阅读说明：本技术 预防或治疗眼科疾病的方法 (Method for preventing or treating ophthalmic diseases ) 是由 亚历山大·鲍什 马修·赖特 于 2018-04-03 设计创作，主要内容包括：本发明涉及药物组合在预防或治疗对象的眼科疾病或障碍的方法中的应用,所述药物组合包含：(a)PPAR激动剂；(b)p38激酶抑制剂；和任选地(c)一种或多种药用稀释剂、赋形剂或载体。(The present invention relates to the use of a pharmaceutical combination in a method for preventing or treating an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising: (a) a PPAR agonist; (b) p38 kinase inhibitors; and optionally (c) one or more pharmaceutically acceptable diluents, excipients or carriers.)

1. Use of a pharmaceutical combination in a method of preventing or treating an ophthalmic disease or disorder in a subject, the pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

2. The use of a pharmaceutical combination according to claim 1, wherein the p38 kinase inhibitor inhibits p38-a and/or p38- β.

3. The use of a pharmaceutical combination according to claim 1, wherein the p38inhibitor is a compound of formula I or formula II or a pharmaceutically acceptable salt thereof,

wherein

Z is N or CH;

w is NR²；

X^lIs O, NR⁴(wherein R is⁴Is hydrogen or alkyl), S or CR⁵R⁶(wherein R is⁵And R⁶Independently hydrogen or alkyl) or C ═ O;

X²is O or NR⁷；

Ar¹Is aryl or heteroaryl;

R²is hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkylcarbonyl, heteroalkoxycarbonyl or-R²¹-R²²Wherein R is²¹Is alkylene or-C (═ O) -, and R²²Is alkyl or alkoxy;

R¹is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cyclicAlkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, R¹²-SO₂-heterocyclylamino (wherein R is¹²Is haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl), -Y¹-C(O)-Y²-R¹¹(wherein Y is¹And Y²Independently is absent or alkylene, and R¹¹Is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), (heterocyclyl) (cycloalkyl) alkyl or (heterocyclyl) (heteroaryl) alkyl;

R³is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R³¹(wherein R is³¹Is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino or NR³²-Y³-R³³(wherein Y is³is-C (O), -C (O) O-, -C (O) NR³⁴、S(O)₂Or S (O)₂NR³⁵；R³²、R³⁴And R³⁵Independently hydrogen or alkyl; and R is³³Is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or optionally substituted phenyl) or acyl;

R⁷is hydrogen or alkyl; and is

R⁸And R⁹Independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, -C (O) -R^8l(wherein R is⁸¹Is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkoxy, aryloxy, amino, monoalkylamino or dialkylamino, arylamino or aryl (alkyl) amino), or R⁸And R⁹Together form ═ CR⁸²R⁸³(wherein R is⁸²And R⁸³Independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl), and optionally,

one or more pharmaceutically acceptable diluents, excipients or carriers.

4. The use of a pharmaceutical combination according to claim 3, wherein the p38inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof,

wherein Ar is¹、W、X¹、X²、Z、R¹And R³As defined in claim 3.

5. The use of a pharmaceutical combination according to claim 1, wherein the p38 kinase inhibitor is selected from the group consisting of pamimod, apilimod, rossimod, dirimod, samimod, AZD7624, ARRY-371797, LY2228820, R9111, PH-797804, BIRB 796, VX-702, VX-745, SB239063, SB202190, SCIO469, BMS 582949 and pharmaceutically acceptable salts thereof.

6. The use of a pharmaceutical combination according to claim 1 wherein the p38 kinase inhibitor is pamamold (6- (2, 4-difluorophenoxy) -2- [ 3-hydroxy-1- (2-hydroxyethyl) -propylamino ] -8-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one, formula III) or a pharmaceutically acceptable salt thereof,

7. the use of a pharmaceutical combination according to any one of claims 1 to 6 wherein the PPAR agonist activates PPAR γ and/or PPAR α.

8. The use of a pharmaceutical combination according to any one of claims 1 to 6 wherein the PPAR agonist activates PPAR γ.

9. The use of a pharmaceutical combination according to any one of claims 1 to 6, wherein the PPAR agonist is selected from pioglitazone, rosiglitazone, troglitazone, fenofibrate, bezafibrate and pharmaceutically acceptable salts thereof.

10. The use of a pharmaceutical combination according to any one of claims 1 to 6 wherein the PPAR agonist is pioglitazone or a pharmaceutically acceptable salt thereof.

11. The use of a pharmaceutical combination according to any one of claims 1 to 10, wherein the combination is administered to the subject orally.

12. A compound of formula I or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable diluents, excipients or carriers, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject,

wherein

Z is N or CH;

w is NR²；

X^lIs O, NR⁴(wherein R is⁴Is hydrogen or alkyl), S or CR⁵R⁶(wherein R is⁵And R⁶Independently hydrogen or alkyl) or C ═ O;

X²is O or NR⁷；

Ar¹Is aryl or heteroaryl;

R²is hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkylcarbonyl, heteroalkoxycarbonyl or-R²¹-R²²Wherein R is²¹Is alkylene or-C (═ O) -, and R²²Is alkyl or alkoxy;

R¹is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, R¹²-SO₂-heterocyclylamino (wherein R is¹²Is halogenated alkyl, arylAlkyl, heteroaryl or heteroaralkyl), -Y¹-C(O)-Y²-R¹¹(wherein Y is¹And Y²Independently is absent or alkylene, and R¹¹Is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), (heterocyclyl) (cycloalkyl) alkyl or (heterocyclyl) (heteroaryl) alkyl;

R³is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R³¹(wherein R is³¹Is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino or NR³²-Y³-R³³(wherein Y is³is-C (O), -C (O) O-, -C (O) NR³⁴、S(O)₂Or S (O)₂NR³⁵；R³²、R³⁴And R³⁵Independently hydrogen or alkyl; and R is³³Is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or optionally substituted phenyl) or acyl; and is

R⁷Is hydrogen or alkyl.

13. The pharmaceutical combination according to any one of claims 1 to 11 or the use of a compound of formula I according to claim 12 or a pharmaceutically acceptable salt thereof, wherein the ophthalmic disease or disorder is macular degeneration.

14. The pharmaceutical combination according to claim 13 or the use of a compound of formula I according to claim 13 or a pharmaceutically acceptable salt thereof, wherein the macular degeneration is age-related macular degeneration (AMD).

15. Use of a kit comprising a pharmaceutical combination and instructions for use of the kit in a method for preventing or treating an ophthalmic disease or disorder, wherein the pharmaceutical combination comprises:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

Technical Field

The present invention relates to methods of preventing or treating ophthalmic diseases or disorders.

Background

Ophthalmic diseases or disorders are usually devastating diseases that lead to complete or partial blindness. For example, age-related macular degeneration (AMD) is the leading cause of blindness in people over 60 years of age in developed countries. Recent systematic review and meta-analysis shows that 8.7% of the world population has AMD, and with increasing longevity, the inferred number of people with the disease will be about 1.96 billion in 2020 and 2.88 billion in 2040. About 175 million americans are affected by AMD, and this figure is expected to grow to nearly 3 million by the year 2020. No therapy is currently available for the dry, slowly developing atrophic form of AMD. In summary, there is a great unmet medical need for the treatment of ophthalmic diseases or disorders, such as AMD.

Disclosure of Invention

It has now surprisingly been found that a pharmaceutical combination comprising a PPAR agonist, e.g. pioglitazone, and a p38inhibitor, e.g. a compound of formula I or II as defined hereinafter, e.g. pamapimod, is useful in the prevention or treatment of ophthalmic diseases or disorders, in particular macular degeneration, e.g. AMD.

Furthermore, it has been surprisingly found that a compound of formula I, or a pharmaceutically acceptable salt thereof (as defined below), alone, i.e. not in combination with a PPAR agonist, is useful in the prevention or treatment of an ophthalmic disease or disorder. In a standard model established in the study of AMD, it was surprisingly found that treatment with the combination provided a synergistic effect.

Accordingly, in a first aspect, the present invention provides the use of a pharmaceutical combination in a method of preventing or treating an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

In another aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable diluents, excipients or carriers, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject,

wherein

Z is N or CH;

w is NR²；

X^lIs O, NR⁴(wherein R is⁴Is hydrogen or alkyl), S or CR⁵R⁶(wherein R is⁵And R⁶Independently hydrogen or alkyl) or C ═ O;

X²is O or NR⁷；

Ar¹Is aryl or heteroaryl;

R²is hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkylcarbonyl, heteroalkoxycarbonyl or-R²¹-R²²Wherein R is²¹Is alkylene or-C (═ O) -, and R²²Is alkyl or alkoxy;

R¹is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, R¹²-SO₂-heterocyclylamino (wherein R is¹²Is haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl), -Y¹-C(O)-Y²-R¹¹(wherein Y is¹And Y²Independently is absent or alkylene, and R¹¹Is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), (heterocyclyl) (cycloalkyl) alkyl or (heterocyclyl) (heteroaryl) alkyl;

R³is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R³¹(wherein R is³¹Is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino or NR³²-Y³-R³³(wherein Y is³is-C (O), -C (O) O-, -C (O) NR³⁴、S(O)₂Or S (O)₂NR³⁵；R³²、R³⁴And R³⁵Independently hydrogen or alkyl; and R is³³Is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or optionally substituted phenyl) or acyl; and is

R⁷Is hydrogen or alkyl.

In another aspect, the invention provides a kit and instructions for using the kit for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, comprising a pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

Drawings

Fig. 1 shows the difference in retinal thickness in the CNV region compared to total retinal thickness. (STR001 ═ pioglitazone HCl; STR002 ═ pamimod).

Figure 2 shows identified isolectin positive regions in each CNV lesion site (Kruskal-Wallis test followed by Dunn's multiple comparison test, P ═ 0.025, × P ═ 0.07, × P ═ 0.0001, × P < 0.0001). (STR001 ═ pioglitazone HCl; STR002 ═ pamimod).

Detailed Description

The following definitions are used for the purpose of explaining the present specification, and where appropriate, terms used in the singular also include the plural and vice versa. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any embodiment. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

The terms "comprising," "having," and "including" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted.

The term "pharmaceutically acceptable diluent, excipient or carrier" as used herein, means a diluent, excipient or carrier which is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio. A "diluent" is an agent added to the total volume of active agent to supplement the solid composition. As a result, the size of the solid composition is increased, making it easier to handle. Diluents are convenient when the pharmaceutical dose per solid composition is low, otherwise the solid composition will be too small. An "excipient" may be a binder, lubricant, glidant, coating additive, or combination thereof. Thus, excipients are intended for a variety of purposes. A "carrier" can be a solvent, suspending agent or vehicle for delivering the instant compound to a subject.

The term "ophthalmic disease or disorder" means a medical condition of the eye commonly referred to as an ophthalmic disease or disorder and known in the art. Thus, the term "ophthalmic disease or disorder" is meant to include, but is not limited to, diseases or disorders selected from the group consisting of:

choroidal and retinal disorders, such as those selected from focal, diffuse and non-specific chorioretinal inflammations, such as chorioretinitis, choroiditis, retinitis, retinochoroiditis, syphilitic chorioretinitis (advanced), cytomegalovirus retinitis, chorioretinitis caused by toxoplasma, and tuberculous chorioretinitis; posterior ciliary inflammation, such as pars plana inflammation; native field disease; choroidal retinal scars, such as the posterior pole macular scar (post-inflammatory or post-traumatic) or solar retinopathy; choroidal degeneration, such as atrophy or sclerosis; hereditary choroidal dystrophy, such as choroideremia, central areolar choroidal dystrophy, generalized choroidal dystrophy or perioptic choroidal dystrophy; choroidal convoluted atrophy; choroidal hemorrhage and rupture; and choroidal detachment;

retinal detachment and breakdown, such as primary and secondary retinal detachment and retinoschisis; retinal vascular occlusions, such as retinal artery occlusion and retinal vein occlusion;

other retinal disorders, such as retinopathies such as hypertensive retinopathy, retinopathy of prematurity and central serous retinopathy; idiopathic retinopathy, proliferative retinopathy, vitreoretinopathy; vascular lesions associated with telangiectasia or aneurysm; retinopathy associated with lupus erythematosus, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, uveal retinitis, or diabetes; macular degeneration, such as age-related macular degeneration (AMD), hereditary macular degeneration (juvenile macular degeneration) such as retinitis pigmentosa (retinitis pigmentosa), morbus best, morbus Stargardt and Sorsby's disease, diabetic retinopathy (diabetic retinopathy), myopic macular degeneration, macular degeneration caused by inflammation (retinitis) such as Presumed Ocular Histoplasmosis Syndrome (POHS), and systemic drug retinopathies such as chloroquine retinopathy (bovine ocular macular degeneration); the epiretinal membrane; peripheral retinal degeneration; hereditary retinal dystrophy; retinal hemorrhage; retinal detachment and macular edema;

glaucoma of all etiologies and manifestations, such as primary and secondary open-angle glaucoma, primary angle-closure glaucoma, glaucoma associated with intraocular inflammation, steroid-induced glaucoma, glaucoma associated with intraocular hemorrhage, pseudoexfoliative syndrome and glaucomatous optic neuropathy;

optic neuropathy; and

ocular hypertension.

The term "macular degeneration" refers to a group of ophthalmic diseases or disorders and disorders affecting the macula, such as age-related macular degeneration (AMD), hereditary macular degeneration (juvenile macular degeneration) such as retinitis pigmentosa (retinitis pigmentosa), morbus Best, morbus Stargardt, Sorsby's disease, diabetic retinopathy (diabetic retinopathy), myopic macular degeneration, macular degeneration caused by inflammation (retinitis) such as Presumed Ocular Histoplasmosis Syndrome (POHS), and systemic drug retinopathies such as chloroquine retinopathy (bovine ocular macular degeneration).

The term "age-related macular degeneration" (AMD) is generally known to those skilled in the art and is meant to include both wet (exudative) AMD and dry (non-exudative) AMD. The term "dry AMD" is meant to include Geographic Atrophy (GA), which is commonly known by those skilled in the art as the advanced form of dry AMD.

The term "pharmaceutically acceptable salt" of a compound means a pharmaceutically acceptable salt, and which possesses the desired pharmacological activity of the parent compound. These salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxy-benzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbenzenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene 1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, laurylsulfuric acid, and the like, Gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, myfuroic acid, etc.; or (2) a salt formed when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or complexes with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Preferred salts include the acid addition salts formed with hydrochloric acid.

The terms "subject" and "patient" are used interchangeably herein and refer to a mammal, particularly a human.

As used herein, the term "about" refers to +/-10% of a given measurement.

In a first aspect, the present invention provides the use of a pharmaceutical combination in a method of preventing or treating an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

PPAR agonists

As used herein, the term "PPAR agonist" refers to a drug that activates a peroxisome proliferator-activated receptor (PPAR) such as a PPAR γ receptor, a PPAR α receptor, a PPAR δ receptor, or a combination thereof, and includes PPAR γ agonists such as pioglitazone, troglitazone, or rosiglitazone, PPAR α agonists such as fibrates such as bezafibrate, fenofibrate (fenofibric acid), clofibrate, or gemfibrozil, PPAR dual agonists (PPAR α/γ or PPAR α/δ agonists) such as argraza, mogrosiglicla, tixaglicla, rogarecla, GFT505, or nateglinide, PPAR δ agonists such as GW 516, PPAR pan agonists (PPAR α/δ/γ agonists), or selective PPAR modulators such as INT131, as well as pharmaceutically acceptable salts of these compounds. In general, a PPAR γ agonist, a PPAR modulator, a PPAR α agonist and/or a PPAR α/γ dual agonist is used in the pharmaceutical combination of the invention, in particular a PPAR γ agonist, a PPAR α agonist and/or a PPAR α/γ dual agonist is used in the pharmaceutical combination of the invention, more in particular a PPAR γ agonist and/or a PPAR α agonist selected from pioglitazone, rosiglitazone, troglitazone, fenofibrate, bezafibrate and pharmaceutically acceptable salts thereof, even more in particular a PPAR γ agonist selected from pioglitazone, rosiglitazone, troglitazone and pharmaceutically acceptable salts thereof, preferably pioglitazone or pharmaceutically acceptable salts thereof. The PPAR α agonist used in the pharmaceutical combination of the present invention is selected from bezafibrate, fenofibrate (fenofibric acid), clofibrate, gemfibrozil and pharmaceutically acceptable salts thereof, preferably bezafibrate, fenofibrate (fenofibric acid) or pharmaceutically acceptable salts thereof, more preferably bezafibrate or pharmaceutically acceptable salts thereof. The PPAR α/γ dual agonist used in the pharmaceutical combination of the invention is selected from the group consisting of aleglitazar, mogglicla, tegaserod, rogolazine, saroglossa, GFT505, nateglinide and pharmaceutically acceptable salts thereof, preferably mogglicla, tegaserod or pharmaceutically acceptable salts thereof. Preferably, a PPAR γ agonist and/or a PPAR α agonist is used in the pharmaceutical combination of the invention, more preferably a PPAR γ agonist or modulator and/or a PPAR α agonist selected from pioglitazone, rosiglitazone, troglitazone, fenofibrate, bezafibrate, INT131 and pharmaceutically acceptable salts thereof, even more preferably a PPAR γ agonist selected from pioglitazone, rosiglitazone, troglitazone and pharmaceutically acceptable salts thereof. Even more preferably, pioglitazone or a pharmaceutically acceptable salt thereof, especially pioglitazone hydrochloride, is used in the pharmaceutical combination of the present invention.

In one embodiment, thiazolidinedione PPAR agonists are used in the pharmaceutical combinations of the present invention. Suitable thiazolidinedione PPAR agonists are for example pioglitazone, troglitazone, rosiglitazone or pharmaceutically acceptable salts thereof. Particularly suitable thiazolidinone PPAR agonists are pioglitazone or a pharmaceutically acceptable salt thereof, especially pioglitazone hydrochloride.

Pioglitazones are described, for example, in U.S. Pat. No. 4,687,777 or Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lef ex bvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Kor a nyi L, Laak M, Mok a n M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Scherntanhaner G, Schmittz O, Skrha J, Smith U, Taton J; proactivetestimators. lancet.2005oct8; 366(9493) 1279-89, and is represented by the structural formula indicated below:

troglitazones are described, for example, in Florez JC, Jablonski KA, Sun MW, Bayley N, Kahn SE, Shamoon H, Hamman RF, Knowler WC, Nathan DM, Altsuhler D; diabetes PreventionProgramm Research group.J. Clin Endocrinol Metab.2007 Apr; 92(4) 1502-9, and is represented by the structural formula indicated below:

rosiglitazone is described, for example, in Nissen SE, Wolski K.N Engl J med.2007jun14; 356(24) 2457-71.Erratum in N Engl J Med.2007Jul 5; 357(1) and 100. Fenofibrate is described, for example, in Bonds DE, Craven TE, Buse J, Crouse JR, Cuddihy R, Elam M, Ginsberg HN, Kirchner K, Marcovina S, mycleckyj JC, O' Connor PJ, Sperl-Hillen ja. 55(6) 1641-50, and is represented by the structural formula indicated below:

bezafibrate is described, for example, in i.golden berg, m.benderly, u.goldbort, Vascular health and risk management.2008,4(1): 131-:

chlorobenzyl esters are described, for example, in Rabkin SW, Hayden M, Frohlich j. athero sclero, 1988 Oct; 73(2-3):233-40, and is represented by the structural formula indicated below:

fenofibrate (fenofibric acid) is described, for example, in Schima SM, macejewski SR, Hilleman DE, Williams MA, mohaudin SM. expert Opin pharmacother.2010apr; 11(5) 731-8, and is represented by the structural formula indicated below:

gemfibrozil is described, for example, in Adabag AS, Mithani S, Al Aloul B, Collins D, Bertog S, Bloomfield HE; veterans Affoars High-sensitivity Lipoprotein Cholesterol interaction Trial Study group. am Heart J.2009 May; 157(5) 913-8, and is represented by the structural formula indicated below:

alglitazar is described, for example, in Lincoff AM, Tardif JC, Schwartz GG, Nichols SJ, Ryd e n L, Neal B, Malmberg K, Wedel H, Buse JB, Henry RR, Weichert A, Cannata R, Svensson A, Volz D, Grobbe DE; alecdio investators.jama.2014apr 16; 311(15) 1515-25, and is represented by the structural formula indicated below:

moglitazone is described, for example, in Fernandez M, Gastalcelli A, Triplitt C, Hardia J, Casolaro A, Petz R, Tantiwong P, Musi N, Cersosimo E, Ferranini E, DeFronzoRA. diabetes Obes Metab.2011Oct; 13(10) 893-902, and is represented by the structural formula indicated below:

teggenta is described, for example, in Bays H, McElhattan J, Bryzinski BS; GALLANT 6Study group, diab Vasc Dis res.2007sep; 181-93, and is represented by the structural formula indicated below:

roglitaza is described, for example, in Saad MF, Greco S, Osei K, Lewis AJ, Edwards C, Nunez M, Reinhardt RR; ragaglitazar Dose-Ranging Study group. diabetes Care.2004Jun; 27(6) 1324-9 and is represented by the structural formula indicated below:

sarogeliza is described, for example, in Agrawal r. curr Drug targets.2014 Feb; 15(2) 151-5, and is represented by the structural formula indicated below:

nateglinide is described, for example, in Ahlawat P, Srinivas nr. eur J Drug meta pharmacokinet.2008jul-Sep; 33(3) 187-90. GW501516 is described in, for example, Wang X, Sng MK, FooS, Chong HC, Lee WL, Tang MB, Ng KW, Luo B, Chong C, Wong MT, Tong BM, Chiba S, LooSC, Zhu P, Tan NS.J Control Release.2015Jan 10; 197:138-47, and is represented by the structural formula indicated below:

GFT505 is described, for example, in Cariou B, stages B. expert Opin Investig drugs.2014 Oct; 23(10) 1441-8, and is represented by the structural formula indicated below:

INT131 is described in, for example, Taygerly JP, McGee LR, Rubenstein SM, Houze JB, Cushing TD, Li Y, Motani A, Chen JL, Frankmolell W, Ye G, Learned MR, Jaen J, Miao S, Timmermans PB, Thoolen M, Kearney P, Flygare J, Beckmann H, Weiszmann J, Lindstrom, Walker N, Liu J, Biermann D, Wang Z, Hagiwara A, Iida T, Arakaki H, Kitao Y, Shinkai H, Furukawa N, Nishiu J, Nakamura M.Bioorg Med.2013 Feb 15; 979-92, and is represented by the structural formula indicated below:

PPAR activation by PPAR agonists is generally strong in the low nanomolar to low micromolar range, for example in the range 0.1nM to 100. mu.M. In certain embodiments, the PPAR activation is weak or partial, i.e., the PPAR agonist used in the methods of the invention produces a maximum activation of the PPAR receptor in a reporter assay system of 10% to 100% compared to a reference PPAR agonist known to cause maximum PPAR activation.

P38 kinase inhibitors

The terms "p 38 kinase inhibitor" or "p 38 inhibitor" as used interchangeably herein, refer to drugs that inhibit p38mitogen-activated protein (MAP) kinases such as p38-a (MAPK14), p38- β (MAPK11), p38- γ (MAPK12/ERK6) and/or p38- δ (MAPK13/SAPK 4). Examples of p38 inhibitors include compounds of formula I and formula II as defined herein and pharmaceutically acceptable salts thereof. Other examples of p38 inhibitors include pamimod (pamapimod), apimod (acuumamod), losimod (lossmamod), dirimod (dilapimod), semapimod (semapimod), AZD7624, ARRY-371797, LY2228820, R9111, PH-797804, BIRB 796, VX-702, VX-745, SB239063, SB202190, SCIO469, BMS 582949 and pharmaceutically acceptable salts thereof.

In one embodiment, the pharmaceutical combination according to the invention comprises:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers;

wherein the p38inhibitor inhibits p38-a, p 38-p, p38- γ or p38- δ or a combination thereof, preferably inhibits p38-a and/or p38- β, more preferably inhibits p 38-a.

In another embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I or formula II or a pharmaceutically acceptable salt thereof,

wherein

Z is N or CH;

w is NR²；

X^lIs O, NR⁴(wherein R is⁴Is hydrogen or alkyl), S or CR⁵R⁶(wherein R is⁵And R⁶Independently hydrogen or alkyl) or C ═ O;

X²is O or NR⁷；

Ar¹Is aryl or heteroaryl;

R²is hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkylcarbonyl, heteroalkoxycarbonyl or-R²¹-R²²Wherein R is²¹Is alkylene or-C (═ O) -, and R²²Is alkyl or alkoxy;

R¹is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, R¹²-SO₂-heterocyclylamino (wherein R is¹²Is haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl), -Y¹-C(O)-Y²-R¹¹(wherein Y is¹And Y²Independently is absent or alkylene, and R¹¹Is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), (heterocyclyl) (cycloalkyl) alkyl or (heterocyclyl) (heteroaryl) alkyl;

R³is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R³¹(wherein R is³¹Is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino or NR³²-Y³-R³³(wherein Y is³is-C (O), -C (O) O-, -C (O) NR³⁴、S(O)₂Or S (O)₂NR³⁵；R³²、R³⁴And R³⁵Independently hydrogen or alkyl; and R is³³Is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or optionally substituted phenyl) or acyl;

R⁷is hydrogen or alkyl; and is

R⁸And R⁹Independently hydrogen, alkylAryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, -C (O) -R^8l(wherein R is⁸¹Is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkoxy, aryloxy, amino, monoalkylamino or dialkylamino, arylamino or aryl (alkyl) amino), or R⁸And R⁹Together form ═ CR⁸²R⁸³(wherein R is⁸²And R⁸³Independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl), and optionally one or more pharmaceutically acceptable diluents, excipients or carriers.

In a preferred embodiment, the p38inhibitor used in the pharmaceutical combination of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof,

wherein

Z is N or CH;

w is NR²；

X^lIs O, NR⁴(wherein R is⁴Is hydrogen or alkyl), S or CR⁵R⁶(wherein R is⁵And R⁶Independently hydrogen or alkyl) or C ═ O;

X²is O or NR⁷；

Ar¹Is aryl or heteroaryl;

R²is hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkylcarbonyl, heteroalkoxycarbonyl or-R²¹-R²²Wherein R is²¹Is alkylene or-C (═ O) -, and R²²Is alkyl or alkoxy;

R¹is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, R¹²-SO₂-heterocyclylamino (wherein R is¹²Is halogenated alkyl, arylAlkyl, aralkyl, heteroaryl or heteroaralkyl), -Y¹-C(O)-Y²-R¹¹(wherein Y is¹And Y²Independently is absent or alkylene, and R¹¹Is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), (heterocyclyl) (cycloalkyl) alkyl or (heterocyclyl) (heteroaryl) alkyl;

R³is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R³¹(wherein R is³¹Is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino or NR³²-Y³-R³³(wherein Y is³is-C (O), -C (O) O-, -C (O) NR³⁴、S(O)₂Or S (O)₂NR³⁵；R³²、R³⁴And R³⁵Independently hydrogen or alkyl; and R is³³Is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or optionally substituted phenyl) or acyl; and is

R⁷Is a hydrogen or an alkyl group,

and optionally one or more pharmaceutically acceptable diluents, excipients or carriers.

In another embodiment, the p38inhibitor used in the pharmaceutical combination of the invention is a compound of formula I, wherein X is¹Is NR⁴And X²Is NR⁷Or X¹And X²Each is O, wherein R⁴And R⁷As defined above.

In another embodiment, the p38inhibitor used in the pharmaceutical combination of the invention is a compound of formula I, wherein X is¹Is NR⁴Or O and X²Is NR⁷Or O, wherein R⁴And R⁷As defined above.

In another embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein W is NR²And wherein R is²Is hydrogen, alkyl, heteroalkyl, acyl or alkoxycarbonylPreferably hydrogen or alkyl, more preferably hydrogen.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein R is¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl or (heterocyclyl) (cycloalkyl) alkyl.

In a preferred embodiment, the p38inhibitor used in the pharmaceutical combination of the invention is a compound of formula I, wherein R is²Is hydrogen and R¹Is heteroalkyl, or vice versa.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein R is¹Is hydrogen, alkyl, haloalkyl, heteroalkyl, or cyanoalkyl.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein R is¹Is cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heterocyclyl, heterocyclylalkyl or (heterocyclyl) (cycloalkyl) alkyl.

In a preferred embodiment, the p38inhibitor used in the pharmaceutical combination of the invention is a compound of formula I, wherein R is¹And R²Each independently selected from hydrogen and hydroxyalkyl, preferably from hydrogen, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl, 2- (hydroxymethyl) -3-hydroxypropyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl and 2-hydroxy-1-methylethyl, more preferably from hydrogen, 2-hydroxyethyl, 2, 3-dihydroxypropyl and 1- (hydroxymethyl) 2-hydroxyethyl, most preferably selected from hydrogen, 2-hydroxy-propyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl and 2-hydroxy-1-methylethyl.

In yet another embodiment, the p38inhibitor used in the pharmaceutical combination of the invention is of formula (la)A compound of formula I, wherein R³Is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R³¹(wherein R is³¹Is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or acyl.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein R is³Is hydrogen, alkyl, haloalkyl, heteroalkyl, cyanoalkyl, cycloalkyl or cycloalkylalkyl.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein R is³Is hydrogen, alkyl, haloalkyl, heteroalkyl, or cyanoalkyl.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein R is³Is cycloalkyl or cycloalkylalkyl.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein X is¹And X²Both are O.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein R is¹Is alkyl or heteroalkyl.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein R is¹Is heteroalkyl, preferably 3-hydroxy-1- (2-hydroxyethyl) -propyl or 2-hydroxy-1-methylethyl.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein R is³Is alkyl or heteroalkyl.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein R is³Is an alkyl group, preferably a C1-C5 alkyl group, more preferably a C1-C4 alkyl group, more preferably a C1-C3 alkyl group. In a particularly preferred embodiment, R³Is ethyl or methyl, preferably methylAnd (4) a base.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein R is³Is heteroalkyl, preferably 2-hydroxy-propyl.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein W is NH.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein Z is N.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein Ar is¹Is aryl, preferably phenyl optionally substituted with 1,2 or 3 halo substituents, most preferably phenyl substituted with two halo substituents in the ortho and para positions. In a particularly preferred embodiment, Ar¹Is 2, 4-difluorophenyl.

In a further embodiment, the p38inhibitor for use in the pharmaceutical combination of the invention is a compound of formula I, wherein X is¹Is NR⁴And X²Is NR⁷Or X¹And X²Each is O, wherein R⁴And R⁷As defined above; and wherein

R¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl or (heterocyclyl) (cycloalkyl) alkyl; and wherein

R³Is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R³¹(wherein R is³¹Is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or acyl; and wherein

W is NR²Wherein R is²Is hydrogen, alkyl, acyl or alkoxycarbonyl; and wherein

Ar¹Is an aryl group; and wherein

Z is N.

In a preferred embodiment, the p38inhibitor used in the pharmaceutical combination of the invention is a compound of formula I, wherein X¹And X²Each is O, and wherein Z is N, and wherein W is NH, and wherein Ar¹Is phenyl optionally substituted with 1,2 or 3 halogen substituents, and wherein R is¹Is heteroalkyl, and wherein R³Is alkyl or heteroalkyl.

In another embodiment, the p38inhibitor used in the pharmaceutical combination of the invention is a compound of formula II or a pharmaceutically acceptable salt thereof,

wherein Ar is¹、W、X¹、Z、R¹、R⁸And R⁹As defined in any of the embodiments above.

Unless otherwise indicated, the following terms have the meanings given below:

"acyl" means a group-C (O) R, wherein R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, or phenylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, and phenylalkyl are as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

"acylamino" means a group-NR 'C (O) R, wherein R' is hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl and phenylalkyl are as defined herein. Representative examples include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, phenylmethylcarbonylamino, and the like.

"alkoxy" means a group-OR, where R is alkyl as defined herein. Examples are methoxy, ethoxy, phenoxy, butoxy and the like.

"alkoxycarbonyl" means a group R-O-C (O) -, where R is alkyl as defined herein.

"alkyl" means a straight chain saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group of 3 to 6 carbon atoms. Examples include methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, n-butyl, pentyl, and the like. Preference is given to C1-C3 alkyl, especially ethyl and methyl.

"alkylsulfonyl" means the radical R-S (O)₂-, wherein R is alkyl as defined herein.

"alkylene" means a straight chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. Examples are methylene, ethylene, 2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene and the like.

"aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon group optionally substituted independently with one or more substituents, preferably 1,2 or 3 substituents, preferably selected from alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, Y-c (o) -R (wherein Y is absent or alkylene and R is hydrogen, alkyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), heteroalkyl, heteroalkoxy, heteroalkylamino, halogen, nitro, cyano, amino, monoalkylamino, dialkylamino, alkylsulfonylamino, heteroalkylsulfonylamino, sulfonamido, methylenedioxy, ethylenedioxy, heterocyclyl or heterocyclylalkyl. Monocyclic aryl groups optionally substituted as described above are preferred. More specifically, the term aryl includes, but is not limited to, phenyl optionally independently substituted with 1,2, or 3 substituents preferably selected from alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, Y-c (o) -R (wherein Y is absent or alkylene and R is hydrogen, alkyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, amino, monoalkylamino, or dialkylamino), heteroalkyl, heteroalkoxy, heteroalkylamino, halogen, nitro, cyano, amino, monoalkylamino, dialkylamino, alkylsulfonylamino, heteroalkylsulfonylamino, sulfonamido, methylenedioxy, ethylenedioxy, heterocyclyl, and heterocyclylalkyl. Particularly preferred aryl groups are substituted phenyl groups selected from chlorophenyl, methoxyphenyl, 2-fluorophenyl, 2, 4-difluorophenyl, 1-naphthyl and 2-naphthyl.

"arylsulfonyl" means a radical R-S (O)₂-, wherein R is aryl as defined herein.

"aralkyl" refers to an aryl group as defined herein, such as benzyl, bonded directly through an alkylene group.

"aryloxy" means the group-OR, where R is aryl as defined herein, e.g., phenoxy.

By "aryloxycarbonyl" is meant the group R-C (═ O) -, where R is an aryloxy group, such as phenoxycarbonyl.

"cycloalkyl" refers to a saturated monovalent cyclic hydrocarbon group of 3 to 7 ring carbon atoms, or more specifically to cycloalkyl groups of the particular compounds listed in the accompanying tables or described in the examples. It is to be understood that these groups may also be grouped in groups that only encompass these groups, but are preferred first or second or both, such as cyclopropyl, cyclobutyl, cyclohexyl, 4-methyl-cyclohexyl, and the like.

"cycloalkylalkyl" means the group-R^aR^bWherein R is^aIs alkylene and R^bAre cycloalkyl groups as defined herein, such as cyclohexylmethyl and the like.

"substituted cycloalkyl" means a cycloalkyl group as defined herein, 1,2 or 3 (preferably 1) ring hydrogen atoms of which are independently replaced by cyano or-Y-c (o) R (wherein Y is absent or alkylene and R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino or optionally substituted phenyl), or more specifically substituted cycloalkyl of the specific compounds listed in the accompanying tables or described in the examples.

"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.

"haloalkyl" means an alkyl group substituted with one or more of the same or different halogen atoms, e.g., -CH₂C1、-CF₃、-CH₂CF₃、-CH₂CC1₃And the like.

"heteroalkyl" means an alkyl group as defined herein wherein 1,2 OR 3 hydrogen atoms have been replaced with a substituent independently selected from-OR^a、-N(O)_nR^bR^c(wherein if R is^bAnd R^cIf both are independently alkyl, cycloalkyl or cycloalkylalkyl, n is 0 or 1, otherwise n is 0) and-S (O)_nR^d(wherein n is an integer from 0 to 2), and it is understood that the point of attachment of the heteroalkyl group is through a carbon atom, where R is^aIs hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl or cycloalkylalkyl; r^bAnd R^cIndependently of one another, hydrogen, acyl, alkoxycarbonyl, alkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl or dialkylaminosulfonyl, aminoalkyl, monoalkylaminoalkyl or dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkylsulfonyl or alkoxyalkylsulfonyl; and when n is 0, R^dIs hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl, and when n is 1 or 2, R is^dIs alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino, acylamino, monoalkylamino or dialkylamino. Preferred heteroalkyl groups include hydroxyalkyl groups, preferably C1-C6 hydroxyalkyl groups. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxy-propyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2-hydroxy-1-methylethyl, 2, 3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2, 3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.Particularly preferred heteroalkyl groups are 2-hydroxy-propyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl or 2-hydroxy-1-methylethyl.

"hydroxyalkyl" means an alkyl group as defined herein which is substituted by one or more, preferably by 1,2 or 3 hydroxyl groups, provided that the same carbon atom does not carry more than one hydroxyl group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl, 2- (hydroxymethyl) -3-hydroxypropyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl, and 2-hydroxy-1-methylethyl, preferably 2-hydroxyethyl, 2, 3-dihydroxypropyl, and 1- (hydroxymethyl) -2-hydroxyethyl, more preferred are 2-hydroxy-propyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl and 2-hydroxy-1-methylethyl. Thus, as used herein, the term "hydroxyalkyl" is used to define a subset of heteroalkyl groups.

"Heteroalkylcarbonyl" means a radical R^a-C (═ O) -, where R is^aIs a heteroalkyl group. Representative examples include acetoxymethylcarbonyl, aminomethylcarbonyl, 4-acetoxy-2, 2-dimethyl-but-2-yl, 2-amino-4-methyl-pent-2-yl, and the like.

"Heteroalkoxy" means a group R^a-O-wherein R^aIs a heteroalkyl group. Representative examples include Me-C (═ O) -O-CH₂-O-, etc.

"Heteroalkoxycarbonyl" means a radical R^a-C (═ O), wherein R^aIs a heteroalkoxy group. Representative examples include 1-acetyloxy-methoxycarbonyl (Me-C (═ O) -OCH)₂-O-C (═ O) -), and the like.

"heteroaryl" means a monovalent monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring containing 1,2 or 3 ring heteroatoms selected from N, O or S, the remaining ring atoms being C, wherein it is understood that the attachment point of the heteroaryl group will be on an aromatic ring. The heteroaryl ring is optionally independently substituted with one or more substituents, preferably 1 or 2 substituents, selected from alkyl, haloalkyl, heteroalkyl, hydroxy, alkoxy, halogen, nitro or cyano. More specifically, the term heteroaryl includes, but is not limited to, pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuryl, tetrahydrobenzofuryl, isobenzofuryl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, benzimidazolyl, benzisoxazolyl or benzothienyl, imidazo [1,2-a ] -pyridyl, imidazo [2,1-b ] thiazolyl, and derivatives thereof.

"Heteroaralkyl" means a group-R^aR^bWherein R is^aIs alkylene and R^bIs heteroaryl, such as pyridin-3-ylmethyl, imidazolylethyl, pyridylethyl, 3- (benzofuran-2-yl) propyl, and the like.

"heteroalkyl-substituted cycloalkyl" means a cycloalkyl group as defined herein wherein 1,2 or 3 hydrogen atoms in the cycloalkyl group have been replaced with a heteroalkyl group, wherein it is understood that the heteroalkyl group is attached to the cycloalkyl group through a carbon-carbon bond. Representative examples include, but are not limited to, 1-hydroxymethylcyclopentyl, 2-hydroxymethylcyclohexyl, and the like.

"hetero-substituted cycloalkyl" means a cycloalkyl group as defined herein wherein 1,2 or 3 hydrogen atoms in the cycloalkyl group have been replaced by a substituent independently selected from hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, oxo (C ═ O), imino, hydroxyimino (═ NOH), NR' SO₂R^d(wherein R' is hydrogen or alkyl, and R^dIs alkyl, cycloalkyl, hydroxyalkyl, amino, monoalkylamino or dialkylamino), -X-Y-C (O) R (wherein X is O or NR ', Y is alkylene or absent, R is hydrogen, alkyl, haloalkyl, alkoxy, amino, monoalkylamino, dialkylamino or optionally substituted phenyl, and R' is H or alkyl) or-S (O)_nR (wherein n is an integer from 0 to 2 such that when n is 0, R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl or thienyl, and when n is 1 or 2, R is alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, thienyl, amino, acylamino, monoalkylamino or dialkylamino). Representative examples include, but are not limited to, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl or 4-hydroxycyclohexyl, 2-aminocyclohexyl, 3-aminocyclohexyl or 4-aminocyclohexyl, 2-methanesulfonamido-cyclohexyl, 3-methanesulfonamido-cyclohexyl or 4-methanesulfonamido-cyclohexyl and the like, preferably 4-hydroxycyclohexyl, 2-aminocyclohexyl or 4-methanesulfonamido-cyclohexyl.

"Heterosubstituted cycloalkyl-alkyl" means the group R^aR^b-, wherein R^aIs a hetero-substituted cycloalkyl radical, and R^bIs an alkylene group.

"heterocyclylamino" means a saturated monovalent cyclic group of4 to 8 ring atoms, wherein one ring atom is N and the remaining ring atoms are C. Representative examples include piperidine and pyrrolidine.

"Heterocyclyl" means a saturated or unsaturated non-aromatic cyclic group of 3 to 8 ring atoms, wherein one or more ring atoms are selected from N, O or S (O)_n(wherein n is an integer from 0 to 2) and the remaining ring atoms are C, wherein one or two C atoms may optionally be replaced by a carbonyl group. The heterocyclyl ring may be optionally substituted independently with 1,2 or 3 substituents selected from alkyl, haloalkyl, heteroalkyl, halogen, nitro, cyano, cyanoalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, aralkyl, - (X)_n-C (O) R (wherein X is O or NR ', n is 0 or 1, R is hydrogen, alkyl, haloalkyl, hydroxy (when n is 0), alkoxy, amino, monoalkylamino, dialkylamino or optionally substituted phenyl and R' is H or alkyl), -alkylene-C (O) R^a(wherein R is^aIs alkyl or NR ' R ' and R is hydrogen, alkyl or haloalkyl, and R ' are independently hydrogen or alkyl) or-S (O)_nR (wherein n is an integer of 0 to 2, such thatWhen n is 0, R is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, and when n is 1 or 2, R is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, dialkylamino or heteroalkyl. More specifically, the term heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl, piperazinyl, N-methylpyrrolidin-3-yl, 3-pyrrolidinyl, morpholinyl, thiomorpholinyl-1-oxide, thiomorpholinyl-1, 1-dioxide, 4- (1, 1-dioxan-tetrahydro-2H-thiopyranyl), pyrrolinyl, imidazolinyl, N-methanesulfonyl-piperidin-4-yl, and derivatives thereof.

"Heterocyclylalkyl" means the group-R^aR^bWherein R is^aIs alkylene and R^bIs a heterocyclic radical as defined above, such as tetrahydropyran-2-ylmethyl, 2-piperidinylmethyl or 3-piperidinylmethyl, 3- (4-methyl-piperazin-1-yl) propyl and the like.

"(heterocyclyl) (cycloalkyl) alkyl" means an alkyl group in which two hydrogen atoms have been replaced by a heterocyclyl and a cycloalkyl.

"(heterocyclyl) (heteroaryl) alkyl" means an alkyl group in which two hydrogen atoms have been replaced by a heterocyclyl and a heteroaryl.

"amino" means the radical-NH₂。

"Monoalkylamino" means a radical-NHR where R is alkyl, hydroxyalkyl, cycloalkyl or cycloalkylalkyl as defined above, for example methylamino, (1-methylethyl) amino, hydroxymethylamino, cyclohexylamino, cyclohexylmethylamino, cyclohexylethylamino, and the like.

"dialkylamino" means a group-NRR ', where R and R' independently represent alkyl, hydroxyalkyl, cycloalkyl or cycloalkylalkyl as defined herein. Representative examples include, but are not limited to, dimethylamino, methylethylamino, bis (1-methylethyl) amino, (methyl) (hydroxymethyl) amino, (cyclohexyl) (methyl) amino, (cyclohexyl) (ethyl) amino, (cyclohexyl) (propyl) amino, (cyclohexylmethyl) (methyl) amino, (cyclohexylmethyl) (ethyl) amino, and the like.

"optionally substituted phenyl" means a phenyl ring optionally independently substituted with one or more substituents, preferably 1,2 or 3 substituents, more preferably 2 substituents, selected from alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, halo, nitro, cyano, amino, methylenedioxy, ethylenedioxy, and acyl, preferably halo, most preferably fluoro.

Thus, in a preferred embodiment, the p38inhibitor used in the pharmaceutical combination of the invention is selected from the group consisting of pamimod, acamod, rossimod, dirimod, samimod, AZD7624, ARRY-371797, LY2228820, R9111, PH-797804, BIRB 796, VX-702, VX-745, SB239063, SB202190, SCIO469 and BMS 582949 and pharmaceutically acceptable salts thereof. More preferably, the p38inhibitor used in the pharmaceutical combination of the invention is selected from pamimod, rossimod, LY2228820, BMS 582949 or a pharmaceutically acceptable salt thereof and mixtures thereof, even more preferably pamimod or a pharmaceutically acceptable salt thereof.

In a particularly preferred embodiment, the p38inhibitor is pamamomod, or a pharmaceutically acceptable salt thereof, pamamond having the chemical name 6- (2, 4-difluorophenoxy) -2- [ 3-hydroxy-1- (2-hydroxyethyl) -propylamino ] -8-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one and formula III,

pamamond and its synthesis are described, for example, in WO2008/151992 and WO2002/064594, and, for example, Hill RJ, Dabbagh K, phipard D, Li C, Suttmann RT, Welch M, Papp E, Song KW, Chang KC, leaf filter D, Kim Y-N, Roberts RT, zabk TS, Aud D, Dal Porto J, Manning AM, Peng SL, Goldstein DM and Wong BR, "pamamond, a novel p38mitogen-activated protein kinase inhibitor: preclinical Analysis of potency and Selectivity "(Pamapimod, a Novel p38Mitogen-Activated Protein kinase: clinical Analysis of Efficacy and Selectivity), J Pharmacol ExpTher. Decumber 2008327: 610-.

Another particularly preferred inhibitor of p38 is Rosemomod, having the chemical name 6- (5- ((cyclopropylamino) carbonyl) -3-fluoro-2-methylphenyl) -N- (2, 2-dimethylpropyl) -3-pyridinecarboxamide and formula IV,

rosemomod is described, for example, in Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM,KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB, "Inhibition of p38mitogen-activated protein kinase in hypercholesterolemia improves nitric oxide-mediated vasodilation and reduces inflammation" (Inhibition of p38mitogen-activated protein kinases and reduce inflammation), Circulation,2011Feb 8; 123(5) 515-23.

Another particularly preferred inhibitor of p38 is LY2228820, or a pharmaceutically acceptable salt thereof, LY2228820 having the chemical name 3- (2, 2-dimethylpropyl) -5- [4- (4-fluorophenyl) -2- (2-methyl-2-propyl) -1H-imidazol-5-yl ] -3H-imidazo [4,5-b ] pyridin-2-amine and formula V,

LY2228820 is described in, for example, Campbell RM, Anderson BD, Brooks NA, Brooks HB, Chan EM, De Dios A, Gilmour R, Graff JR, Jambrina E, Mader M, McCann D, Na S, Parsons SH, Pratt SE, Shih C, Stancato LF, Starling JJ, Tate C, Veasco, Wang Y, Jambrin XS, "Characterization of the potent and selective inhibitor LY2228820dimesylate of p38 MAPK having antitumor activity" (Characterization of Characterisation of LY2228820dimesylate, a potential and selective inhibitor of p 38K with activity), Mol Cancer The feber; 364-74 in (13), (2).

Another particularly preferred p38inhibitor is BMS 582949 or a pharmaceutically acceptable salt thereof, BMS 582949 having the chemical name 4- (5- (cyclopropylcarbamoyl) -2-methylphenylamino) -5-methyl-N-propylpyrrolo [1,2-f ] [1,2,4] triazine-6-carboxamide and formula VI,

BMS 582949 is described in e.g.Liu C, Lin J, Wrobleski ST, Lin S, Hynes J, Wu H, Dyckman AJ, Li T, Wityak J, Gillooly KM, Pitt S, Shen DR, Zhang RF, McIntyre KW, Salter-Cid L, Shuster DJ, Zhang H, Marathe PH, Doweyko AM, SaakJS, Kiefer SE, KishKF, Newitt, McKinnon M, Dodd JH, Barrish JC, Schieven GL, Leftheis K, "4- (5- (cyclopropylcarbamoyl) -2-methylphenylamino) -5-methyl-N-propylpyrrolo [1,2-f ] [1,2,4] triazine-6-carboxamide (BMS-582949), a clinically discovered inhibitor of the clinical p38-alpha kinase" (Discoyl) -5- (propylcarbamoyl) -5-propyl-N-propylpyrrolo [1,2-f ] [1,2,4] triazine-6-carboxamide-582949), 2-f ] [1,2,4] triazine-6-carboxamide (BMS-582949), a clinical p38-alpha MAP kinase inhibitor for the treatment of fluidic diseases), J MedChem.2010Sep 23; 6629-39 in 53 (18).

Acamod has the chemical name 3- [ 5-amino-4- (3-cyanobenzoyl) -1H-pyrazol-1-yl ] -N-cyclopropyl-4-methylbenzamide and is described, for example, in De Buck S, Hueber W, Vitaliti a, Straube F, emotte c, Bruin G, Woessner R, "Population PK-PD Model for the assessment of Tolerance of the p38 MAP kinase inhibitor BCT 197" (medication PK-PD Model for medication Evaluation to the p38 MAP kinase inhibitor BCT197), CPT pharmacologics system medicine.2015dec; 691 (4) (12) and 700, and is represented by the structural formula indicated below:

delimods are described, for example, in Christie JD, vasref S, Chang PK, May AK, Gunn SR, Yang S, Hardes K, Kahl L, Powley WM, Lipson DA, Bayliffe AI, Lazaar AL, "random Dose Escalation Study of the Safety and anti-Inflammatory Activity of the p38Mitogen-Activated Protein kinase inhibitor dirimod in Severe Trauma Subjects at Risk of Acute respiratory distress Syndrome" (randomised Dose-assessment Activity of the p38Mitogen-Activated Protein kinase inhibitor in driver metal substrate at Risk of loss of kidney failure), Crit drop; 43(9) 1859-69, and is represented by the structural formula indicated below:

samimod is described, for example, in Bianchi, m.; ulrich, p.; bloom, o.; meisrell m, m., i.i.; zimmerman, g.a.; schmidmayerova, h.; bukrinsky, m.; donnelley, t.; bucala, r.; sherry, b.; manogue, k.r.; tortolani, a.j.; cerami, a.; tracey, K.J, (Mar 1995). molecular medicine (Cambridge, Mass.).1(3): 254-266 or, for example Wang J, Grishin AV, Ford HR, "Experimental Anti-Inflammatory Drug Sammamomod Inhibits TLR Signaling by Targeting TLR chaperone protein gp 96" (Experimental Anti-Inflammatory Drug amplified inhibitors TLR Signaling by Targeting the TLR agonist gp96), J Immunol.2016Jun 15; 196(12) 5130-7, and is represented by the structural formula indicated below:

AZD7624 is described, for example, in Patel N, Cunosamay D, Hegelund-Myrback T, Pehrson R, Taib Z, Jansson P, Lundin S, Greenaway S, Clarke G, Siew L, AZD7624 this P38inhibitor for inhalation of COPD attenuates pulmonary and systemic inflammation following LPS challenge in humans (AZD7624, an inhaled P38inhibitor for COPD, inflammatory lung and systemic inflammation in humans), Eur Resp J.DOI: 10.1183/13993003.1T 2015 and is represented by the structural formulae indicated below:

ARRY-371797 is described, for example, in mucher a, Wu W, Choi JC, Iwata S, Morrow J, Homma S, Worman HJ, "Abnormal p38-alpha mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by mutations in the lamin a/C gene" (Abnormal p38-alpha mitogen-activated protein kinase signaling cardiac gene mutation), Hum molgene.2012oct 1; 4325-33, and is represented by the structural formula indicated below:

r9111 and its synthesis are described in WO2005/047284 and are described, for example, in Hill RJ, Dabbagh K, Phippard, Li C, Suttmann RT, Welch M, Papp E, Song KW, Chang KC, Leafer D, Kim Y-N, RobertsrT, Zabka TS, Aud, Dal Porto J, Manning AM, Peng SL, Goldstein DM and Wong BR, "Pamamode, a novel p38mitogen-activated protein kinase inhibitor: preclinical Analysis of potency and Selectivity "(Pamapimod, a Novel p38Mitogen-Activated Protein Kinase Inhibitor: clinical Analysis of efficacy and Selectivity), J pharmaceutical Exp the. Decumber 2008327: 610-:

PH-797804 is described, for example, in Xing L, Devadas B, Devraj RV, Selness SR, Shieh H, Walker JK, Mao M, Messing D, Samas B, Yang JZ, Anderson GD, Webb EG, Monahan JB, "atropisomer PH-797804 as a clinical drug candidate the Discovery and characterization of p38 MAP kinase inhibitors (Discovery and characterization of atropisomers PH-797804, a p38 MAP kinase inhibitor, as a clinical drug candidate), ChemMedderm.2012Feb 6; 273 to 80, and is represented by the structural formula indicated below:

BIRB 796 is described, for example, in Dietrich J, Hulme C, Hurley LH, "design, synthesis and evaluation of 8hybrid DFG-out allosteric kinase inhibitors: structural analysis of The binding interaction of Gleevec, Nexavar and BIRB-796 "(The design, synthesis, and evaluation of 8hybrid DFG-out adaptive kinetics: a structural analysis of The binding interactions of Gleevec, Nexavar, and BIRB-796), Bioorg Med chem.201Aug1; 18(15) 5738-48, and is represented by the structural formula indicated below:

VX-702 describes the efficacy, pharmacodynamics and safety of the novel p38 MAPK inhibitor in rheumatoid arthritis, for example, as described in Damjanov N, Kauffman RS, Spencer-Green GT, "VX-702: results of two randomized, double-blind, placebo-controlled clinical studies "(Efficacy, pharmacodynamics, and safety of VX-702, a novelp38 MAPK inhibitor, in rhematoid Arthritis: results of two random-randomised, double-blind, placebo-controlled clinical trials), Arthritis Rheum.2009May; 60(5) 1232-41, and is represented by the structural formula indicated below:

VX-745 is described, for example, in Duffy JP, Harrington EM, Salituro FG, Cochran JE, Green J, Gao H, Bemis GW, Evindar G, Galllo VP, Ford PJ, Germann UA, Wilson KP, Bellon SF, Chen G, Taslimi P, Jones P, Huang C, Pazhansamy S, Wang YM, Murcko MA, Su MS, "discovery of VX-745: a Novel selective p38-alpha Kinase Inhibitor (The Discovery of VX-745: A Novel and selective p38-alpha Kinase Inhibitor), ACS Med Chem Lett.2011Jul 28; 758-63, and is represented by the structural formula indicated below:

SB239063is described in, for example, Strassburger M, Braun H, Reymann KG, "Anti-inflammatory therapy with the p38mitogen-activated protein kinase inhibitor SB239063is neuroprotective, reduces the number of activated microglia and promotes neurogenesis in oxygen-glucose deprived hippocampal slice cultures" (Anti-inflammatory therapy with the p38mitogen-activated protein kinase inhibitor SB239063 immunoreactivity, mutations of the number of activated microglia and fasciation neurogenesis in oxyden-glucose-purified platelet fractions), Eur JR 2008Sep 11; 592(1-3):55-61, and is represented by the structural formula indicated below:

SB202190 is described, for example, in Hirosawa M, Nakahara M, Otosaka R, Imoto A, Okazaki T, Takahashi S, "p 38pathway inhibitor SB202190activates MEK/MAPK to stimulate growth of leukemic cells" (The p38pathway inhibitor SB202190 activators MEK/MAPK to stimulate The growth of leukemic cells), Leuk Res.2009 May; 33(5) 693-9, and is represented by the structural formula indicated below:

SCIO469 is described, for example, in Sokol L, Cripe L, Kantarjan H, Sekeres MA, Parmar S, Greenberg P, Goldberg SL, Bhushan V, Shammo J, Hohl R, Verma A, Garcia-Manero G, LiYP, Lowe A, Zhu J, List AF, "Randomized dose escalation study of the P38-alpha MAPK inhibitor SCIO-469in patients with myelodysplastic syndrome" (Randomized, dose-evolution study of the P38-alpha MAPK inhibitor SCIO-469in patients with myelodysplastic syndrome), Leukemia.2013Apr; 977 to 80, and is represented by the structural formula indicated below:

pharmaceutical combination

As outlined above, in a first aspect, the present invention provides the use of a pharmaceutical combination in a method for the prevention or treatment of an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

Useful PPAR agonists are as defined above. In one embodiment, the PPAR agonist activates PPAR γ and/or PPAR α. In a preferred embodiment, the PPAR agonist is selected from the group consisting of pioglitazone, rosiglitazone, troglitazone, fenofibrate, bezafibrate and pharmaceutically acceptable salts thereof. In a more preferred embodiment, the PPAR agonist is a PPAR γ agonist, in particular pioglitazone or a pharmaceutically acceptable salt thereof. In a particularly preferred embodiment, the PPAR agonist is pioglitazone hydrochloride.

Useful p38 kinase inhibitors are as defined above. In a preferred embodiment, the p38 kinase inhibitor inhibits p38-a, p38- β, p38- γ or p38- δ or a combination thereof, preferably inhibits p38-a and/or p38- β, more preferably inhibits p 38-a. Other useful p38 kinase inhibitors are compounds of formula I or formula II as defined above or pharmaceutically acceptable salts thereof. Other useful p38 kinase inhibitors are p38 kinase inhibitors selected from the group consisting of pamimod, apilimod, rossimod, dirdanimod, samimod, AZD7624, ARRY-371797, LY2228820, R9111, PH-797804, BIRB 796, VX-702, VX-745, SB239063, SB202190, SCIO469, BMS 582949 and pharmaceutically acceptable salts thereof, particularly pamimod, rossimod, LY2228820, BMS 582949 or pharmaceutically acceptable salts thereof and mixtures thereof, more particularly pamimod or pharmaceutically acceptable salts thereof.

The pharmaceutical combination of the present invention is, for example, a combined preparation or a pharmaceutical composition, for simultaneous, separate or sequential use. The term "combined preparation" as used herein defines especially a "kit of parts" in the sense that the PPAR agonist and the p38inhibitor can be administered separately, in separate forms, for example as separate tablets, or using different fixed combinations of the active ingredients in distinguishable amounts. The ratio of the amount of PPAR agonist to the amount of p38inhibitor administered in the combined preparation may be varied, for example to address the needs of a sub-population of patients to be treated or the needs of individual patients, which may vary depending on the age, sex, body weight, etc. of the patients. The parts of the combined preparation (kit of parts) may be administered simultaneously or sequentially, i.e. chronologically staggered, e.g. at different time points and with equal or different time intervals for any part of the kit of parts.

The term "pharmaceutical composition" refers to a Fixed Dose Combination (FDC) comprising a PPAR agonist and a p38inhibitor combined in a single dosage form, with the corresponding doses of the predetermined combination.

The pharmaceutical combination may also be used as an add-on therapy. As used herein, "add" or "add therapy" means a combination of agents used in therapy, a subject receiving the therapy initiating a first treatment regimen of one or more agents, followed by initiation of a second treatment regimen of one or more different agents in addition to the first treatment regimen, such that not all agents used in the therapy begin at the same time. For example, p38inhibitor therapy is added to patients who have already received PPAR agonist therapy, and vice versa.

In a particularly preferred embodiment, the pharmaceutical combination of the invention is a pharmaceutical composition, i.e. a fixed dose combination.

In another preferred embodiment, the pharmaceutical combination of the invention is a combined preparation.

The amounts of PPAR agonist and p38inhibitor to be administered will vary depending on a number of factors, such as the particular compound, the disease condition and its severity, the particular circumstances surrounding the case including, for example, the particular PPAR agonist to be administered, the route of administration, the condition to be treated, the target area to be treated and the subject or host to be treated.

In one embodiment, the present invention provides a pharmaceutical combination comprising a PPAR agonist and a p38inhibitor, wherein the PPAR agonist and the p38inhibitor are present in therapeutically effective amounts.

In a preferred embodiment, the present invention provides a pharmaceutical combination comprising a PPAR agonist and a p38inhibitor, wherein said PPAR agonist and said p38inhibitor produce a synergistic therapeutic effect, i.e. wherein said PPAR agonist and said p38inhibitor are present in amounts such as to produce a synergistic therapeutic effect.

The term "synergistic" as used herein means that the effect obtained using the pharmaceutical combination of the invention is greater than the sum of the effects obtained from using the agents, i.e. the PPAR agonist and the p38inhibitor, as monotherapy. Advantageously, this synergy provides higher potency at the same dose.

In one embodiment, the present invention provides a pharmaceutical combination comprising a p38inhibitor and a PPAR agonist, wherein the amount of PPAR agonist in the combination is from about 0.1mg to about 20mg or from about 0.1mg to about 15mg or from about 0.1mg to about 10mg or from about 0.1mg to about 7.5mg or from about 0.1mg to about 5mg or from about 5mg to about 15mg or from about 2mg to about 10 mg. In a preferred embodiment, the amount of the PPAR agonist in the combination is from about 2mg to about 10mg, preferably about 5 mg. In the case where the PPAR agonist is in the form of a pharmaceutically acceptable salt, the amount of PPAR agonist provided herein is calculated on the basis of the corresponding free base.

In a preferred embodiment, the present invention provides a pharmaceutical combination comprising a p38inhibitor and a PPAR agonist, wherein the amount of PPAR agonist in the combination is about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg or about 12mg, preferably about 5 mg.

In a particularly preferred embodiment, the present invention provides a pharmaceutical combination comprising a p38inhibitor and pioglitazone or a pharmaceutically acceptable salt thereof, preferably pioglitazone hydrochloride, wherein the amount of pioglitazone in the combination is about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg or about 12mg, preferably about 5mg (based on pioglitazone free base).

In a preferred embodiment, the present invention provides a pharmaceutical combination comprising a p38inhibitor and pioglitazone or a pharmaceutically acceptable salt thereof, wherein the amount of pioglitazone or a pharmaceutically acceptable salt thereof in the combination is lower than the dose normally required for the treatment of diabetes using pioglitazone or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical combination comprising a p38inhibitor and a PPAR agonist, wherein the amount of the p38inhibitor in the combination is from about 1mg to about 500mg or from about 1mg to about 450mg or from about 1mg to about 400mg or from about 1mg to about 350mg or from about 1mg to about 300mg or from about 1mg to about 250mg or from about 1mg to about 200mg or from about 1mg to about 150mg or from about 1mg to about 125mg or from about 1mg to about 100mg or from about 10mg to about 125mg or from about 10mg to about 100mg or from about 20mg to about 100mg or from about 30mg to about 100mg or from about 40mg to about 100mg or from about 50mg to about 100mg or from about 75mg to about 100 mg.

In a preferred embodiment, the present invention provides a pharmaceutical combination comprising a p38inhibitor and a PPAR agonist, wherein the amount of the p38inhibitor in the combination is about 25mg, about 50mg, about 75mg, about 125mg, about 150mg or about 300 mg.

In another preferred embodiment, the present invention provides a pharmaceutical combination comprising a p38inhibitor and a PPAR agonist, wherein the amount of the p38inhibitor in the combination is about 2mg, about 6mg, about 12mg, about 25mg, about 50mg, about 75mg or about 150 mg.

In a particularly preferred embodiment, the present invention provides a pharmaceutical combination comprising a p38inhibitor and a PPAR agonist, wherein the amount of the p38inhibitor in the combination is about 50mg, about 75mg or about 150mg, most preferably about 75 mg.

In a particularly preferred embodiment, the present invention provides a pharmaceutical combination comprising pamimod or a pharmaceutically acceptable salt thereof and a PPAR agonist, wherein the amount of pamimod in the combination is about 2mg, about 6mg, about 12mg, about 25mg, about 50mg, about 75mg or about 150 mg.

In one embodiment, the present invention provides a pharmaceutical combination comprising a p38inhibitor and a PPAR agonist, wherein the amount of PPAR agonist in the combination is from about 0.1mg to about 20mg or from about 0.1mg to about 15mg or from about 0.1mg to about 10mg or from about 0.1mg to about 7.5mg or from about 0.1mg to about 5mg or from about 1mg to about 15mg or from about 2mg to about 10 mg; and wherein the amount of the p38inhibitor in the combination is from about 1mg to about 500mg or from about 1mg to about 450mg or from about 1mg to about 400mg or from about 1mg to about 350mg or from about 1mg to about 300mg or from about 1mg to about 250mg or from about 1mg to about 200mg or from about 1mg to about 150mg or from about 1mg to about 125mg or from about 1mg to about 100mg or from about 10mg to about 125mg or from about 10mg to about 100mg or from about 20mg to about 100mg or from about 30mg to about 100mg or from about 40mg to about 100mg or from about 50mg to about 100mg or from about 75mg to about 100 mg.

In a preferred embodiment, the present invention provides a pharmaceutical combination comprising a p38inhibitor and a PPAR agonist, wherein the amount of PPAR agonist in the combination is about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, or about 12 mg; and wherein the amount of the p38inhibitor in the combination is about 2mg, about 6mg, about 12mg, about 25mg, about 50mg, about 75mg, or about 150 mg.

In a particularly preferred embodiment, the present invention provides a pharmaceutical combination comprising pamimod or a pharmaceutically acceptable salt thereof and pioglitazone or a pharmaceutically acceptable salt thereof (e.g. pioglitazone hydrochloride), wherein the amount of pamimod or a pharmaceutically acceptable salt thereof in such combination is from about 30mg to about 100mg, preferably from about 40mg to about 80mg, most preferably about 75mg (based on pamamold free base); and the amount of pioglitazone or a pharmaceutically acceptable salt thereof in such a combination is from about 0.5mg to about 10mg, preferably from about 0.5mg to about 7.5mg, most preferably about 5mg (based on pioglitazone free base).

In a preferred embodiment, the pharmaceutical combination of the invention is a pharmaceutical composition (i.e. a fixed dose combination as outlined above). In one embodiment, the pharmaceutical combination of the invention is a pharmaceutical composition and comprises other pharmaceutical or pharmaceutic agents, such as one or more pharmaceutically acceptable diluents, excipients or carriers.

Compounds of formula I for use in a method of preventing or treating an ophthalmic disease or disorder in a subject

As indicated above, the compounds of formula I or pharmaceutically acceptable salts thereof are useful, alone, i.e. not in combination with PPAR agonists, in the prevention or treatment of ophthalmic diseases or disorders.

Thus, in one aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable diluents, excipients or carriers, in a method of preventing or treating an ophthalmic disease or disorder in a subject,

wherein

Z is N or CH;

w is NR²；

X^lIs O, NR⁴(wherein R is⁴Is hydrogen or alkyl), S or CR⁵R⁶(wherein R is⁵And R⁶Independently hydrogen or alkyl) or C ═ O;

X²is O or NR⁷；

Ar¹Is aryl or heteroaryl;

R²is hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkylcarbonyl, heteroalkoxycarbonyl or-R²¹-R²²Wherein R is²¹Is alkylene or-C (═ O) -, and R²²Is alkyl or alkoxy;

R¹is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, R¹²-SO₂-heterocyclylamino (wherein R is¹²Is haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl), -Y¹-C(O)-Y²-R¹¹(wherein Y is¹And Y²Independently is absent or alkylene, and R¹¹Is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), (heterocyclyl) (cycloalkyl) alkyl or (heterocyclyl) (heteroaryl) alkyl;

R³is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R³¹(wherein R is³¹Is hydrogen, alkyl, hydroxyl, alkoxy, amino, monoalkylamino or dialkylamino),Amino, monoalkylamino, dialkylamino or NR³²-Y³-R³³(wherein Y is³is-C (O), -C (O) O-, -C (O) NR³⁴、S(O)₂Or S (O)₂NR³⁵；R³²、R³⁴And R³⁵Independently hydrogen or alkyl; and R is³³Is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or optionally substituted phenyl) or acyl; and is

R⁷Is hydrogen or alkyl.

In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X is¹Is NR⁴And X²Is NR⁷Or X¹And X²Each is O, wherein R⁴And R⁷As defined above.

In another embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein X¹Is NR⁴Or O and X²Is NR⁷Or O, wherein R⁴And R⁷As defined above.

In another embodiment, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein W is NR²And wherein R is²Is hydrogen, alkyl, heteroalkyl, acyl or alkoxycarbonyl, preferably hydrogen or alkyl, more preferably hydrogen.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl or (heterocyclyl) (cycloalkyl) alkyl.

In a preferred embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in prophylaxis or therapyIn a method of treating an ophthalmic disease or disorder in a subject, wherein R²Is hydrogen and R¹Is heteroalkyl, or vice versa.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is¹Is hydrogen, alkyl, haloalkyl, heteroalkyl, or cyanoalkyl.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is¹Is cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heterocyclyl, heterocyclylalkyl or (heterocyclyl) (cycloalkyl) alkyl.

In a preferred embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R is¹And R²Each independently selected from hydrogen and hydroxyalkyl, preferably from hydrogen, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl, 2- (hydroxymethyl) -3-hydroxypropyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl and 2-hydroxy-1-methylethyl, more preferably from hydrogen, 2-hydroxyethyl, 2, 3-dihydroxypropyl and 1- (hydroxymethyl) 2-hydroxyethyl, most preferably selected from hydrogen, 2-hydroxy-propyl, 3-hydroxy-1- (2-hydroxyethyl) -propyl and 2-hydroxy-1-methylethyl.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is³Is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R³¹(wherein R is³¹Is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or acyl.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is³Is hydrogen, alkyl, haloalkyl, heteroalkyl, cyanoalkyl, cycloalkyl or cycloalkylalkyl.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is³Is hydrogen, alkyl, haloalkyl, heteroalkyl, or cyanoalkyl.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is³Is cycloalkyl or cycloalkylalkyl.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein X¹And X²Both are O.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is¹Is alkyl or heteroalkyl.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is¹Is heteroalkyl, preferably 3-hydroxy-1- (2-hydroxyethyl) -propyl or 2-hydroxy-1-methylethyl.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is³Is alkyl or heteroalkyl.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is³Is an alkyl group, preferably a C1-C5 alkyl group, more preferablyIs C1-C4 alkyl, more preferably C1-C3 alkyl. In a particularly preferred embodiment, R³Is ethyl or methyl, preferably methyl.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein R is³Is heteroalkyl, preferably 2-hydroxy-propyl.

In yet another embodiment, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is NH, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject.

In yet another embodiment, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein Z is N, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject.

In yet another embodiment, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein Ar is¹Is aryl, preferably phenyl optionally substituted with 1,2 or 3 halo substituents, most preferably phenyl substituted with two halo substituents in the ortho and para positions. In a particularly preferred embodiment, Ar¹Is 2, 4-difluorophenyl.

In a further embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein X¹Is NR⁴And X²Is NR⁷Or X¹And X²Each is O, wherein R⁴And R⁷As defined above; and wherein

R¹Is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl-substituted cycloalkyl, hetero-substituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl or (heterocyclyl) (cycloalkyl) alkyl; and wherein

R³Is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C (O) -R³¹(wherein R is³¹Is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) or acyl; and wherein

W is NR²Wherein R is²Is hydrogen, alkyl, acyl or alkoxycarbonyl; and wherein

Ar¹Is an aryl group; and wherein

Z is N.

In a preferred embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X is¹And X²Each is O, and wherein Z is N, and wherein W is NH, and wherein Ar¹Is phenyl optionally substituted with 1,2 or 3 halogen substituents, and wherein R is¹Is heteroalkyl, and wherein R³Is alkyl or heteroalkyl.

In a particularly preferred embodiment, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a method for preventing or treating an ophthalmic disease or disorder in a subject, wherein the compound of formula I is pamamomid (6- (2, 4-difluorophenoxy) -2- [ 3-hydroxy-1- (2-hydroxyethyl) -propylamino ] -8-methyl-8H-pyrido [2,3-d ] pyrimidin-7-one, formula III),

in another aspect, the present invention provides the use of a pharmaceutical composition in a method of preventing or treating an ophthalmic disease or disorder in a subject, the pharmaceutical composition comprising:

(a) a compound of formula I as defined above or a pharmaceutically acceptable salt thereof; and optionally (c) a second set of instructions,

(b) one or more pharmaceutically acceptable diluents, excipients or carriers.

In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the amount of the compound of formula I or the pharmaceutically acceptable salt thereof in the composition is from about 1mg to about 500mg or from about 1mg to about 450mg or from about 1mg to about 400mg or from about 1mg to about 350mg or from about 1mg to about 300mg or from about 1mg to about 250mg or from about 1mg to about 200mg or from about 1mg to about 150mg or from about 1mg to about 125mg or from about 1mg to about 100mg or from about 10mg to about 125mg or from about 10mg to about 100mg or from about 20mg to about 100mg or from about 30mg to about 100mg or from about 40mg to about 100mg or from about 50mg to about 100mg or from about 75mg to about 100 mg.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the amount of said compound of formula I or a pharmaceutically acceptable salt thereof in said composition is about 25mg, about 50mg, about 75mg, about 125mg, about 150mg or about 300 mg.

In another preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the amount of said compound of formula I or a pharmaceutically acceptable salt thereof in said composition is about 2mg, about 6mg, about 12mg, about 25mg, about 50mg, about 75mg or about 150 mg.

In a particularly preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the amount of said compound of formula I or a pharmaceutically acceptable salt thereof in said composition is about 50mg, about 75mg or about 150mg, most preferably about 75 mg.

Modes of administration and treatment

As used herein, the term "treatment"/"for treatment" includes: (1) delaying the onset of clinical symptoms of a condition, disorder or condition occurring in an animal, particularly a mammal, particularly a human, that may be afflicted with or predisposed to the condition, disorder or condition but does not yet experience or exhibit clinical or subclinical symptoms of the condition, disorder or condition; (2) inhibiting the state, disorder or condition (e.g., halting, reducing or delaying the progression of the disease, at least one clinical or subclinical symptom thereof, or halting, reducing or delaying the recurrence thereof in the case of maintenance therapy); and/or (3) alleviating the condition (i.e., causing regression of the state, disorder or condition, or at least one clinical or subclinical symptom thereof). The benefit to the treated patient is statistically significant or at least perceptible by the patient or physician. It should be recognized, however, that when a drug is administered to a patient to treat a disease, the results may not always be an effective treatment.

As used herein, "delay in progression" means increasing the time to appearance of a symptom of an ophthalmic disease or disorder or a marker associated with an ophthalmic disease or disorder or slowing an increase in severity of a symptom of an ophthalmic disease or disorder. Furthermore, as used herein, "delay of progression" includes reversal or inhibition of disease progression. By "inhibition" of disease progression or disease complication in a subject is meant preventing or alleviating disease progression and/or disease complication in said subject.

Prophylactic treatment includes prophylactic treatment. In prophylactic applications, the pharmaceutical combination of the invention or the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a subject suspected to suffer from or at risk of developing an ophthalmic disease or disorder. In therapeutic applications, the pharmaceutical combination of the invention or the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a subject, e.g. a patient, already suffering from an ophthalmic disease or disorder in an amount sufficient to cure or at least partially arrest the symptoms of said disease. The amount effective for this use will depend on the severity and course of the disease, previous therapy, the health status of the subject and the response to the drug and the judgment of the treating physician. In the case where the condition of the subject is not improved, the pharmaceutical combination of the invention or the compound of formula I or a pharmaceutically acceptable salt thereof may be administered chronically, that is, over a prolonged period of time, including throughout the life of the subject, in order to ameliorate or otherwise control or limit the symptoms of the disease or disorder in the subject.

In case the condition of the subject is improved, the pharmaceutical combination of the invention or the compound of formula I or a pharmaceutically acceptable salt thereof may be administered continuously or the dose of the drug being administered may be temporarily reduced or temporarily stopped for a certain length of time (i.e. a "drug holiday").

The pharmaceutical combination of the present invention or a compound of formula I or a pharmaceutically acceptable salt thereof is preferably suitable for oral, topical, injection, ocular local (e.g. subconjunctival, intravitreal, retrobulbar or intracameral) or systemic (i.e. enteral or parenteral) administration, more preferably for oral, topical and/or injection administration, most preferably for oral administration to a subject, and comprises a therapeutically effective amount of the active ingredient and one or more suitable pharmaceutically acceptable diluents, excipients or carriers.

If not indicated otherwise, the pharmaceutical combinations of the invention or the compounds of the formula I or their pharmaceutically acceptable salts are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes. In preparing the combination for oral dosage form, any of the usual pharmaceutical media, carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed.

In one embodiment, the pharmaceutical combination of the invention or the compound of formula I or a pharmaceutically acceptable salt thereof is a combination for oral administration. As indicated above, the pharmaceutical combination for oral administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In one embodiment, the pharmaceutical combination of the invention or the compound of formula I or a pharmaceutically acceptable salt thereof is a combination for topical administration to the eye. As indicated above, the pharmaceutical combination for ocular topical administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In one embodiment, the pharmaceutical combination of the invention or the compound of formula I or a pharmaceutically acceptable salt thereof is a combination for administration by injection. As indicated above, the pharmaceutical combination for injectable administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In one embodiment, the pharmaceutical combination of the invention or the compound of formula I or a pharmaceutically acceptable salt thereof is a combination for topical administration to the eye. As indicated above, the pharmaceutical combination for ocular topical administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In one embodiment, the pharmaceutical combination of the invention or the compound of formula I or a pharmaceutically acceptable salt thereof is a combination for systemic, i.e. enteral or parenteral administration. Preferred are combinations for oral administration. As indicated above, the pharmaceutical combination for systemic administration is preferably a pharmaceutical composition, i.e. a fixed dose combination.

In a preferred embodiment, the pharmaceutical combination of the invention or the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally, topically or by injection, more preferably orally to said subject.

The pharmaceutical combination or the compound of formula I or a pharmaceutically acceptable salt thereof for oral or systemic, i.e. enteral or parenteral administration is, for example, in unit dosage form, such as tablets, capsules or suppositories.

In one embodiment, the present invention provides a pharmaceutical composition comprising a PPAR agonist, e.g., pioglitazone, and a p38inhibitor, e.g., pamimod, and at least one pharmaceutically acceptable carrier, wherein the composition is a solution or suspension (i.e., eye drops) or an ophthalmic ointment for ophthalmic administration.

In one embodiment, the present invention provides a pharmaceutical composition comprising pamimod or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, wherein the composition is a solution or suspension (i.e., eye drops) or an ophthalmic ointment for ocular administration.

In one embodiment, the present invention provides a pharmaceutical composition comprising a PPAR agonist, e.g., pioglitazone, and a p38inhibitor, e.g., pamimod, and at least one pharmaceutically acceptable carrier, wherein the composition is a tablet or capsule, preferably a tablet.

In one embodiment, the present invention provides a pharmaceutical composition comprising pamimod or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, wherein the composition is a tablet or capsule, preferably a tablet.

In another embodiment, the pharmaceutical combination of the invention is suitable for ocular administration for delivering said PPAR agonist and said p38 kinase inhibitor to the eye of said subject. Likewise, in another embodiment, the pharmaceutical composition of the invention comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, is suitable for ocular administration for delivering said compound of formula I, or said pharmaceutically acceptable salt thereof, to the eye of said subject.

The unit content of active ingredient in a single medicament does not necessarily per se constitute a therapeutically effective amount, since such an amount can be achieved by administration of a plurality of dosage units. The compositions of the present invention may contain, for example, from about 10% to about 100% of the therapeutically effective amount of the active ingredient.

In case the pharmaceutical combination of the invention is a combined preparation, the PPAR agonist and the p38inhibitor need not be administered in the same dosage form.

In certain embodiments, the pharmaceutical combination of the present invention is administered to the subject in a medicament comprising a PPAR agonist in a dose that is lower than the dose required to treat diabetes using the PPAR agonist. In certain embodiments, the pharmaceutical combination of the invention is administered to the subject in a medicament comprising a PPAR agonist at a dose that is estimated and tested to be 8-20 times lower than the highest dose for treating diabetes, in particular 8-20 times lower than the highest dose estimated and tested for treating diabetes in a human. For example, PPAR γ agonists such as pioglitazone hydrochloride, the highest dose evaluated and tested for the treatment of diabetes in humans is typically in the range of about 30-45 mg/day. In certain embodiments, at the dosage of PPAR agonist used, the side effects seen in the treatment of diabetes with said PPAR agonist are reduced or absent.

In certain embodiments, the pharmaceutical combination of the invention is administered to said subject in a medicament comprising a PPAR agonist in a dose that is lower than the dose effective for the therapeutically relevant anti-diabetic or anti-dyslipidemic effect of said PPAR agonist, in particular lower than the dose effective for the therapeutically relevant anti-diabetic or anti-dyslipidemic effect of said PPAR agonist in a human.

In the treatment of diabetes, a typical dosing regimen for pioglitazone or a pharmaceutically acceptable salt thereof comprises from 15mg to 45mg of pioglitazone once daily.

In certain embodiments, the pharmaceutical combination of the invention is administered orally to a human in a medicament comprising a PPAR agonist, typically a PPAR γ agonist, a PPAR α agonist and/or a PPAR α/γ dual agonist, preferably a PPAR γ agonist and/or a PPAR α agonist, more preferably a PPAR γ agonist and/or a PPAR α agonist selected from the group consisting of pioglitazone, rosiglitazone, troglitazone, fenofibrate, bezafibrate and pharmaceutically acceptable salts thereof, even more preferably a PPAR γ agonist, more preferably pioglitazone or a pharmaceutically acceptable salt thereof, most preferably a dose of pioglitazone hydrochloride of 0.1 to 45 mg/day, preferably 0.1 to 10 mg/day, more preferably about 5 mg/day; and the dose of the p38inhibitor, e.g. a compound of formula I or formula II, in particular a compound of formula I, preferably a p38inhibitor, more preferably pamimod or a pharmaceutically acceptable salt thereof, selected from pamimod, acantomod, rossimod, dirimod, samimod, AZD7624, ARRY-371797, LY2228820, R9111, PH-797804, BIRB 796, VX-702, VX-745SB239063, SB202190, SCIO469 and BMS 582949 or a pharmaceutically acceptable salt thereof is 1-500 mg/day, preferably 10-250 mg/day, more preferably 25-150 mg/day, most preferably about 75 mg/day.

Methods of identifying patients suspected of having or at risk of developing an ophthalmic disease or disorder are also encompassed by the present invention. In certain embodiments, a patient suspected of having or at risk of developing an ophthalmic disease or disorder is identified by, for example, a blood test, an ocular test such as visual activity, or fundus imaging. In certain embodiments, the monitoring of the success of the treatment and/or the identification of the subject, e.g., a subject suspected of having or at risk of developing an ophthalmic disease or disorder, is achieved by an improvement in visual symptoms, e.g., less strabismus (metamorphosis), faster recovery of visual function after exposure to bright light (light stress test), increased visual acuity, less blurred vision, better ability to distinguish colors, particularly dark from dark and light from light, improved contrast sensitivity, and the like.

Dosing regimens

Exemplary treatment regimens require administration once daily, twice daily or three times daily, preferably once daily and/or twice daily. The combination of the invention is typically administered multiple times. The time interval between individual doses may be, for example, less than 1 day, daily, or every two days. The combination of the invention may be provided as a continuous uninterrupted therapy. The combination of the invention may also be provided in a regimen wherein the subject receives a treatment cycle interrupted by a drug holiday or a period of no treatment. Thus, the combination of the invention may be administered for a period of one week or part thereof, two weeks, three weeks, four weeks, five weeks or six weeks at selected intervals as described above, followed by a rest of the period of one week or part thereof, two weeks, three weeks, four weeks, five weeks or six weeks. The combination of the treatment period and the treatment-free period is referred to as a cycle. The cycle may be repeated one or more times. Two or more different cycles may be used in combination to repeat the treatment one or more times. The time intervals may also be irregular and guided by the worsening or improvement of the patient's condition as indicated by the appearance or remission of symptoms or objective evidence of the appearance or remission of the disease. In this case, therapy can be started and suspended as needed, and only restarted when symptoms or objective measures indicate that the disease has recurred. In a preferred embodiment, the pharmaceutical combination of the invention is administered once daily.

Medicament box/finished product

In one aspect, the invention also provides a kit for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, comprising a pharmaceutical combination disclosed herein and instructions for using the kit. The preferred PPAR agonists and the preferred p38 kinase inhibitors comprised by the pharmaceutical combination are as described above.

In certain embodiments, a kit comprises a carrier, package, or container partitioned to receive one or more containers, e.g., vials, tubes, etc., each of which comprises one of the separate elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In other embodiments, the container is formed from a variety of different materials, such as glass or plastic.

The articles of manufacture provided herein generally comprise one or more of the pharmaceutical combinations and packaging materials disclosed herein. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for the selected composition and intended mode of administration and treatment.

Prevention or treatment of ophthalmic diseases or disorders

In one aspect, the present invention provides a pharmaceutical combination as described herein, i.e. a pharmaceutical combination comprising the following components, for use in a method for preventing or treating an ophthalmic disease or disorder in a subject:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

Also provided is the use of a pharmaceutical combination described herein in the manufacture of a medicament for the prevention or treatment of an ophthalmic disease or disorder in a subject.

Also provided is the use of a pharmaceutical combination as described herein for the prevention or treatment of an ophthalmic disease or disorder in a subject.

Also provided is a method of preventing or treating an ophthalmic disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination described herein.

As indicated above, it has surprisingly been found that a compound of formula I or a pharmaceutically acceptable salt thereof, alone, i.e. not in combination with a PPAR agonist, is useful in the prevention or treatment of ophthalmic diseases or disorders. Accordingly, in a further aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a method of preventing or treating an ophthalmic disease or disorder in a subject.

Also provided is the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of an ophthalmic disease or disorder in a subject.

Also provided is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the prevention or treatment of an ophthalmic disease or disorder in a subject.

Also provided is a method of preventing or treating an ophthalmic disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein the ophthalmic disease or disorder is macular degeneration, preferably macular degeneration selected from the group consisting of age-related macular degeneration (AMD), hereditary macular degeneration (juvenile macular degeneration) such as retinitis pigmentosa (retinitis pigmentosa), morbus Best, morbus Stargardt and Sorsby's disease, diabetic retinopathy (diabetic retinopathy), myopic macular degeneration, macular degeneration caused by inflammation (retinitis), such as Presumed Ocular Histoplasmosis Syndrome (POHS) and systemic drug retinotoxicity such as chloroquine retinopathy (bovine ocular macular degeneration).

In another embodiment, the invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method of preventing or treating an ophthalmic disease or disorder selected from the group consisting of age-related macular degeneration (AMD), hereditary macular degeneration (juvenile macular degeneration) such as retinitis pigmentosa (retinitis pigmentosa), morbus Best, morbus Stargardt and Sorsby's disease, diabetic retinopathy (diabetic retinopathy), myopic macular degeneration, macular degeneration caused by inflammation (retinitis) such as Presumed Ocular Histoplasmosis Syndrome (POHS) and systemic drug retinotoxicity such as chloroquine retinopathy (bovine ocular macular degeneration) in a subject.

In another embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method for preventing or treating an ophthalmic disease or disorder selected from uveoretinitis, retinitis, immune choroiditis, age-related macular degeneration and glaucoma in a subject.

In another embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method for preventing or treating an ophthalmic disease or disorder selected from the group consisting of age-related macular degeneration, exudative macular degeneration, atrophic macular degeneration, systemic drug retinal toxicity and macular edema in a subject.

In another embodiment, the present invention provides a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof for use in a method of preventing or treating an ophthalmic disease or disorder selected from the group consisting of wet (exudative) age-related macular degeneration, dry (non-exudative) age-related macular degeneration, Geographic Atrophy (GA), retinitis pigmentosa (retinitis pigmentosa), morbus Stargardt and diabetic retinopathy (diabetic retinopathy) in a subject.

In a preferred embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method of preventing or treating an ophthalmologic disease or disorder in a subject, wherein the ophthalmologic disease or disorder is age-related macular degeneration (AMD).

In another preferred embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method for the prevention or treatment of an ophthalmic disease or disorder in a subject, wherein the ophthalmic disease or disorder is wet (exudative) age-related macular degeneration, dry (non-exudative) age-related macular degeneration or geographic atrophy.

In a particularly preferred embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method of preventing or treating an ophthalmic disease or disorder in a subject, wherein the ophthalmic disease or disorder is wet (exudative) age-related macular degeneration.

In another particularly preferred embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method for the prevention or treatment of an ophthalmic disease or disorder in a subject, wherein the ophthalmic disease or disorder is dry (non-exudative) age-related macular degeneration.

In another particularly preferred embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method for the prevention or treatment of an ophthalmic disease or disorder in a subject, wherein the ophthalmic disease or disorder is geographic atrophy.

In another particularly preferred embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method for the prevention or treatment of an ophthalmic disease or disorder in a subject, wherein the ophthalmic disease or disorder is morbus Stargardt.

In another particularly preferred embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method for the prevention or treatment of an ophthalmic disease or disorder in a subject, wherein the ophthalmic disease or disorder is retinitis pigmentosa (retinitis pigmentosa).

In another particularly preferred embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method for the prevention or treatment of an ophthalmic disease or disorder in a subject, wherein the ophthalmic disease or disorder is diabetic retinopathy (diabetic retinopathy).

In a most preferred embodiment, the present invention provides the use of a pharmaceutical combination as described herein or a compound of formula I or a pharmaceutically acceptable salt thereof in a method for the prevention or treatment of an ophthalmic disease or disorder in a subject, wherein the ophthalmic disease or disorder is wet (exudative) age-related macular degeneration.

In one embodiment, the present invention provides a use of a pharmaceutical combination in a method for preventing or treating an ophthalmic disease or disorder in a subject, the pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers,

wherein the p38 kinase inhibitor preferably inhibits p38-a, p38- β, p38- γ or p38- δ or a combination thereof, more preferably inhibits p38-a and/or p38- β.

In one embodiment, the present invention provides a use of a pharmaceutical combination in a method for preventing or treating an ophthalmic disease or disorder in a subject, the pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers,

wherein the p38 kinase inhibitor is selected from the group consisting of pamimod, apilimod, rossimod, dirdanimod, samimod, AZD7624, ARRY-371797, LY2228820, R9111, PH-797804, BIRB 796, VX-702, VX-745, SB239063, SB202190, SCIO469 and BMS 582949 or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a pharmaceutical combination according to the invention for use in a method of preventing or treating an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) a compound of formula I as defined herein; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

In another embodiment, the present invention provides a use of a pharmaceutical combination in a method for preventing or treating an ophthalmic disease or disorder in a subject, the pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) a compound of formula II as defined herein; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

In a preferred embodiment, the present invention provides the use of a pharmaceutical combination in a method of preventing or treating an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) pamimod or a pharmaceutically acceptable salt thereof; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

In another embodiment, the present invention provides a use of a pharmaceutical combination in a method for preventing or treating an ophthalmic disease or disorder in a subject, the pharmaceutical combination comprising:

(a) PPAR gamma agonists;

(b) a compound of formula I as defined herein; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

In another embodiment, the present invention provides a use of a pharmaceutical combination in a method for preventing or treating an ophthalmic disease or disorder in a subject, the pharmaceutical combination comprising:

(a) PPAR gamma agonists;

(b) a compound of formula II as defined herein; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

In a preferred embodiment, the present invention provides the use of a pharmaceutical combination in a method of preventing or treating an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) PPAR gamma agonists;

(b) a compound of formula I as defined herein; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers;

wherein the PPAR γ agonist is selected from pioglitazone, rosiglitazone, troglitazone and INT131 or a pharmaceutically acceptable salt thereof; and is

Wherein X in the compound of formula I¹And X²Each is O; and is

Wherein Z in the compound of formula I is N; and is

Wherein W in the compound of formula I is NH; and is

Wherein Ar in the compound of formula I¹Is an aryl group; and is

Wherein R in the compound of formula I¹Is a heteroalkyl group; and is

Wherein R in the compound of formula I³Is an alkyl group.

In another preferred embodiment, the present invention provides a use of a pharmaceutical combination in a method for the prevention or treatment of an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) PPAR gamma agonists;

(b) pamimod, R9111, samimod or a pharmaceutically acceptable salt thereof, preferably pamimod or a pharmaceutically acceptable salt thereof; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers;

wherein the PPAR γ agonist is selected from pioglitazone, troglitazone, bezafibrate and pharmaceutically acceptable salts thereof.

In one embodiment, the present invention provides a use of a pharmaceutical combination in a method for preventing or treating an ophthalmic disease or disorder in a subject, the pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers,

wherein the PPAR agonist activates PPAR α, PPAR γ, or PPAR δ, or a combination thereof.

In one embodiment, the present invention provides a use of a pharmaceutical combination in a method for preventing or treating an ophthalmic disease or disorder in a subject, the pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers,

wherein the PPAR agonist is selected from pioglitazone, troglitazone, rosiglitazone, bezafibrate, fenofibrate, clofibrate, gemfibrozil, aleglitazar, moglitazone, tegaserod, rogazepride, sarpogazepride, GFT505, nateglinide, GW501516 and INT131 or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a use of a pharmaceutical combination in a method for preventing or treating an ophthalmic disease or disorder in a subject, the pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers,

wherein the PPAR agonist is selected from pioglitazone, troglitazone, bezafibrate and pharmaceutically acceptable salts thereof.

In a preferred embodiment, the present invention provides the use of a pharmaceutical combination in a method of preventing or treating an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) a PPAR agonist;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers,

wherein the PPAR agonist is pioglitazone or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a use of a pharmaceutical combination in a method for the prevention or treatment of an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) pioglitazone or a pharmaceutically acceptable salt thereof;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

In another preferred embodiment, the present invention provides a use of a pharmaceutical combination in a method for the prevention or treatment of an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) pioglitazone hydrochloride;

(b) p38 kinase inhibitors; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

In a particularly preferred embodiment, the present invention provides the use of a pharmaceutical combination in a method of preventing or treating an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) pioglitazone or a pharmaceutically acceptable salt thereof, preferably pioglitazone hydrochloride;

(b) pamimod or a pharmaceutically acceptable salt thereof; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers.

In another particularly preferred embodiment, the present invention provides the use of a pharmaceutical combination in a method of preventing or treating an ophthalmic disease or disorder in a subject, said pharmaceutical combination comprising:

(a) pioglitazone or a pharmaceutically acceptable salt thereof, preferably pioglitazone hydrochloride;

(b) pamimod or a pharmaceutically acceptable salt thereof; and optionally (c) a second set of instructions,

(c) one or more pharmaceutically acceptable diluents, excipients or carriers,

wherein the ophthalmic disease or disorder is Crohn's disease or ulcerative colitis.

Examples

The examples are intended to illustrate the invention and not to limit it.