WO2004098612A2

WO2004098612A2 - Calcitriol analogs of uses thereof

Info

Publication number: WO2004098612A2
Application number: PCT/IB2004/001871
Authority: WO
Inventors: Alain Moussy; Jean-Pierre Kinet
Original assignee: AB Science SA
Current assignee: AB Science SA
Priority date: 2003-05-07
Filing date: 2004-05-07
Publication date: 2004-11-18
Anticipated expiration: 2005-11-07
Also published as: WO2004098612A3

Abstract

The present invention relates to a method of treating mast cells associated diseases comprising administrating calcitriol or analogs thereof to a mammal in need of such treatment. It is also aimed at new analogs and to the combined use of these compounds with a c-kit inhibitor.

Description

New calcitriol analogs of uses thereof

Mast cells are key elements participating directly or indirectly to the pathogenesis of numerous diseases. A review of the implication of mast cells in these diseases is presented in the applicant patent applications WO03024386, WO03004007, WO03004006, WO03003006, WO03003004, WO03002114, WO03002109, WO03002108, WO03002107, WO03002106 and WO03002105. In these applications, emphasis is made on the importance of targeting c-kit for depleting mast cells.

It was found that mast cells present in tissues of patients are implicated in or contribute to the genesis of diseases such as autoimmune diseases, allergic diseases, tumor angiogenesis, inflammatory diseases, polyarthritis, inflammatory bowel diseases (H3D), interstitial cystitis, CNS disorders and ischemia. In these diseases, it was postulated that mast cells participate in the destruction of tissues by releasing a cocktail of different proteases and mediators such as histamine, proteoglycans, neutral proteases), lipid- derived mediators (prostaglandins, thromboxanes and leucotrienes), and various cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, L-6, IL-8, TNF- , GM-CSF, MlP-la, MDP-lb, MIP-2 and LFN-γ).

On the other hand, calcitriol treatment has been shown to induce a decrease of both c-kit protein expression and c-kit mRNA transcription in mast cells (Toyota et al, Arch Dermatol Res 1996 Oct;288(l l):709-15). hi addition, it has be demonstrated that calcitriol selectively promotes ICAM-3 expression in HMC-1 cells (Babina et al, Biochem Biophys Res Commun 2000 Jul 14;273(3): 1104-10).

Here, we show that calcitriol as well as analogs thereof selectively inhibits stem cell factor-dependent mast cell proliferation and that calcitriol do not inhibits IL-3/IL-4- dependent mast cell proliferation. We further experienced that Vitamin D(3) receptors are constitutively present in both human leukaemic mast cells (HMC-1) and skin mast cells, human mast cells are direct targets to calcitriol.

Therefore, calcitriol and analogs represent an alternative to inhibit mast cell activation by specifically agonizing VDR in order to induce a decrease in c-kit expression and activity in MC. In this regards, we discovered new calcitriol analogs (compounds of formula in described below) efficient to induce proliferative mast cells apoptosis.

We further observed that combined use of calcitriol and analogs with a retinoid shows a cooperative effect which leads to the differentiation of undifferentiated mast cells. This action not only decreases mast cells aptitude for proliferation but mostly to the inhibition of mast cells activity and function which participate in the pathogenesis of numerous diseases.

We also found that combined use of calcitriol and analogs (together with a retinoid) with a c-kit inhibitor leads to a synergistic effect for depleting mast cells.

Description

Therefore, in a first aspect, the invention is directed to a method of treating mast cells associated diseases comprising administrating calcitriol or analogs thereof to a mammal in need of such treatment. The expression "calcitriol or analogs thereof encompasses herein the following compounds:

- Calcitriol, also well known in the art as 1,25 dihydroxycholecalciferol, designates active vitamin D and has the following structure :

- Natural precursors extracted from plants and from animal tissues which are ergosterol and 7-dehydrocholesterol. They are modified in skin by sunlight radiation in vitamin D3 or "cholecalciferol" while the plant substance becomes vitamin D2 or "ergocalciferol". From here we will follow the animal origin hormone as it is the most metabolically active. Liver modification leads to 25-D3 or "calcidiol" which circulates to the kidney for another addition of a hydroxyl group to form 1 ,25 dihydroxylcholecalciferol.

- l.alpha.-hydroxy Vitamin D derivatives described in US 4,391,802 and US 4,717,721, cyclopentano- Vitamin D analogs (US 4,851,401), Vitamin D.sub.3 analogs with alkynyl, alkenyl, and alkanyl side chains (US 4,866,048 and US 5,145,846), trihydroxycalciferol (US. 5,120,722), fluoro-cholecalciferol analogs (US. 5,547,947), methyl substituted Vitamin D (US 5,446,035), 23-oxa-derivatives (US. 5,411,949), 19-Nor-Vitamin D compounds (US 5,237,110), hydroxylated 24-homo-Vitamin D derivatives (US 4,857,518) as well as other vitamin D analogs shown in US 4,804,502, US 5,374,629, US 5,403,940, US 5,446,034 and US 5,447,924. Calcitriol derivatives of the following formula I:

Formula I

Wherein OX^ OX₂, R5, R6 and Z have the meaning depicted at column 18 of US 5,976,784 incorporated herein by reference : R5 and R6 each represent hydrogen, or taken together a methylene group, Z is selected from Y, OY, CH2OY, C≡£Y and CH=CHY, where the double bond may have the cis or trans stereochemical configuration, and where Y is selected from a radical of the structure :

R1 R2 R3 R4 -(CH2)m-C-(CH2)n-C-OX3

wherein m and n are independently integers from 0 to 5, Rl is selected from the group consisting of hydrogen, OX4, fluoro, trifluoromethyl, CI to C5 alky, which may be straight chain or branched and, optionally, bear a hydroxy substituent, R2 is selected from the group consisting of hydrogen, fluoro, trifluoromethyl and CI to C5 alky, which may be straight-chain or branched, and optionally, bear a hydroxy substituent, and where each of R3 and R4, is selected from trifluoromethyl and CI to C5 alky, which may be straight chain or branched and optionally bear a hydroxy substituent, and where Rl and R2, taken together, represent an oxo group, or an alkylidene group, =CR2R2, =CR2R3, or the group -(CH2)p-, where p is an integer from 2 to 5, and wherein R3 and R4, taken together, represent the group -(CH2)q-, where q is an integer from 2 to 5, and where XI, X2, and X4 are each hydrogen, an acyl group, or a hydrocarbyloxycarbonyl group, and wherein X3 represents an acyl group or a hydrocarbyloxycarbonyl group.

Calcitriol derivatives of the following formula II:

Formula II

Wherein R and R2 have the meaning depicted at columns 65 and 66 of US 5,830,885, incorporated herein by reference : wherein R is C_nH _nF or C_nH_2nOH, wherein n=l to 6; and R2 is a C,D-ring side chain, said analogue having a stereochemical configuration of lα, 3/3- or^" 1/3, 3a.-.

- and more particularly, compounds of the invention of formula III:

Formula III

Wherein X represents: - a phenyl optionally substituted with one, two or three R group(s) and wherein R is CR1R2R3; Rl, R2 and R3 being independently chosen from H, OH, an halogen atom such as I, CI, Br, and F and an organic group that can be selected from a linear or branched alkyl or acyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom;

- a group represented by the following formula:

Wherein Rl, R2 and R3 are as indicated above and n is 0, 1, 2 or 3. (see preferred compounds below).

The expression "mast cells associated diseases" herein refers to diseases related to the c- kit transduction pathway thereby activating mast cell proliferation and degranulation, which includes, but is not limited to:

- neoplastic diseases such as mastpcytosis, canine mastocytoma, human gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinomas, gastric carcinomas, gastrointestinal stromal tumors, testicular cancers, glioblastomas, and astrocytomas. - tumor angiogenesis.

- metabolic diseases such as diabetes mellirus and its chronic complications; obesity; hyperlipidemias and dyslipidemias; atherosclerosis; hypertension; and cardiovascular disease.

- allergic diseases such as asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis and insect bite skin inflammation and blood sucking parasitic infestation.

- interstitial cystitis.

- bone loss (osteoporosis) mast cells related. - inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions.

- autoimmune diseases such as multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy, as well as proliferative glomerulonephritis.

- graft- versus-host disease or graft rejection in any organ transplantation including kidney, pancreas, liver, heart, lung, and bone marrow. - Other autoimmune diseases embraced by the invention active chronic hepatitis and chronic fatigue syndrome.

- subepidermal blistering disorders such as pemphigus.

- Vasculitis.

- melanocyte dysfunction associated diseases such as hypermelanosis resulting from melanocyte dysfunction and including lentigines, solar and senile lentigo,

Dubreuilh melanosis, moles as well as malignant melanomas.

- CNS disorders such as psychiatric disorders, migraine, pain, memory loss and nerve cells degeneracy. More particularly, the method according to the invention is useful for the treatment of the following disorders: Depression including dysthymic disorder, cyclothymic disorder, bipolar depression, severe or

"melancholic" depression, atypical depression, refractory depression, seasonal depression, anorexia, bulimia, premenstrual syndrome, post-menopause syndrome, other syndromes such as mental slowing and loss of concentration, pessimistic worry, agitation, self-deprecation, decreased libido, pain including, acute pain, postoperative pain, chronic pain, nociceptive pain, cancer pain, neuropathic pain, psychogenic pain syndromes, anxiety disorders including anxiety associated with hyperventilation and cardiac arrhythmias, phobic disorders, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, psychiatric emergencies such as panic attacks, including psychosis, delusional disorders, conversion disorders, phobias, mania, delirium, dissociative episodes including dissociative amnesia, dissociative fugue and dissociative identity disorder, depersonalization, catatonia, seizures, severe psychiatric emergencies including suicidal behaviour, self- neglect, violent or aggressive behaviour, trauma, borderline personality, and acute psychosis, schizophrenia including paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, and undifferentiated schizophrenia,

- neurodegenerative diseases including Alzheimer's disease , Parkinson's disease, Huntington's disease, the prion diseases, Motor Neurone Disease (MND), and

Amyotrophic Lateral Sclerosis (ALS).

- Ischemia, and in particular hypoxic-ischemic encephalopathy induced by stroke, traumatic brain injury such as cerebral edema and embolic or thromboembolic occlusions of cerebral arteries, and ischemic insults following reperfusion. - substance use disorders as referred herein include but are not limited to drug addiction, drug abuse, drug habituation, drug dependence, withdrawal syndrome and overdose.

Regarding mastocytosis, the invention contemplates the above method for treating the different categories which can be classified as follows:

The category I is composed by two sub-categories (IA and IB). Category IA is made by diseases in which mast cell infiltration is strictly localized to the skin. This category represents the most frequent form of the disease and includes : i) urticaria pigmentosa, the most common form of cutaneous mastocytosis, particularly encountered in children, ii) diffuse cutaneous mastocytosis, iii) solitary mastocytoma and iv) some rare subtypes like bullous, erythroderaiic and teleangiectatic mastocytosis. These forms are characterized by their excellent prognosis with spontaneous remissions in children and a very indolent course in adults. Long term survival of this form of disease is generally comparable to that of the normal population and the translation into another form of mastocytosis is rare. Category IB is represented by indolent systemic disease (SM) with or without cutaneous involvement. These forms are much more usual in adults than in children. The course of the disease is often indolent, but sometimes signs of aggressive or malignant mastocytosis can occur, leading to progressive impaired organ function.

The category II includes mastocytosis with an associated hematological disorder, such as a myeloproliferative or myelodysplastic syndrome, or acute leukemia. These malignant mastocytosis does not usually involve the skin. The progression of the disease depends generally on the type of associated hematological disorder that conditiones the prognosis.

The category III is represented by aggressive systemic mastocytosis in which massive infiltration of multiple organs by abnormal mast cells is common. In patients who pursue this kind of aggressive clinical course, peripheral blood features suggestive of a myeloproliferative disorder are more prominent. The progression of the disease can be very rapid, similar to acute leukemia, or some patients can show a longer survival time.

Finally, the category IV of mastocytosis includes the mast cell leukemia, characterized by the presence of circulating mast cells and mast cell progenitors representing more than 10% of the white blood cells. This entity represents probably the rarest type of leukemia in humans, and has a very poor prognosis, similar to the rapidly progressing variant of malignant mastocytosis. Mast cell leukemia can occur either de novo or as the terminal phase of urticaria pigmentosa or systemic mastocytosis.

The invention also contemplates the method as depicted above for the treatment of recurrent bacterial infections, resurging infections after asymptomatic periods such as bacterial cystitis. More particularly, the invention can be practiced for treating FimH expressing bacteria infections such as Gram-negative enterobacteria including E. coli, Klebsiella pneumoniae, Serratia marcescens, Citrobactor freudii and Salmonella typhimurium.

In this method for treating bacterial infection, separate, sequential or concomitant administration of at least one antibiotic selected from bacitracin, the cephalosporins, the penicillins, the aminoglycosides, the tetracyclines, the streptomycins and the macrolide antibiotics such as erythromycin; the fluoroquinolones, actinomycin, the sulfonamides and trimethoprim, is of interest.

In a particular embodiment, the invention relates to the above method which further comprises the combined, sequential, simultaneous or separate administration of vitamin A or derivatives thereof. It can also be referred to Retinoids represented as follows:

wherein R is CH2OH, CH2NH2, CHO, CH=NOH, CO2H, CH=N[CH2]4CHNH2CO2H, CH3, CO2C2H5 or CH2OCOCH3 Retinoids that are preferably administered herein include retinol derivatives such as 13- cw-Retinol and Retinoic Acid (RA), in particular 13-cis RA and 9-cis RA.

R=CH₂OH 13-c s-Retinol or (7E,9E,1 lE,13Z)-retinol (also known as neovitamin A)

R = CO₂H 13-c s-Retinoic acid or (7E,9E,l lE,13Z)-retinoic acid (also known as isotretinom). Review of these compounds can be found at International Union of Biochemistry (1978) Biochemical Nomenclature and Related Documents, The Biochemical Society, London, the 1992 second edition.

In another particular embodiment, the invention relates to the above method which further comprises the combined, sequential, simultaneous or separate administration of a tyrosine kinase inhibitor.

Tyrosine kinase inhibitors may be selected for example from bis monocyclic, bicyclic or heterocyclic aryl compounds (WO 92/20642), vinylene-azaindole derivatives (WO 94/14808) and l-cycloproppyl-4-pyridyl-quinolones (US 5,330,992), Styryl compounds (US 5,217,999), styryl-substituted pyridyl compounds (US 5,302,606), seleoindoles and selenides (WO 94/03427), tricyclic polyhydroxylic compounds (WO 92/21660) and benzylphosphonic acid compounds (WO 91/15495), pyrimidine derivatives (US 5,521,184 and WO 99/03854), indolinone derivatives and pyrrol-substituted indolinones (US 5,792,783, ΕP 934 931, US 5,834,504, US 5,883,116, US 5,883,113, US 5, 886,020, WO 96/40116 and WO 00/38519), as well as bis monocyclic, bicyclic aryl and heteroaryl compounds (EP 584 222, US 5,656,643 and WO 92/20642), quinazoline derivatives (EP 602 851, EP 520 722, US 3,772,295 and US 4,343,940) and aryl and heteroaryl quinazoline (US 5,721,237, US 5,714,493, US 5,710,158 and WO 95/15758).

Preferably, said tyrosine kinase inhibitor is a non-toxic, selective and potent c-kit inhibitor.

Such inhibitors can be selected from the group consisting of pyrimidine derivatives, pyrrolopyrimidine derivatives, indolinones, quinazoline derivatives, quinoxaline derivatives, pyrazoles derivatives, bis monocyclic, bicyclic or heterocyclic aryl compounds, vinylene-azaindole derivatives and pyridyl-quinolones derivatives, styryl compounds, styryl-substituted pyridyl compounds, seleoindoles, selenides, tricyclic polyhydroxylic compounds and benzylphosphonic acid compounds.

Among preferred compounds, it is of interest to focus on 2-(3-amino)arylamino-4-aryl- thiazoles, pyrimidine derivatives such as N-phenyl-2-pyrimidine-amine derivatives (US 5,521,184 and WO 99/03854), indolinone derivatives and pyrrol-substituted indolinones (US 5,792,783, EP 934 931, US 5,834,504), US 5,883,116, US 5,883,113, US 5, 886,020, WO 96/40116 and WO 00/38519), as well as bis monocyclic, bicyclic aryl and heteroaryl compounds (EP 584 222, US 5,656,643 and WO 92/20642), quinazoline derivatives (EP 602 851, EP 520 722, US 3,772,295 and US 4,343,940), 4-amino- substituted quinazolines (US 3,470,182), 4-thienyl-2-(lH)-quinazolones, 6,7- dialkoxyquinazolines (US 3,800,039), aryl and heteroaryl quinazoline (US 5,721,237, US 5,714,493, US 5,710,158 and WO 95/15758), 4-anilinoquinazoline compounds (US 4,464,375), and 4-thienyl-2-(lH)-quinazolones (US 3,551,427), For example, the c-kit inhibitor may be selected from a N-phenyl-2-pyrimidine-amine derivatives of formula:

wherein the Rl, R2, R3, R13 to R17 groups have the meanings depicted in EP 564 409 B 1 , incorporated herein in the description.

Preferably, the N-phenyl-2-pyrimidine-amine derivative is selected from the compounds corresponding to formula IV :

Wlierein Rl, R2 and R3 are independently chosen from H, F, CI, Br, I, a C1-C5 alkyl or a cyclic or heterocyclic group, especially a pyridyl group;

R4, R5 and R6 are independently chosen from H, F, CI, Br, I, a C1-C5 alkyl, especially a methyl group; and R7 is a phenyl group bearing at least one substituent, which in turn possesses at least one basic site, such as an amino function. Preferably, R7 is the following group :

Among these compounds, the preferred are defined as follows :

Rl is a heterocyclic group, especially a pyridyl group, R2 and R3 are H,

R4 is a C1-C3 alkyl, especially a methyl group,

R5 and R6 are H, and R7 is a phenyl group bearing at least one substituent, which in turn possesses at least one basic site, such as an amino function, for example the group :

Therefore, in a preferred embodiment, the invention relates to a method for treating mast cells associated diseases comprising the administration of calcitriol or analogs thereof as defined above and further comprising the administration of an effective amount of the compound known in the art as CGP57148B :

4-(4-mehylpiperazme-l-ylmemyl)-N-[4-memyl-3-(4-pyridme-3-yl)pyrimidine-2 ylamino)phenyl]-benzamide corresponding to the following formula :

The preparation of this compound is described in example 21 of EP 564 409 and the β- form, which is particularly useful is described in WO 99/03854.

Alternatively, the c-kit inhibitor can be selected from : - indolinone derivatives, more particularly pyrrolrsubstituted indolinones,

- monocyclic, bicyclic aryl and heteroaryl compounds, quinazoline derivatives, - and quinaxolines, such as 2-phenyl-quinaxoline derivatives, for example 2-phenyl- 6,7-dimethoxy quinaxoline.

These c-kit inhibitors are chosen their non-ability to promote death of IL-3 dependent cells cultured in presence of IL-3.

In a still another preferred embodiment, the c-kit inhibitor is chosen from compounds belonging to the 2-(3-amino)arylamino-4-aryl-thiazoles of formula V for which the applicant filed US 60/400064 :

FORMULA V

wherein R¹ is : a) a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, or bearing a pendant basic nitrogen functionality; b) an aryl or heteroaryl group optionally substituted by an alkyl or aryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; c) a sulfonyl or a -SO2-R group wherein R is an alkyl, aryl or heteroaryl substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; d) a -CO-NH-R, -CO-R, -CO-OR or a -CO-NRR' group, wherein R and R' are independently chosen from H or an aryl, heteroaryl, alkyl and cycloalkyl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, or bearing a pendant basic nitrogen functionality;

R² is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁴ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁵ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁶ is one of the following:

(i) an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy; (ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

(iii) a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from

1 to 10 carbon atoms, trifluoromethyl, and alkoxy, iv) H, an halogen selected from I, F, CI or Br; NH2, NO2 or SO2; and R⁷ is one of the following: (i) an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;

(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

1 to 10 carbon atoms, trifluoromethyl, and alkoxy. iv) H, an halogen selected from I, F, CI or Br; NH2, NO2 or SO2.

Examples of preferred compounds of formula I in which Rl corresponds to the definition given in a) (alkyl), b) (aryl) and d) (amide) are depicted below:

AB1

4-Diemylammomemyl-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide

AB2 N-[4-Me yl-3-(4-pyridin-3-yl-tMazol-2-ylammo)-phenyl]-4-morpholm-4-ylmethyl- benzamide

AB3

4-Dipropylammomemyl-N-[4-memyl-3-(4-pyridm-3-yl-1mazol-2-ylamino)-phenyl]- benzamide

AB4

N-[4-Me yl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-4-piperidin-l-ylmethyl- benzamide

AB4 3-Iodo-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide

AB6

4-Hydroxyme yl-N-[4-memyl-3-(4-pyridm-3-yl-1l iazol-2-ylamino)-phenyl]-benzamide

AB8

4-{[4-Methyl-3-(4-pyridm-3-yl-tiιiazol-2-ylaιnino)-phenylamino]-methyl}-benzoic acid methyl ester

AB10

3-Phenyl-propynoic acid [4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-aιrιide

ABU

4-Amino-N-[4-memyl-3-(4-pyridm-3-yl-lMazol-2-ylamino)-phenyl]-benzamide AB12

2-Iodo-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide

AB13

4-Iodo-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide

AB14 4-(3- {4-[4-Memyl-3-(4-pyriάin-3-yl-1 azol-2-ylamino)-phenylcarbamoyl]-phenyl} - ureido)-benzoic acid ethyl ester

AB16 N-[4-Memyl-3-(4-pyridin-3-yl-lMazol-2-ylamino)-phenyl]-4-[3-(4-trifluoromethyl- phenyl)-ureido] -benzamide

AB17

4-[3-(4-Bromo-phenyl)-ureido]-N-[4-memyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl] -benzamide

AB18

{4-[4-Methyl-3-(4-pyridin-3-yl-tlιiazol-2-ylamino)-phenylcarbamoyl]-benzyl}-carbamic acid tert-butyl ester

AB19 4-Hydroxy-N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzamide

AB20

4- [(Diisopropylamino)-methyl] -N- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)- phenyl] -benzamide

AB21 N-[4-Methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -4-(3 -thiophen-2-yl-ureido)- benzamide

AB22

4-[3-(3,5-Dimemyl-isoxazol-4-yl)-ureido]-N-[4-memyl-3-(4-pyridin-3-yl-thiazol-2- ylamino)-phenyl] -benzamide AB23

4-[3-(4-Memoxy-phenyl)-ureido]-N-[4-memyl-3-(4-pyridm-3-yl-thiazol-2-ylamino)- phenyl] -benzamide

AB24

4-[3-(4-Difluoromemoxy-phenyl)-ureido]-N-[4-memyl-3-(4-pyridin-3-yl-thiazol-2- ylamino)-phenyl] -benzamide

AB25

Thiophene-2-sulfonic acid 4- [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)- phenylcarbamoyl] -phenyl ester AB26

4-Iodo-benzenesulfonic acid 4-[4-memyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenylcarbamoyl]-phenyl ester

AB27 N-[4-Methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -4-pyrrolidin- 1 -ylmethyl- benzamide

AB28

3-Memyl-N-[4-memyl-3-(4-pyridm-3-yl-thiazol-2-ylamino)-phenyl]-benzamide

AB29 N- [4-Methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -3 -trifluoromethyl-benzamide

AB30

4-[3-(2,4-Dimemoxy-phenyl)-ureido]-N-[4-memyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl] -benzamide

AB31 N-[4-Methyl-3-(4-pyridin-3-yl-t azol-2-ylammo)-phenyl]-4-[3-(4-trifluoromethyl- phenyl)-ureidomethyl] -benzamide

AB32

N-[4-Memyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-4-[3-(3,4,5-trimethoxy- phenyl)-ureido]-benzamide AB33

4-[3-(2-Iodo-phenyl)-ureido]-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide

AB34

4-[3-(4-Fluoro-phenyl)-ureido]-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl]-benzamide

AB35

2-Fluoro-benzenesulfonic acid 4-[4-memyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenylcarbamoyl] -phenyl ester AB36

3-Fluoro-benzenesulfonic acid 4-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenylcarbamoyl] -phenyl ester

In another preferred embodiment, when R¹ has the meaning depicted in c) above, the invention is directed to sulfonyl compounds of the following formula VI:

Formula VI wherein R is H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality, or an aryl or heteroaryl group optionally substituted by an alkyl, cycloalkyl, aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality.

Such compounds can be selected for example from:

AB40

AB37

3 -Fluoro-N-[4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -benzenesulfonamide

AB38

2-Fluoro-N-[4-memyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzenesulfonamide AB39

Thiophene-2-sulfonic acid [4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] - amide

AB40

4-Iodo-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzenesulfonamide

In another preferred embodiment, when R¹ has the meaning depicted in d) above, the invention is directed to compounds of the following formula VII:

Formula VII wherein R is H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality.

Such compounds can be selected for example from:

AB5 AB6

Among the particular compounds in which Rl has the meaning as depicted in d) above, the invention is directed to amide-aniline compounds of the following formulaVffl:

Formula VIII

wherein R is H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; or a a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; a sulfonyl or a -SO2-R group wherein R is H, an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; or a -CO-R or a -CO-NRR' group, wherein R and R' are independently chosen from H, an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably selected from I, CI, Br and F, or bearing a pendant basic nitrogen functionality.

Examples of such compounds are as follows:

AB16

AB17 AB21

AB22 AB23

AB24

Among the particular compounds in which Rl has the meaning as depicted in d) above, the invention is directed to amide-benzylamine compounds of the following formula DC:

wherein R is H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, or bearing a pendant basic nitrogen functionality; a cycloalkyl, aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; or an alkyl, cycloalkyl, aryl or heteroaryl group substituted by a alkyl, cycloalkyl, aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; a sulfonyl or a -SO2-R group wherein R is H or an alkyl, cycloalkyl, aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; or a -CO-R or a -CO-NRR' group, wherein R and R' are independently chosen from H or an aryl heteroaryl, alkyl and cycloalkyl group optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality.

For example, this compound has the following formula:

AB18

Among the particular compounds in which Rl has the meaning as depicted in d) above, the invention is directed to amide-phenol compounds of the following formula X:

Formula X

Examples of such compounds are as follows:

Among the particular compounds in which Rl has the meaning as depicted in d) above, the invention is directed to urea compounds of the following formula XI:

Formula XI

wherein R is H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom (for example an halogen) or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality. Examples of such compounds are as follows:

AB50

1 -(4-Methoxy-phenyl)-3 -[4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -urea

AB51 l-(4-Bromo-phenyl)-3-[4-methyl-3-(4-pyridm-3-yl-miazol-2-ylamino)-phenyl]-urea

AB52

1 - [4-Methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-phenyl] -3 -(4-trifluoromethyl-phenyl)- urea

AB53 l-(4-Fluoro-phenyl)-3-[4-me yl-3-(4-pyridm-3-yl-thiazol-2-ylamino)-phenyl]-urea

AB54 l-[4-Metiιyl-3-(4-pyridm-3-yl-1mazol-2-ylammo)-phenyl]-3-(3,4,5-trimethoxy-phenyl)- urea

AB55 4-{3-[4-Memyl-3-(4-pyridm-3-yl-tfύazol-2-ylamino)-phenyl]-ureido}-benzoic acid ethyl ester

AB56 l-[4-Me yl-3-(4-pyridm-3-yl-thiazol-2-ylammo)-phenyl]-3-thiophen-2-yl-urea

AB57 l-Cyclohexyl-l-(N-Cyclohexyl-formamide)-3-[4-methyl-3-(4-pyridm-3-yl-thiazol-2- ylamino)-phenyl] -urea

AB58 l-(2,4-Dimethoxy-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- urea AB59 l-(2-Iodo-phenyl)-l-(N-(2-Iodo-phenyl)-formamide)-3-[4-me yl-3-(4-pyridin-3-yl- thiazol-2-ylamino)-phenyl]-urea

AB60 l-(3,5-Dimethyl-isoxazol-4-yl)-3-[4-memyl-3-(4-pyriα^-3-yl-t azol-2-ylanιino)- phenyl]-urea

AB61 l-(2-Iodo-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-urea AB62 l-(4-Difluoromemoxy-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl]-urea

AB63 l-(4-Dimethylammo-phenyl)-3-[4-memyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- urea

Among the compounds of formula V, the invention is particularly embodied by the compounds of the following formula XII:

FORMULA XII

wherein X is R or NRR' and wherein R and R' are independently chosen from H, an aryl, an heteroaryl, an alkyl and a cycloalkyl group optionally substituted with at least one heteroatom, such as for example a halogen chosen from F, I, CI and Br and optionally bearing a pendant basic nitrogen functionality; or an aryl, an heteroaryl, an alkyl and a cycloalkyl group substituted with an aryl, an heteroaryl, an alkyl and a cycloalkyl group optionally substituted with at least one heteroatom, such as for example a halogen chosen from F, I, CI and Br and optionally bearing a pendant basic nitrogen functionality, R² is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R³ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R⁴ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁵ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R⁶ is one of the following: (i) an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy; (ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

(iii) a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy.

Among the preferred compounds corresponding formula XII, the invention is directed to compounds in which X is a substituted alkyl, aryl or heteroaryl group bearing a pendant basic nitrogen functionality represented for example by the structures a to f shown below, wherein the wavy line corresponds to the point of attachment to core structure of formula XII:

Among group a to f, R¹ is preferentially group d.

Furthermore, among the preferred compounds of formula V or XII, the invention concerns the compounds in which R² and R³ are hydrogen. Preferentially, R⁴ is a methyl group and R⁵ is H. h addition, R⁶ is preferentially a 3 -pyridyl group (cf. structure g below) wherein the wavy line corresponds to the point of attachment to core structure of formula V or XII.

More specifically, the invention relates to the above method which further comprises the combined, sequential, simultaneous or separate administration of calcitriol or analogs thereof and a c-kit inhibitor selected from compounds of formula XII as depicted above, wherein :

- X is group d and R⁶ is a 3-pyridyl group,

- X is group d and R⁴ is a methyl group,

- R¹ is group d and R² is H, - R¹ is group d and R³ is H,

- R¹ is group d and R² and/or R³ and/or R⁵ is H, - R⁶ is a 3 -pyridyl group and R³ is a methyl group,

- R⁶ is a 3-pyridyl group and R² is H,

- R² and/or R³ and/or R⁵ is H and R⁴ is a methyl group,

- R² and/or R³ and/or R⁵ is H, R⁴ is a methyl group and R⁶ is a 3-pyridyl group.

Such compound may be for example the AB70 compound (2-(2-methyl-5-amino)phenyl- 4-(3-pyridyl)-thiazole) of formula :

In a third aspect, the invention relates to a calcitriol analog of formula III:

Formula III Wherein X represents :

- a phenyl optionally substituted with one, two or three R group(s) and wherein R is CR1R2R3; Rl, R2 and R3 being independently chosen from H, OH, an halogen atom such as I, CI, Br, and F and an organic group that can be selected from a linear or branched alkyl or acyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom;

- a group represented by the following formula:

Wherein Rl, R2 and R3 are as indicated above and n is 0, 1, 2 or 3.

Among compounds of formula III, the invention contemplates more particularly the compounds of the following structure:

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula m as depicted above and a pharmaceutically acceptable carrier.

In still another aspect, the invention contemplates a pharmaceutical composition comprising calcitriol or analogs thereof and a tyrosine kinase inhibitor, more particularly a c-kit inhibitor as depicted above and a pharmaceutically acceptable carrier. This composition may be a combined preparation a combined or simultaneous use or can take a form suitable for a separate or sequential administration.

For example, the pharmaceutical composition of the invention may comprise a compound of formula III as described above and a compound of formula IV, or a compound of formula V, VI, VII, VIII, DC, X, XI, or XII, preferably of formula XII as mentioned above.

These compositions can take the form of a medicament adapted for oral administration, which can be formulated using pharmaceutically acceptable carriers well known in the art in suitable dosages. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient. In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically-acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).

The compositions of the invention can also take the form of a pharmaceutical or cosmetic composition for topical administration. Such compositions may be presented in the form of a gel, paste, ointment, cream, lotion, liquid suspension aqueous, aqueous-alcoholic or, oily solutions, or dispersions of the lotion or serum type, or anhydrous or lipophilic gels, or emulsions of liquid or semi-solid consistency of the milk type, obtained by dispersing a fatty phase in an aqueous phase or vice versa, or of suspensions or emulsions of soft, semi-solid consistency of the cream or gel type, or alternatively of microemulsions, of microcapsules, of microparticles or of vesicular dispersions to the ionic and/or nonionic type. These compositions are prepared according to standard methods.

The composition according to the invention comprises any ingredient commonly used in dermatology and cosmetic. It may comprise at least one ingredient selected from hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, emollients, viscosity enhancing polymers, humectants, surfactants, preservatives, antioxidants, solvents, and fillers, antioxidants, solvents, perfumes, fillers, screening agents, bactericides, odor absorbers and coloring matter.

As oils which can be used in the invention, mineral oils (liquid paraffin), vegetable oils (liquid fraction of shea butter, sunflower oil), animal oils, synthetic oils, silicone oils (cyclomethicone) and fluorinated oils may be mentioned. Fatty alcohols, fatty acids (stearic acid) and waxes (paraffin, carnauba, beeswax) may also be used as fatty substances.

As emulsifiers which can be used in the invention, glycerol stearate, polysorbate 60 and the PEG-6/PEG-32/glycol stearate mixture are contemplated.

As hydrophilic gelling agents, carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, clays and natural gums may be mentioned, and as lipophilic gelling agents, modified clays such as bentones, metal salts of fatty acids such as aluminum stearates and hydrophobic silica, or alternatively ethylcellulose and polyethylene may be mentioned.

As hydrophilic active agents, proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, vitamins, starch and plant extracts, in particular those of Aloe vera may be used.

As lipophilic active, agents, retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives, essential fatty acids, ceramides and essential oils may be used. These agents add extra moisturizing or skin softening features when utilized.

In addition, a surfactant can be included in the composition so as to provide deeper penetration of the compound capable of depleting mast cells, such as a tyrosine kinase inhibitor, preferably a c-kit inhibitor.

Among the contemplated ingredients, the invention embraces penetration enhancing agents selected for example from the group consisting of mineral oil, water, ethanol, triacetin, glycerin and propylene glycol; cohesion agents selected for example from the group consisting of polyisobutylene, polyvinyl acetate and polyvinyl alcohol, and thickening agents.

Chemical methods of enhancing topical absorption of drugs are well known in the art. For example, compounds with penetration enhancing properties include sodium lauryl sulfate (Dugard, P. H. and Sheuplein, R. J., "Effects of Ionic Surfactants on the Permeability of Human Epidermis: An Electrometric Study," J. Ivest. Dermatol., V.60, pp. 263-69, 1973), lauryl amine oxide (Johnson et. al., US 4,411,893), azone (Rajadhyaksha, US 4,405,616 and 3,989,816) and decylmethyl sulfoxide (Sekura, D. L. and Scala, J., "The Percutaneous Absorption of Alkyhnethyl Sulfides," Pharmacology of the Skin, Advances In Biolocy of Skin, (Appleton-Century Craft) V. 12, pp. 257-69, 1972). It has been observed that increasing the polarity of the head group in amphoteric molecules increases their penetration-enhancing properties but at the expense of increasing their skin irritating properties (Cooper, E. R. and Berner, B., "Interaction of Surfactants with Epidermal Tissues: Physiochemical Aspects," Surfactant Science Series, V. 16, Reiger, M. M. ed. (Marcel Dekker, Inc.) pp. 195-210, 1987).

A second class of chemical enhancers are generally referred to as co-solvents. These materials are absorbed topically relatively easily, and, by a variety of mechanisms, achieve permeation enhancement for some drugs. Ethanol (Gale et. al., US. 4,615,699 and Campbell et. al., USs. 4,460,372 and 4,379,454), dimethyl sulfoxide (US 3,740,420 and 3,743,727, and US 4,575,515), and glycerine derivatives (US 4,322,433) are a few examples of compounds which have shown an ability to enhance the absorption of various compounds.

The pharmaceutical compositions of the invention can also be intended for administration with aerosolized formulation to target areas of a patient's respiratory tract.

Devices and methodologies for delivering aerosolized bursts of a formulation of a drug is disclosed in US 5,906,202. Formulations are preferably solutions, e.g. aqueous solutions, ethanoic solutions, aqueous/ethanoic solutions, saline solutions, colloidal suspensions and microcrystalline suspensions. For example aerosolized particles comprise the active ingredient mentioned above and a carrier, (e.g., a pharmaceutically active respiratory drug and carrier) which are formed upon forcing the formulation through a nozzle which nozzle is preferably in the form of a flexible porous membrane. The particles have a size which is sufficiently small such that when the particles are formed they remain suspended in the air for a sufficient amount of time such that the patient can inhale the particles into the patient's lungs.

The invention encompasses the systems described in US 5,556,611:

- liquid gas systems (a liquefied gas is used as propellent gas (e.g. low-boiling FCHC or propane, butane) in a pressure container,

- suspension aerosol (the active substance particles are suspended in solid form in the liquid propellent phase),

- pressurized gas system (a compressed gas such as nitrogen, carbon dioxide, dinitrogen monoxide, air is used. Thus, according to the invention the pharmaceutical preparation is made in that the active substance is dissolved or dispersed in a suitable nontoxic medium and said solution or dispersion atomized to an aerosol, i.e. distributed extremely finely in a carrier gas. This is technically possible for example in the form of aerosol propellent gas packs, pump aerosols or other devices known per se for liquid misting and solid atomizing which in particular permit an exact individual dosage.

Therefore, the invention is also directed to aerosol devices comprising the compound as defined above and such a formulation, preferably with metered dose valves.

The pharmaceutical compositions of the invention can also be intended for intranasal administration.

In this regard, pharmaceutically acceptable carriers for administering the compound to the nasal mucosal surfaces will be readily appreciated by the ordinary artisan. These carriers are described in the Remington's Pharmaceutical Sciences" 16th edition, 1980, Ed. By Arthur Osol, the disclosure of which is incorporated herein by reference.

The selection of appropriate carriers depends upon the particular type of administration that is contemplated. For administration via the upper respiratory tract, the composition can be formulated into a solution, e.g., water or isotonic saline, buffered or unbuffered, or as a suspension, for intranasal administration as drops or as a spray. Preferably, such solutions or suspensions are isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0. Buffers should be physiologically compatible and include, simply by way of example, phosphate buffers. For example, a representative nasal decongestant is described as being buffered to a pH of about 6.2 (Remington's, Id. at page 1445). Of course, the ordinary artisan can readily determine a suitable saline content and pH for an innocuous aqueous carrier for nasal and/or upper respiratory administration.

Common intranasal carriers include nasal gels, creams, pastes or ointments with a viscosity of, e.g., from about 10 to about 3000 cps, or from about 2500 to 6500 cps, or greater, may also be used to provide a more sustained contact with the nasal mucosal surfaces. Such carrier viscous formulations may be based upon, simply by way of example, alkylcelluloses and/or other biocompatible carriers of high viscosity well known to the art (see e.g., Remington's, cited supra. A preferred alkylcellulose is, e.g., methylcellulose in a concentration ranging from about 5 to about 1000 or more mg per 100 ml of carrier. A more preferred concentration of methyl cellulose is, simply by way of example, from about 25 to about mg per 100 ml of carrier.

Other ingredients, such as art known preservatives, colorants, lubricating or viscous mineral or vegetable oils, perfumes, natural or synthetic plant extracts such as aromatic oils, and humectants and viscosity enhancers such as, e.g., glycerol, can also be included to provide additional viscosity, moisture retention and a pleasant texture and odor for the formulation. For nasal administration of solutions or suspensions according to the invention, various devices are available in the art for the generation of drops, droplets and sprays. A premeasured unit dosage dispenser including a dropper or spray device containing a solution or suspension for delivery as drops or as a spray is prepared containing one or more doses of the drug to be administered and is another object of the invention. The invention also includes a kit containing one or more unit dehydrated doses of the compound, together with any required salts and/or buffer agents, preservatives, colorants and the like, ready for preparation of a solution or suspension by the addition of a suitable amount of water.

Another aspect of the invention is directed to the use of a compound of formula III to manufacture a medicament, notably a medicament for treating a disease related to mast cells and/or c-kit signal pathway. More particularly, the invention is aimed at the use of a compound of formula III to manufacture a medicament for treating a disease selected from autoimmune diseases, allergic diseases, bone loss, cancer such as leukemia and GIST, tumor angiogenesis, inflammatory diseases, inflammatory bowel diseases (IBD), interstitial cystitis, mastocytosis, infections diseases, metabolic disorders, fibrosis, diabetes, ischemia and CNS. This medicament is applicable to mammals, especially to human but also to dogs and cats regarding mastocytoma.

In another embodiment, the invention is directed to the combined use of a compound of formula III as described above and a compound of formula IV, or a compound of formula V, VI, V1T, VIII, IX, X, XI, or XII, preferably of formula XII as mentioned above for preparing a medicament. Such medicament may be used for treating a disease related to mast cells and/or c-kit signal pathway, and more particularly for treating a disease selected from autoimmune diseases, allergic diseases, bone loss, cancer such as leukemia and GIST, tumor angiogenesis, inflammatory diseases, inflammatory bowel diseases (IBD), interstitial cystitis, mastocytosis, infections diseases, metabolic disorders, fibrosis, diabetes, ischemia and CNS. This medicament is applicable to mammals, especially to human but also to dogs and cats regarding mastocytoma. FIGURE LEGENDS

Figure 1: Combined treatment of calcitriol and derivatives with a retinoid. A- Effect of (XE-02) and 13-cis RA on HMCl 5C6 proliferation (mast cells bearing the double mutation).

B- Effect of ATRA + calcitriol lμM on HMCl 5C6 proliferation. C- Effect of 13 cis RA + calcitriol lμM proliferation.

Figure 2-5: Combined treatment of calcitriol derivatives XE-01, XE-02, XE-03, XE- 04 with a retinoid such as ATRA or 13-cis RA.

EXAMPLE 1: Potentialization of XE-02 with 13-cis RA

Results of this experiment are shown at figure 1 and give: IC₅₀ XE-02 = 10 μM

IC₅₀ 13cis RA = > 10 μM

ICso XE-02 administered with 0,1 μM 13cis RA = 0,01 μM

We conclude that there is a potentialisation of the antiproliferative action of a calcitriol derivative by 13cis-retinoic acid. These results maybe explained by several mechanisms: First, the binding of these compounds on their respective receptors VDR and RXR leads to the formation of the heterodimer VDR-RXR, which turns out to activate transcription of several genes promoting differentiation of HCMl cells. At last, differentiation of

HCMl cells decreases proliferation.

It was previously reported that the antiproliferative responses to two human colon cancer cell lines to vitamin D3 are differently modified by 9-cis-retinoic acid (Kane KF et al,

Cancer Res; 56(3):623-32 1996). But here, we show that this antiproliferative mechanism works with mast cells

Therefore, we propose for the first time that the combined use of a calcitriol derivative and a retinoid is a good candidate therapy for treating mast cells associated diseases.

Claims

1. A method of treating mast cells associated diseases comprising administrating calcitriol or analogs thereof to a mammal in need of such treatment.

2. A method according to claim 1, wherein said analog is selected from:

- Natural precursors extracted from plants and from animal tissues such as ergosterol and 7-dehydrocholesterol, cholecalciferol, ergocalciferol, 25-D3 or calcidiol.

- 1. alpha. -hydroxy Vitamin D derivatives, cyclopentano- Vitamin D analogs, Vitamin D.sub.3 analogs with alkynyl, alkenyl, and alkanyl side chains, trihydroxycalciferol, fluoro-cholecalciferol analogs, methyl substituted Vitamin D, 23-oxa-derivatives, 19- Nor- Vitamin D compounds, hydroxylated 24-homo-Vitamin D derivatives.

- Calcitriol derivatives of the following formula I:

Formula I

- Calcitriol derivatives of the following formula II:

and compounds of formula III:

Formula III

Wherein X represents:

- a group represented by the following formula:

Wherein Rl, R2 and R3 are as indicated above and n is 0, 1, 2 or 3.

3. A method according to claim 1, wherein said analog is a compound of formula HI:

Formula III

Wherein X represents:

- a group represented by the following formula:

Wherein Rl, R2 and R3 are as indicated above and n is 0, 1, 2 or 3.

4. A method according to claim 3, wherein said analog is chosen from:

5. A method according to one of claims 1 to 4, wherein said mast cells associated diseases is selected from the group consisting of :

- neoplastic diseases such as mastocytosis, canine mastocytoma, human gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinomas, gastric carcinomas, gastrointestinal stromal tumors, testicular cancers, glioblastomas, and astrocytomas.

- tumor angiogenesis.

- metabolic diseases such as diabetes mellitus and its chronic complications; obesity; hyperlipidemias and dyslipidemias; atherosclerosis; hypertension; and cardiovascular disease.

- interstitial cystitis.

- subepidermal blistering disorders such as pemphigus.

- Vasculitis.

Dubreuilh melanosis, moles as well as malignant melanomas.

Amyotrophic Lateral Sclerosis (ALS).

6. A method according to claim 5 further comprising the combined, sequential, simultaneous or separate administration of a Retinoid, in particular 13-cis RA or 9-cis RA and/or a tyrosine kinase inhibitor.

7. A method according to claim 6, wherein said tyrosine kinase inhibitors is selected from bis monocyclic, bicyclic or heterocyclic aryl compounds, vinylene-azaindole derivatives, l-cycloproppyl-4-pyridyl-quinolones, Styryl compounds, styryl-substituted pyridyl compounds, seleoindoles and selenides, tricyclic polyhydroxylic compoxmds, benzylphosphonic acid compounds, pyrimidine derivatives, indolinone derivatives, pyrrol-substituted indolinones, bis monocyclic, bicyclic aryl and heteroaryl compounds, quinazoline derivatives and aryl or heteroaryl quinazoline.

8. A method according to claim 6, wherein said tyrosine kinase inhibitor is a non-toxic, selective and potent c-kit inhibitor.

9. A method according to claim 8, wherein said c-kit inhibitor is chosen from pyrimidine derivatives such as N-phenyl-2-pyrimidme-amine derivatives, indolinone derivatives and pyrrol-substituted indolinones, bis monocyclic, bicyclic aryl and heteroaryl compounds, quinazoline derivatives, 4-ammo-substituted quinazolines, 4-thienyl-2-(lH)- quinazolones, 6,7-dialkoxyquinazolines, aryl and heteroaryl quinazoline, 4- anilinoquinazoline compounds, and 4-thienyl-2-(lH)-quinazolones.

10. A method according to claim 8, wherein said c-kit inhibitor is selected from N- phenyl-2-pyrimidine-amine derivatives is of formula IV:

Wherein Rl, R2 and R3 are independently chosen from H, F, CI, Br, I, a C1-C5 alkyl or a cyclic or heterocyclic group, especially a pyridyl group;

11. A method according to claim 9, wherein

Rl is a heterocyclic group, especially a pyridyl group,

R2 and R3 are H,

R4 is a C1-C3 alkyl, especially a methyl group,

12. A method according to claim 9, wherein said c-kit inhibitor is 4-(4-mehylpiperazine- 1 -ylmethyl)-N- [4-methyl-3 -(4-pyridine-3 -yl)pyrimidine-2ylamino)phenyl] -benzamide corresponding to the following formula :

13. A method according to claim 8, wherein said c-kit inhibitor is selected from compounds belonging to the 2-(3-ammo)arylamino-4-aryl-thiazoles of formula V:

FORMULA V

R² is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R³ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁴ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R⁵ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁶ is one of the following:

(i) an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;

14. A method according to claim 8, wherein said c-kit inhibitor is selected from compounds belonging to the 2-(3-amino)arylamino-4-aryl-thiazoles of formula XII:

FORMULA XII

R³ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R⁴ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R⁵ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁶ is one of the following:

(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; (iii) a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from

1 to 10 carbon atoms, trifluoromethyl, and alkoxy.

15. A method according to claim 14, wherein X is a substituted alkyl, aryl or heteroaryl group bearing a pendant basic nitrogen functionality represented for example by the structures a to f shown below, wherein the wavy line corresponds to the point of attachment to core structure of formula XII:

|^N-

H / . -NU

^•N^¹ N •

16. A method according to claim 15, wherein said c-kit inhibitor is (2-(2-methyl-5- amino)phenyl-4-(3-pyridyl)-thiazole) of fonnula :

17. A calcitriol analog of formula III:

Formula III

Wherein X represents: - a phenyl optionally substituted with one, two or three R group(s) and wherein R is CR1R2R3; Rl, R2 and R3 being independently chosen from H, OH, an halogen atom such as I, CI, Br, and F and an organic group that can be selected from a linear or branched alkyl or acyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom; - a group represented by the following formula:

Wherein Rl, R2 and R3 are as indicated above and n is 0, 1, 2 or 3.

18. A calcitriol analog according to claim 17 selected from

19. A pharmaceutical composition comprising a compound according to claim 17 or 18 and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising calcitriol or analogs thereof and a tyrosine kinase inhibitor, more particularly a c-kit inhibitor as depicted above and a pharmaceutically acceptable carrier.

21. A combined composition according to claim 20 suitable for a simultaneous use or for a separate or sequential administration.

22. A pharmaceutical composition according to claim 21 comprising a compound of formula III as described above and a compound of formula IV, or a compound of formula V, VI, VII, VIII, IX, X, XI, or XII, preferably of formula XII as mentioned above.

23. A pharmaceutical composition according to one of claim 19 to 22, adapted for oral, topical, intranasal administration or via the upper respiratory tract.

24. The use of a compound of formula III to manufacture a medicament, notably a medicament, notably for treating a disease related to mast cells and/or c-kit signal pathway.

25. The use according to claim 24 to manufacture a medicament for treating a disease selected from autoimmune diseases, allergic diseases, bone loss, cancer such as leukemia and GIST, tumor angiogenesis, inflammatory diseases, inflammatory bowel diseases (IBD), interstitial cystitis, mastocytosis, infections diseases, metabolic disorders, fibrosis, diabetes, ischemia and CNS.

26. The combined use of a compound of formula III as described above and a compound of formula IV, or a compound of formula V, VI, VII, VIII, IX, X, XI, or XII, preferably of formula XII as mentioned above for preparing a medicament.

27. The use according to claim 26 for preparing a medicament for treating a disease related to mast cells and/or c-kit signal pathway, and more particularly for treating a disease selected from autoimmune diseases, allergic diseases, bone loss, cancer such as leukemia and GIST, tumor angiogenesis, inflammatory diseases, inflammatory bowel diseases (IBD), interstitial cystitis, mastocytosis, infections diseases, metabolic disorders, fibrosis, diabetes, ischemia and CNS.