Conjugates of montelukast and peptides

Abstract

There is provided a peptide-containing compound that comprises a peptide component which is an amino acid sequence of from 2 to 45 (e.g. from 6 to 15) amino acids, which peptide component is covalently bonded to one or more compounds of the formula I: wherein: R 1 is selected from the group consisting of —C(CH 3 ) 2 OH, —COCH 3 , —C(CH 3 )═CH 2 and —C(CH 3 ) 2 H; and n is 0, 1 or 2, as well as regioisomers, stereoisomers, and pharmaceutically- or cosmetically-acceptable salts of said peptide-containing compound. The compound of formula I is preferably montelukast, montelukast styrene or hydrogenated montelukast styrene. The peptide-containing compound is particularly useful in the treatment of conditions characterised by inflammation, including wounds, hemorrhoids, burns, psoriasis, acne, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, chronic obstructive pulmonary disease, inflammatory bowel disease (such as ulcerative colitis). Compounds of the invention are also useful in the treatment of idiopathic pulmonary fibrosis.

1 . A method of treatment of inflammation, an inflammatory disorder, and/or of a disorder characterised by inflammation, which method comprises the administration of a peptide-containing compound that comprises:
 a peptide component comprising the amino acid sequence X-Pro-Y-Z (SEQ ID NO: 5)   
       wherein:
 X represents 1 to 2 amino acid residues each independently selected from the group consisting of Ala and Lys; 
 Y is selected from the group consisting of Ser and pSer; 
 Z represents 1 to 7 amino acid residues each independently selected from the group consisting of Tyr, pTyr, 3Hyp, 4Hyp, Thr, pThr, DOPA and Lys; and 
 at least one of the Ala and/or Lys residues is covalently bonded to one or more compounds of formula I by an amide bond formed by reaction of the carboxylic acid group in formula I and one or more free amino groups in the Ala and/or Lys residues: 
 
       
         
           
           
               
               
           
         
         wherein: 
         the squiggly bond represents cis or trans orientation relative to the carbon-carbon double bond; 
         R 1  is selected from the group consisting of —C(CH 3 ) 2 OH, —COCH 3 , —C(CH 3 )═CH 2  and —C(CH 3 ) 2 H; and 
         n is 0, 1 or 2, 
       
       as well as regioisomers, stereoisomers, and pharmaceutically- or cosmetically-acceptable salts of said peptide-containing compound, or a pharmaceutical formulation comprising said compound or salt, to a patient in need of such treatment. 
     
     
         2 . The method as claimed in  claim 1 , wherein the inflammatory disorder is selected from psoriasis, acne, eczema, dermatitis, rhinitis, conjunctivitis, hemorrhoids, chronic obstructive pulmonary disease or inflammatory bowel disease. 
     
     
         3 . The method as claimed in  claim 2 , wherein the disorder is chronic obstructive pulmonary disease. 
     
     
         4 . The method as claimed in  claim 2 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         5 . The method as claimed in  claim 2 , wherein the disorder is allergic rhinitis or allergic conjunctivitis. 
     
     
         6 . The method as claimed in  claim 1 , wherein the disorder characterised by inflammation is, or results in, a wound or a burn. 
     
     
         7 . The method as claimed in  claim 6 , wherein the wound is an abrasion, a scratch, an incision, a laceration, a skin puncture, an avulsion, a bruise, a scar or a blister. 
     
     
         8 . The method as claimed in  claim 6 , wherein the disorder resulting in a wound is hemorrhoids or ulcerative colitis. 
     
     
         9 . The method as claimed in  claim 1 , wherein the compound(s) or salt thereof is administered topically in the form of a topical formulation. 
     
     
         10 . The method as claimed in  claim 9 , wherein the relevant condition is treated by way of direct topical administration to the skin. 
     
     
         11 . The method as claimed in  claim 9 , wherein the relevant condition is treated by way of direct topical administration to a mucosal surface. 
     
     
         12 . The method as claimed in  claim 1 , wherein the compound(s) is/are administered by oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, pulmonary or anorectal delivery. 
     
     
         13 . The method as claimed in  claim 3 , wherein the administration is pulmonary by way of a spray comprising a powder aerosol or an aqueous mist using atomization. 
     
     
         14 . The method as claimed in  claim 13 , wherein the spray is liquid comprising a water (aerosol) spray and the excipients may comprise one of more of a viscosity modifier, a sugar, an emulsifier, a buffering agent, an alcohol and a preservative. 
     
     
         15 . The method as claimed in  claim 13 , wherein administration is conducted from an inhalation device selected from a pressurized metered-dose inhaler, a dry powder inhaler, a soft mist inhaler or a nebulizer. 
     
     
         16 . The method as claimed in  claim 6 , wherein the wounds is acute, chronic or may result from an inflammatory disorder. 
     
     
         17 . The method as claimed in  claim 16 , wherein the wound comprises an ulcer of the skin or the mucosa. 
     
     
         18 . The method of  claim 17 , wherein the ulcer is a hard to heal skin ulcer. 
     
     
         19 . The method as claimed in  claim 6 , wherein the peptide-containing compound treats one or more of the symptoms associated with the wound or burn or the healing process associated therewith, selected from: inflammation, pain and aching, itching or the peptide-containing compound prevents the exudation of body fluids, the risk of infection or a physiological reaction resulting from inflammation and/or the wound healing process. 
     
     
         20 . The method as claimed in  claim 19 , wherein the physiological reaction comprises scarring and/or melanin pigmentation. 
     
     
         21 . The method as claimed in  claim 2 , wherein the dermatitis is selected from contact dermatitis, allergic dermatitis, atopic dermatitis, seborrheic dermatitis, steroid-dependent dermatitis, light-sensitive seborrheid, perioral dermatitis, rosacea-like dermatitis, steroid-rosacea, steroid-induced rosacea, iatrosacea, steroid dermatitis resembling rosacea, topical corticosteroid-induced rosacea-like dermatitis, facial corticosteroid addictive dermatitis and facial corticosteroid-dependent dermatitis. 
     
     
         22 . The method as claimed in  claim 21 , wherein the dermatitis is atopic dermatitis. 
     
     
         23 . The method as claimed in  claim 1 , wherein the inflammatory disorder is one of the skin, selected from the group: herpes, drug eruptions, polymorphous light eruptions, sunburn, early manifestations of skin cancers, erythema-like skin lesions, pathological hair loss, including pathological hair loss following skin grafting, chemo rash, erythema multiforme, folliculitis, and external otitis. 
     
     
         24 . The method as claimed in  claim 1 , wherein the inflammatory disorder is one of the eye and surrounding area, selected from the group: conjunctivitis, keratitis, acute epithelial keratitis, nummular keratitis, interstitial keratitis, disciform keratitis, neurotrophic keratitis, mucous plaque keratitis, herpes simplex keratitis, herpes zoster keratitis, bacterial keratitis, fungal keratitis acanthamoebic keratitis, onchocercal keratitis, superficial punctate keratitis, ulcerative keratitis, exposure keratitis photokeratitis and contact lens acute red eye, and optic neuritis. 
     
     
         25 . The method as claimed in  claim 1 , wherein the disorder characterized by inflammation is a disorder of the respiratory system and is selected from the group: pulmonary cystic fibrosis, usual interstitial pneumonia, allergic pneumonia, asbestosis, emphysema, pulmonary heart disease, pulmonary embolism, silicosis, acute bronchitis, chronic bronchitis, tracheobronchitis, asthma, bronchial asthma, status asthmatics, bronchiectasis, upper respiratory tract infections, including the common cold and influenza), allergic airway inflammation, bacterial pneumonia, viral pneumonia, mycoplasma pneumonia, reckettsia, radiaton pneumonia, pneumococcal (including staphylococcal, streptococcal and gram-negative bacillus) pneumonia, pulmonary candidiasis (including aspergillosis, mucormycosis, histoplasmosis, actinomycosis and nocardiosis), pulmonary mycosis, cryptococcosis, lung abscesses, anaphylactic pneumonia (Leoffer's syndrome), extrinsic allergic alveolitis, pulmonary eosinophia (eosinophilosis), obstructive pulmonary emphysema, pulmonary edema, pulmonary tuberculosis, respiratory alkalosis (acidosis), acute lung injury, interstitial lung disease, empyema, lung fibroma and cor pulmonale. 
     
     
         26 . The method as claimed in  claim 25 , wherein the disorder is selected from the group: usual interstitial pneumonia, asthma, bronchial asthma, acute or chronic bronchitis and acute lung injury. 
     
     
         27 . The method as claimed in  claim 1 , wherein the disorder characterized by inflammation is characterized by mucosal inflammation and is selected from the group: oral mucositis, aphthous ulcers, otitis media, laryngitis, tracheitis, esophagitis, gastritis, enteritis and enterocolitis, bacillary dysentery, chronic amoebic dysentery, schistosomiasis, nonspecific ulcerative colitis and regional enteritis, cervicitis, endocervicitis, endometritis, and mucosal inflammation associated with inhalation injury, cancers, and infections. 
     
     
         28 . The method as claimed in  claim 27 , wherein the disorder is selected from: oral mucositis, enterocolitis, and a viral infection selected from the common cold, influenza, severe acute respiratory syndrome, herpes zoster and varicella-zoster. 
     
     
         29 . The method as claimed in  claim 1 , wherein the disorder characterized by inflammation is selected from the group: pericarditis, myocarditis, endocarditis, pneumonia, hepatitis, splenitis, nephritis pancreatitis, cystitis, oophoritis, prostatitis and gastric ulcers. 
     
     
         30 . The method as claimed in  claim 29 , wherein the disorder is cystitis. 
     
     
         31 . The method as claimed in  claim 1 , wherein the inflammatory disorder comprises inflammation of the vaginal mucosa, the cervical mucosa or the anorectal mucosa. 
     
     
         32 . The method as claimed in  claim 1 , wherein the inflammatory disorder is associated with melanin pigmentation. 
     
     
         33 . The method as claimed in  claim 32 , wherein the disorder comprises chloasma, freckles, melanosis, malar rash, a chromatosis, a skin cancer with melanoma, or a chromatosis that is caused by exposure to the sun or a skin disease. 
     
     
         34 . The method as claimed in  claim 1 , wherein the peptide component of the peptide-containing compound is covalently bonded through an N-terminal Ala or Lys residue and/or a C-terminal Lys residue. 
     
     
         35 . The method as claimed in  claim 1 , wherein:
 (a) at least one of the amino acids in the peptide component of the peptide-containing compound is lysine; and/or   (b) at least about 10% of the amino acids in the peptide component peptide-containing compound contain an aromatic group.   
     
     
         36 . The method as claimed in  claim 35 , wherein the amino acids that contain an aromatic group are selected from the group consisting of tyrosine and 3,4-dihydroxyphenylalanine. 
     
     
         37 . The method as claimed in  claim 1 , wherein the peptide component of the peptide-containing compound comprises or consists of the amino acid sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID No: 7) 
                 
                     
                   G 1 -Lys-Pro-G 2 -T-Hyp-G 3 -Lys, 
                 
             
                
                
               
            
           
         
         wherein 
         G 1  is absent or represents Ala; 
         G 2  is selected from the group consisting of Ser and pSer; 
         T is selected from the group consisting of DOPA, Tyr and pTyr; 
         Hyp is selected from the group consisting of 3Hyp and 4Hyp; 
         G 3  represents 1 to 4 amino acid residues each independently selected from the group consisting of Tyr, pTyr, 3Hyp, 4Hyp, Thr, pThr and DOPA. 
       
     
     
         38 . The method as claimed in  claim 37 , wherein G 1  represents Ala. 
     
     
         39 . The method as claimed in  claim 37 , wherein the peptide component of the peptide-containing compound comprises or consists of the amino acid sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID No: 9) 
                 
                     
                   Ala-Lys-Pro-G 2 -T-Hyp-Hyp-Thr-G 4 -Lys, 
                 
             
                
                
               
            
           
         
         wherein G 4  is selected from the group consisting of Tyr, pTyr, 3Hyp, 4Hyp, Thr, pThr and DOPA. 
       
     
     
         40 . The method as claimed in  claim 39 , wherein:
 (a) G 2  represents Ser;   (b) T represents Tyr; and/or   (c) G 4  represents Tyr or DOPA.   
     
     
         41 . The method as claimed in  claim 39 , wherein the peptide component of the peptide-containing compound comprises or consists of the amino acid sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 4) 
                 
                     
                   Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys; 
                 
                     
                 
                     
                   (SEQ ID NO: 11) 
                 
                     
                   Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA- Lys; 
                 
                     
                 
                     
                   (SEQ ID NO: 12) 
                 
                     
                   Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys; 
                 
                     
                 
                     
                   (SEQ ID NO: 13) 
                 
                     
                   Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Lys; 
                 
                     
                 
                     
                   (SEQ ID NO: 18) 
                 
                     
                   Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys; 
                 
                     
                 
                     
                   (SEQ ID NO: 19) 
                 
                     
                   Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys; 
                 
                     
                 
                     
                   (SEQ ID NO: 20) 
                 
                     
                   Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys; 
                 
                     
                 
                     
                   (SEQ ID NO: 21) 
                 
                     
                   Ala-Lys-Pro-pSer-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys; 
                 
                     
                 
                     
                   (SEQ ID NO: 22) 
                 
                     
                   Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys, 
                 
                     
                 
                     
                   (SEQ ID NO: 23) 
                 
                     
                   Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-DOPA-Hyp-Lys; 
                 
                     
                 
                     
                   (SEQ ID NO: 24) 
                 
                     
                   Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys; 
                 
                     
                   or 
                 
                     
                 
                     
                   (SEQ ID NO: 25) 
                 
                     
                   Ala-Lys-Pro-pSer-Tyr-Hyp-Thr-Tyr-Hyp-Lys. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         42 . The method as claimed in  claim 41 , wherein the peptide component of the peptide-containing compound comprises or consists of the amino acid sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 12) 
                 
                     
                   Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys; 
                 
                     
                   or 
                 
                     
                 
                     
                   (SEQ ID NO: 24) 
                 
                     
                   Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         43 . The method as claimed in  claim 1 , wherein the one or more compounds of formula I is selected from the group consisting of montelukast, montelukast styrene, or hydrogenated montelukast styrene. 
     
     
         44 . The method according to  claim 43 , wherein the peptide component of the peptide-containing compound comprises the amino acid sequence of 
       
         
           
                 
                 
               
                     
                   (SEQ ID No: 24) 
                 
                     
                   Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys, 
                 
             
                
                
               
            
           
         
         the compound of formula I is montelukast, and wherein the montelukast is covalently bonded to the N-terminal Ala residue.