-hydroxy-2-naphthyl,

R ^1, R ² and R ⁶ are individually hydrogen,

R ^{3 is -} (CH ₂ ) ₃ NHC (= NH) NH ₂ ,

R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxyl-substituted 5-membered N-heterocycle and

R ⁷ is -NH ₂ , in particular 1-hydroxy-2-naphthoyl-L-arginyl-L-prolinamide.

Another suitable derivative within the scope of Formula I wherein:

Ar is 2-hydroxy-1-naphthyl,

R ¹ , R ² and R ⁶ denote hydrogen,

R ^{3 is -} (CH ₂ ) ₃ NHC (= NH) NH ₂ ,

R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxyl-substituted 5-membered N-heterocycle and

-5GB 289930 B6

R ⁷ is-NH ₂₎ is specifically 2-hydroxy-1-naphthoyl-L-arginyl-L-prolinamide.

A further preferred group of compounds of the present invention are those of formula (I) wherein:

Ar is 1-hydroxy-2-naphthyl, 2-hydroxy-1-naphthyl, 3-hydroxy-2-pyridyl or 2-hydroxy-3-quinoxalyl,

R ^1, R ^2, R ³ and R ⁶ are individually hydrogen,

R ³ is selected from the group consisting of radicals of formulas II to V wherein m to w are integers wherein m is 3 to 6, n is 0 to 3, p is 0 to 2, q is 0 to 2 and w is 0 to 3, A is -CH = CH- or -C = C- and X is -NH- or -CH 2 -,

R ⁴ is C 1-4 alkyl, or

R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxy-substituted 4-, 5 or 6-membered N-heterocycle and

R ⁷ is -OH, -OCH 3, -NH ₂ , -3'-carbamoyl-1'-piperidyl or -N (CH ₃ ) ₂ .

A further preferred group consists of derivatives of the general formula I in which:

Ar is 1-hydroxy-2-naphthyl,

R, R and R are each hydrogen,

R ^{3 is -} (CH ₂ ) ₃ NHC (= NH) NH ₂ ,

R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxyl-substituted 5-membered N-heterocycle and

R ⁷ is -NH ₂ .

Yet another preferred group is a compound of formula (I) wherein:

Ar is 2-hydroxy-1-naphthyl,

R ¹ , R ² and R ⁶ denote hydrogen,

R ³ is - (CH ₂ ) ₃ NHC (= NH) NH ₂ ,

R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxyl-substituted 5-membered N-heterocycle and

R ⁷ is -NH ₂ .

The present invention also provides pharmaceutical compositions for the treatment of inflammatory diseases in mammals caused by immunodeficiency, which contain, in an effective amount, the aryl and heteroaryl peptide derivatives of the invention in combination with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the invention include, as a pharmaceutically acceptable carrier, a non-toxic pharmaceutically acceptable carrier.

-6GB 289930 B6

The pharmaceutical compositions according to the invention are particularly suitable for the treatment of inflammatory diseases of the respiratory tract, such as asthma and allergic rhinitis, and contain as active ingredients the aryl and heteroaryl peptide derivatives of the invention in a solution of an aerosolizable pharmaceutically acceptable carrier or dry powder.

The pharmaceutical compositions of the invention comprise means for converting an aerosolizable pharmaceutically acceptable carrier or dry powder into an aerosol form suitable for inhalation and intranasal administration.

Another embodiment of the present invention are pharmaceutical compositions comprising the active ingredient of the present invention in said carrier solution at a concentration of 0.1 to 30 mg / ml.

The pharmaceutical compositions of the invention further comprise a β-adrenergic agonist.

Preferably, the pharmaceutical compositions of this invention comprise a β-adrenergic agonist selected from the group consisting of albuterol, tetrabutaline, formoterol, phenoterol and prenalin.

The pharmaceutical compositions of the invention further comprise an anti-inflammatory corticosteroid.

Preferably, the pharmaceutical compositions of the invention comprise an anti-inflammatory corticosteroid selected from the group comprising beclomethasone, triamcinolone, flurisolide and dexamethasone.

The pharmaceutical compositions of the invention are suitable for the treatment of inflammatory conditions of the skin caused by immunodeficiency and contain as active ingredient the aryl and heteroaryl peptidyl derivatives of the invention in association with a pharmaceutically acceptable carrier.

Particularly preferred tryptase inhibitors are compounds 3 and 15 of Tables I and II, formulas X and XI

(X)

CXI)

The compounds described herein are used for the prevention and treatment of inflammatory diseases caused by immunity, particularly those associated with the respiratory tract, including asthma. In particular, the stage of hypersensitivity associated with chronic asthma and allergic rhinitis. Thus, the present invention provides methods for treating an inflammatory disease caused by an immune response, wherein the patient with an inflammatory disease caused by the immune response responds to treatment with a tryptase inhibitor and administers a therapeutically effective dose or amount of a compound of the invention.

The invention also provides pharmaceutical compositions comprising the compounds described herein. These pharmaceutical compositions can exist in various forms - they can be administered orally, by injection and as infusion solutions. Usually, when used to treat or prevent asthma, particularly hypersensitivity associated with chronic asthma, these pharmaceutical compositions are in the form of an aerosol of powder or solutions.

When used in the treatment of immune-mediated inflammatory conditions of the skin, the compounds of the invention are used in combination with non-toxic pharmaceutically acceptable carriers. The compounds of the invention may be used in combination with anti-inflammatory agents, other asthma therapeutics such as β-adrenergic agonists, anti-inflammatory corticosteroids, anticholinergics and others.

Brief description of the pictures

Figure 1 is a graph showing specific lung resistance in sheep as a function of time in hours post exposure. Open squares represent control values and solid circles represent values for the same animal after administration of compound 3 of Tables I and II.

Fig. 2 is a graph showing the development of sheep hypersensitivity in bronchoconstriction due to carbachol, 24 hours after allergen exposure when compound 3 of Tables I and II is administered prior to carbachol. Dark, single column corresponds to control, blank sample. The lighter solid column corresponds to the drug, the blank sample. The striped bar corresponds to the control, after antigen administration. The white bar corresponds to the drug after antigen administration.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions and general parameters

The following definitions further illustrate and define the meaning and scope of the various terms used herein to describe the invention.

"Immune inflammatory diseases" generally include diseases that are associated with the release of messenger mediators and respond to treatment with a tryptase inhibitor. Examples of such diseases include direct type hypersensitivity diseases such as asthma, allergic rhinitis, urticaria and vascular edema, and eczematic dermatitis (atopic dermatitis), and anaphylaxis as well as hyperproliferative skin diseases, gastrointestinal ulcers, inflammatory bowel diseases, inflammatory conditions of the skin, and the like .

“Hypersensitivity” refers to the late phase bronchoconstriction and airway hyperreactivity associated with chronic asthma. Hypersensitivity of asthmatic bronchiolar tissue is considered to be a chronic inflammatory reaction that irritates and destroys the epithelium lining the airway walls and promotes pathological thickening of subsurface tissue.

"Halogen" refers to fluorine, bromine, chlorine and iodine atoms.

"Hydroxyl" refers to the group -OH.

-8EN 289930 B6 "Lower alkyl" refers to a cyclic, branched, or straight chain alkyl group of one to six carbon atoms. Exemplary groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl (or 2-methylpropyl), cyclopropylmethyl, i-amyl, nyl, and hexyl are further exemplified herein.

"Aryl" or "Ar" refers to an aromatic carbocyclic group having a single ring (eg, phenyl), a multiple ring (eg, biphenyl), or multiple condensed rings of which at least one is aromatic (eg, 1,2,3,4- tetrahydronaphthyl, naphthyl, anthryl or phenanthryl), which may be optionally substituted, eg, by halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl and hydroxyl. However, according to the present invention, the aromatic ring bearing the amide side chain cannot be further substituted with halogen. In addition, the aromatic ring bearing the side amide chain cannot have a lower alkyl group located ortho to the hydroxyl group (i.e., meta to the amide side chain).

"Heterocycle" means a saturated, unsaturated or aromatic carbocyclic group having a single ring (eg morpholine ring, pyridyl or furyl) or multiple condensed rings (eg naphthyridinyl, quinoxalyl, quinolinyl, indolizinyl or benzo [b] thienyl) and having at least one heteroatom, such as N, O or S, within the ring, which may be unsubstituted or substituted with, for example, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy and hydroxy. The term "heteroaryl" or "HetAr" refers to a heterocycle having at least one heterocyclic ring aromatic.

"Arylalkyl" refers to the group -R-Ar, where Ar is an aryl group and R is a straight or branched chain aliphatic group. The arylalkyl group may be unsubstituted or substituted, for example, by halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy and hydroxy.

"Heteroarylalkyl" refers to the group -R-HetAr, wherein HetAr is a heteroaryl group and R is a straight or branched chain aliphatic group. The heteroarylalkyl group may be unsubstituted or substituted, eg, by halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy and hydroxy.

"Pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the parent compound and that are not biologically or otherwise undesirable.

"Pharmaceutically or therapeutically acceptable carrier" refers to a carrier medium that does not interfere with the biological action of the active ingredients and that is not toxic to the patient and the environment.

"Stereoisomer" refers to a chemical compound that has the same molecular weight and chemical composition but the atoms are otherwise grouped. Chemically identical groups differ in spatial orientation, and when pure they rotate the plane of polarized light, but some pure stereoisomers have optical rotation which is also subtle to be undetectable by current instruments. The compounds of the invention may have one or more asymmetric carbon atoms and thus may include various stereoisomers. All stereoisomers are included within the scope of the invention.

"Treatment" or "treatment" refers to any administration of a tryptase inhibitor in vitro or in vivo, and includes:

(i) stopping the symptoms of the disease; (ii) reducing or stopping the long-term effects of the disease and / or (iii) eliminating the symptoms of the disease.

-9EN 289930 B6

II. Tryptase inhibitors

The present invention discloses compositions comprising potent serine protease inhibitors, more particularly tryptase inhibitors, which are used to alleviate inflammatory diseases caused by immune, in particular bronchoconstriction caused by an allergic stimulus in an asthmatic animal.

Tryptase inhibitors are agents that slow or prevent tryptase activity. According to one aspect of the present invention, a tryptase inhibitor comprises a compound of formula I:

or a pharmaceutically acceptable salt, characterized in that: Ar is a hydroxyl substituted aryl or a hydroxy substituted heteroaryl, wherein the hydroxyl is located ortho to the amide side chain and when Ar is a hydroxy substituted aryl, the aromatic ring bearing the amide side chain is not substituted halogen and does not carry a lower alkyl group ortho to the hydroxyl; R ¹ is hydrogen, lower alkyl, arylalkyl or heteroarylalkyl, R ² is hydrogen or lower alkyl; R ³ is selected from the group consisting of radicals of the formulas Π-ΙΧ:

(II)

NH IF (III)

(IV)

(VI)

-10GB 289930 B6

7 ^c »^,. ^NH (CH & NH ₂ (VII))

(VIII)

- (CHjVNHj (IX) where m is an integer from 3 to 6, n is an integer from 0 to 3, p is an integer from 0 to 2, q is an integer from 0 to 2, r is an integer from 0 to 2 5, s is an integer from 0 to 2, t is an integer from 1 to 3, u is 1 or 2, 5 v is an integer from 3 to 6, w is an integer from 0 to 3, A is -CH = CH or -CH = CH-; and X is -NH or -CH ₂ -; R ⁴ is lower alkyl, substituted arylalkyl or substituted heteroarylalkyl, and R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, lower alkyl, substituted arylalkyl, and or R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a substituted four, five or six-membered heterocycle and R ⁶ is also hydrogen, or R ⁴ and R ⁶ together with the nitrogen and carbon to which they are attached form a substituted a four, five, or six membered heterocycle and R ⁵ is hydrogen, and R ⁷ is -OR ⁸ or -NR ⁸ R, where R ⁸ and R ⁹ are independently is selected from the group consisting of hydrogen, lower alkyl, aryl, arylalkyl or heteroarylalkyl, or R ⁸ and R ⁹ together with the nitrogen to which they are attached form a substituted 5- or 6-membered heterocycle.

In a preferred example, Ar is 1-hydroxy-2-naphthyl, 2-hydroxyl-1-naphthyl, 3-hydroxy-2-pyridyl or 2-hydroxy-3-quinoxalyl; R ¹ is hydrogen; R ² is hydrogen; R ³ is selected from the group consisting of radicals of formulas II to V.

NH

II • (CH3VX NH,

NH

II

- (CH ₂ ) _n -A- (CH ₂ ) _w -X ^{X 1} NH ₂ (II>)

(III)

(IV)

Where m is an integer from 3 to 6, n is an integer from 0 to 3, p is an integer from 0 to 2, q is an integer from 0 to 2, and w is an integer from 0 to 3, A is -CH = CH- or -CH = CH-; and X is -NH- or -CH 2 -; either R ⁴ is lower alkyl and R ⁵ and R ⁶ is hydrogen; or or R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a substituted four, five or six membered heterocycle and R ⁶ is hydrogen;

and R ⁷ is -OH, -OCH ₃ , -NH ₂ , 3'-aminocarboxy-1'-piperidyl or -N (CH ₃ ) ₂ .

A particularly preferred tryptase inhibitor is compound 3 of Tables I and II of formula ΧΠ:

(ΧΠ)

Another preferred tryptase inhibitor of formula XIII is compound 15 of Table I and Π:

(xiii)

Another preferred tryptase inhibitor is Compound 21 of Tables I and II of Formula XIV:

(XIV)

-12GB 289930 B6

The tryptase inhibitors described in the present invention can be obtained by known techniques from readily available starting materials, as described in more detail below.

Depending on the nature of the functional groups, the compounds described herein may further form salts with various inorganic and organic acids and bases. These salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, hydroxy succinic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

Salts may also be formed from the rest of the carboxylic acid by treatment with alkali metals or bases containing alkali metals such as alkali metal hydroxides and alkali metal alkoxides, or by treatment with alkaline earth metals or bases containing alkaline earth metals such as alkaline earth metal hydroxides and alkaline earth metal alkoxides. Further, they can be formed from carboxylic acid and organic bases such as trimethylamine, diethylamine, ethanolamine, piperidine, isopropylamine, choline, caffeine and others.

Salts may be formed in a conventional manner, such as by reacting the free acid or base of the product with one or more equivalents of a suitable base or acid in a solvent in which the salt is insoluble or in a solvent such as water, which is then removed by vacuum evaporation or freeze-drying or exchange cation of an existing base for another cation on a suitable ion exchanger.

III. In vitro and in vivo testing

In vitro protocols for screening potential inhibitors for their ability to inhibit tryptase are known in the art. See, eg, Sturzebecher et al. (1992) Biol. Chem. Hoppe-Syeler 173: 1025-1030. Typically, these assays measure tryptase-induced hydrolysis of a chromogenic substance of the peptide type. The details of the procedure exemplified herein are described below.

Further, the activity of the compounds described herein can be evaluated by in vivo testing in one of many animal asthma models. See Larson, "Experimental Models of Reversible Airway Obstruction," in The Lung: Scientific Foundantions, Crystal, West et al., Editors, Raven Press, New York, 1991; Wamer et al. (1990) Am. Roar. Respir. Dis. 141: 253-257. The ideal animal model should replicate the main clinical and physiological features of human asthma, including airway hypersensitivity to chemical mediators and physical stimuli; the disappearance of airway obstruction when administering drugs useful in human asthma (β-adrenergics, methylxanthines, corticosteroids and others; airway inflammation with activated leukocyte infiltration; and chronic inflammatory degenerative changes such as base membrane thickening, smooth muscle hypertrophy and epithelial destruction. , used as animal models, include mice, rats, guinea pigs, rabbits, dogs, and sheep.All species have some limitations, and the appropriate choice depends on the problem being solved.

The initial asthmatic response can be evaluated in guinea pigs and dogs, and especially in greyhound-basset crosses, which develops non-specific airway hypersensitivity to numerous non-allergenic substances such as methacholine and citric acid. Selected sheep show a double response to antigenic stimulation by Ascaris proteins. In animals with a double response, the early asthmatic response (IAR) is followed by a late asthmatic response (LAR) 6 to 8 hours after exposure. Hypersensitivity to carbachol, a cholinergenic agonist, increases 24 hours after antigen stimulation in which the animal exhibits LAR.

-13GB 289930 B6

Sheep as an allergic model was used to determine the potential antiasthmatic effects of the compounds of the present invention. Administration of compositions containing aerosolized solutions of the compound of the invention to allergic sheep prior to or after exposure to specific allergens has shown that such compositions substantially reduce or eliminate the late asthmatic response 5 and, consequently, hypersensitivity.

The compounds described in this invention are also used for the treatment of other immune-related diseases in which tryptase activity contributes to pathological conditions. Such diseases include inflammatory diseases associated with mast cells such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory diseases of the internal organs, gastrointestinal ulcers, and various skin conditions.

The efficacy of the compounds of this invention in the treatment of the vast majority of immune-related diseases can be ascertained by either in vitro or in vivo procedures. Thus, the anti-inflammatory activity of the 15 compounds of this invention can be demonstrated by assays well known in the art, for example, the Reversed Passive Arthus Reaction - (RPAR) -PAW technique (see, eg, Ganguly et al. (1992) US No. 5, 126, 352) Assays for determining the therapeutic importance of compounds in the treatment of various skin conditions, such as hyperproliferative skin diseases, are well known in the art, for example, Arachidonic Acid 20 Mouse Ear Test (id). be evaluated for their anti-ulcer activity according to the methods described by Chiu et al (1984) Archives Intemationales de Pharmacodynamie et de Therapie 270: 128-140.

IV. In vivo administration

According to the present invention, a therapeutically or pharmaceutically effective amount of a tryptase inhibitor, and in particular a compound of formula I, is administered to patients suffering from an immune disorder. In one example, the compounds of the invention can be used to prevent or ameliorate asthma. When using the compositions of the present invention in the treatment of asthma, the compound may be administered preventively before or after exposure to an allergen or other factor. The compounds of the invention are particularly useful for improving the late-stage tissue destruction seen in seasonal or permanent rhinitis. Another aspect of the present invention is directed to the prevention and treatment of other immune-related inflammatory diseases associated with mast cells such as urticaria and vascular edema, ematic dermatitis (atopic dermatitis) and anaphylaxis, as well as hyperproliferative skin diseases, gastrointestinal ulcers and others.

Compositions containing the compounds may be administered in preventive and / or therapeutic treatment. In therapeutic application, the compositions are administered to patients already suffering from the disease as described above in an amount sufficient to treat or at least partially arrest the symptoms of the disease or its complications. An amount adequate to achieve these goals is defined as a "therapeutically effective amount or dose". The amount effective for such ingestion will depend upon the course and condition of the disease, prior therapy, the patient's health and response to drugs, and the judgment of the attending physician.

For preventive administration, compositions containing the compounds of this invention are administered to patients who are susceptible or at risk for a particular disease. The amount in this case is defined as a "preventively effective amount or dose". In this use, the exact amount again depends on the patient's health, weight 50 and others.

Once the patient's condition has improved, a maintenance dose is administered if necessary. Further, dosages or frequency of administration, or both, may be reduced depending on the symptoms to maintain a level of amelioration of the symptoms. When symptoms stabilize at the desired level, healing

- 14GB 289930 B6 may end. However, patients may require intermittent long-term treatment if the symptoms of the disease recur.

Generally, a suitable effective dose of the tryptase inhibitor will be in the range of 0.1 to 1000 milligrams (mg) per recipient per day, more preferably in the range of 1 to 100 mg per day. Most preferably, the required dose will be administered in one, two, three, four smaller doses administered at appropriate intervals throughout the day. These smaller doses may be administered in unit dosage form, for example containing from 5 to 1000 mg, preferably from 10 to 100 mg of active ingredient per dosage unit.

The compositions used in this therapy may take various forms. Such forms include, for example, solid, semi-solid or liquid doses such as tablets, powders, solutions or suspensions, liposomes, injectable and infusion solutions. The choice of form depends on the intended route of administration and therapeutic application.

While it is possible to administer the active ingredient of the invention alone, it is preferable to administer it as part of a pharmaceutical composition. The compositions of the present invention comprise at least one agent or inhibitor of the invention in a therapeutically or pharmaceutically effective dose together with one or more therapeutically or pharmaceutically acceptable carriers and other possible therapeutic ingredients. Various options are described, for example, in Gilman et al. (eds.) (1990) Goodman and Gilman ' s: The Pharmacological Bases of Therapeutics, 8th Edition, Pergamon Press; and Remingtons, supra. Methods of administration are discussed herein, such as oral, intravenous, intraperitoneal or intramuscular administration, and others. Pharmaceutically acceptable carriers include water, saline, buffers, and other compounds described, for example, in Gauge Index, Gauge & Co., Rahway, NJ.

Usually, when used to treat asthma or allergic rhinitis, the compounds of the present invention will be in the form of an aerosol. The term "aerosol" includes any phase of the present invention in which a gas is suspended to allow inhalation into bronchioles or the nose. The aerosol comprises a suspension of gas and droplets of the compounds of the present invention formed in an inhaler or nebulizer, or a nebulizer mist. The aerosol also includes a dry powder composed of a compound of the invention suspended in air or other carrier gas, which can be delivered, for example, by blowing from an inhaler.

For the solutions used to prepare aerosols in the present invention, a preferred concentration range of the compounds of this invention is from 0.1 to 100 milligrams (mg) / ml (ml), more preferably 0.1 to 30 mg / ml, and most preferably from 1 to 100 mg / ml. 10 mg / ml. Typically, solutions are buffered with a physiologically compatible buffer such as phosphate or bicarbonate. A typical pH range is from 5 to 9, more preferably from 6.5 to 7.8, and most preferably from 7.0 to 7.6. Sodium chloride, preferably in the range of 10% isotonic, is usually added to achieve osmolarity in the physiological range. The compositions of these solutions for the preparation of aerosol inhalants are discussed in Remington's Pharmaceutical Sciences, see also Ganderton and Jones, Tract Delivery to the Respirators, Ellis Horwood (1987); Gonda (1990) Critical Reviews in Therapeutic Species Carrier Systems 6: 273-313; and Reabum et al. (1992) J. Pharmacol. Toxicol. Metods 27: 143-159.

Solutions of the compounds of this invention can be aerosolized by any known method commonly used to prepare aerosol inhalation pharmaceutical compositions. Essentially, these methods include compression or means for compressing the container of solution, usually an inert carrier gas, and passing the compressed gas through a small opening, so that the droplets of solution penetrate the mouth and trache of the animal to which the drug is being administered. A mouthpiece is usually fitted to the outlet opening to facilitate the penetration of the fabric.

In one example of administration, the compositions of the present invention consist of solutions of the compounds of the present invention in or without aerosol formulations for the treatment of asthma, such as measurable inhalers,

-15EN 289930 B6 nebulisers and ultrasonic nebulisers. The means may also include a mouthpiece mounted on the outlet orifice.

In another mode of administration in the treatment of allergic rhinitis, the composition optionally comprises a nasal spray solution of a compound of the invention.

A dry powder comprising a compound of the present invention with an excipient is another method of applying the present invention. It may be administered by a powder inhaler containing the powder described above.

It is to be understood that the methods of the invention can be used in combination with other agents for the treatment of diseases caused by immune and in particular asthma. In particular, β-adrenergic agonists are used in these combinations because they eliminate the symptoms of early asthmatic reaction, while the compounds of the present invention eliminate the symptoms of late asthmatic reaction. Preferred β-adrenergic agonists in these solutions include any conventional β-agonist used to control asthma, such as albuterol, terbutaline, formoterol, fanoterol or prenalin.

Other agents used in combination with the compounds of this invention include anticholinergics such as ipratropium bromide and anti-inflammatory corticosteroids (adrenocortical steroids) such as beclomethasone, trimacinolone, flurisolide or dexamethasone.

The compounds of the invention can be used in the treatment of immune-mediated inflammatory conditions of the skin, such as urticaria and vascular edema, eczematic dermatitis, and hyperproliferative skin diseases, e.g., psoriasis, in mammals. As a consequence of topical application of the compound of formula I, symptom remission is expected. Its effects on immune-mediated inflammatory skin conditions can be expected to reduce scaling, erythema, focal extent, pruritus and other symptoms associated with skin conditions. The dosage and duration of treatment required for successful treatment may vary from patient to patient, but a person skilled in the art will be able to determine these variations and determine the course of treatment accordingly.

The invention also encompasses compositions for topical application to the skin comprising a compound of Formula I, usually in concentrations ranging from 0.001% to 10%, together with a non-toxic pharmaceutically acceptable surface carrier. These topical compositions are prepared by combining the active ingredient of the present invention with conventional pharmaceutical solvents and carriers, usually surface-applied in dry, liquid, cream and aerosol form. Ointments and creams have an aqueous or oily base with the addition of a suitable thickener and / or gelling agent. They may contain as a base water and / or liquid paraffin or a vegetable oil such as peanut oil or castor oil. Thickening agents that are used according to the nature of the base include solid paraffin, aluminum stearate, ketostearyl alcohol, propylene glycol, polyethylene glycols, lanolin, hydrogenated lanolin, beeswax and others.

Lotions may be composed of an aqueous or oily base and generally also contain one or more of the following components: stabilizing agents, emulsifiers, dispersing agents, suspending agents, thickeners, coloring agents, perfumes, and others.

The powders may be composed of any suitable powder base, for example talc, lactose, starch and the like. The drops are comprised of an aqueous or non-aqueous base and may further comprise one or more dispersing agents, suspending agents, solubilizing agents, and others.

The topical pharmaceutical compositions of the invention may include one or more preservative or bacteriostatic agents, e.g., methylhydroxybenzoate, propylhydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and others. The topical pharmaceutical compositions also optionally contain other active ingredients such as antimicrobial agents, in particular antibiotics, anesthetics, analgesics and anti-itching agents.

-16GB 289930 B6

The compounds of this invention are also useful in the treatment of gastrointestinal ulcers. More specifically, they exhibit chemotherapeutic activity that allows the relief of symptoms of gastrointestinal ulcers and promotes the treatment of gastric and / or duodenal ulcers. The compounds may be used in conjunction with other therapeutic agents such as anti-inflammatory agents and / or analgesics such as aspirin, indomethacin, phenylbutazone, ibuprofen, naproxen, tolemtim and others.

The pharmaceutical compositions may be administered parenterally or orally in preventative and / or therapeutic treatments. The pharmaceutical compositions may be administered in different dosage units depending on the mode of administration. For example, dosage unit forms suitable for oral administration include powders, tablets, capsules, and dragees.

The pharmaceutical compositions may be administered intravenously. The present invention provides compositions for intravenous administration comprising a solution of the compound dissolved or suspended in an acceptable carrier, most preferably an aqueous carrier. Various carriers can be used, for example, water, buffered water, 0.4% saline, and others. These compositions are optionally sterilized by conventional, well known sterilization techniques, or may be sterilized by filtration. The resulting aqueous solutions may be packaged for immediate use or lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration. The compositions may contain pharmaceutically acceptable excipients to achieve physiological conditions such as pH adjustment and buffering agents, tonicity adjusting agents, humectants and others, e.g., sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, oleate triethanolamine and others.

For solid compositions, solid carriers are used, for example, pharmaceutically pure mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, sodium carbonate and others. For oral administration, a pharmaceutically acceptable non-toxic composition is comprised of admixing any commonly used ingredient, such as the aforementioned carriers, and 0.1 to 95% of the active ingredient, most preferably 20%.

Therefore, for the invention described herein to be fully understood, the following examples serve. It is understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

I. General methods

Starting materials not described herein are commercially available, are known or can be prepared by methods well known in the art. The compound of formula (I) may be prepared by techniques known in the art using solid or liquid phase systetic techniques. The starting materials for preparing the compounds of formula I are known in the art or can be prepared by methods well known to those skilled in the art. For example, solid phase polypeptide synthesis techniques are described, for example, in Solid Phase Peptide Synthesis: A Practical Approach, (eds. E. Atherton and R. C. Sheppard), IRL Press at Oxford University Press (1989) and in Merrifield, J. Amer. Chem. Soc., 85: 2149-2156 (1963). The chemistry of peptide bonds is also described in The Peptides, Vol. 1, (edited by Gross, E. and J. Meienhofer), Academic Press, Orlando (1979). Other techniques including these Geysen et al., J. Imm. Meth., (1987) 102: 259-274; Houghten et al., Nature (1991) 154: 84-86.

In the process described herein for preparing a compound of this invention, the requirements for protecting groups are well known to those skilled in the art of organic chemistry. The use of suitable protecting groups is necessarily included in the process herein, although not explicitly described herein.

-17GB 289930 B6

The isolation and purification of the compounds and intermediates described herein may be performed, if desired, by a suitable separation or purification process such as filtration, extraction, crystallization, column chromatography, thin layer chromatography or preparative chromatography, high pressure liquid chromatography, or a combination of these methods. Specific examples of suitable separation and isolation procedures can be obtained by reference to the examples below. However, other equivalent separation or isolation methods may of course be used.

The Sakaguchi test is for the detection of arginine and arginine-containing peptides. See Stewart and Young " Solid Phase Peptide Synthesis, 2nd Ed., Pierce Chemical Company, p. 114. A solution was prepared.

I, containing 0.01% α-naphthol and 5% urea in 95% ethanol. Solution II was prepared by dissolving 2 grams (g) of bromine in 100 ml (ml) of an 8% solution of sodium hydroxide in water. To the solution I was added 5 pellets of sodium hydroxide. The sample to be analyzed was spot-loaded onto a thin-layer chromatography (TLC) plate. The TLC plate was then sprayed with solution I. The TLC plate was dried and then sprayed with solution II. Red dots indicated the occurrence of aminoiminomethane groups.

II. Solid phase synthesis of the compound of formula (I)

A. Preparation of Compound of Formula 3 of Tables I and II

4- (2 ', 4'-dimethoxyphenyl-fluorenylmethyloxycarbonyl (Fmoc) -aminomethyl) -phenoxy resin (Rink resin; Bachem, CA; 3.5 grams (g) in bulk 0.289 milliequivalents / gram (meq / g), 1, 01 millimoles (mmol) was suspended in 30 ml of a solution of N, N-dimethylformamide (DMF): toluene (1: 1 by volume) containing 30% by volume piperidine. The reaction mixture was stirred for 5 minutes and then filtered. Another portion of piperidine solution (30 mL) was added and the mixture stirred for an additional 5 minutes. After filtration, the resin particles were washed sequentially with DMF (6X) and methylene chloride ( ^6X ).

Fmoc-L-proline (Milligen; 6.06 mmol), benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium nexafluorophosphate (BOP, Novabiochem; 6.06 mmol), 1-hydrodoxybenzotriazole (HOBT; Aldrich; 0, 06 mmol) was dissolved in 30 ml DMF. The resulting clear solution was added to the Rink resin and the resulting slurry was stirred for 4 hours (bubbling with nitrogen). The reaction mixture was filtered and the resin particles were washed as described above. The Fmoc group was removed with piperidine as described above.

A solution of Fmoc-L-arginine (PMC) (Milligen; 6.06 mmol), BOP (6.06 mmol), and HOBT (6.06 mmol) in DMF (30 mL) was added to the resin particles and the slurry was stirred 4 hours and then filtered, washed, treated with piperidine and washed again as described above.

A solution of 1-hydroxy-2-naphthoic acid (Aldrich; 1.14 mg, 6.06 mmol), 1,3-diisopropylcarbodiimide (DIPCDI; Aldrich; 0.949 mL, 6.06 mmol) and HOBT (0.819 g, 6.06) ml) in DMF (45 ml) were added to the reaction mixture and the mixture was shaken for 7 hours. After filtration, washing and addition of piperidine (as described above), the resin was washed sequentially with DMF (6X), methylene chloride (6X) and methanol ( ^6X ). The resin was suspended in methanol and shaken on a shaker overnight (15 hours). It was filtered and washed twice with methanol.

The white bulk was then suspended in a solution containing trifluoroacetic acid (TFA): anisole: water 90: 5: 5 (30 mL). The resin immediately turned pink and then darkened to a deep red color within one to two minutes. After 5 minutes, the reaction mixture was filtered. This procedure was repeated 2 ^χ with fresh cleavage reagent, except that contact time was increased to 10 minutes in each repetition.

The TFA solutions were combined and the resulting clear orange solution was allowed to sediment at room temperature for 3.5 hours. Concentration in vacuo afforded a pale yellow oil which was

289930 B6 was maintained under vacuum (<1 torr) for 3 hours. The oil was dissolved in 50% aqueous acetonitrile (100 mL) and lyophilized to give the crude product as an off-white solid (471 mg).

The product was analyzed by HPLC (Polymer Labs 100A PLRP column, 1.0 x 150 mm (mm), eluting with a linear gradient of 20 to 45% acetonitrile over 13 minutes at a flow rate of 0.1 mL / min). Analysis showed that the crude product was essentially a single compound (retention time 10.35 minutes,> 98% determined by UV absorbance). Purification was performed by HPLC using a column packed with C 18 silica gel (Vydac; 22 x 250 mm, 15-20 µm, 300 a, eluting with a linear gradient of 20 to 35% over 30 minutes at a flow rate of 10 mL / min). It was necessary to repeat the injection at 3035 mg. Similar fractions (retention time 44-48 minutes) were combined and lyophilized to give a free-flowing white solid (351 mg), which was a single compound (by HPLC).

Electrospray mass spectrometry (calculated molecular weight 440.49, found M ⁺¹ = 441.1) and NMR spectroscopy (proton and ¹³ C) are consistent with the expected structure. 1 H NMR (CD ₃ OD) δ 7.89 (d, J = 8Hz, 1H), 7.78 (d, J = 6Hz, 1H), 7.76 (d, J = 6Hz, 1H) 7.57 (dt, J = 8.1Hz, 1H), 7.48 (dt, J = 8.1Hz, 1H), 7.29 (d, J = 8Hz, 1H), -4, 95 (unclear, 1H), 4.49 (dd, J = 8.5Hz, 1H), 3.97 (dt, J = 10.7Hz, 1H), 3.73 (dt, J = 10.7Hz, 1H), 3.23 (t, J = 7 Hz, 2H), 2.29 (m, 1H), 1.7-2.2 (m, 8H).

B. Procedure for Other Compounds of Formula I

Following the procedure of Part A above and using the following compounds instead of 1-hydroxy-2-naphthoic acid:

2-hydroxy-4-methylbenzoic acid;

3-hydroxy-2-quinocalinecarboxylic acid;

3-hydroxy-2-naphthoic acid;

2-hydroxy-1-naphthoic acid;

3-hydroxy-2-pyridinecarboxylic acid;

4-hydroxy-7-methyl-3-naphthyridine carboxylic acid;

2-hydroxy-3-pyridinecarboxylic acid;

2-hydroxybenzoic acid;

2,5-dihydroxybenzoic acid; and

The following compounds were prepared from 2-hydroxy-5-phenylbenzoic acid (see E below):

Compound 2 of Tables I and II; Compound 9 of Tables I and II;

compound 14 of Tables I and II; compound 15 of Tables I and II; Compound 16 of Tables I and II; compound 17 of Tables I and II; compound 18 of Tables I and II; compound 19 of Tables I and II;

compound 20 of Tables I and II; and compound 21 of Tables I and II.

C. Preparation of Other Compounds of Formula I

Following the procedure in Part A above, using Fmoc-D-proline instead of Fmoc-L-proline, compound 12 of Table III was obtained.

-19GB 289930 B6

D. Preparation of Other Compounds of Formula I

The compound of Tables I and II was prepared by coupling the Fmoc-L-phenylalanine to the resin by a procedure analogous to the procedure for binding Fmoc-L-proline in Part A above. The Fmoc group was removed and phenylalanine was coupled to the Fmoc proline. Further synthesis of compound 13 was performed using the techniques described in Part A.

Similarly, the preparation of compounds 6 and 7 of Tables I and II involves coupling the Fmoc-piperidine-3-carboxylic acid or Fmoc-piperidine-4-carboxylic acid to the resin, removing the Fmoc group and then coupling the Fmoc-L-proline. The remainder of the synthesis was carried out as described in Part A above.

E. Preparation of 2-hydroxy-5-phenylbenzoic acid

2-Hydroxy-5-phenylbenzoic acid was synthesized as follows. A solution of tetrahydropyran THP-protected 4-phenylphenol (474 mg, 2 mmol, prepared from 4-phenylphenol by standard methods described in Green and Wuts on pages 31-34) in anhydrous THF (5 mL) was cooled to -78 ° C and was cooled to -78 ° C. n-Butyllithium (2 mL of 1.6 M in hexane) was added. The reaction mixture was stirred and warmed to ambient temperature to give a light brown suspension. After 2 hours, the reaction mixture was cooled to -78 ° C and an excess of anhydrous CO ₂ was added to the mixture for several minutes. The reaction mixture was stirred and warmed to ambient temperature. After 2 hours, the reaction mixture was partitioned between ethyl ether and aqueous 1 N NaOH solution. The aqueous layer was ice-cooled to 0 ° C, acidified to pH 2 with aqueous 1 N HCl. The aqueous solution was shaken with methylene chloride. The organic layer was dried over magnesium sulfate. Concentration in vacuo gave the crude product as an off-white solid (258 mg, 2-hydroxy-5-phenylbenzoic acid). The NMR spectroscopy of the crude product was consistent with the proposed structure. 1 H NMR (DMSO-d 6) δ 8.04 (d,> 3Hz, 1H), 7.78 (dd, J = 9.3Hz, 1H), 7.62 (d, J = 7Hz, 2H), 7, 44 (t, J = 7 Hz, 2H), 7.32 (t,> 7 Hz, 1H), 7.00 (d, J = 9 Hz, 1H). Calculated molecular weight: 466.5. Found molecular weight 467.2. LC gradient 25 to 45% acetonitrile over 13 minutes. LC retention time 3.5 minutes. The material was used without further purification.

III. Synthesis of a compound of formula I in solution

A. Preparation of Compound 10 of Tables I and III

To 20 g of (L) -phenylalanine cooled to -5 ° C in a salt / ice bath was added 74 ml of concentrated sulfuric acid. The reaction mixture was allowed to equilibrate and then 9.4 ml of concentrated nitric acid was added dropwise over 5 minutes. The reaction mixture was stirred for 30 minutes and then added to 700 ml of crushed ice with water; The pH was adjusted to 8-9 concentrated with ammonium hydroxide. The solution was allowed to crystallize at room temperature and then cooled to 4 ° C overnight. The light yellow crystalline product was filtered through a solid filter paper, washed with cold water and dried. The product was recrystallized in hot water and the filtrate was evaporated and recrystallized (2x) with a total yield of 55%. Melting point: 218-222 ° C (crude product). TLC: R _f (F) 0.18. NMR: (D ₂ O / NaOD), γ 2.99 (dd,> 13.4, 7.2 Hz, 1H), 3.10 (dd,> 13.4, 6.0 Hz, 1H) 3.57 (dd,> 7.2, 6.0 Hz, 1 H), 7.48 (d,> 8.6 Hz, 2 H), 8.21 (d,> 8.7 Hz, 2H ).

T-Butyloxycarbonyl (BOC) -protected amino acids can be prepared by standard techniques. See, e.g., Greene and Wuts Protective Groups in Organic Synthesis, 2nd Ed., John Willey & Sons, Inc .: New York, pp. 327-328 (1991).

To a solution (-20 ° C) of BOC-protected p-nitrophenylalanine (3.00 g, 9.67 mmol) in anhydrous methylene chloride (5 mL) was added N-methylmorpholine (NMM, 1.07 mL, 9.67). mmol) followed by isobutyl chloroformate (1.26 mL, 9.67 mmol). The reaction mixture was stirred at -20 ° C for 15 minutes. Methyl L-proline hydrochloride (L-Pro-OMe, 1.60 g, 9.67 mmol) was added to the mixture.

-20GB 289930 B6 as a solid followed by additional NMM (1.07 mL, 9.67 mmol). After stirring at -20 ° C for 1 hour and stirring at room temperature for 1 hour, the reaction mixture was concentrated in vacuo and then diluted with ethyl acetate. The ethyl acetate solution was washed with 10% aqueous citric acid solution, water and brine, dried over magnesium sulfate and concentrated in vacuo. Column chromatography gave 2.4 g of the product (yield> 60%).

The BOC group was removed by treatment with HCl in dioxane using standard conditions. See, eg, Greene and Wuts, pp. 328-329. To a solution of 1-hydroxy-2-naphthoic acid (160 mg, 0.84 mmol) in methylene chloride and N, N-dimethylformanide (1: 1, 3 mL) was added 1-hydroxybenzotriazole (159 mg, 1.17 mmol). The solution was cooled to 0 ° C and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 161 mg, 0.84 mmol) was added. The solution was stirred for 45 minutes at 0 ° C and then the dipeptide solution (300 mg, 0.84 mmol) prepared above was added followed by NMM (93 µΐ, 0.84 mmol). The reaction mixture was stirred at 0 ° C for one hour and at room temperature for 45 minutes. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate and water. The organic layer was separated, washed (4 *) with water and then brine, dried and concentrated in vacuo. Chromatography gave the condensed product (300 mg, 73%).

To a solution of the condensed product (410 mg, 0.83 mmol) in ethyl acetate (20 mL) was added glacial acetic acid (10 drops) and 10% palladium on charcoal (100 mg). This solution was hydrogenated for 5 hours. The reaction mixture was then filtered through celite and the solution was concentrated in vacuo to yield 375 mg (98%) of the product which was used without further purification.

To a solution of the above hydrogenation reaction product (200 g, 0.45 mmol) in anhydrous methanol (10 mL) was added formamidine sulfonic acid (118 mg, 0.95 mmol) prepared by oxidation of commercially available formamidine sulfonic acid according to the procedure described by Mryanoff et al. (1986) J. Org. Chem. 1882). The reaction mixture was stirred for three days. The reaction mixture was concentrated in vacuo and the product was isolated by chromatography (eluting with methanol: methylene chloride) to yield 17 mg of the desired product, compound 10 of Table III.

IV. Alternative Synthesis of Compound of Formula I

A. Preparation of Compound 3 of Tables I and II

A solution of 1-benzyloxy-2-naphthoic acid (2.247 g) in thionyl chloride (15 mL) was refluxed for 4 hours. Excess reagent was evaporated in vacuo. The residue was diluted with anhydrous DMF (9 mL) and concentrated to 2 mL. To this solution was added 4-dimethylaminopyridine (1.02 g). The mixture was stirred overnight at ambient temperature. The resulting pyridine complex was added to a stirred solution of nitro-L-arginine (1.77 g), tetramethylguanidine (1 mL) and lithium chloride (4.56 g) in DMF (60 mL). The mixture was stirred at ambient temperature for 48 hours. Most of the DMF was evaporated in vacuo and the residue was partitioned between 1.5 N (aq) aqueous HCl and ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. Concentration in vacuo gave the crude product (3.5 g, 1-benzyloxy-2-naphthoyl-N-nitro-L-arginic acid). TLC: Rf of the product is 0.22 (using a silica gel plate and eluting with 10% methanol / acetic acid in chloroform). This material was used without further purification.

A solution of 1-benzyloxy-2-naphthoyl-N-nitro-L-arginic acid (150 mg) in anhydrous DMF (5 mL) was cooled to -25 ° C and treated with isobutyl chloroformate (0.053 mL). The reaction mixture was stirred and warmed to room temperature. After 20 minutes solid Lprolinamide (as its hydrochloric acid salt, 65.9 mg) was added. The mixture is stirred for 16 hours and then diluted with ethyl acetate. The ethyl acetate solution was washed with 5% aqueous citric acid solution, saturated sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solution was concentrated in vacuo and the residue was dissolved in ethanol (40 mL containing 10% methanol and 10% acetic acid) and hydrogenated at 52 pounds per square foot (psi) with 10% palladium on carbon (10 mg) until completion of the reaction.

(TLC on silica gel, eluting with chloroform: methanol 9: 1), indicated by the disappearance of the faster moving spots. The reaction mixture was filtered through celite, washed with ethanol and methanol. The mixture was concentrated in vacuo and purified by high pressure liquid chromatography to give 1-hydroxy-2-naphthoyl-L-arginyl-L-proline amide (41 mg, electrospray mass spectrum: M + 1 = 441) isolated as its acid salt. trifluoroacetic.

C. Preparation of Compound 1 of Table III

Following the procedure in Part A above, using 2-benzyloxy-1-naphthoic acid instead of 1-benzyloxy-2-naphthoic acid and sarcosinamide instead of L-proline amide, compound 1 of Table III was obtained.

D. Preparation of Other Compounds of Formula I

Following the procedure of Part B above and using the following compounds instead of sarcosine:

L-proline-N, N-dimethylamide;

L-proline methyl ester; and trans -4-hydroxy-L-proline methyl ester;

the following compounds were obtained:

compound 5 of Tables I and II;

Compound 8 of Tables I and II; and compound 4 of Table III.

V. Physical data

Table I

Compound Molecules, mass calculated Molecules, mass found (M ⁺¹ ) ' Liquid chromate. Gradient ² Liquid chrome. - Retention times (min) 1 414.24 415.1 D 5.8 2 404.26 405.5 (B) 11.5 3 440.26 441.1 AND 10.3 4 471.26 472.2 D 6.2 5 468.29 469.1 D 6.8 6 ^J 551.34 552.3 D 7.5 7 551.34 552.1 D 7.3 8 455.26 456.0 D 7.0 9 442.26 443.0 D 5.5 10 - - - - 11 456.26 456.7 C 24.4 12 440.26 441.2 C 25.4 13 587.34 588.0 C 26.9 14 440.26 440.5 AND 9.0 15 Dec 440.26 440,2 ⁴ (B) 8.4 16 391.5 391,8 ⁴ D 5.6 17 456.49 456.7 ⁴ (B) 9.0 18 393.22 391,8 ⁴ (B) 5.5 19 Dec 390.4 391.1 AND 4.7 20 May 406.4 407.2 C 20.7 21 466.5 467.2 E 3.5

-22EN 289930 B6

1. All molecular weights were determined using a Finnigan electrospray mass spectrometer unless otherwise indicated.

2. A binary gradient system containing acetonitrile and water was used in all cases. All eluents contained 0.1% trifluoroacetic acid. A: 20 to 45% acetonitrile for 13 minutes. B: 10 to 35% acetonitrile for 13 minutes. C: 5-95% acetonitrile over 45 minutes. D: 2 to 95% acetonitrile for 10 minutes. E: 25 to 45% acetonitrile for 13 minutes.

3. The test material was a mixture of diastereomers.

4. Molecular weights were determined by Biolon Mass Spectrometry. Values are M ⁺ .

VI. Determination of tryptase inhibition in vitro

Compounds (about 1 mg) to be determined against tryptase were diluted in dimethylsulfoxide (DMSO) and diluted 1:10 with a buffer containing 50 millimolar (mM) Tris-HCl at pH 8.2, and containing 10 mM NaCl, 0.05 % Tween-20. From the original dilution, 7 additional 3-fold dilutions were prepared in the same buffer with the addition of 10% DMSO. Aliquots (50 μΐ) from each of the 8 dilution series were plated into individual wells of a 96-well microtiter plate (U-bottom). Tryptase (25 μΐ; 0.5 mM final concentration) was added to each well and the samples were mixed and incubated for one hour at room temperature either under ambient light (ie light available in the room during the experiment) or under controlled conditions. conditions of "light" or "dark". "Light" here means the light intensity of 400 to 450 foot candels from a fluorescent lamp. "Darkness" here means that the sample containers are wrapped in aluminum foil. The enzyme reaction is then initiated by the addition of a synthetic tripeptide substrate, tosyl-GlyProLys-p-nitroanilide (25 μΐ; 0.5 mM final concentration). The microtiter plates were immediately transferred to a UV / MAX Kinetic Microplate Reader (Molecular Devices) and the hydrolysis of the chromogenic substrate was monitored spectrophotometrically at 405 mM for 5 minutes. Enzyme assays provided the usual linear rise curves under these conditions. Measurement of the initial velocity calculated from the ascension curves using a kinetic analysis program called "BatchKi" (commercially available from Biokin Ltd., Madison WI), the program was used to determine the apparent inhibition constants for each inhibitor. This program is designed to display regression and display curve from nonlinear data.

Table II lists the inhibition constants (Κ /, micromolar (pm)) that were determined for several compounds of the invention wherein R ¹ is hydrogen; R ² is hydrogen; R ³ is - (CH ₂ ) ₃ -NH- (C = NH) -NH ₂ ; R ⁴ and R ⁵ , together with the nitrogen and carbon to which they are attached, form a five membered heterocycle; and R ⁶ is hydrogen. According to the present invention, a compound is designated as "active" or effective as a tryptase inhibitor when its K / is less than 1000 μΜ. Unlike K i, K i cannot be the actual distociation constant of the enzyme inhibitor complex; K i 'corresponds to K i for a non-competitive inhibitor and directly corresponds to K i for competitive and acompetitive inhibitors.

Exposure to light of test compound solutions in test media may reduce K i '. In general, the assay conditions are light sensitive and variations in ambient light intensity may affect the reproducibility of the assay. In order to eliminate this potential source of error, some analyzes were performed in the dark. K 1 ', shown in Tables II and III without parentheses, were determined under ambient lighting conditions. The k i 'indicated with parentheses were determined under "dark" conditions as defined above. The K i 'indicated with an asterisk (*) were measured under "light" conditions as defined above (ie a light intensity of 400 to 450 foot candelas).

Table III lists the inhibition constants (K i ', micromolar (µ m)) that were determined for several compounds of the present invention. According to the present invention, a compound is designated as "active" or effective as a tryptase inhibitor when its K / is less than 1000 μΜ.

-23GB 289930 B6

Table II

Compound «4 ' R ⁷ Ar 2 > 500 -nh ₂ 3 Drawbar 3 * (82) -nh ₂ OH 1 scrap 5 15 Dec -N (CH ₃ ) ₂ cá 6 82 CONH, - OH g cá 7 664 - / COHH, WITH 208 -och ₃ 9 23 * (55) -nh ₂ ca.

-24GB 289930 B6

Table II - continued

Compound R ⁷ Ar 13 0.6 * (110) H CONH. \ / 14 752 * (708) -nh ₂ ca. 15 Dec 0 _; 84 -nh ₂ 16 8 * (64) -nh ₂ and. 17 900 -nh ₂ OH

-25GB 289930 B6

Table II - continued

Compound R ⁷ Ar i 18 452 ~ nh ₂ and 19 Dec 8 * (2450) -nh ₂ and. 20 May 20 May -nh ₂ 21 18 * (149) -nh ₂ oó-

-26GB 289930 B6

Table III

Compound Structure 1 3 * (636) COHH, OH 0 K. CH, IN 4 749 H 0 's> - OH ^0CH 3 of HRF ^ee ^ J HH _s

-27GB 289930 B6

Table III - continued

Compound *and· ------------------------'----------------- 11 Structure || 10 2 ^ 5 * (17) [ ^<:> Ύ ^ίΓΧ |] ”ř ř ^0MH « OH 0 ŽHj Lv Φ Η-γ 'NH 11 0y3 * (43) y $ ° ^{ηη ι ι <Λ} γ ^χ γ ^Η 'γ ^Α' Α OH 0 1 - / HN ^ NH

-28GB 289930 B6

Table III - continued

Compound Structure II 12 2.5 * (818) H O COHH, OH O '- / IN

VII. Another characteristic of tryptase inhibition by Compound 3 of Tables I and II

A. Dependence on pH

Compound 3 was determined against tryptase at four different pH values in the following buffer system: 120 mM NaCl, 2.7 mM KCl, 0.13 mM NaH ₂ PO 4, 0.896 mM Na ₂ HPO 4. The resulting buffer system used comprises 0.05% Tween-20. Table IV shows Kf (M) for compound 3 at various pH values.

Table IV

pH 6.5 7.0 7.5 8.0 K / (μΜ) 14 8.0 5.4 6.1

B. Optimized assay at pH 7.5

The inventors have discovered that the compound is less sensitive to light in the following buffer system: 120 mM NaCl, 2.7 mM KCl, 0.13 mM NaH ₂ PO ₄ , 0.896 mM NaHPO _4, and 0.05% Tween20 at pH 7.5 . The assay was performed according to the procedure above and dilution of compound 3 and addition of tryptase was performed under ambient lighting at room temperature (22-26 ° C). The sample plate was wrapped in aluminum foil for 1 hour incubation before addition of the substrate, which was also prepared under ambient lighting. All dilution steps and addition of tryptase had to be performed within 5 minutes. In addition, compound 3 must be diluted with DMSO.

VIII. In vivo testing

In these studies, it was used as a model of asthma in sheep. These methods have been previously published (see Abraham et al. (1983) Am. Rev. Respir. Dis. 128: 839-844; Allegra et al. (1983) J. Appl. Physiol. 55; 726-730; Russi et al. (1985) J. Appl Physiol 59: 1416-1422, Soler et al (1989) J. Appl Physiol 67: 406-413.

-29GB 289930 B6

Each sheep served as its own control. The weight of these animals was from 20 to 50 kg.

In these studies, 9 mg of Compound 3 of Tables I and II was dissolved in 3 mL of buffered saline and the resulting solution was administered as an aerosol 0.5 hours before allergen challenge, 4 hours after challenge and 24 hours after challenge (total dose = 27; n = 6). Compound 3 showed a tendency to reduce early response and attenuate late response as shown in Figure 1. In a control (vehicle only) antigen challenge, the increase in early response above baseline specific pulmonary resistance (SRL) was 374 ± 104% and 212 ± 21, respectively. % (ie ± standard error). In contrast, when a sheep is treated with Compound 3 of Tables I and II, the early and late rise of SRL was 280 ± 39% and 72 ± 9% (p <0.05 vs control, Wicoxon rank test).

The peak of early responses was found as the mean of maximum values that occurred immediately after exposure. The peak of late responses was calculated by averaging the maximum response values for each animal over a time period between 6 and 8 hours. This procedure is stable and eliminates the possibility of reducing the late response by simple averaging.

hours after antigen challenge, both control and treated samples developed airway hypersensitivity. (Airway hypersensitivity is expressed as PC400, ie the concentration of carbachol which caused a 400% increase in SRL. Thus, a decrease in PC400 means that the airways have become hypersensitive). Compound 3 of Tables I and II blocks 24 h hypersensitivity, see Fig. 2. The PC400 baseline was 22.0 ± 3.7 breath units in the control, dropping to 9.1 ± 1.3 breath units after allergen exposure ( p <0.05 vs baseline). In contrast, in the drug treated sample, P400 was unchanged from baseline (16.0 ± 3.8 breath units versus 17.6 ± 3.5 breath units after allergen exposure). Thus, treatment with Compound 3 of Tables I and II of the table shows a statistically demonstrable improvement in airway function in sheep exposed to allergen exposure.

Discoveries of this use in all articles and references, including patents, are incorporated herein by reference.

It is understood that the above description is illustrative and not restrictive. Numerous uses will be apparent to those skilled in the art in summary of the above description. However, the scope of the invention should not be determined by reference to the above description, but should be determined by reference to the appended claims, together with a complete framework of equivalents that are entitled as claims.

PATENT CLAIMS

Claims (19)

Aryl and heteroaryl peptide derivatives of the general formula I (I), in which Ar is C 6-10 aryl or C 6-10 heteroaryl having 1 or 2 ring nitrogen atoms, each of said aryl groups being substituted with hydroxyl in the ortho position relative to the amide side chain and optionally having additional substituents selected from -30CZ 289930 B6 halogen, C _M alkyl, C ^ alkoxy, Ci ^ alkylthio, trifluoromethyl, Ci ^ acyloxy, C, and _O-aryl, C-ioheteroaryl defined above, and hydroxy, with the proviso that the aromatic ring bearing the amide side chain is not further substituted with halogen, and with the further proviso that the aromatic ring bearing the amide side chain does not have C 1-4 alkyl 5 ortho to the hydroxyl, R ¹ is hydrogen, C ^ alkyl, C6-ioaryl-Ci_4alkyl and C ^ oheteroaryl-C ^ alkyl, in which ₀ C6_i heteroaryl is as defined above, 10 R ² is hydrogen or C₁₋₄ alkyl, R ³ is selected from the group consisting of radicals II to IX (II) (III) (IV) (V) (VI) (VII) (VIII) - (CH) -NH _{2 in} (IX) Wherein m to w are integers wherein m is 3 to 6, n is 0 to 3, p is 0 to 2, q is 0 to 2, r is 0 to 5, s is 0 to 2, t is 1 to 3, u is 1 or 2, v is 3 to 6, and w is 0 to 3, A is -CH = CH- or-C = C-aX is -NH- or-Cl L -, R ⁴ is C 1-4 alkyl, hydroxy substituted C 6-10 aryl-C 1-4 alkyl or hydroxy substituted C 6-10 heteroaryl-C 1-4 alkyl and wherein C 1-4 heteroaryl is as defined above, R ⁵ and R ^{6 are} each independently hydrogen, C 1-6 alkyl, hydroxy substituted C 6-10 aryl-C 1-4 alkyl or hydroxy substituted C 6-10 heteroaryl-C 1-4 alkyl, in which C 6-10 heteroaryl is as defined above, or R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxy substituted 4-, 5 or 6-membered heterocycle and R ⁶ is hydrogen, or R ⁴ and R ⁶ together with the nitrogen and carbon to which they are attached form a hydroxy substituted 4-, 5 or 6-membered heterocycle and R ⁵ is hydrogen, and R ⁷ is OR ⁸ or -NR ⁸ R ⁹ wherein R ⁸ and R ^{9 are} each independently hydrogen, C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkyl or C 1-4 heteroaryl-C 1-4 alkyl wherein C 1-4 heteroaryl has as defined above, or R ⁸ and R ⁹ together with the nitrogen to which they are attached form a hydroxyl and / or carbamoyl substituted 5- or 6-membered heterocycle, and pharmaceutically acceptable salts thereof. Derivatives according to claim 1, wherein said general formula (I), wherein: Ar is 1-hydroxy-2-naphthyl, 2-hydroxy-1-naphthyl, 3-hydroxy-2-pyridyl, 2-hydroxy-3-pyridyl, 2-hydroxy-3-quinoxalyl, 2-hydroxy-4-methylphenyl, 4-hydroxy-7-methyl-3- (1,8) naphthyridin-3-yl, 2-hydroxyphenyl, 2 ', 5'-dihydroxyphenyl or 4-hydroxy-3-biphenyl, R ¹ , R ² , R ⁵ and R ⁶ denote hydrogen, R ³ is selected from the group consisting of the radicals of formulas II-IX above wherein m to w are integers wherein m is 3 to 6, n is 0 to 3, p is 0 to 2, q is 0 to 2, r is 0 to 5, s is 0 to 2, t is 1 to 3, u is 1 or 2, v is 3 to 6 and w is 0 to 3, A is -CH = CH- or -CsC- and X is -NH- or -CH 2 -, R ⁴ is methyl, or R ⁴ and R ⁵ form with the nitrogen and carbon to which they are attached a hydroxyl-substituted 5-membered heterocycle, and R ⁷ is -OH, -OCH ₃ , -NH ₂ , -3'-carbamoyl-1-piperidyl, -4'-carbamoyl-1-piperidyl, -carbamoyl-2-phenylamino or -N (CH ₃ ) ₂ , and and pharmaceutically acceptable salts thereof. -32GB 289930 B6 3. A compound according to claim 2, wherein: Ar is 1-hydroxy-2-naphthyl, 2-hydroxy-1-naphthyl, 3-hydroxy-2-pyridyl or 2-hydroxy-3-quinoxalyl, R ¹ and R ² is hydrogen, R ³ is selected from the group consisting of radicals of formulas II to V wherein m to w are integers wherein m is 3 to 6, n is 0 to 3, p is 0 to 2, q is 0 to 2, and v is 0 to 3, A is -CH = CH- or -C = C- and X is -NH- or -CH ₂ and the other substituents have the meanings given above. A compound according to claim 3, wherein: A is 1-hydroxy-2-naphthyl, R ¹ , R ² and R ⁶ denote hydrogen, R ³ is - (CH ₂ ) ₃ NHC (= NH) NH ₂ , R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxyl-substituted 5-membered heterocycle and R ⁷ is-NH ₂ , which is specifically 1-hydroxy-2-naphthoyl-L-arginyl-L-prolinamide. 5. A compound according to claim 3 wherein: Ar is 2-hydroxy-1-naphthyl, R ¹ , R ² and R ⁶ denote hydrogen, R ³ is ~ (CH ₂ ) ₃ NHC (= NH) NH ₂ , R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxyl-substituted 5-membered N-heterocycle and R ⁷ is -NH ₂ , which is specifically 2-hydroxy-1-naphthoyl-L-arginyl-L-prolinamide. 6. Compounds according to claim 2, in which: Ar is 1-hydroxy-2-naphthyl, 2-hydroxy-1-naphthyl, 3-hydroxy-2-pyridyl or 2-hydroxy-3-quinoxalyl, R ¹ , R ² , R ⁵ and R ⁶ denote hydrogen, -33GB 289930 Β6 R ³ is selected from the group consisting of radicals of formulas II to V wherein m to w are integers wherein m is 3 to 6, n is 0 to 3, p is 0 to 2, q is 0 to 2 and w is 0 to 3, A is -CH = CH- or -OC- and X is -NH- or -CH ₂ R ⁴ is C 1-4 alkyl, or R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxy substituted 4-, 5 or 6-membered heterocycle and R ⁷ is -ΌΗ, -OCH ₃ , -NH ₂ , -3'-carbamoyl-1-piperidyl or -N (CH ₃ ) ₂ . 7. Compounds according to claim 6, in which: Ar is 1-hydroxy-2-naphthyl, R ^1, R ² and R ⁶ are individually hydrogen, R ³ is - (CH ₂ ) ₃ NHC (= NH) NH ₂ , R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxyl-substituted 5-membered N-heterocycle and R ⁷ is -NH ₂ . 8. A compound according to claim 6, wherein: Ar is 2-hydroxy-1-naphthyl, R ^1, R ² and R ⁶ are individually hydrogen, R ³ is - (CH ₂ ) ₃ NHC (= NH) NH ₂ , R ⁴ and R ⁵ together with the nitrogen and carbon to which they are attached form a hydroxyl-substituted 5-membered N-heterocycle and R ⁷ is -NH ₂ . Pharmaceutical compositions for the treatment of inflammatory diseases in mammals caused by immunodeficiency, characterized in that they contain, in an effective amount, aryl and heteroaryl peptide derivatives according to claims 1 to 8 in combination with a pharmaceutically acceptable carrier. Pharmaceutical compositions according to claim 9, characterized in that they comprise a non-toxic pharmaceutically acceptable carrier as a pharmaceutically acceptable carrier. Pharmaceutical compositions according to claim 9 for the treatment of inflammatory diseases of the respiratory tract, such as asthma and allergic rhinitis, characterized in that they contain as active ingredients the aryl and heteroaryl peptide derivatives according to claims 1 to 8 in a solution of an aerosolizable pharmaceutically acceptable carrier or dry powder. -34GB 289930 B6 Pharmaceutical compositions according to claim 11, characterized in that they comprise means for converting an aerosolizable pharmaceutically acceptable carrier or dry powder into an aerosol form suitable for inhalation and intranasal administration. Pharmaceutical compositions according to claim 11, characterized in that they contain the active ingredient according to claims 1 to 8 in said carrier solution in a concentration of 0.1 to 30 mg / ml. Pharmaceutical compositions according to claims 9 and 11, further comprising a β-adrenergic agonist. Pharmaceutical compositions according to claim 14, characterized in that they comprise a βadrenergic agonist selected from the group consisting of albuterol, tetrabutaline, formoterol, phenoterol and prenalin. Pharmaceutical compositions according to claims 9 and 11, further comprising an anti-inflammatory corticosteroid. Pharmaceutical compositions according to claim 16, characterized in that they comprise an anti-inflammatory corticosteroid selected from the group comprising beclomethasone, triamcinolone, flurisolide and dexamethasone. 18. The pharmaceutical composition of claim 12, further comprising ipratropium bromide. Pharmaceutical compositions according to claim 9 for the treatment of inflammatory conditions of the skin caused by immunodeficiency, characterized in that they contain as active ingredient aryl and heteroaryl peptide derivatives according to claims 1 to 8 in association with a pharmaceutically acceptable carrier.