Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• This invention relates to organic compounds which are VLA-4 antagonists, the preparation of such compounds and their use as pharmaceuticals
• Cell adhesion (i.e., a process bv which cells associate with each other, migrate towards a specific target, or localize within the extracellular matrix) underlies many biological phenomena.
• Cell adhesion causes adhesion of hemoatopoie ⁇ c to endothehal cells and the subsequent migration of those hemopoietic cells out of blood vessels and to the site of injury, thus playing a role in mammalian pathologies such as inflammation and immune reactions.
• Integrins are the key mediators in adhesive interactions between hematopoietic and other cells Integrins are non- covalent heterodime ⁇ c complexes consisting of two subunits, ⁇ and ⁇ . Depending on the type of its ⁇ and ⁇ subunit components, each integ ⁇ n molecule is categorized into its own subfamil) There are at least 12 different ⁇ subunits ( l- ⁇ 6, ⁇ -L, ⁇ -M, ⁇ -X, ⁇ -IIB, -V, and ⁇ -E) and at least 9 different ⁇ subunits ( ⁇ l- ⁇ 9).
• VLA-4 very late ant ⁇ gen-4
• VCAM-1 vascular cell adhesion molecule-1
• FN extracellular matrix protein fibronectin
• Ri is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aryl- substituted alkvl (aralkyl), aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkoxy, alkenoxy, alkynoxy, aryl- substituted alkoxy (aralkoxy), aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, N-alkylureido-substi
• R 3 is H, alkyl, alkenyl, aryl, or heteroaryl
• R4 is H, aryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and aryl-substituted alkyl, heterocyclyl, heterocyclylcarbonyl, aminocarbonyl, amido, mono- or dialkylaminocarbonyl, mono- or diarylaminocarbonyl, alkylarylaminocarbonyl, diarylaminocarbonyl, mono- or diacylaminocarbonyl, aromatic or aliphatic acyl, or alkyl optionally substituted by substituents selected from the group consisting of amino, halo, hydroxy, mercapto, mono- or dialkylamino, mono- or diarylamino, alkylarylamino, mono- or diacylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thioalkenoxy, thioalkynoxy, thioaryloxy, and heterocyclyl; R 5
• R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, aralkoxy-substituted alkyl, amino-substituted alkyl, (aryl-substituted alkyloxycarbonylamino)-substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted alkyl, (hydroxy-substituted alkylthio)-substituted alkyl, thioalkoxy-substituted alkyl, acylamino-substituted alkyl, alkylsulfonylamino-substituted alkyl, arylsulf
• R 7 and R 8 are independently H, alkyl, alkenyl, carbocyclic aryl, heteroaryl, or alkyl, alkenyl, carbocyclic aryl or heteroaryl substituted by 1-3 substituents selected from the group consisting of amino, hydroxy, mercapto, mono- or dialkylamino, mono- or diarylamino, alkylarylamino, diarylamino, mono- or diacylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thioalkenoxy, thioalkynoxy, thioaryloxy, and heterocyclyl;
• R 2 and R 6 taken together with the atoms to which they are attached may form a heterocycle
• V is O, NH, S, SO, or SO 2 ;
• X is CO 2 R 5 , PO 3 H, SO 2 R 5) SO 3 H, OPO 3 H, CO 2 H, or CON(R4) 2 ;
• W is CH or N;
• Y is CO, S0 2 , or P0 2 ;
• Z is (CH 2 ) nl , CHR 6 , or NR 7 ; n and n' are independently 0-4; m is 1-4; p is 1-4; q and q 1 are independently 1-5; and r is 0 or 1; or pharmaceutically acceptable salts thereof.
• VLA-4 antagonists are VLA-4 antagonists and useful to prevent, suppress, or inhibit cell adhesions.
• VLA-4-mediated cell adhesion disease states particularly inflammation and autoimmune diseases.
• They are particularly useful in surgery-induced inflammation, especially transplant surgery.
• the compounds of the invention may be used alone or in combination with other agents active in the prevention, suppression, or inhibition of cell adhesion.
• Another embodiment of the invention is a pharmaceutical composition, particularly a composition for VLA-4 antagonism, comprising an effective amount of a compound of the invention, optionally together with a pharmaceutically acceptable carrier.
• the present invention also provides compounds of the invention, i.e. compounds of formula I or pharmaceutically acceptable salts thereof, for use as pharmaceuticals, particularly in VLA-4 antagonism.
• the invention provides a method of antagonizing VLA-4 in a mammal which comprises administering to a mammal, preferably man, in need of such treatment an effective amount of a compound of the invention.
• the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a disease mediated by VLA-4.
• Preferred compounds of the invention are those of formula la wherein
• R 2 is C].4alkyl-oxy-C ⁇ . 8 alkyl
• R 4 is H, alkyl, alkenyl, carbocyclic aryl or heteroaryl
• X is CO 2 H or C0 2 alkyl; and the other symbols are as defined for formula I; or pharmaceutically acceptable salts thereof.
• More-preferred compounds of the invention are those of formula la wherein Rj is aryl; R 2 is methoxy-n-propyl; R 3 is H; R 4 is alkenyl or aryl; X is CO 2 H; n is 0; and W is CH; or pharmaceutically acceptable salts thereof.
• R1 is N-arylureidophenyl
• R 2 is C ⁇ -C 4 -alkyl-oxy-C 2 -C 4 -alkyl
• R 3 is H
• R 4 is H, C ⁇ -C -alkyl, C 2 -C 4 -alkenyl or carbocyclic aryl; n is 1 or 2; m is 1, 2 or 3;
• X is COOH or CO 2 R 5 ;
• R 5 is optionally substituted lower alkyl; or pharmaceutically acceptable salts thereof.
• Preferred are the compounds of formula lb wherein
• Ri is N-(optionally substituted phenyl)-ureidophenyl
• R is methoxypropyl
• R 3 is H
• R 4 is C 2 -C 4 -alkenyl or optionally substituted phenyl; n is 1; m is 1; and
• X is COOH; or pharmaceutically acceptable salts thereof.
• R a is H, CH 3 , Cl or NH 2 ;
• R 2 is (CH 2 ) 3 OCH 3 or (CH 2 ) 4 OCH 3 ;
• Alkyl means a straight-chain or branched-chain alkyl radical containing from 1 to 10, preferably from 1 to 6, and more preferably from 1 to 4, carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, and decyl.
• Alkenyl means a straight-chain or branched-chain alkenyl radical containing from 2 to 10, preferably from 2 to 6, and more preferably from 2 to 4, carbon atoms.
• examples of such radicals include etheryl, E- and Z-propenyl, isopropenyl, E- and Z- butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, and decenyl.
• “Lower” in conjunction with the above terms means a said radical containing up to 6 carbon atoms.
• Substituted in conjunction with the above terms means a said radical substituted by e.g. amino, halo, hydroxy, mercapto, mono- or dialkylamino, mono- or di- arylalkylamino, mono- or diarylamino, alkoxy, aryloxy, aryl, thioaryloxy, thioalkoxy or heterocyclyl.
• Alkynyl means a straight-chain or branched-chain alkynyl radical containing from 2 to 10, preferably from 2 to 6, and more preferably from 2 to 4, carbon atoms. Examples of such radicals include ethynyl (acetylenyl), propynyl, propargyl, butynyl, hexynyl, and decynyl.
• Cycloalkyl means a cyclic alkyl radical containing from 3 to 8, preferably from 3 to 6, carbon atoms. Examples of such cycloalkyl radicals include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopropyl methyl.
• Cycloalkenyl means a cyclic carbocycle containing from 4 to 8, preferably 5 to 6, carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include cyclopentenyl, cyclohexenyl, cyclopentadienyl, and 2-methyl-2-butenyl.
• Aryl means carbocyclic or heterocyclic aryl (heteroaryl).
• Aryl (carbocyclic aryl and heteroaryl) means a 5- or 6-membered carbocyclic aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, and S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, and S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, and S; each of which rings is optionally substituted with 1-3 substituents selected from e.g.
• alkenyl, alkynyl, substituted lower alkyl, substituted alkenyl, substituted alkynyl, O, NO 2 , halogen, hydroxy, alkoxy, cyano, -NR ' R', acylamino, phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, and heteroaryloxy, wherein each of said phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, and heteroaryloxy is optionally substituted with 1-3 substituents selected from e.g.
• the carbocyclic aromatic ring systems comprise phenyl, naphthyl, indenyl, indanyi, azuienyl, fluorenyl, anthracenyl.
• the heterocyclic aromatic ring systems comprise furyl, thienyl, pyridyl, pyrrolyl, oxazolyly, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purin
• Aryl as it relates in particular to the grouping Ri in the above formulae, means carbocyclic or heterocyclic aryl, particularly phenyl optionally substituted by one to three substituents which are independently selected from e.g. halo, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, cyano, carboxy, carboalkoxy, Ar'-substituted alkyl, Ar'-substituted alkenyl or alkynyl, 1,2- dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy or alkynoxy, Ar'-substituted alkoxy, Ar'-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, Ar'-substituted alkylamino, Ar'-substituted alkenylamino or alkynyl
• Alkoxy means an alkyl ether radical.
• alkyl ether radicals include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert- butoxy.
• Alkenoxy means a radical of formula alkenyl-O-, provided that the radical is not an enol ether.
• alkenoxy radicals include allyloxy and E- and Z-3- methyl-2-propenoxy.
• Alkynyloxy means a radical of formula alkynyl-O-, provided that the radical is not an ynol ether.
• alkynoxy radicals examples include propargyloxy and 2-butynyloxy.
• Thioalkoxy means a thioether radical of formula alkyl-S-.
• Alkylamino means a mono- or di-alkyl-substituted amino radical (i.e., a radical of formula alkyl-NH- or (alkyl) 2 -N-).
• alkylamino radicals include methylamino, ethylamino, propylamino, isopropylamino, t-butylamino, and N,N- diethylamino.
• Alkenylamino means a radical of formula alkenyl-NH- or (alkenyl) 2 N-, provided that the radical is not an enamine.
• An example of an alkenylamino radical is the allylamino radical.
• Alkynylamino means a radical of formula alkynyl-NH-or (alkynyl) 2 N-, provided that the radical is not an ynamine.
• An example of an alkynylamino radical is the propargyl amino radical.
• Aryloxy means a radical of formula aryl-O-. Examples of aryloxy radicals include phenoxy, naphthoxy, and pyridyloxy.
• Arylamino means a radical of formula aryl-NH-.
• arylamino radicals include phenylamino (anilido), naphthylamino, 2-, 3- or 4-pyridylamino.
• Biaryl means a radical of formula aryl-aryl-.
• Thioaryl means a radical of formula aryl-S-.
• An example of a thioaryl radical is the thiophenyl radical.
• Aryl-fused cycloalkyl means a cycloalkyl radical which shares two adjacent atoms with an aryl radical.
• An example of an aryl-fused cycloalkyl radical is the benzofused cyclobutyl radical.
• Aliphatic acyl means a radical of the formula alkyl-CO-, alkenyl-CO-, or alkynyl-CO- derived from a carboxylic acid.
• aliphatic acyl radicals include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl, crotyl, propiolyl, and methylpropiolyl.
• Aromatic acyl means a radical of the formula aryl-CO-. Examples of aromatic acyl radicals include benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyl, and pyridylcarbonyl.
• “Morpholinocarbonyl” and “thiomorpholinocarbonyl” mean an N-carbonylated morpholino and an N- carbonylated thiomorpholino radical, respectively.
• “Alkylcarbonylamino” means a radical of formula alkyl-CONH-.
• “Alkoxycarbonylamino” means a radical of formula alkyl-OCONH-.
• “Alkylsulfonylamino” means a radical of formula alkyl-SO 2 NH-.
• “Arylsulfonylamino” means a radical of formula aryl-SO 2 NH-.
• N-alkylurea or “N- alkylureido” means a radical of formula alkyl-NH-CO-NH-.
• N-arylurea or “N- arylureido” means a radical of formula aryl-NH-CO-NH-.
• Halogen or “halo” means fluoro, chloro, bromo, and iodo.
• Heterocycle unless otherwise defined herein, means a stable 3-7 membered monocyclic heterocyclic ring or an 8-11 membered bicyclic heterocyclic ring which is saturated or unsaturated, and which may be optionally benzofused.
• Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from nitrogen, oxygen, and sulfur, any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Any ring nitrogen may be optionally substituted with a substituent R 4 , as defined herein for compounds of formula I.
• a heterocycle may be attached at any endocyclic carbon or heteroatom which results in the creation of a stable structure. Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles. Heterocycles may be optionally oxo-substituted at 1-3 ring positions and may optionally be independently substituted with 1-4 aryl substituents. Included are heteroaryl groups as defined herein and saturated heterocycles such as piperidine, morpholine, pyrrolidine, thiazolidine, piperazine and the like.
• -N(R 4 ) 2 represents -NH 2 , -NHCH 3 , -N(CH 3 ) 2 etc.
• compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and may also contain a pharmaceutically acceptable carrier and, optionally, other therapeutic ingredients.
• pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including organic and inorganic acids or bases.
• salts may be prepared from pharmaceutically acceptable non-toxic bases.
• Salts derived from all stable forms of inorganic bases include aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, etc. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethyl- aminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc.
• basic ion-exchange resins such as arginine, betaine, caffeine,
• salts may be prepared from pharmaceutically acceptable non-toxic acids.
• acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, etc.
• Particularly preferred are citric, hydrobromic, maleic, phosphoric, sulfuric, and tartaric acids.
• Base salts also include ammonium, alkali metal, and alkaline earth metal salts, salts with organic bases, such as dicyclohexylamine salts, and salts with amino acids such as arginine and lysine.
• basic nitrigen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl chloride, dialkyl sulfates, such as dimethyl, sulfates, long chain halides such as stearyl chlorides, and aralkyl halides, such as benzyl chlorides.
• the compounds of the invention are particularly useful in mammals as VLA-4 antagonists and as inhibitors of VLA-4 associated cell adhesion.
• the ability of the compounds of formula I to inhibit VLA-4-associated cell adhesions makes them useful for treating, ameliorating, or preventing a variety of inflammatory, immune and autoimmune diseases.
• the diseases to be treated with the methods of this invention are selected from respiratory disorders (such as asthma), arthritis, psoriasis, transplantation rejection, multiple sclerosis, type I diabetes, and inflammatory bowel disease, stem cell mobilization and engraphment, and sickle cell anemia.
• the compounds of formula I are also useful in transplantation surgery; specifically, for the treatment of xenograft and allograft rejection, both chronic and acute.
• the compounds of the invention are useful as agents for the symptomatic or prophylactic treatment of inflammatory airways diseases.
• Such diseases include asthma of whatever type or genesis including both intrinsic (non- allergic) asthma and, especially, extrinsic (allergic) asthma. They are useful for the treatment of bronchitic asthma, exercise-induced asthma, occupational asthma, asthma induced following bacterial infection and other non-allergic asthmas.
• Treatment of asthma is also to be understood as embracing treatment of patients of less than 4 or 5 years of age exhibiting wheezing symptoms, particularly at night and diagnosed or diagnosable as "whez infants".
• Prophylactic efficacy in the treatment of asthma may be manifested by reduced frequency or reduced severity of symptomatic attack, improvement in lung function or improved airways hypereactivity. It may be further evidenced by reduced requirement for symptomatic therapy, i.e. therapy for, or intended to restrict or abort, symptomatic attack when it occurs, for example for anti-inflammatory therapy using a corticosteroid.
• symptomatic therapy i.e. therapy for, or intended to restrict or abort, symptomatic attack when it occurs, for example for anti-inflammatory therapy using a corticosteroid.
• pneumoconiosis an inflammatory, commonly occupational, disease of the lungs occasioned by repeated inhalation of dusts
• pneumoconiosis an inflammatory, commonly occupational, disease of the lungs occasioned by repeated inhalation of dusts
• aluminosis asbestosis, chalicosis, siderosis, silicosis, tabacosis and byssinosis.
• inflammatory airways diseases which may be treated with compounds of the invention include adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) in the exacerbation phase thereof and exacerbation of airways hyperactivity consequent to other drug therapy, e.g. aspirin or b-agonist bronchodilator therapy.
• ARDS adult respiratory distress syndrome
• COPD chronic obstructive pulmonary disease
• compounds of the invention are also useful for the treatment of related disorders of the airways, e.g. eosinophilia, hypereosinophilia, eosinophilic pneumonia, parasitic infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa, eosinophilic granuloma and eosinophil-related disorders affecting the airways caused by drug- reaction.
• related disorders of the airways e.g. eosinophilia, hypereosinophilia, eosinophilic pneumonia, parasitic infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa, eosinophilic granuloma and eosinophil-related disorders affecting the airways caused by drug- reaction.
• Compounds of the invention may also be used in the treatment of allergic inflammatory diseases such as allergic rhinitis.
• the invention includes: (A) the use of a compound of the invention, i.e. a compound of formula I or a pharmaceutically acceptable salt thereof, as hereinbefore described, for the preparation of a medicament for the treatment of inflammatory, immune or autoimmune diseases, particularly arthritis, transplant rejection or inflammatory airways diseases, especially asthma; and
• the dosage in vitro may range between about 10 6 and 10 10 molar concentrations, preferably between about 10 7 and 10 9 molar concentrations.
• the magnitude of the prophylactic or therapeutic dose of the compounds of the invention will vary with the nature and severity of the condition to be treated with the mammal involved and with the particular compound of the invention and its route of administration.
• the daily dose range lies in the range of 200 to 0.001 mg/kg body weight of a mammal, preferably 50 to 0.05 mg/kg, and most preferably 1.0 to 0.1 mg/kg, in single or divided doses. In some cases, it may be necessary to use doses outside these ranges.
• a suitable daily dosage range is from about 50 to 0.0005 mg (preferably 20 to 0.01 mg) compound of the invention per kg body weight.
• a suitable daily dosage range is from about 20 to 0.001 mg (preferably 10 to 0.01 mg) compound of the invention per kg body weight.
• a suitable daily dosage range is from about 10-0.01 % (preferably 5.0-0.5% compound of the invention, typically prepared as a 2.0-0.1 % by weight solution or suspension of the compound in an acceptable ophthalmic formulation.
• a typical ocular formulation may comprise the compound alone or in combination with a b-adrenergic blocking agent such as ⁇ molol maleate or a parasympathomimetic agent such as pilocarpine.
• a b-adrenergic blocking agent such as ⁇ molol maleate or a parasympathomimetic agent such as pilocarpine.
• the two active ingredients are present in approximately equal parts.
• Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the invention.
• oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. routes may be employed.
• Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
• compositions of the present invention comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, as an active ingredient, and may also contain a pharmaceutically acceptable carrier and, optionally, other therapeutically active ingredients.
• the invention includes such compositions for use in the treatment of an inflammatory, immune or autoimmune disease, particularly arthritis, transplant rejection or an inflammatory airways disease, especially asthma.
• compositions include compositions suitable for oral, rectal, topical (including transdermal devices, aerosols, creams, ointments, lotions, and dusting powders), parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration; although the most suitable route in any given case will depend largely on the nature and severity of the condition being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
• compounds of the invention may be administered orally, for example in tablet form, or by inhalation, for example in aerosol or other atomisable formulations or in dry powder formulations, using an appropriate inhalation device such as those known in the art.
• inhalation for example in aerosol or other atomisable formulations or in dry powder formulations, using an appropriate inhalation device such as those known in the art.
• the compounds of the invention may also be administered intranasally.
• a compound of the invention may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier may take a wide variety of forms depending on the nature of the preparation desired for administration, i.e., oral, parenteral, etc.
• any of the usual pharmaceutical media may be used, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (e.g., suspensions, elixirs, and solutions); or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc.
• capsules in the case of oral solid preparations such as powders, capsules, and tablets. Solid oral preparations are preferred over liquid oral preparations. Because of their ease of administration, tablets and capsules are the preferred oral dosage unit form. If desired, capsules may be coated by standard aqueous or non-aqueous techniques.
• the compounds of the invention may be administered by controlled release means and devices.
• compositions of the present invention suitable for oral administration may be prepared as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient in powder or granular form or as a solution or suspension in an aqueous or nonaqueous liquid or in an oil-in-water or water-in-oil emulsion.
• Such compositions may be prepared by any of the methods known in the art of pharmacy.
• the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers, finely divided solid carriers, or both and then, if necessary, shaping the product into the desired form.
• a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granule optionally mixed with a binder, lubricant, inert diluent, or surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Ophthalmic inserts are made from compression molded films which are prepared on a Carver Press by subjecting the powdered mixture of active ingredient and HPC to a compression force of 12,000 lb. (gauge) at 149°C for 1-4 min. The film is cooled under pressure by having cold water circulate in the platen.
• a free-flowing form such as powder or granule optionally mixed with a binder, lubricant, inert diluent, or surface active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine, a mixture of the
• the inserts are then individually cut from the film with a rod-shaped punch. Each insert is placed in a vial, which is then placed in a humidity cabinet (88% relative humidity at 30°C) for 2-4 days. After removal from the cabinet, the vials are capped and then autoclaved at 121°C for 0.5 hr.
• compositions containing a compound of this invention may also comprise an additional agent selected from the group consisting of cortiocosteroids, bronchodilators, antiasthmatics (mast cell stabilizers), anti-inflammato ⁇ es, antirheumatics, immunosuppressants, antimetabohtes, immunonodulators, antipso ⁇ atics, and antidiabetics.
• an additional agent selected from the group consisting of cortiocosteroids, bronchodilators, antiasthmatics (mast cell stabilizers), anti-inflammato ⁇ es, antirheumatics, immunosuppressants, antimetabohtes, immunonodulators, antipso ⁇ atics, and antidiabetics.
• Specific compounds include theophyllme, sulfasalazine and aminosalicylates (anti-inflammato ⁇ es); cyclospo ⁇ n, FK-506, and rapamycin (immunosuppressants); cyclophosphamide and methotrexate (antimetabohtes); and interferons (immunomodulators).
• the invention includes a compound of the invention as hereinbefore described in inhalable form and an inhalable medicament comprising such a compound in inhalable form optionally together with a pharmaceutically acceptable carrier in inhalable form.
• the inhalable form may be, for example, an atomisable composition such as an aerosol comprising the compound of the invention in solution or dispersion in a propellant or a nebulizable composition comprising a dispersion of the compound of the invention in an aqueous, organic or aqueous/organic medium, or a finely divided paniculate form comprising the compound of the invention in finely divided form optionally together with a pharmaceutically acceptable carrier in finely divided form.
• an atomisable composition such as an aerosol comprising the compound of the invention in solution or dispersion in a propellant or a nebulizable composition comprising a dispersion of the compound of the invention in an aqueous, organic or aqueous/organic medium, or a finely divided paniculate form comprising the compound of the invention in finely divided form optionally together with a pharmaceutically acceptable carrier in finely divided form.
• An aerosol composition suitable for use as the inhalable form may comprise the compound of the invention in solution or dispersion in a propellant, which may be chosen from any of the propellants known in the art.
• propellants include hydrocarbons such as n-propane, n-butane or isobutane or mixtures of two or more such hydrocarbons, and halogen-substituted hydrocarbons, for example fluorine- substituted methanes, ethanes, propanes, butanes, cyclopropanes or cyclobutanes, particularly 1,1,1,2-tetrafluoroethane (HFA134a) and heptafluoropropane (HFA227), or mixtures of two or more such halogen-substituted hydrocarbons.
• hydrocarbons such as n-propane, n-butane or isobutane or mixtures of two or more such hydrocarbons
• halogen-substituted hydrocarbons for
• the aerosol composition may also contain a lubricant and a surfactant, which may be chosen from those lubricants and surfactants known in the art.
• the aerosol composition may contain up to about 5% by weight, for example 0.002 to 5%, 0.01 to 3 %, 0.015 to 2%, 0.1 to 2%, 0.5 to 2% or 0.5 to 1 %, by weight of the compound of the invention, based on the weight of the propellant.
• the lubricant and surfactant may be in an amount up to 5% and 0.5% respectively by weight of the aerosol composition.
• the aerosol composition may also contain ethanol as co-solvent in an amount up to 30% by weight of the composition, particularly for administration from a pressurised metered dose inhalation device.
• a finely divided particulate form i.e. a dry powder, suitable for use as the inhalable form may comprise the compound of the invention in finely divided particulate form, optionally together with a finely divided particulate carrier, which may be chosen from materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides and polysaccharides such as arabinose, glucose, fructose, ribose, mannose, sucrose, lactose, maltose, starches or dextran. As especially preferred carrier is lactose.
• the dry powder may be in capsules of gelatin or plastic, or in blisters, for use in a dry powder inhalation device, preferably in dosage units of 5 ⁇ g to 40 mg of the active ingredient.
• the dry powder may be contained as a reservoir in a multi-dose dry powder inhalation device.
• the compound of the invention may have an average particle diameter of up to about 10 ⁇ m, for example 1 to 5 ⁇ m.
• the particle size of the compound of the invention, and that of a solid carrier where present in dry powder compositions, can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, microprecipitation, spray-drying, lyophilisation or recrystallisation from supercritical media.
• the inhalable medicament may be administered using an inhalation device suitable for the inhalable form, such devices being well known in the art.
• the invention also provides a pharmaceutical product comprising a compound of the invention in inhalable form as hereinbefore described in association with an inhalation device.
• the invention provides an inhalation device containing a compound of the invention in inhalable form as hereinbefore described.
• the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, such as 10 to 100 ⁇ l, e.g. 25 to 50 ⁇ l, of the composition, i.e. a device known as a metered dose inhaler.
• a metered dose such as 10 to 100 ⁇ l, e.g. 25 to 50 ⁇ l
• Suitable such aerosol vials and procedures for containing within them aerosol compositions under pressure are well known to those skilled in the art of inhalation therapy.
• the inhalation device may be a known nebulizer, for example a conventional pneumatic nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion; or a hand-held nebulizer such as an AERx (ex Aradigm, US) or BINEB (Boehringer Ingelheim) nebulizer which allows much smaller nebulized volumes, e.g. 10 to 100 ⁇ l, than conventional nebulizers.
• a conventional pneumatic nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion
• a hand-held nebulizer such as an AERx (ex Aradigm, US) or BINEB (Boehringer In
• the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dosage unit of the dry powder or a multidose dry powder inhalation device adapted to deliver, for example, 25 mg of dry powder per actuation. Suitable such dry powder inhalation devices are well known.
• the activities and VLA-4 specificities of the compounds of this invention may be determined using in vitro and in vivo assays.
• the cell adhesion inhibitory activity of these compounds may be measured by determining the concentration of inhibitor required to block the binding of VLA-4- expressing cells to fibronectin-, CS1- or VCAM-I-coated plates.
• microtiter wells are coated with either fibronectin (containing the CS-1 sequence) or CS-1 or VCAM-I. If CS-1 is used, it must be conjugated to a carrier protein, such as bovine serum albumin, in order to bind to the wells.
• a carrier protein such as bovine serum albumin
• VLA-4-expressing cells that may be utilized in this assay include Ramos cells, Jurkat cells, A375 melanoma cells, as well as human peripheral blood lymophocytes (PBLs).
• the cells used in this assay may be fluorescently or radioactively labeled.
• a direct binding assay may also be employed to quantitate the inhibitory activity of the compounds of this invention.
• a VCAM-IgG fusion protein containing the first two immunoglobin domains of VCAM (D1D2) attached above the hinge region of an IgGl molecule (VCAM 2D-IgG) is conjugated to a marker enzyme, such as alkaline phosphatase (AP).
• AP alkaline phosphatase
• VCAM-IgG enzyme conjugate is then placed in the wells of a multi-well filtration plate, such as that contained in the Millipore Multiscreen Assay System (Millipore Corp., Bedford, MA). Varying concentrations of the test inhibitory compound are then added to the wells followed by addition of VLA-4-expressing cells. The cells, compound and VCAM-IgG enzyme conjugate are mixed together and allowed to incubate at room temperature. Following incubation, the wells are vacuum drained, leaving behind the cells and any bound VCAM. Quantitation of bound VCAM is determined by adding an appropriate colorimetric substrate for the enzyme conjugated to VCAM-IgG and determining the amount of reaction cell adhesion inhibitory activity.
• assays for other major groups of integrins i.e., ⁇ 2 and ⁇ 3, as well as other ⁇ l integrins, such as VLA-5, VLA-6 and Ct4 ⁇ 7 are performed.
• these assays may be similar to the adhesion inhibition and direct binding assays described above, substituting the appropriate integrin-expressing cell and corresponding ligand.
• polymorphonuclear cells (PMNs) express ⁇ 2 integrins on their surface and 11
• VLA-5 binds specifically to Arg- Gly-Asp sequences
• VLA-6 binds to laminin.
• Compounds of the Examples are found to be selective for VLA-4 versus related integrins.
• the compounds of the invention may also be tested in the following assay.
• mice Male B6D2F1/J mice are sensitized by i.p. injection of 0.5 mL alum-precipitated antigen containing 8 ⁇ g of ovalbumin (OVA) adsorbed to 2 mg of aluminum hydroxide gel in a saline vehicle. Five days later the mice are given a booster injection with OVA/alum. Control animals are sensitized with alum only. Ten mice are used for each group.
• OVA ovalbumin
• Low molecular weight antagonists are dissolved in 2% DMSO and 150 mM TRIS, pH 8.8. A solvent control is included for each experiment. Drugs are administered orally 30 min prior to OVA exposure, and 6 hour after the first OVA exposure.
• BAL fluid collection and analysis Animals are sacrificed by CO 2 asphyxiation 24 hour after the first antigen challenge. The tracheas are exposed and cannulated. The lungs are lavaged with 0.6 mL buffer (Hanks buffered saline with 10 mM Hepes, 0.5% BSA and 10 U/mL heparin). The number of eosinophils in the lavage is assessed by counting the total number of leukocytes and the percentage of eosinophils for each sample. The % inhibition is calculated by the formula:
• R l5 p and Y have meaning as defined hereinabove, or a reactive functional derivative thereof, with a compound of the formula III
• the starting materials of formula II such as optionally substituted phenylureidophenylacetic acids, are in turn known in the art or are prepared according to methods known in the art, e.g. by, for example, condensing a p-aminophenylacetic acid ester with the appropriate aryl isocyanate to obtain the corresponding phenylureidophenylacetic acid ester and hydrolyzing the resulting ester.
• R 4 wherein the carboxyl group is in protected form (e.g. as an alkyl ester) and R 3 , 4 and m have meaning as defined hereinabove, with a compound of the formula V
• n, n' and R 6 have meaning as defined hereinabove and L is a leaving group, such as halo or (alkyl or aryl)-sulfonyloxy, in the presence of a base, such as triethylamine, to obtain a compound of the formula VI
• R has meaning as defined hereinabove under conditions well-known in the art, to obtain a starting material of formula III in protected form (e.g. as an alkyl ester).
• Hydrolysis e.g. with base, such as aqueous lithium hydroxide, gives a starting material of formula III.
• EDAC l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
• step 1 Following the procedure of Example 1, step 1, but starting with 0.834 g (4.5 mmol) 1,1-dimethyl ethyl(3S)-3-amino-4-hexeneoate there is obtained 01.46 g thick yellow oil, which shows one spot on TLC. The product is carried on to the next step.
• Step 3 To 10 mL DMF is added 0.31 g (1 mmol) A. Then 0.18 g (2 mmol) 3- methoxypropylamine is added. At room temp. 0.23 mL (2 mmol) TEA is added. The mixture is stirred 16 hrs. at room. temp. TLC, using 10% CH OH/90% CH 2 C1 2 , is used to monitor the reaction. The mixture is reduced to dryness and flash chromatographed using 12 g silica gel, starting with 2% and gradually increasing to 4% CH 3 OH CH 2 Cl 2 , to yield O.lg yellow oil, which shows one spot on TLC. The product is carried on to the next step. Step 3
• the mixture is reduced to dryness and flash chromatographed using 30 g silica gel, Merck, grade 9385, 230-400 mesh, 60 A, using 25% ethyl acetate/75% hexanes, to yield 0.237 g thick yellow oil, which shows one spot on TLC.
• the product is carried on to next step.
• Step 6 To 10 mL DMF are added 0.36 g (1 mmol) D and 0.18 g (2 mmol) 3- methoxypropylamine. At room temp. 0.23 mL TEA is added. The mixture is stirred 16 hrs. at room. temp. TLC, using 10% CH OH/90% CH 2 C1 2 , is used to monitor the reaction. The mixture is reduced to dryness and flash chromatographed using 12 g silica gel, starting with 2% and gradually increasing to 4% CH OH/CH 2 Cl 2 , to yield 0.1 g yellow oil, which shows one spot on TLC. The product is carried on to the next step. Step 6
• the mixture is reduced to dryness and flash chromatographed using 30 g silica gel, Merck, grade 9385, 230-400 mesh, 60 A, using 25% ethyl acetate/75% hexanes, to yield 0.1.3 g thick yellow oil, which shows one spot on TLC.
• the product is carried on to next step.

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