EP1337250A2 - Use of p38 inhibitors for the treatment of smoke inhalation - Google Patents

Use of p38 inhibitors for the treatment of smoke inhalation

Info

Publication number
EP1337250A2
EP1337250A2 EP01987743A EP01987743A EP1337250A2 EP 1337250 A2 EP1337250 A2 EP 1337250A2 EP 01987743 A EP01987743 A EP 01987743A EP 01987743 A EP01987743 A EP 01987743A EP 1337250 A2 EP1337250 A2 EP 1337250A2
Authority
EP
European Patent Office
Prior art keywords
smoke
alkyl
inhibitor
airway inflammation
induced airway
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01987743A
Other languages
German (de)
French (fr)
Inventor
Don E. Griswold
David C. Underwood
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1337250A2 publication Critical patent/EP1337250A2/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • the present invention relates to the use of a CSBP/p38 inhibitor in the treatment of smoke exposure related disorders which are CSBP/p38 mediated.
  • Pulmonary or airway inflammatory responses are thought to be orchestrated by macrophage, epithelial- and pulmonary vascular endothelial derived cytokines, such as TNF- and IL-l ⁇ which enhance the expression of vascular adhesion molecules (ICAM-1, E-selectin) and neutrophil chemotaxins or chemokines, such as IL-8, to generate the release of destructive oxidants and proteases [Warner et al., Am J. Respir Crit Care Med. 160:S1-S79 (1999)].
  • IAM-1 vascular adhesion molecules
  • chemokines such as IL-8
  • pro-inflammatory cytokines TNF- ⁇ , IFN- ⁇ , IL-4, IL-5 and IL-6) and chemokines (IL-8, RANTES, eotaxin) are capable of regulating or supporting chronic airway inflammation [Barnes et al., Pharmacol Rev. 50:515-596 (1998)].
  • the production and action of many of the potential mediators of airway inflammation have been shown to be dependent upon the stress induced MAP kinase or p38 kinase cascade.
  • a vaiiety of inflammatory mediators activate p38 MAPK which may then activate downstream targets of the MAPK system including other kinases or transcription factors, thus creating the potential for an amplified inflammatory process in the lung.
  • This invention is directed to the novel discovery of treatment, including prophylaxis, of smoke induced pathology resulting from acute and chronic inflammation in the lung.
  • the present invention relates to the use of a CSBP/p38 kinase inhibitor for the treatment, including prophylaxis, of the airway inflammation caused by inhalation of smoke, such as cigarette smoke, or other smoke of other natural extracts.
  • smoke such as cigarette smoke, or other smoke of other natural extracts.
  • IL-1, TNF, and other cytokines affect a wide variety of cells and tissues and these cytokines, as well as other leukocyte derived cytokines, are important and critical inflammatory mediators of a wide variety of disease states and conditions. Thus inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
  • the present invention is directed to the treatment of inhaled smoke induced airway inflammation, lung chemokine production and cytokine production.
  • the invention may be directed to treatment of the airway induced inflammation which is secondary to other respiratory disorders such as viral infections that exacerbate asthma (induced by such infections), chronic bronchitis, chronic obstructive pulmonary disease, otitis media, and sinusitis.
  • a respiratory viral infection treated in conjunction with the smoke related airway inflammation may also be associated with a secondary bacterial infection, such as otitis media, sinusitis, or pneumonia.
  • treatment may include prophylaxis for use in a treatment group who may be susceptible to such airway inflammation. It may also include reducing the symptoms of, ameliorating the symptoms of, reducing the severity of, reducing the incidence of, or any other change in the condition of the patient, which improves the therapeutic outcome. Suitable patient populations for whom this may be prophylatically beneficial could be firemen who routinely inhale smoke in the course of their duties; use in the military, and by civilians in wartime exposure.
  • CSAID cytokine suppressive anti-inflammatory drug
  • smoke of natural causes such as plant extracts, natural plants products, synthetic material, chemically treated natural materials, or natural products such as oil and gas
  • the treatment including prophylaxis is related to cigarette smoke or synthetic/composites, such as occur in fires associated with burning buildings or homes.
  • Suitable CSAID compounds are well known in the art, and an assay for determining CBSP/p38 inhibition is also readily available using assays disclosed in the below noted patents or applications. For instance, see US Patents 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991, US
  • Preferred compounds of this invention include those contained in WO 99/01131, and a representative genus is described below. Also preferred for use herein are the compounds disclosed in WO 99/61426 Scios, Inc.; and those compounds disclosed in WO 98/27098 containing the compound known as NX-745; (also known as 5-(2,6-Dichloro-phenyl)-2-(2,4-difluoro-phenylsulfanyl)-l ,7,8a- triaza-naphthalen-6-one), the Johnson & Johnson compound RWJ-68354 disclosed in WO 98/47899, RPR compound RPR-200765A, the Zeneca compound ZM 336372 disclosed in WO 99/15164; the Sugen compound SU 4984 disclosed in WO
  • Rl is 4-pyridyl, pyrimidinyl, 4-pyridazinyl, l,2,4-triazin-5-yl, quinolyl, isoquinolinyl, or quinazolin-4-yl ring, which ring is substituted with Y-Ra and optionally with an additional independent substituent selected from Ci-4 alkyl, halogen, hydroxyl, C ⁇ _4 alkoxy, Ci-4 alkylthio, C ⁇ _4 alkylsulfinyl, CH2OR12, amino, mono and di- Ci-6 alkyl substituted amino, an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15, N(Rio)C(O)Rb or NHR a ; Y is oxygen or sulfur;
  • R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-l-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR7Ri , C(Z)ORi6, (CRioR20)vCORi2, SR5, SOR5, OR12, halo-substituted-Ci-4 alkyl, Ci-4 alkyl, ZC(Z)Ri2, NR ⁇ oC(Z)Ri6, or (CRioR2 ⁇ ) NRl ⁇ R20 and which, for other positions of substitution, is halogen, cyano, C(Z)NRi3Ri4, C(Z)OR3, (CRioR20)m"COR3, S(
  • Z is oxygen or sulfur; n is an integer having a value of 1 to 10; m is 0, or the integer 1 or 2; m' is an integer having a value of 1 or 2, m" is 0, or an integer having a value of 1 to 5; v is 0, or an integer having a value of 1 or 2;
  • R 2 is -C(H) (A) (R 22 );
  • A is an optionally substituted aryl, heterocyclyl, or heteroaryl ring, or A is a substituted C1 -10 alkyl; R22 is an optionally substituted CJ. ⁇ Q alkyl;
  • Ra is aryl, arylCi-6alkyl, heterocyclic, heterocyclylCi-6 alkyl, heteroaryl, heteroarylC ⁇ _6alkyl, wherein each of these moieties may be optionally substituted;
  • Rb is hydrogen, C ⁇ - alkyl, C3-7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCi_4alkyl, heterocyclyl, or heterocyclylC ⁇ _4 alkyl, wherein each of these moieties may be optionally substituted;
  • R3 is heterocyclyl, heterocyclylCi-io alkyl or R ⁇ ;
  • R5 is hydrogen, Cj . _4 alkyl, C2-4 alke ⁇ yl, C2-4 alkynyl or NR7R17, excluding the moieties SR5 being SNR7R17 and SOR5 being SOH;
  • R6 is hydrogen, a pharmaceutically acceptable cation, Ci-io alkyl, C3-.7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylC ⁇ _4alkyl, heterocyclyl, aroyl, or Ci-io alkanoyl;
  • R7 and R17 is each independently selected from hydrogen or C ⁇ _4 alkyl or R7 and Rl7 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR15;
  • R ⁇ is Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl
  • Rl2 is hydrogen or Ri6
  • Rl3 and R1 is each independently selected from hydrogen or optionally substituted Ci-4 alkyl, optionally substituted aryl or optionally substituted aryl-C ⁇ _4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9 ;
  • Rl5 is Rio or C(Z)-Ci-4 alkyl;
  • Rl6 is C ⁇ _4 alkyl, halo-substituted-Ci-4 alkyl, or C3-.7 cycloalkyl
  • Rl8 is C ⁇ _ ⁇ o alkyl, C3-.7 cycloalkyl, heterocyclyl, aryl, aryl ⁇ _ ⁇ oalkyl, heterocyclyl, heterocy clyl-C 1 _ 1 oalkyl, heteroaryl or heteroaryl 1 _ 1 oalkyl
  • Rl6 is C ⁇ _4 alkyl, halo-substituted-Ci-4 alkyl, or C3-.7 cycloalkyl
  • Rl8 is C ⁇ _ ⁇ o alkyl, C3-.7 cycloalkyl, heterocyclyl, aryl, aryl ⁇ _ ⁇ oalkyl, heterocyclyl, heterocy clyl-C 1 _ 1 oalkyl, heteroaryl or heteroaryl 1 _ 1
  • R2 is a substituted alkyl derivative. It is recognized that the first methylene carbon in this chain is a tertiary carbon, and it will contain one hydrogen moiety. This methylene group will have has two additional substituents, an R22 moiety and an A moiety, -C(H)(A)(R22)- Both A and R22 m y not be unsubstituted C1 0 alkyl moieties.
  • R2 is a -C(AAj)(A) moiety, wherein AAj is the
  • R22 moiety but is specifically the side chain residue (R) of an amino acid, as is further described herein.
  • A is an optionally substituted C3-.7 cycloalkyl, aryl, heteroaryl, or heterocyclic ring, or A is a substituted C _IQ alkyl moiety.
  • the ring may be substituted independently one or more times, preferably, 1 to 3 times by Ci-io alkyl; halogen; halo substituted Ci-io alkyl, such as CF3; (CR ⁇ oR2 ⁇ )tORn; (CR ⁇ oR2 ⁇ )t Rl3Rl4, especially amino or mono- or di-C ⁇ _4 alkylamino; (CRioR2 ⁇ )tS(O) m Ri8, wherein m is 0, 1 or 2; SH; NRioC(Z)R3 (such NHCO(CMO alkyl)); or NRioS(O) m R8 (such as NHSO2(Ci-io alkyl)).
  • t is 0, or an integer of 1 to 4.
  • A is an optionally substituted cycloalkyl it is as defined below with the R22 substitution.
  • the ring is preferably a morpholino, pyrrolidinyl, piperazinyl or a piperidinyl ring.
  • A is an optionally substituted aryl moiety, it is preferably a phenyl ring.
  • A is an optionally substituted heteroaryl ring, it is as defined below in the definition section.
  • the alkyl chain may be straight or branched. The chain is substituted independently 1 or more times, preferably 1 to 3 times by halogen, such as fluorine, chlorine, bromine or iodine; halosubstituted Ci-io alkyl, such as CF3; C3-7 cycloalkyl, Ci-io alkoxy, such as methoxy or ethoxy; hydroxy substituted Ci-io alkoxy; halosubstituted Ci_io alkoxy, such as OCF2CF2H; OR ⁇ ; S(O)mR ⁇ g (wherein m is 0, 1 or 2); NR13R14; C(Z)NRi3Ri4;
  • A is a C3--7 cycloalkyl, or a C ⁇ .g alkyl, more preferably a C ⁇ _2 alkyl, i.e. a methylene or ethylene moiety, more preferably a methylene moiety which is substituted by one of the above noted groups.
  • A when A is a C ⁇ - 0 alkyl, it is substituted by OR where R ⁇ is preferably hydrogen, aryl or arylalkyl; NR13R14; OC(Z)Rn; or C(Z)ORn. More preferably, A is substituted by ORj ⁇ where R ⁇ ⁇ is hydrogen.
  • R22 i C ⁇ _ ⁇ Q alkyl chain which chain may be straight or branched and which may be optionally substituted independently, one or more times, preferably 1 to 3 times, by halogen, such as fluorine, chlorine, bromine or iodine; halo substituted Cl-10 alkyl; Ci-io alkoxy, such as methoxy or ethoxy; hydroxy substituted C ⁇ _ ⁇ o alkoxy; halosubstituted Ci-io alkoxy, such as OCF2CF2H; ORn; S(O) m R ⁇ s; NR13R14; C(Z)NRi 3 Rl4; S(O) m 'NR ⁇ 3 Rl4; NR 2 3C(Z)R ⁇ ; NHS(O) 2 Rl8; C(Z)R ⁇ ; OC(Z)Rn; C(Z)OR ⁇ ; C(Z)NRnOR 9 ; N(OR 6 )C(Z)NRi 3 Rl4; N(OR 6 )
  • the R22 group may, for instance, be a carboxy, an aldehyde, or an amide, as well as being a substituent off a methylene unit, such as carbamoylmethyl, or acetamidomethyl.
  • R22 is a C ⁇ - unsubstituted or substituted alkyl group, such as a C1.3 alkylene, such as methyl, ethyl or isopropyl, or a methylene or ethylene moiety substituted by one of the above noted moieties, or as noted above those substituent groups which contain a carbon may substitutent for the first methylene unit of the alkyl chain, such as carboxy, C(O)ORj ⁇ , C(O)NRi3Ri4, or R22 is an optionally substituted aryl group, such as a benzyl or phenethyl.
  • R22 can be an optionally substituted alkyl group, or R22 can be C(Z)OR ⁇ 1, C(Z)NR ⁇ iOR9, C(Z)R ⁇ 1,
  • R22 is a C ⁇ .g unsubstituted or substituted alkyl group, more preferably a C ⁇ _2 alkylene chain, such as a methylene or ethylene moiety, more preferably methylene.
  • the alkyl chain is substituted by OR ⁇ ⁇ , where Rj ⁇ is preferably hydrogen, aryl or arylalkyl; S(O)mRi8, where m is 0 and R ⁇ is a C ⁇ . ⁇ alkyl; or an optionally substituted aryl, i.e. a benzyl or phenethyl moiety. More preferably, R22 i phenyl, benzyl, CH2OH, or CH2-O-aryl.
  • one or both of A and R22 contain hydroxy moieties, such as in C ⁇ .g alkyl OR ⁇ , wherein ⁇ is hydrogen, i.e.CH ⁇ CF- ⁇ OH.
  • AA ⁇ is the (R) side chain residue of an amino acid
  • it is a C ⁇ _ alkyl group, which may be straight or branched.
  • the R residue term is for example, CH3 for alanine, (CH 3 ) 2 CH- for valine, (CH 3 )2CH-CH2-for leucine, phenyl-CH 2 - for phenylalanine, CH3-S-CH2-CH-2- for methionine, etc.
  • All generally recognized primary amino acids are included in this groups, such as but not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, hydroxylysine, methylhistidine, and other naturally occurring amino acids not found in proteins, such as ⁇ -alanine, ⁇ -aminobutyric acid, homocysteine, homoserine, citrulline, ornithine, canavanine, djenkolic acid, and ⁇ - cyanoalanine, or other naturally occurring non-mammalian amino acids.
  • AAj is the residue of phenylalanine, or alanine.
  • A is a hydroxy substituted C ⁇ _ ⁇ o alkyl
  • R22 is a alkyl or a hydroxy substituted C ⁇ _ ⁇ Q alkyl.
  • a preferred compound for use herein is l-(l,3-Dihydroxyprop-2-yl)-4-(4- fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole, or a pharmaceutically acceptable salt thereof.
  • Suitable compounds for use herein include but are not limited to, tr ⁇ n-y- l-(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4- yl]imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4- pyrimidinyl)imidazole; or (4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4- pyridyl)-imidazole.
  • the daily oral dosage regimen will be from about 0J to about 80 mg/kg of total body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5 mg to 15mg.
  • the daily parenteral dosage regimen about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from about 0.5 mg to 15mg/kg.
  • the daily topical dosage regimen will preferably be from 0J mg to 150 mg, administered one to four, preferably two or three times daily.
  • the daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day.
  • the novel use of CSAID compounds herein may also be used in association with the veterinary treatment of mammals, other than humans, in need of such inhibition of CSBP/p38 or cytokine inhibition.
  • the CSBP/p38 inhibitor may also be administered with a second therapeutic agent, such as a generally accepted non-sedating antihistamines, such as loratadine (Claritin®), descarboethoxyloratadine (DCL), fexofenadine (Allegra®), and cetirizine hydrochloride (Zyrtec®) etc.; a steroid, such as dexamethasone, prednisone, or prenisolone, etc.; various antibiotics, such as the quinolones, cephalosporins, ⁇ -lactamase inhibitors, etc.; anti-inflammatory agents, such as an NSAID, a COX-1 or COX-2 inhibitor, ASA, or indomethacin, etc.
  • a second therapeutic agent such as a generally accepted non-sedating antihistamines, such as loratadine (Claritin®), descarboethoxyloratadine (DCL),
  • compositions may be administered sequentially, in combination with, or contemporaneously (concomitant use) with a CSAID agent.
  • administration route of the second agent may also differ from that of the CSAID agent, and hence the dosing schedule may vary accordingly.
  • Cetirizine HC1 manufacture and dosing is described in US Patent 4,525,358; fexofenadine manufacture and dosing is described in US Patents 4,524,129; US 5,375,693; US 5,578,610; US 5,855,912; US 5,932,247; and US 6,037,353.
  • Loratadine and DCL manufacture and dosing are described in US patent 4,282,233; US 4,371,516; US 4,659,716; US 4,863,931; US 5,314,697; and US 5,595,997.
  • CSPB/p38 inhibitor may be administered systemically or non- systemically, such as orally, bucally, topically (intranasal) or via inhalation (aerosol), or both topically and via inhalation.
  • a second therapeutic agent may also be administered by any suitable means, including parenteral, suppository, etc. which means of administration is not necessarily by the same route, nor concurrent therewith.
  • topically shall include non-systemic administration. This includes the application of a compound externally to the epidermis or the buccal cavity and/or the instillation of such a compound into the ear, eye and nose.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration, subcutaneous intranasal, intrarectal, or intravaginal.
  • the optimal quantity and spacing of individual dosages of a CSBP/p38 inhibitor will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a CSBP/p38 inhibitor given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests. BIOLOGICAL EXAMPLES
  • a murine model of cigarette smoke inhalation was developed to explore a relationship to leukocyte trafficking and lung chemokine and cytokine production.
  • Balb/c mice are exposed to smoke generated from commercial unfiltered cigarettes for a specified period of time and samples are obtained at varying times during the post-exposure. This model is demonstrated in greater detail as shown below, in contrast to other smoke extract models known in the art.
  • Cigarette Smoke Exposure Model A model of cigarette smoke exposure in the mouse was established in which mice were placed 6 at a time into a small animal plexiglass dosing chamber attached to a peristaltic pump whose intake was connected to a holder for a commercial unfiltered cigarette (Lucky StrikeTM). Along with fresh air, smoke was delivered into the chamber until the cigarette was consumed (approximately 5 minutes). Varying numbers of cigarettes (2-4 per day, 2-3 hr apart) were utilized for 1-3 consecutive days. Animals were euthanized by pentobarbital overdose approximately 18 hours after the final exposure.
  • Bronchoalveolar lavage with phosphate-buffered saline was performed for inflammatory cell enumeration, and BAL aliquots and lungs were frozen for cytokine analysis.
  • Smoke exposure resulted in time- and cigarette number-related increases in airway neutrophils, and lung chemokine (KC) and cytokine (IL-6) content.
  • KC lung chemokine
  • IL-6 cytokine
  • mice are treated with the p38 kinase inhibitor, trans-l-(4- Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole), also referred to as Compound I herein (30 mg/kg, p.o. b.i.d.) which resulted in reduction in lung KC (a murine homologue of IL-8) levels assessed 1 day after exposure (prior to neutrophilia), and attenuated airway neutrophilia and lung IL-6 levels assessed following 3 days of cigarette exposure.
  • Compound I trans-l-(4- Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole

Abstract

The present invention is directed to the novel use of a CSBP/p38 inhibitor for the treatment, including prophylaxis of smoke induced pathology resulting from acute and chronic inflammation in the lung.

Description

Use of p38 Inhibitors for the Treatment of Smoke Inhalation
Field of Invention The present invention relates to the use of a CSBP/p38 inhibitor in the treatment of smoke exposure related disorders which are CSBP/p38 mediated.
Background of the Invention
Pulmonary or airway inflammatory responses are thought to be orchestrated by macrophage, epithelial- and pulmonary vascular endothelial derived cytokines, such as TNF- and IL-lβ which enhance the expression of vascular adhesion molecules (ICAM-1, E-selectin) and neutrophil chemotaxins or chemokines, such as IL-8, to generate the release of destructive oxidants and proteases [Warner et al., Am J. Respir Crit Care Med. 160:S1-S79 (1999)]. It is well known that pro-inflammatory cytokines (TNF-α, IFN-γ, IL-4, IL-5 and IL-6) and chemokines (IL-8, RANTES, eotaxin) are capable of regulating or supporting chronic airway inflammation [Barnes et al., Pharmacol Rev. 50:515-596 (1998)]. The production and action of many of the potential mediators of airway inflammation have been shown to be dependent upon the stress induced MAP kinase or p38 kinase cascade. A vaiiety of inflammatory mediators activate p38 MAPK which may then activate downstream targets of the MAPK system including other kinases or transcription factors, thus creating the potential for an amplified inflammatory process in the lung.
By interfering with the biochemical processes produced in this cascade, there represents a viable and new use for intervention with an inhibitor of CSBP/p38.
This invention is directed to the novel discovery of treatment, including prophylaxis, of smoke induced pathology resulting from acute and chronic inflammation in the lung.
Summary of the Invention
The present invention relates to the use of a CSBP/p38 kinase inhibitor for the treatment, including prophylaxis, of the airway inflammation caused by inhalation of smoke, such as cigarette smoke, or other smoke of other natural extracts. Detailed Description of the Invention
IL-1, TNF, and other cytokines affect a wide variety of cells and tissues and these cytokines, as well as other leukocyte derived cytokines, are important and critical inflammatory mediators of a wide variety of disease states and conditions. Thus inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
In particular, the present invention is directed to the treatment of inhaled smoke induced airway inflammation, lung chemokine production and cytokine production. The invention may be directed to treatment of the airway induced inflammation which is secondary to other respiratory disorders such as viral infections that exacerbate asthma (induced by such infections), chronic bronchitis, chronic obstructive pulmonary disease, otitis media, and sinusitis. A respiratory viral infection treated in conjunction with the smoke related airway inflammation may also be associated with a secondary bacterial infection, such as otitis media, sinusitis, or pneumonia.
It is noted that the inflammation may be due to cytokines and chemokine release from neutrophil activation and other leukocytes, as well as vascular and airway endothelial cell activation. For use herein treatment may include prophylaxis for use in a treatment group who may be susceptible to such airway inflammation. It may also include reducing the symptoms of, ameliorating the symptoms of, reducing the severity of, reducing the incidence of, or any other change in the condition of the patient, which improves the therapeutic outcome. Suitable patient populations for whom this may be prophylatically beneficial could be firemen who routinely inhale smoke in the course of their duties; use in the military, and by civilians in wartime exposure.
The mechanism of action for inhibition of a cytokine by a cytokine suppressive anti-inflammatory drug (CSAID) is well known in the art. The present invention will demonstrate that CSAID inhibitors are useful in the treatment of airway neutrophilia induced by smoke inhalation. As noted, smoke of natural causes, such as plant extracts, natural plants products, synthetic material, chemically treated natural materials, or natural products such as oil and gas, may be treated within the scope of this invention. Suitably, the treatment including prophylaxis is related to cigarette smoke or synthetic/composites, such as occur in fires associated with burning buildings or homes.
Suitable CSAID compounds are well known in the art, and an assay for determining CBSP/p38 inhibition is also readily available using assays disclosed in the below noted patents or applications. For instance, see US Patents 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991, US
5,663,334, US 5,670,527, US 5,559,137, 5,658,903, US 5,739,143, US 5,756,499, and US 5,716,955; WIPO publications WO 98/25619, WO 97/25048, WO 99/01452, WO 97/25047, WO 99/01131, WO 99/01130, WO 97/33883, WO 97/35856, WO 97/35855, WO 98/06715, WO 98/07425, WO 98/28292, WO 98/56377 , WO 98/07966 , WO 99/01136 , WO 99/17776 , WO 99/01131 , WO 99/01130, WO 99/32121, WO 00/26209, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO 99/59960, WO 99/59959, WO 00/18738, WO 00/17175, WO 99/17204, WO 00/20402, WO 99/64400, WO 00/01688, WO 00/07980, WO 00/07991, WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO 00/41698, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876, WO 98/7966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52941, WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098 , WO 99/00357, WO 98/47892, WO 98/47899, WO 99/03837, WO 99/01441, WO 99/01449, WO 99/03484, WO 95/09853, WO 99/15164, WO 98/50356; WO 95/09851, WO 95/09847, WO 95/09852, WO 92/12154, WO 94/19350, DE 19842833, JP 2000 86657 and De Laszlo et al, Bioorg. Med. Chem. Lett 8 (1998) 2689-2694 whose disclosures are all incorporated herein by reference in their entirety.
Preferred compounds of this invention include those contained in WO 99/01131, and a representative genus is described below. Also preferred for use herein are the compounds disclosed in WO 99/61426 Scios, Inc.; and those compounds disclosed in WO 98/27098 containing the compound known as NX-745; (also known as 5-(2,6-Dichloro-phenyl)-2-(2,4-difluoro-phenylsulfanyl)-l ,7,8a- triaza-naphthalen-6-one), the Johnson & Johnson compound RWJ-68354 disclosed in WO 98/47899, RPR compound RPR-200765A, the Zeneca compound ZM 336372 disclosed in WO 99/15164; the Sugen compound SU 4984 disclosed in WO
98/50356. A review of various inhibitors of p38 kinase is taught in Boehm et al., Exp. Opin. Ther. Patents 10(l):25-37 (2000).
Compounds of Formula (I) are represented by the formula:
wherein
Rl is 4-pyridyl, pyrimidinyl, 4-pyridazinyl, l,2,4-triazin-5-yl, quinolyl, isoquinolinyl, or quinazolin-4-yl ring, which ring is substituted with Y-Ra and optionally with an additional independent substituent selected from Ci-4 alkyl, halogen, hydroxyl, Cι_4 alkoxy, Ci-4 alkylthio, Cι_4 alkylsulfinyl, CH2OR12, amino, mono and di- Ci-6 alkyl substituted amino, an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15, N(Rio)C(O)Rb or NHRa; Y is oxygen or sulfur;
R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-l-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR7Ri , C(Z)ORi6, (CRioR20)vCORi2, SR5, SOR5, OR12, halo-substituted-Ci-4 alkyl, Ci-4 alkyl, ZC(Z)Ri2, NRιoC(Z)Ri6, or (CRioR2θ) NRlθR20 and which, for other positions of substitution, is halogen, cyano, C(Z)NRi3Ri4, C(Z)OR3, (CRioR20)m"COR3, S(O)mR3, OR3, halo-substituted-Ci_4 alkyl, Cι_4 alkyl, (CRιoR2θ)m"NRlθC(Z)R3, NRioS(O)m'R8, NRιoS(O)m'NR7Rl7, ZC(Z)R3 or (CRioR20)m"NRl3Rl4;
Z is oxygen or sulfur; n is an integer having a value of 1 to 10; m is 0, or the integer 1 or 2; m' is an integer having a value of 1 or 2, m" is 0, or an integer having a value of 1 to 5; v is 0, or an integer having a value of 1 or 2;
R2 is -C(H) (A) (R22);
A is an optionally substituted aryl, heterocyclyl, or heteroaryl ring, or A is a substituted C1 -10 alkyl; R22 is an optionally substituted CJ.^Q alkyl;
Ra is aryl, arylCi-6alkyl, heterocyclic, heterocyclylCi-6 alkyl, heteroaryl, heteroarylCι_6alkyl, wherein each of these moieties may be optionally substituted; Rb is hydrogen, C\- alkyl, C3-7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCi_4alkyl, heterocyclyl, or heterocyclylCι_4 alkyl, wherein each of these moieties may be optionally substituted; R3 is heterocyclyl, heterocyclylCi-io alkyl or Rβ;
R5 is hydrogen, Cj._4 alkyl, C2-4 alkeηyl, C2-4 alkynyl or NR7R17, excluding the moieties SR5 being SNR7R17 and SOR5 being SOH; R6 is hydrogen, a pharmaceutically acceptable cation, Ci-io alkyl, C3-.7 cycloalkyl, aryl, arylCi-4 alkyl, heteroaryl, heteroarylCι_4alkyl, heterocyclyl, aroyl, or Ci-io alkanoyl; R7 and R17 is each independently selected from hydrogen or Cι_4 alkyl or R7 and Rl7 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; Rδ is Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-.7 cycloalkyl, C5.-7 cycloalkenyl, aryl, arylCi-io alkyl, heteroaryl, heteroarylCi-io alkyl, (CRioR20)nORl l, (CRioR2θ)nS(O)mRι8, (CRιoR2θ)nNHS(O)2Rl8, (CRioR20)n Rl3Rl4; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted; R9 is hydrogen, C(Z)Rι 1 or optionally substituted Ci_io alkyl, S(O)2Rl8> optionally substituted aryl or optionally substituted aryl-Ci-4 alkyl; RlO and R20 is each independently selected from hydrogen or Ci-4 alkyl; Rll is hydrogen, Ci-io alkyl, C3-.7 cycloalkyl, heterocyclyl, heterocyclyl
Cl-10alkyl, aryl, arylCi-io alkyl, heteroaryl or heteroarylCi-io alkyl, wherein these moieties may be optionally substituted;
Rl2 is hydrogen or Ri6;
Rl3 and R1 is each independently selected from hydrogen or optionally substituted Ci-4 alkyl, optionally substituted aryl or optionally substituted aryl-Cι _4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9 ; Rl5 is Rio or C(Z)-Ci-4 alkyl;
Rl6 is Cι_4 alkyl, halo-substituted-Ci-4 alkyl, or C3-.7 cycloalkyl; Rl8 is Cι_ιo alkyl, C3-.7 cycloalkyl, heterocyclyl, aryl, arylι_ιoalkyl, heterocyclyl, heterocy clyl-C 1 _ 1 oalkyl, heteroaryl or heteroaryl 1 _ 1 oalkyl ; or a pharmaceutically acceptable salt thereof.
R2 is a substituted alkyl derivative. It is recognized that the first methylene carbon in this chain is a tertiary carbon, and it will contain one hydrogen moiety. This methylene group will have has two additional substituents, an R22 moiety and an A moiety, -C(H)(A)(R22)- Both A and R22 m y not be unsubstituted C1 0 alkyl moieties.
In a preferred embodiment, R2 is a -C(AAj)(A) moiety, wherein AAj is the
R22 moiety, but is specifically the side chain residue (R) of an amino acid, as is further described herein.
Suitably, A is an optionally substituted C3-.7 cycloalkyl, aryl, heteroaryl, or heterocyclic ring, or A is a substituted C _IQ alkyl moiety. When A is an aryl, heteroaryl and heterocyclic ring, the ring may be substituted independently one or more times, preferably, 1 to 3 times by Ci-io alkyl; halogen; halo substituted Ci-io alkyl, such as CF3; (CRιoR2θ)tORn; (CRιoR2θ)t Rl3Rl4, especially amino or mono- or di-Cι_4 alkylamino; (CRioR2θ)tS(O)mRi8, wherein m is 0, 1 or 2; SH; NRioC(Z)R3 (such NHCO(CMO alkyl)); or NRioS(O)mR8 (such as NHSO2(Ci-io alkyl)).
Suitably, t is 0, or an integer of 1 to 4.
When A is an optionally substituted cycloalkyl it is as defined below with the R22 substitution. When A is an optionally substituted heterocyclyl ring, the ring is preferably a morpholino, pyrrolidinyl, piperazinyl or a piperidinyl ring.
When A is an optionally substituted aryl moiety, it is preferably a phenyl ring.
When A is an optionally substituted heteroaryl ring, it is as defined below in the definition section. When A is a substituted Cι_ιo alkyl moiety, the alkyl chain may be straight or branched. The chain is substituted independently 1 or more times, preferably 1 to 3 times by halogen, such as fluorine, chlorine, bromine or iodine; halosubstituted Ci-io alkyl, such as CF3; C3-7 cycloalkyl, Ci-io alkoxy, such as methoxy or ethoxy; hydroxy substituted Ci-io alkoxy; halosubstituted Ci_io alkoxy, such as OCF2CF2H; ORχ ; S(O)mRι g (wherein m is 0, 1 or 2); NR13R14; C(Z)NRi3Ri4;
S(O)m'NRi3Ri4; NR23C(Z)Rπ; NHS(O)2Rl8; C(Z)Ri i ; OC(Z)Rli; C(Z)ORi i ; C(Z)NRi iOR9; N(OR6)C(Z)NRi3Rl4; N(OR6)C(Z)Ri i; C(=NOR6)Rl i; NR23C(=NRi9)NRi3Ri4; OC(Z)NRi3Ri4; NR23C(Z)NRi3Ri4; or Preferably A is a C3--7 cycloalkyl, or a C^.g alkyl, more preferably a C}_2 alkyl, i.e. a methylene or ethylene moiety, more preferably a methylene moiety which is substituted by one of the above noted groups.
Preferably, when A is a Cι- 0 alkyl, it is substituted by OR where R \ is preferably hydrogen, aryl or arylalkyl; NR13R14; OC(Z)Rn; or C(Z)ORn. More preferably, A is substituted by ORj \ where R^ \ is hydrogen.
Suitably, R22 i C\_\Q alkyl chain, which chain may be straight or branched and which may be optionally substituted independently, one or more times, preferably 1 to 3 times, by halogen, such as fluorine, chlorine, bromine or iodine; halo substituted Cl-10 alkyl; Ci-io alkoxy, such as methoxy or ethoxy; hydroxy substituted Cι_ιo alkoxy; halosubstituted Ci-io alkoxy, such as OCF2CF2H; ORn; S(O)mRιs; NR13R14; C(Z)NRi3Rl4; S(O)m'NRι3Rl4; NR23C(Z)Rπ; NHS(O)2Rl8; C(Z)Rπ; OC(Z)Rn; C(Z)ORπ; C(Z)NRnOR9; N(OR6)C(Z)NRi3Rl4; N(OR6)C(Z)Rn; C(=NOR6)Rl i; NR23C(=NRι9)NRi3Rl4; OC(Z)NRl3Rl4; NR23C(Z)NRi3Ri4; NR23C(Z)ORιo; optionally substituted C3.7 cycloalkyl; optionally substituted aryl, such as phenyl; optionally substituted heteroaryl; or an optionally substituted heterocyclic. The optional substituents on these cycloalkyl, aryl, heteroaryl, and heterocyclic moieties are as defined herein below.
It is noted that those R22 substituent groups which contain carbon as the first connecting group, i.e. C(Z)ORπ; C(Z)NRπOR95 C(Z)Rπ, C(Z)NRi3Rl4, and C(=NOR6)Rl 1, may be the sole carbon in alkyl chain. Therefore, the R22 group may, for instance, be a carboxy, an aldehyde, or an amide, as well as being a substituent off a methylene unit, such as carbamoylmethyl, or acetamidomethyl.
Preferably R22 is a C\- unsubstituted or substituted alkyl group, such as a C1.3 alkylene, such as methyl, ethyl or isopropyl, or a methylene or ethylene moiety substituted by one of the above noted moieties, or as noted above those substituent groups which contain a carbon may substitutent for the first methylene unit of the alkyl chain, such as carboxy, C(O)ORj \, C(O)NRi3Ri4, or R22 is an optionally substituted aryl group, such as a benzyl or phenethyl. In other words, R22 can be an optionally substituted alkyl group, or R22 can be C(Z)ORι 1, C(Z)NRι iOR9, C(Z)Rι 1,
C(Z)NRi3Rl4, or C(=NOR6)Rl 1-
Preferably R22 is a C^.g unsubstituted or substituted alkyl group, more preferably a C^_2 alkylene chain, such as a methylene or ethylene moiety, more preferably methylene.
Preferably the alkyl chain is substituted by OR\ \, where Rj \ is preferably hydrogen, aryl or arylalkyl; S(O)mRi8, where m is 0 and R^ is a C^.β alkyl; or an optionally substituted aryl, i.e. a benzyl or phenethyl moiety. More preferably, R22 i phenyl, benzyl, CH2OH, or CH2-O-aryl.
Preferably, one or both of A and R22 contain hydroxy moieties, such as in C^.g alkyl OR^, wherein \\ is hydrogen, i.e.CH^CF-^OH.
Suitably, when AA^ is the (R) side chain residue of an amino acid, it is a C\_ alkyl group, which may be straight or branched. This means the R group off the core amino acid of the structure R-C(H)(COOH)(NH-2). The R residue term is for example, CH3 for alanine, (CH3)2CH- for valine, (CH3)2CH-CH2-for leucine, phenyl-CH2- for phenylalanine, CH3-S-CH2-CH-2- for methionine, etc. All generally recognized primary amino acids are included in this groups, such as but not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, hydroxylysine, methylhistidine, and other naturally occurring amino acids not found in proteins, such as β-alanine, γ-aminobutyric acid, homocysteine, homoserine, citrulline, ornithine, canavanine, djenkolic acid, and β- cyanoalanine, or other naturally occurring non-mammalian amino acids. Preferably AAj is the residue of phenylalanine, or alanine.
Preferably, A is a hydroxy substituted Cι_ιo alkyl, and R22 is a alkyl or a hydroxy substituted C \ _ \ Q alkyl.
For further definitions please refer to the descriptions in WO 99/01131, or in WO 99/01136, supra.
A preferred compound for use herein is l-(l,3-Dihydroxyprop-2-yl)-4-(4- fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole, or a pharmaceutically acceptable salt thereof.
Other suitable compounds for use herein include but are not limited to, trαn-y- l-(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4- yl]imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4- pyrimidinyl)imidazole; or (4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4- pyridyl)-imidazole.
Methods of using and dosage amounts are the same as those disclosed in the references cited above. See for instance, Adams et al., US patent 5,756,499, issued 26 May 1998. In order to use a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
For all methods of use disclosed herein (or the compounds of Formula (I) and other CSAID compounds), suitably, the daily oral dosage regimen will be from about 0J to about 80 mg/kg of total body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5 mg to 15mg. The daily parenteral dosage regimen about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from about 0.5 mg to 15mg/kg. The daily topical dosage regimen will preferably be from 0J mg to 150 mg, administered one to four, preferably two or three times daily. The daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day. The novel use of CSAID compounds herein may also be used in association with the veterinary treatment of mammals, other than humans, in need of such inhibition of CSBP/p38 or cytokine inhibition.
The CSBP/p38 inhibitor may also be administered with a second therapeutic agent, such as a generally accepted non-sedating antihistamines, such as loratadine (Claritin®), descarboethoxyloratadine (DCL), fexofenadine (Allegra®), and cetirizine hydrochloride (Zyrtec®) etc.; a steroid, such as dexamethasone, prednisone, or prenisolone, etc.; various antibiotics, such as the quinolones, cephalosporins, β-lactamase inhibitors, etc.; anti-inflammatory agents, such as an NSAID, a COX-1 or COX-2 inhibitor, ASA, or indomethacin, etc.
It is recognized that the above noted agents may be administered as immediate release, or as extended release dosage forms, either together with a suitable CSAID compound, or separately. The compositions may be administered sequentially, in combination with, or contemporaneously (concomitant use) with a CSAID agent. The administration route of the second agent may also differ from that of the CSAID agent, and hence the dosing schedule may vary accordingly.
Cetirizine HC1 manufacture and dosing is described in US Patent 4,525,358; fexofenadine manufacture and dosing is described in US Patents 4,524,129; US 5,375,693; US 5,578,610; US 5,855,912; US 5,932,247; and US 6,037,353. Loratadine and DCL manufacture and dosing are described in US patent 4,282,233; US 4,371,516; US 4,659,716; US 4,863,931; US 5,314,697; and US 5,595,997.
Zamanivar dosing is disclosed in US Patents 4,627,432; US 4,778,054; US 4,811,731; US 5,035,237; US 5,360,817; and US 5,648,379. Oseltamivir dosing is disclosed in US Patents US 5,763,483; US 5,866,601; and US 5,952,375. The CSPB/p38 inhibitor may be administered systemically or non- systemically, such as orally, bucally, topically (intranasal) or via inhalation (aerosol), or both topically and via inhalation. As noted above, a second therapeutic agent may also be administered by any suitable means, including parenteral, suppository, etc. which means of administration is not necessarily by the same route, nor concurrent therewith.
As used herein "topically" shall include non-systemic administration. This includes the application of a compound externally to the epidermis or the buccal cavity and/or the instillation of such a compound into the ear, eye and nose. As used herein "systemic administration" refers to oral, intravenous, intraperitoneal and intramuscular administration, subcutaneous intranasal, intrarectal, or intravaginal.
It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a CSBP/p38 inhibitor will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a CSBP/p38 inhibitor given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests. BIOLOGICAL EXAMPLES
A murine model of cigarette smoke inhalation was developed to explore a relationship to leukocyte trafficking and lung chemokine and cytokine production. Balb/c mice are exposed to smoke generated from commercial unfiltered cigarettes for a specified period of time and samples are obtained at varying times during the post-exposure. This model is demonstrated in greater detail as shown below, in contrast to other smoke extract models known in the art.
Cigarette Smoke Exposure Model A model of cigarette smoke exposure in the mouse was established in which mice were placed 6 at a time into a small animal plexiglass dosing chamber attached to a peristaltic pump whose intake was connected to a holder for a commercial unfiltered cigarette (Lucky Strike™). Along with fresh air, smoke was delivered into the chamber until the cigarette was consumed (approximately 5 minutes). Varying numbers of cigarettes (2-4 per day, 2-3 hr apart) were utilized for 1-3 consecutive days. Animals were euthanized by pentobarbital overdose approximately 18 hours after the final exposure. Bronchoalveolar lavage with phosphate-buffered saline was performed for inflammatory cell enumeration, and BAL aliquots and lungs were frozen for cytokine analysis. Smoke exposure resulted in time- and cigarette number-related increases in airway neutrophils, and lung chemokine (KC) and cytokine (IL-6) content.
To evaluate the role of a p38 MAP kinase inhibitor in this inflammatory response, mice are treated with the p38 kinase inhibitor, trans-l-(4- Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole), also referred to as Compound I herein (30 mg/kg, p.o. b.i.d.) which resulted in reduction in lung KC (a murine homologue of IL-8) levels assessed 1 day after exposure (prior to neutrophilia), and attenuated airway neutrophilia and lung IL-6 levels assessed following 3 days of cigarette exposure.
These findings support the utility of this model and of the efficacy of the p38 MAP kinase inhibitors in inhibiting this type of airway inflammation.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is Claimed Is:
1. A method of treatment, including prophylaxis, of smoke induced airway inflammation in a human in need thereof, which comprises administering to said human an effective amount of a CBSP/p38 inhibitor.
2. The method according to Claim 1 wherein the inflammation is caused by inhalation of cigarette smoke.
3. The method according to Claim 1 wherein the smoke induced airway inflammation is caused by inhalation of smoke produced from a burning plant.
4. The method according to Claim 3 wherein the plant is composed of natural and chemically treated components.
5. The method according to Claim 1 wherein the smoke induced airway inflammation is caused by inhalation of smoke produced from non-natural man-made material.
6. The method according to Claim 1 wherein the smoke induced airway inflammation is caused by inhalation of smoke produced from chemically alternated or synthetic man-made material.
7. The method according to any one of Claims 1 to 6 wherein the smoke induced airway inflammation exacerbates a pre-existing asthmatic condition.
8. The method according to Claim 1 wherein the smoke induced airway inflammation exacerbates a pre-existing chronic bronchitis in said human
9. The method according to Claim 1 wherein the smoke induced airway inflammation exacerbates chronic obstructive pulmonary disease in said human.
10. The method according to Claim 1 wherein the smoke induced airway inflammation exacerbates a condition associated with a secondary bacterial infection which is selected from otitis media, sinusitis, or pneumonia.
11. The method according to any one of Claims 1 to 6 wherein the CSBP/p38 inhibitor is administered with a second therapeutic agent.
12. The method according to Claim 8 wherein the second therapeutic agent is an antihistamine; a steroid; a PDE4 agent, an antibiotic; or an anti-inflammatory agent selected from an NSAID, a COX-1 or COX-2 inhibitor, ASA, or indomethacin.
13. The method according to any one of Claims 1 to 6 wherein the therapeutic agent is administered orally, topically (intranasal) or via inhalation (aerosol), or both topically and via inhalation.
14. The method according to Claim 13 wherein the CSBP/p38 inhibitor is administered with a second therapeutic agent.
15. The method according to Claim 11 wherein the second therapeutic agent may be administered by a different route than the CSBP/p38 inhibitor.
16. The method according to any one of Claims 1 to 6 wherein the CSBP/p38 inhibitor is selected from a compound disclosed in US Patent 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991, US 5,663,334, US 5,670,527, US 5,559,137, 5,658,903, US 5,739,143, US 5,756,499, US 5,716,955, WO 98/25619, WO 97/25048, WO 99/01452, WO 97/25047, WO 99/01131, WO 99/01130, WO 97/33883, WO 97/35856, WO 97/35855, WO
98/06715, WO 98/07425, WO 98/28292, WO 98/56377 , WO 98/07966 , WO 99/01136 , WO 99/17776 , WO 99/01131 , WO 99/01130, WO 99/32121, WO 00/26209, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO 99/59960, WO 99/59959, WO 00/18738, WO 00/17175, WO 99/17204, WO 00/20402, WO 99/64400, WO 00/01688, WO 00/07980, WO
00/07991, WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO 00/41698, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876, WO 98/7966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52941, WO
98/52937, WO 98/52940, WO 98/56788, WO 98/27098 , WO 99/00357, WO 98/47892, WO 98/47899, WO 99/03837, WO 99/01441, WO 99/01449, WO 99/03484, WO 95/09853, WO '95/09851, WO 95/09847, WO 95/09852, WO 92/12154, WO 94/19350, WO 99/15164, WO 98/50356, DE 19842833, or JP 2000 86657.
17. The method according to any one of Claims 1 to 6, or 16 wherein the compound is l-(l,3-Dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(2- phenoxypyrimidin-4-yl)imidazole, or a pharmaceutically acceptable salt thereof.
18. The method according to any one of claims 1 to 6, or 16 wherein the compound is trans- 1 -(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2- methoxy)pyrimidin-4-yl]imidazole; l-(4-Piperidinyl)-4-(4-fluorophenyl)-5- (2-methoxy-4-pyrimidinyl)imidazole; or (4-Fluorophenyl)-2-(4- methylsulfinylphenyl)-5-(4-pyridyl)-imidazole.
19. The method according to Claim 1 or 14 wherein the compound is NX-745, RWJ 67657, RWJ-68354, ZM 336372, SU 4984 or RPR-200765A.
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EP1709965A3 (en) 2001-07-11 2006-12-27 Boehringer Ingelheim Pharmaceuticals, Inc. Methods of treating cytokine mediate diseases
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