USOO963 0949B2
(12) United States Patent (10) Patent No.: US 9,630,949 B2 Bouix-Peter et al. (45) Date of Patent: *Apr. 25, 2017
(54) OXOAZETIDINE DERIVATIVES, PROCESS (52) U.S. Cl. FOR THE PREPARATION THEREOF AND CPC ...... C07D 403/12 (2013.01); A61K 8/494 USE THEREOF IN HUMAN MEDCINE AND (2013.01); A61K 8/4906 (2013.01); A61 K IN COSMETCS 31/4178 (2013.01); A61O 5/10 (2013.01); A61O 1704 (2013.01); A61O 19/004 (71) Applicant: GALDERMA RESEARCH & (2013.01); A61O 19/007 (2013.01); A61O DEVELOPMENT, Biot (FR) 19/008 (2013.01); A61O 19/02 (2013.01); A61O 19/04 (2013.01); C07D 401/12 (72) Inventors: Claire Bouix-Peter, Le Cannet (FR): (2013.01); A61 K 2800/78 (2013.01) Itaru Suzuki, Fayence (FR); Nicolas (58) Field of Classification Search Rodeville, Biot (FR); Pascale Mauvais, None Antibes (FR); Jean-Claude Pascal, See application file for complete search history. Nice (FR) (56) References Cited (73) Assignee: GALDERMA RESEARCH & DEVELOPMENT, Biot (FR) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this 2004/OOO6067 A1 1/2004 Fotsch et al. patent is extended or adjusted under 35 U.S.C. 154(b) by 44 days. FOREIGN PATENT DOCUMENTS FR 2867684 A1 9, 2005 This patent is Subject to a terminal dis WO O1,28555 A1 4/2001 claimer. WO 2002O70511 A1 9, 2002 WO O3,032976 A1 4/2003 (21) Appl. No.: 14/497,600 WO 2005047251 A1 5, 2005 WO 20050472.53 A1 5, 2005 (22) Filed: Sep. 26, 2014 OTHER PUBLICATIONS (65) Prior Publication Data US 2015/OO45559 A1 Feb. 12, 2015 International Search Report for corresponding PCT/EP2009/064646 dated Mar. 1, 2010. Related U.S. Application Data Primary Examiner — Kamal Saeed (63) Continuation of application No. 13/127,643, filed as (74) Attorney, Agent, or Firm — Dentons US LLP application No. PCT/EP2009/064646 on Nov. 4, 2009, now Pat. No. 8,871,187. (57) ABSTRACT (60) Provisional application No. 61/111,130, filed on Nov. The present invention relates to novel compounds derived 4, 2008. from oxoaZetidine corresponding to general formula (I) to the compositions containing same, to the process for prepa (30) Foreign Application Priority Data ration thereof and to the use thereof in pharmaceutical or cosmetic compositions. Nov. 4, 2008 (FR) ...... O8 57496 (51) Int. Cl. (I) CO7D 403/2 (2006.01) A6 IK 8/49 (2006.01) A6 IK 3/478 (2006.01) A61O 5/10 (2006.01) A61O 1704 (2006.01) A61O 19/00 (2006.01) A61O 19/02 (2006.01) A61O 19/04 (2006.01) CO7D 40/12 (2006.01) 19 Claims, No Drawings US 9,630,949 B2 1. 2 OXOAZETIDINE DERIVATIVES, PROCESS MC1R is expressed in melanocytes and is involved in skin FOR THE PREPARATION THEREOF AND pigmentation, the colouration of animal fur and melanocyte USE THEREOF IN HUMAN MEDCINE AND functions. Melanocortins can thus be used to treat hypop IN COSMETCS igmentary and hyperpigmentary disorders. MC1R gene polymorphism data have been associated with the auburn This application is a continuation of U.S. patent applica hair phenotype and with malignant and non-malignant skin tion Ser. No. 13/127,643, filed Jul. 27, 2011, now U.S. Pat. cancers (Xu X et al Nat Genet 1996; 14: 384; Van Der No. 8,871,187, which is the United States national phase of Velden P A et al Am J Hum Gent 2001: 69; 774-779; PCT/EP2009/064.646, filed Nov. 4, 2009, and designating Valverde P et al Hum Mol Genet 1996; 5: 1663-1666: the United States (published in the English language on May 10 Schioth H B Biochem Biophys Res Commun 1999; 260: 488-491; Scott M C et al J Cell Sci 2002; 115; 2349-2355). 14, 2010, as WO 2010/052253 A1), which claims priority Thus, a link exists between MC1R and melanoma; as a under 35 U.S.C. S 119 U.S. Provisional Application No. result, MC1R may be important in the prevention and 61/111,130, filed Nov. 4, 2008, and of FR 0857496, filed treatment of certain forms of skin cancer (Stockfleth E et al Nov. 4, 2008. 15 Recent Results Cancer Res 2002; 160; 259-268; Stander et The invention relates to novel compounds as products that al Exp Dermatol 2002; 11: 42-51). MC1R is also expressed modulate one or more melanocortin receptor(s). It also in macrophages and monocytes (Star et al Proc. Natl. Acad. relates to the process for the preparation thereof and to the Sci. USA 92: 8016-8020: Hartmeyer et al J. Immunol. 159; therapeutic use thereof. 1930-1937), neutrophils (Catania et al Peptides 17; 675 Melanocortins make up the family of regulatory peptides 679), endothelial cells (Hartmeyer et al J. Immunol. 159; which are synthesized by post-translational processing of the 1930-1937), glioma cells and astrocytes (Wong et al Neu hormone proopiomelanocortin (POMC—131 amino acids roimmunomodulation 4, 37-41), fibroblasts (Boston and long). POMC results in the production of 3 classes of Cone, Endocrinology 137, 2043-2050) and keratinocytes hormones, melanocortins, the hormone adrenocorticotropin (Luger et al J. Invest Dermatol. Symp. Proc. 2, 87-93). The and various endorphins, such as, for example, ligotropin 25 localization of MC1R in these cells is associated with the (Cone, et al., Recent Prog. Horm. Res., 51:287-317, (1996): ability of MSH-derived peptides to inhibit inflammatory Cone et al., Ann. N.Y. Acad. Sd., 31:342-363 (1993)). processes. Specifically, C.-MSH has shown a strong inhibi Melanocortin receptors (MCRs) form part of the 7-trans tion of inflammation in chronic models of intestinal inflam membrane domain GPCR superfamily. To date, 5 receptor mation, of arthritis, of ischaemia, of contact hypersensitivity subtypes, MC1-5R, have been identified in mammals. An 30 and of dermatitis, and is also capable of inducing tolerance endogenous group of peptides binds to MCRS with agonist to haptens (Ceriana et al Neuroimmunomodulation 1, 28-32: or antagonist effects, such as melanocyte-stimulating hor Chiao et al. Clin. Invest. 99, 1165-1172; Huh and Lipton mones (MSH), adrenocorticotropic hormone (ACTH), and Neurosurgery 40, 132-139; Luger et al. J. Invest Dermatol. Agouti proteins and derivatives thereof. One exception, Symp. Proc. 2, 87-93; Rajora et al Peptides 18, 381-385; J. however, is the MC2R receptor, which binds only with 35 Neurosci. 17, 2181-2 196; Lipton et al. Neuroimmunomodu ACTH (Major pharmacological distinction of the ACTH lation 5, 178-183). Melanocortins can thus be used to treat receptor from other melanocortin receptors, Schioth et al. inflammatory disorders and immune disorders. It has been Life sciences (1996), 59(10), 797-801). Suggested that the MC1R signalling pathway plays a role in MCRs have varied roles at the physiological level. MC1R the perception of pain and that functional variations in regulates melanin formation in the skin, and has a role in 40 MC1R are associated with a high pain tolerance (Mogiletal immune system regulation. MC2R regulates corticosteroid J Med Genet. 2005 July; 42(7): 583-7). production at the level of the adrenal glands. The MC3R and A strong correlation exists between human hair colour and MC4R receptors play a role in the control of food intake and MC1R variants (Valverde et al Nat Genet. 1995 November; sexual behaviour. MC5R is involved in exocrine gland 11(3): 328-30). Functional variations in MC1R are associ regulation (Wikberg, Jarl E. S., Melanocortin receptors: 45 ated with the auburn hair colour. perspectives for novel drugs. European Journal of Pharma It is also known that the sebaceous gland expresses both cology (1999), 375(1-3) 295-310. Wikberg, Jarl E. S., Mel MC1R (Ganceviciene etal Exp Dermatol. 2007 July; 16(7): anocortin receptors: new opportunities in drug discovery. 547-52) and MC5R (Zhang et al Peptides. 2006 February: Expert Opinion on Therapeutic Patents (2001), 11(1), 27(2): 413-20). It has also been reported that MC1R is 61-76). 50 overexpressed in the sebaceous gland in the case of acne. The potential use of MCRs as a target for medicaments These compounds find uses in human medicine, in par intended to treat significant pathological compositions such ticular in dermatology, and in the cosmetics field. as obesity, diabetes, inflammatory conditions and sexual Among the oXoaZetidine derivatives already known, some dysfunction creates a need for compounds which show great have been described as having antibacterial properties specificity with respect to a particular subtype. However, the 55 (WO9709328, WOO4045616, WOO4087697), antiviral modelling of medicaments that are selective for slightly properties as CCR5 antagonists (WO04055016, different receptor subtypes is a difficult task that would be WO08034731) and analgesic properties (Journal of Medici simplified if detailed knowledge of the determinants of the nal Chemistry (1968), 11, 466-470). ligand-receptor interaction was available. Patent WO9810653 discloses certain piperidine, pyrroli The Applicant has now discovered, unexpectedly and 60 dine and hexahydro-1H-azepin compounds for promoting Surprisingly, that novel compounds of general formula (I) as the synthesis of growth hormone in humans and animals. defined hereinafter exhibit very good activity on melano Patents WO9635.713 and WO9638471 disclose certain cortin receptors, and in particular certain compounds are dipeptides for stimulating growth hormone synthesis. highly selective for MC1R. The publication in the Journal of Medicinal Chemistry It has been demonstrated in particular that MC1R is one 65 (2003), 46, 1123-1126 describes the “discovery of tyrosine of the key proteins in the regulation of melanin synthesis in based potent and selective MC1R receptor small-molecule melanocytes. agonists with anti-inflammatory properties. US 9,630,949 B2 3 4 Patents WO02070511, WO02079146 and WO02069905 According to the present invention, the term “lower alkyl claim the use of compounds as modulators of melanocortin denotes a linear or branched, Saturated hydrocarbon-based receptors, more particularly MC1R and MC4R. chain containing from 1 to 4 carbon atoms or a linear or Now, the Applicant has found, unexpectedly and Surpris branched, unsaturated hydrocarbon-based chain containing ingly, that certain compounds of formula (I), which are the 5 from 2 to 4 carbon atoms. Subject of the present invention, are modulators of one or According to the present invention, the term “alkyl more melanocortin receptors and, in particular, some com denotes a substituted or unsubstituted lower alkyl or higher pounds are highly selective for MC1R. alkyl. Thus, the present invention relates to compounds of According to the present invention, the term “substituted general formula (I) below: 10 lower alkyl denotes a linear or branched, saturated hydro carbon-based chain containing from 1 to carbon atoms, or a linear or branched, unsaturated hydrocarbon-based chain (I) containing from 2 to 4 carbon atoms, and Substituted with one or more halogen atoms or with a hydroxyl, and in 15 particular, for example, methyl, ethyl, propyl, isopropyl or butyl. According to the present invention, the term “higher alkyl denotes a linear or branched, Saturated or unsaturated hydrocarbon-based chain containing from 5 to 10 carbon atOmS. in which: According to the present invention, the term “substituted R1 represents an aryl, a Substituted aryl or a cycloalkyl, higher alkyl is intended to mean a linear or branched, R2 represents a hydrogen atom, a hydroxyl, a lower alkyl, saturated or unsaturated hydrocarbon-based chain contain a substituted lower alkyl, a higher alkyl, a substituted higher ing from 5 to 10 carbon atoms and substituted with one or alkyl, a cycloalkyl, a cycloalkylalkyl, a lower alkoxy, a 25 more halogen atoms or with a hydroxyl. Substituted lower alkoxy, a higher alkoxy, a Substituted According to the present invention, the term "cycloalky higher alkoxy, a cycloalkylalkoxy, or an acyloxy; lalkyl denotes an alkyl substituted with a cycloalkyl. R3 represents an aralkyl or a substituted aralkyl: According to the present invention, the term “lower R4 represents a heteroalkyl, a substituted heteroaralkyl, a alkoxy' denotes an oxygen atom Substituted with a lower heteroalkyl or a substituted heteroalkyl: 30 alkyl, and in particular, for example, methoxy, ethoxy, R5 represents a hydrogen atom, a hydroxyl, an amino, an propoxy, isopropoxy or butoxy. acylamino or a sulphonamide; and also the corresponding According to the present invention, the term "substituted salts and enantiomers of the compounds of general formula lower alkoxy' denotes an oxygen atom Substituted with a (I). substituted lower alkyl. Among the addition salts of the compounds of general 35 According to the present invention, the term “higher formula (I) with a pharmaceutically acceptable acid, men alkoxy' denotes an oxygen atom Substituted with a higher tion may preferably be made of the salts with an organic acid alkyl. or with an inorganic acid. According to the present invention, the term “substituted Suitable inorganic acids are, for example, hydrohalic higher alkoxy' denotes an oxygen atom Substituted with a acids such as hydrochloric acid or hydrobromic acid, Sul 40 substituted higher alkyl. phuric acid, or nitric acid. According to the present invention, the term "cycloalky Suitable organic acids are, for example, picric acid, meth lalkoxy' denotes an oxygen atom Substituted with a anesulphonic acid, ethanesulphonic acid, para-toluenesul cycloalkylalkyl. phonic acid, citric acid, oxalic acid or tartaric acid. According to the present invention, the term “acyloxy” The compounds of general formula (I) may also exist in 45 denotes an oxygen atom Substituted with an acyl. the form of hydrates or of solvates with water or with a According to the present invention, the term “aralkyl solvent. denotes an alkyl substituted with an aryl. Appropriate solvents for forming Solvates or hydrates are, According to the present invention, the term “substituted for example, alcohols such as ethanol or isopropanol, or aralkyl denotes an alkyl substituted with a substituted aryl. Water. 50 According to the present invention, the term "halogen According to the present invention, the term “aryl atom' denotes chlorine, fluorine, iodine and bromine atoms. denotes an unsubstituted phenyl or naphthyl. According to the present invention, the term "hetero According to the present invention, the term “substituted cycle' denotes a saturated or unsaturated, cyclic or bicyclic aryl' denotes a phenyl or a naphthyl substituted with one or hydrocarbon-based chain comprising one or more heteroa more groups of atoms chosen from an alkyl, an alkoxy, a 55 toms chosen from O, S and N. halogen, a hydroxyl, a cyano, a trifluoromethyl and a nitro. According to the present invention, the term “substituted According to the present invention, the term “cycloalkyl heterocycle denotes a Saturated or unsaturated, cyclic or denotes a cyclic, Saturated hydrocarbon-based chain con bicyclic hydrocarbon-based chain comprising one or more taining from 3 to 7 carbon atoms. heteroatoms chosen from O, S and N, substituted with one According to the present invention, the term “hydroxyl 60 or more alkyl groups. denotes the OH group. According to the present invention, the term "heteroaryl According to the present invention, the term "amino' denotes an aromatic heterocycle. denotes the NH group. According to the present invention, the term “substituted According to the present invention, the term “acyl heteroaryl denotes an aromatic heterocycle substituted with denotes a formyl or a carbonyl substituted with an alkyl. 65 one or more alkyl groups. According to the present invention, the term “sulphonyl According to the present invention, the term "het denotes a sulphone substituted with an alkyl. eroaralkyl denotes an alkyl substituted with a heteroaryl.
US 9,630,949 B2 9 10 (S)-2-amino-3-(1H-imidazol-4-yl)-N-1-(4-methoxyben protection with a Boc group, hydrogenation with the appro Zyl)-2-oxo-2-(3-propoxy-3-o-tolylazetidin-1-yl)ethyl priate metal in tetrahydrofuran or methanol, for example, in propionamide the case of protection with a CBZ group, and piperidine in N-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxyben acetonitrile, for example, in the case of protection with an Zyl)-2-oxoethyl-3-(1H-imidazol-4-yl)butyramide Fmoc group. (S)-N-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxy In a final stage, the compounds of general formula (I) are benzyl)-2-oxoethyl-3-(1H-imidazol-4-yl)-2-methanesul prepared by coupling between the amine of formula (V) and phonylaminopropionamide an acid of formula (VI) under conventional peptide coupling N—(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phe conditions, using for example, as coupling agent, 1-(3- nylazetidin-1-yl)ethyl-3-(1-methyl-1H-imidazol-4-yl) 10 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride propionamide or hydroxybenzotriazole or TBTU, and as base, triethylam and also the respective salts and enantiomers thereof. ine or diisopropylethylamine in a solvent such as dichlo The compounds of general formula (I) are prepared romethane or dimethylformamide. according to reaction scheme 1 presented below. 15 The compounds of general formula (VI) are commercially available or are prepared according to the methods described O in the literature or known to those skilled in the art, adapted R1 H H according to the nature of the substituents R4 and R5. N- HON NN -- Depending on the nature of R4 and R5, Schemes 2, 3 and 4 O Pg hereinafter present examples of preparation of the com R2 R3 pounds of general formula (VI). (II) (III) For example, when R5 contains an alkyl substituted with O a 1,2,3-triazole heterocycle, the compound (VI) can be prepared according to Scheme 2: R1 Hos 25
R2 R3 Scheme 2: (IV) Šs Šs O 30
-- -- R1 N H —- R5 R3 R2 HO O O R4 35 (VIII) (V) O (VI) O R5 H R1 N 40 N R4
R2 R3 O
(I) 45 (IX) R4 According to Scheme 1, the compounds of general for mula (IV) can be prepared by coupling between the inter OH mediates of formula (II) and an amino acid of formula (III), R5 the amine function of which is protected with a protective 50 O group Pg (for example, a Boc, CBZ or Fmoc group), under (VI) conventional peptide coupling conditions, using for example, as coupling agent, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or hydroxybenzotriazole The compounds of general formula (VIII) are obtained by or TBTU, and as base, triethylamine or diisopropylethylam 55 esterification of the acid function of the compounds of ine in a solvent such as dichloromethane or dimethylforma general formula (VII), by methods chosen from those known mide. to those skilled in the art. They comprise, interalia, the use The amino acids of general formula (IV) are commer of Sulphuric acid in methanol, for example. The compounds cially available or are prepared by methods described in the of formula (IX) obtained from the compounds of formula literature (Williams, R. M., Synthesis of optically active 60 (VIII) are prepared by methods described in the literature C.-amino acids, Pergamon Press, Oxford, 1989). (Loren J. C., Synlett, 2005, 2847-2850) followed by cleav The compounds of general formula (V) are obtained by age in a basic medium in the presence, for example, of deprotection of the amine function of the compounds of Sodium hydroxide in a water/methanol mixture, so as to general formula (IV), by methods chosen from those known generate the triazole compounds (VI). to those skilled in the art. They comprise, interalia, the use 65 For example, when R5 contains an alkyl substituted with of trifluoroacetic acid or of hydrochloric acid in dichlo an imidazole heterocycle, the compound (VI) is prepared romethane or ethyl acetate, for example, in the case of according to Scheme 3: US 9,630,949 B2 11 12 -continued Scheme 3: Het R4 'y- "Y-" R2 R2 OH (XIII) (II)
O The compounds of general formula (XII) are obtained, for (VI) example, by addition of a magnesium halide derived from 10 R1 to the N-boc-azetidinone (XI) (commercial) followed by alkylation of the tertiary alcohol in the presence of a base The compounds of general formula (X) are commercially which may be sodium hydride, for example, and a haloge available or are prepared according to the methods described nated derivative derived from R2, so as to give the com in the literature or known to those skilled in the art. The pounds (XIII). The compounds of general formula (II) are compounds of general formula (VI) are obtained, for 15 obtained by deprotection of the amine function of the example, by hydrogenation of the compound (X) in the compounds of general formula (XIII), for example in the presence of trifluoroacetic acid or of hydrochloric acid in presence of a catalyst which may be palladium-on-charcoal dichloromethane, or ethyl acetate. in methanol. For example, when R2 contains an alkyl chain, the For example, when R5 contains an alkyl substituted with compound of general formula (II) is prepared according to a heterocycle, the compound (VI) can be prepared according Scheme 6: to Scheme 4:
Scheme 6: Scheme 4: 25 21 Br- P+Ph R- Ho Het H N CN 1 - (XIV) O 30 21 O OH R- -e- (XVI) (XVII) N CN Het
R4 R2 ) OH 35 (XV) -- R5 21 R o -e- O OH O N CN (XVIII) (VI) 40 R2 OH The compounds of general formula (XVIII) are obtained, for example, by Wittig reaction between anylide (XVII) and (XIX) a heterocycle substituted with an aldehyde (XVI) in the R 11 H presence of a base, which may be lithium hexamethyl disilaZane in a solvent such as tetrahydrofuran, for example. 45 N CN R1 N The compounds of general formula (VI) are obtained, for R2 R2 example, by hydrogenation of the compound (XVIII) in the stos presence of a catalyst which may be palladium-on-charcoal (XX) (II) in an acidic medium, for example in acetic acid. 50 The compounds of general formula (II) are prepared The compounds of general formula (XV) can be obtained, according to the methods described in the literature or for example, by addition of a base Such as Sodium hydride known to those skilled in the art, adapted according to the in the presence of a halogenated derivative derived from R2. nature of the substituents R1 and R2. Schemes 5 and The primary alcohols of general formula (XIX) are synthe hereinafter present examples of preparation of the com 55 sized from the nitrile derivatives (XV) in the presence of a pounds of general formula (II). base, for example sodium hydride and paraformaldehyde. For example, when R2 contains an alkoxy chain, the The primary alcohol function of the compounds (XIX) is compound (II) can be prepared according to Scheme 5: converted to a Sulphonate in the presence of a base which may be triethylamine or tosyl chloride, for example. The 60 aZetidine compounds of general formula (II) are synthesized Scheme 5: by intramolecular cyclization between an amine function obtained after reduction of the nitrile function, for example R1 in the presence of lithium aluminium hydride, and the O -C X -boc tosylate function of the compound of general formula (XX). HO 65 According to the present invention, the compounds of (XI) (XII) general formula (I) that are particularly preferred are those for which:
US 9,630,949 B2 17 18 Preferably, the compounds are compounds that at least ris), thrombosis, platelet aggregation induced by modulate MCRs, selectively with respect to subtype 1 thrombin and/or the consequences of thrombosis and/or (MC1R), i.e. they exhibit a ratio of the EC50 MC1R relative of atheroma plaque formation; to the other MCRs of greater than or equal to 10. Preferably, inflammatory diseases of the respiratory and ENT system, this ratio is greater than or equal to 10, advantageously including in particular asthma, acute respiratory dis greater than or equal to 20, and more advantageously greater tress syndrome, hayfever, allergic rhinitis, and chronic than or equal to 50. obstructive pulmonary disease. The compounds Advantageously, the compounds of the present invention according to the invention may also be used for treating exhibit a 50% effective concentration (EC50) value with allergies; respect to the MC1 receptor of less than or equal to 10 LM, 10 inflammatory diseases of the central nervous system, and and more particularly less than or equal to 1 uM. in particular Alzheimer's disease and any form of The invention is therefore directed towards the use of at dementia, Parkinson's disease, Creutzfeldt-Jacob dis least one compound of general formula (I) as defined above, ease, multiple Sclerosis, meningitis; for the preparation of a pharmaceutical or cosmetic compo inflammatory skin diseases, and in particular urticaria, sition in which said compound has a modulatory activity on 15 Scleroderma, contact dermatitis, atopic dermatitis, pso one or more melanocortin receptors, and in particular on riasis, ichthyosis, acne and other forms of folliculitis, subtypes 1, 3, 4 and 5. rosacea and alopecia; In one particular embodiment of the invention, the com autoimmune diseases, and in particular lupus erythema pounds of general formula (I) in the present invention have tosus, thyroid conditions, autoimmune diseases of the an MC1R-selective activity and are particularly useful in the adrenal gland and autoimmune gastritis, vitiligo and treatment of pigmentary disorders, and of inflammatory and alopecia areata; immune disorders. Some other compounds of the invention inflammations accompanying bacterial, viral or fungal are MC4R-selective and are particularly useful in the treat infections, in particular tuberculosis, septicaemia, ment of eating and metabolism disorders and also neurode fever, HIV whatever the location of the infection, generative disorders. 25 herpes, cytomegalovirus, hepatitis A, B and C. The invention also relates to a therapeutic or cosmetic transplant or graft rejection, Such as kidneys, liver, heart, treatment method comprising the administration of a phar lung, pancreas, bone marrow, cornea, intestines, skin maceutical or cosmetic composition comprising said com (skin allograft, homograft and heterograft, etc.). pound, as a modulator of one or more melanocortin recep In addition, these compounds may be used for treating tors, and in particular of Subtypes 1, 3, 4 and 5. In one 30 pain, whatever the origin thereof: post-operative pain, neu particular embodiment, the invention also relates to a thera romuscular pain, headaches, cancer-related pain, dental peutic or cosmetic method comprising the administration of pain, osteoarticular pain. a pharmaceutical or cosmetic composition comprising said These compounds may be useful for modulating pigmen compound, for treating pigmentary disorders, and inflam tation, and as a result for: matory and immune disorders. In one particular embodiment 35 treating diseases with pigmentation disorders, and in of the invention, the compounds are subtype-1-selective particular benign dermatoses such as vitiligo, albinism, modulators. melasma, lentigines, freckles, melanocytic naevi and The invention also relates to the use of a compound of all post-inflammatory pigmentations; and also pig general formula (I) as defined above, in the preparation of a mented tumours such as melanoma and local metasta medicament for use in the treatment of disorders associated 40 ses (permeation nodules), regional metastases or sys with a dysfunction of MC1R. temic metastases thereof. Specifically, the compounds used according to the inven photoprotection against Sunlight with the aim of prevent tion are particularly suitable for the treatment and/or pre ing: vention of the disorders and/or diseases chosen from: the harmful effects of Sunlight Such as actinic erythema, inflammatory diseases of the digestive tract, including in 45 skin ageing, skin cancers (spinocellular, basocellular particular the intestines (and particularly the colon in and melanoma), and in particular in diseases where it the case of irritable bowel syndrome, ulcerative colitis accelerates onset (Xeroderma pigmentosum, basal cell or Crohn's disease); pancreatitis, hepatitis (acute and naevus syndrome, familial melanoma); chronic), inflammatory pathological conditions of the photodermatoses due to exogenous photosensitizing bladder and gastritis; 50 agents, and in particular those caused by contact pho inflammatory diseases of the locomotor system, including tosensitizing agents (for example, furocoumarins, halo rheumatoid arthritis, osteoarthritis, osteoporosis, trau genated Salicylanilides and derivatives, and local Sul matic arthritis, post-infectious arthritis, muscle degen phamides and derivatives) or those caused by eration, dermatomyositis; photosensitizing agents via the systemic route (for inflammatory diseases of the urogenital system, and in 55 example, psoralens, tetracyclines, Sulphamides, phe particular glomerulonephritis; nothiazines, nalidixic acid, tricyclic antidepressants); inflammatory diseases of the cardiac system, and in dermatosis attacks with photosensitivity, and in particular particular pericarditis and myocarditis, and diseases photoaggravated dermatoses (for example, lupus ery including those for which inflammation is an underly thematosus, recurrent herpes, congenital poikiloder ing element. These diseases include, but are not limited 60 mal or telangiectasic conditions with photosensitiv to, atherosclerosis, transplant atherosclerosis, periph ity (Bloom syndrome, Cockayne syndrome, eral vascular diseases, inflammatory vascular diseases, Rothmund-Thomson syndrome), actinic lichen pla intermittent claudication or limping, restenosis, stroke, nus, actinic granuloma, disseminated Superficial transient ischaemic attack, myocardial ischaemia and actinic porokeratosis, acne rosacea, juvenile acne, myocardial infarction. These compounds may also be 65 bullous dermatoses, Darier's disease, cutaneous lym used for treating hypertension, hyperlipidaemia, coro phoma, psoriasis, atopic dermatitis, contact eczema, nary artery diseases, unstable angina (or angina pecto follicular mucinosis, erythema multiforme, fixed US 9,630,949 B2 19 20 drug erythema, lymphocytoma cutis, reticular ery The compounds may also be used for treating cancer, and thema with mucinosis, melasma). in particular lung cancer, prostate cancer, colon cancer, dermatoses with photosensitivity caused by deficiency breast cancer, ovarian cancer and bone cancer, orangiogen of the protection system with melanin formation or esis disorders including the formation or growth of Solid distribution anomalies (for example, oculocutaneous 5 tumourS. albinism, phenylketonuria, anterior hypophyseal A subject of the present invention is also a pharmaceutical insufficiency, vitiligo, piebaldism) and with DNA composition for use in particular in the treatment of the repair system deficiency (for example, Xeroderma abovementioned conditions, and which is characterized in pigmentosum, Cockayne syndrome), that it comprises, in a pharmaceutically acceptable carrier dermatoses with photosensitivity caused by metabolic 10 compatible with the method of administration selected for anomalies, such as cutaneous porphyrias (for said composition, a compound of general formula (I) or an example, late cutaneous porphyria, mixed porphyr enantiomer thereof or a salt thereof with a pharmaceutically ias, erythropoietic protoporphyria, congenital eryth acceptable acid. ropoietic porphyria (Gunther's disease), erythropoi The term “pharmaceutically acceptable carrier is etic coproporphyria), pellagra or pellagroid 15 intended to mean a medium compatible with the skin, the erythemas (for example, pellagra, pellagroid erythe mucous membranes and the skin appendages. mas and tryptophan metabolism disorders); The administration of the composition according to the idiopathic photodermatosis attacks, and in particular invention may be carried out orally, enterally, parenterally, PMLE (polymorphous light eruption), benign Summer topically or ocularly. Preferably, the pharmaceutical com light eruption, actinic prurigo, persistent photosensiti position is conditioned in a form Suitable for topical appli Zations (actino-reticulosis, chronic actinic dermatosis, cation. photosensitive eczema), Solar urticaria, hydroa vaccini When it is for oral administration, the composition may be forme, juvenile spring eruption, Solar pruritus), in the form of tablets, gel capsules, dragees, syrups, Suspen modulating the colour of the skin or of the hair and of sions, solutions, powders, granules, emulsions, Suspensions body hairs, and in particular by causing the skin to tan 25 of microspheres or nanospheres or lipid or polymeric by increasing melanin synthesis or causing it to bleach vesicles for controlled release. When it is for parenteral by interfering with melanin synthesis, but also by administration, the composition may be in the form of preventing hair and body hair turning white or grey (for Solutions or Suspensions for infusion or for injection. example canities and piebaldism); The compounds according to the invention are generally modifying the colour of the hair and of body hairs in 30 administered orally or systemically at a daily dose of cosmetic indications. approximately 0.01 mg/kg to 100 mg/kg of body weight, in These compounds may be useful for modulating seba 1 or more intakes. ceous function for: The compounds are used systemically at a concentration treating conditions with hyperseborrhoea, and in particu generally between 0.001% and 10% by weight, preferably lar acne, seborrhoeic dermatitis, greasy skin and greasy between 0.01% and 1% by weight, relative to the total hair, hyperseborrhoea in Parkinson's and epilepsy, and 35 weight of the composition. hyperandrogenism; When administered topically, the pharmaceutical compo treating conditions with decreased sebaceous secretion, sition according to the invention is more particularly for use and in particular Xerosis and all dry skin; in the treatment of the skin and the mucous membranes, and regulating benign or malignant Sebocyte and sebaceous may be in liquid, pasty or Solid form, and more particularly gland proliferation; 40 in the form of Salves, creams, milks, ointments, powders, treating inflammatory conditions of the pilosebaceous impregnated pads, syndets, solutions, gels, sprays, foams, follicle, and in particular acne, boils, carbuncles and Suspensions, Sticks, shampoos or washing bases. It may also folliculitis. be in the form of Suspensions of microspheres or nano The invention also relates to the use of a compound of spheres or lipid or polymeric vesicles or polymeric or gelled general formula (I) as defined above, for the preparation of 45 patches for controlled release. a medicament for use in the treatment of disorders associ The compositions used for topical application have a ated with an MC4R dysfunction. concentration of compound according to the invention of The compounds of the invention may also be used for generally between 0.001% and 10% by weight, preferably treating neurodegenerative disorders, including depression, between 0.01% and 5% by weight, relative to the total anxiety, compulsive disorders such as obsessive-compulsive 50 weight of the composition. disorders, neuroses, psychoses, insomnia and sleep disorder, The compounds of general formula (I) according to the sleep apnoea, and drug abuse. invention also find use in the cosmetics field, in particular in These compounds may be used for the treatment of male protection against the harmful aspects of Sunlight, for pre or female sexual dysfunctions. The male sexual dysfunc venting and/or combating photoinduced or chronological tions include, but are not limited to, impotence, loss of ageing of the skin and the skin appendages. libido, and erectile dysfunction. 55 A subject of the invention is therefore also a composition The female sexual dysfunctions include, but are not comprising, in a cosmetically acceptable carrier, at least one limited to, sexual stimulation disorders or disorders related of the compounds of general formula (I). The term “cos to desire, sexual receptivity, orgasm, and disturbances of the metically acceptable medium' is intended to mean a major points of sexual function. The female sexual dysfunc medium compatible with the skin, the mucous membranes tions may also include pain, preterm labour, dysmenorrhoea, 60 and the skin appendages. excessive menstruation, and endometriosis. A subject of the invention is also the cosmetic use of a The compounds according to the invention may also be composition comprising at least one compound of general used for treating disorders related to weight but not limited formula (I), for preventing and/or treating the signs of to obesity and anorexia (Such as modification or impairment ageing and/or the skin. of appetite, spleen metabolism, innocent intake of fats or 65 A subject of the invention is also the cosmetic use of a carbohydrates); diabetes mellitus (through glucose dose composition comprising at least one compound of general tolerance and/or decreased insulin resistance). formula (I) for body or hair hygiene. US 9,630,949 B2 21 22 The cosmetic composition according to the invention Material & Methods containing, in a cosmetically acceptable carrier, a compound HPLC Methods: of general formula (I), or an enantiomer thereof or a salt thereof with a pharmaceutically acceptable acid, may be in Method A particular in the form of a cream, a milk, a gel, Suspensions 5 of microspheres or nanospheres or lipid or polymeric vesicles, impregnated pads, solutions, sprays, foams, Sticks, Column: Gemini 150 x 3 mm, 3 p.m. UV detector: 220-420 mm Soaps, washing bases or shampoos. Flow rate: 0.5 ml/min The concentration of compound of general formula (I) in Solvent A: CHCN + 0.05 TFA the cosmetic composition is preferably between 0.001% and 10 Solvent B: HO + 0.05 TFA 10% by weight, relative to the total weight of the compo sition. Gradient: The pharmaceutical and cosmetic compositions as described above may also contain inert additives, or even Time composition pharmacodynamically active additives as regards the phar- 15 maceutical compositions, or combinations of these addi- 0.0 min A = 5%, B = 95% tives, and in particular: 5.0 min A = 5%, B = 95% Wetting agents: 20.0 min A = 95%, B = 5% flavour enhancers; 30.0 min A = 95%, B = 5% preservatives such as para-hydroxybenzoic acid esters: 20 stabilizers; moisture regulators; Method B pH regulators;
osmotic pressure modifiers; ColOllil: Geminiell 150 xX 3 Inn, 3 lm emulsifiers; 25 UV detector: 220-420 mm UV-A and UV-B screening agents; Flow rate: 0.5 ml/min antioxidants, such as C-tocopherol, butylhydroxyanisole Solvent A: CHCN + 0.05 TFA or butylhydroxytoluene, Superoxide dismutase, ubiqui- Solvent B: HO + 0.05 TFA nol Gradient: emollients; 30 moisturizers, such as glycerol, PEG 400, thiamorpholi- Time composition E. s its derivatives or urea; has S-carb 0.0 min A = 5%, B = 95% ant1SebOrr oeic or ant1-acne agents, such as S-carboxym- 20.0 min A = 90%, B = 10% ethylcysteine, S-benzylcysteamine, their salts or their 30.0 min A = 90%, B = 10% derivatives, or benzoyl peroxide. 35 Of course, those skilled in the art will take care to select the optional compound(s) to be added to these compositions Method C in Such a way that the advantageous properties intrinsically associated with the present invention are not, or are not Substantially, impaired by the envisaged addition. 40 Column: Atlantis C18 150 x 3.2 mm, 3 lim UV detector: 220-420 mm Several examples of obtaining. compounds of general Flow rate: 0.3 ml/min formula (I) according to the invention and of the biological Solvent A: CHCN + 0.1 TFA activity results for these compounds will now be given by Solvent B: HO + 0.1 TFA way of illustration that is in no way limiting in nature. The following examples describe the preparation of some 45 Gradient: compounds in accordance with the invention. These Time composition examples are not limiting and merely illustrate the present 0.0 min A = 5%, B = 95% invention. The numbers of the compounds exemplified- 0 refer 5.0 min A = 5%, B = 95% back to those given in Table I hereinafter, which illustrates 25.0 min A = 95%, B = 5% the chemical names and the physical properties of some 50 30.0 min A = 95%, B = 5% compounds according to the invention. The following abbreviations are used: TBTU: N.N.N',N'-tetramethyl-O-(benzotriazol-1-yl)uro- Method D nium tetrafluoroborate HOBt: 1-hydroxy-1,2,3-benzotriazole 55 Col Gemini 150 x 3 3 EDC: 1 ethyl -(3-r(3-dimethylaminopropyl)carbodiimide, UVOllil: detector: 220-420ell mm X Inn, lm hydrochloride Flow rate: 0.5 ml/min BOC: tert-butoxycarbonyl Solvent A: CHCN CBZ: benzyloxycarbonyl Solvent B: HO + 0.02 TFA Fmoc: 6-fluorenylmethoxycarbonyl 60 Gradient: Tos: p-toluenesulphonyl DMF: dimethylformamide Time composition DCM; dichloromethane 0. 0. DIEA: diisopropylethylamine 28 R A. ...% The term “conformers’ is given to stereoisomers which 65 30.0 min A-90%. B = 10% convert from one to the other by rotation around bonds (single bond provided by a doublet of electrons). US 9,630,949 B2
Method E Method I
Column: Xbridge phenyl 150 x 2.1 mm, 3.5 m Column: Gemini C18 150 x 3 mm, 3 um UV detector: 220-420 mm 5 UV detector: 220-420 mm Flow rate: 1.0 ml/min Flow rate: 0.3 ml/min Solvent A: 95% MeOH/5% water + 25 mM NHOAc Solvent A: HO + 0.05% TFA Solvent B: HO + 25 mM NHOAc Solvent B: CHCN + 0.05% TFA 10 Gradient: Gradient:
Time composition Time composition 15 0.0 min A = 5%, B = 95% 0.0 min A = 95%, B = 5.0% 20.0 min A = 98%, B = 2% 20.0 min A = 5%, B = 95% 30.0 min A = 98%, B = 2% 30.0 min A = 5%, B = 95% 2O Method F Method J
Column: Xbridge phenyl 250 x 4.6 mm, 5 Im 25 Column: Gemini C18 150 x 3 mm, 3 um UV detector: 220-420 mm UV detector: 220-420 mm Flow rate: 1.0 ml/min Flow rate: 0.5 ml/min Solvent A: 90% MeOH/10% water + 25 mM NHOAc Solvent A: MeOH - 0.1% TFA Solvent B: HO + 25 mM NHOAc Solvent B: HO + 0.02% TFA Gradient: Gradient: 30 Time composition Time composition
0.0 min A = 5%, B = 95% 0.0 min A = 10%, B = 90% 20.0 min A = 98%, B = 2% 15.0 min A = 95%, B = 5% 30.0 min A = 98%, B = 2% 30.0 min A = 95%, B = 5% 35
Method G Method K
Column: Xbridge phenyl 250 x 4.6 mm, 5 Im 40 Column: Gemini C6-phenyl 150 x 3 mm, 3 um UV detector: 220-420 mm UV detector: 220-420 mm Flow rate: 1.0 ml/min Flow rate: 0.5 ml/min Solvent A: 90% MeOH/10% water + 25 mM NHOAc Solvent A: HO + 0.05% TFA Solvent B: HO + 25 mM NHOAc Solvent B: CHCN + 0.05% TFA
Gradient: 45 Gradient: Time composition Time composition 0.0 min A = 5%, B = 95% 0.0 min A = 95%, B = 5% 15.0 min A = 98%, B = 2% 20.0 min A = 5%, B = 95% 30.0 min A = 98%, B = 2% 50 30.0 min A = 5%, B = 95%
Method H Method L
Column: Gemini C18 150 x 3 mm, 3 um 55 Column: Gemini C18 150 x 3 mm, 3 um UV detector: 220-420 mm UV detector: 220-420 mm Flow rate: 0.3 ml/min Flow rate: 0.5 ml/min Solvent A: 94% MeOH/6% water + 10 mM NHOAc Solvent A: CHCN + 0.1% HCOOH Solvent B: H2O + 10 mM NHOAc Solvent B: HO + 0.1% HCOOH
Gradient: 60 Gradient: Time composition Time Composition 0.0 min A = 5%, B = 95% 0.0 min A = 5%, B = 95.0% 10.0 min A = 95%, B = 5% 10.0 min A = 5%, B = 95% 30.0 min A = 95%, B = 5% 65 30.0 min A = 70%, B = 30% US 9,630,949 B2
Method M Method Q
Column: ThermoHypersil Hypurity C18 150 x 4.6 mm, 5 Im Column: Atlantis T3 150 x 4.6 mm, 5 Im UV detector: 220-420 mm 5 UV detector: 190-420 mm Flow rate: 0.5 ml/min Flow rate: 0.3 ml/min Solvent A: HO + 0.05% TFA Solvent A: HO + 0.05% TFA Solvent B: CHCN + 0.05% TFA Solvent B: CHCN + 0.05% TFA 10 Gradient: Gradient:
Time composition Time composition 15 0.0 min A = 95%, B = 5.0% 0.0 min A = 95%, B = 5.0% 20.0 min A = 5%, B = 95% 20.0 min A = 5%, B = 95% 30.0 min A = 5%, B = 95% 30.0 min A = 5%, B = 95% 2O Method N Method R
Column: Atlantis T3 150 x 2.1 mm, 3 um Column: Gemini C6-phenyl 150 x 3 mm, 3 um UV detector: 220-420 mm 25 UV detector: 190-420 mm Flow rate: 0.3 ml/min Flow rate: 0.3 ml/min Solvent A: HO + 0.05% TFA Solvent A: CHCN + 0.05% TFA Solvent B: CHCN + 0.05% TFA Solvent B: HO + 0.05% TFA Gradient: Gradient: 30 Time composition Time composition
0.0 min A = 95%, B = 5.0% 0.0 min A = 10%, B = 90% 20.0 min A = 5%, B = 95% 15.0 min A = 90%, B = 10% 30.0 min A = 5%, B = 95% 30.0 min A = 90%, B = 10% 35
Method O Method S
Column: Atlantis T3 150 x 4.6 mm, 5 Im 40 Column: Eclipse XDB C8 150 x 4.6 mm, 5 Im UV detector: 220-420 mm UV detector: 190-420 mm Flow rate: 0.3 ml/min Flow rate: 1 ml/min Solvent A: HO + 0.05% TFA Solvent A: CHCN + 0.1% HCOOH Solvent B: CHCN + 0.05% TFA Solvent B: HO + 0.1% HCOOH
Gradient: 45 Gradient: Time composition Time composition 0.0 min A = 95%, B = 5.0% 0.0 min A = 10%, B = 90% 20.0 min A = 5%, B = 95% 20.0 min A = 95%, B = 5% 30.0 min A = 5%, B = 95% 50 30.0 min A = 95%, B = 5%
Method P Method T
Column: Atlantis T3 150 x 4.6 mm, 5 Im 55 Column: Gemini C6-phenyl 150 x 3 mm, 3 um UV detector: 190-420 mm UV detector: 190-420 mm Flow rate: 0.25 ml/min Flow rate: 0.3 ml/min Solvent A: HO + 0.05% TFA Solvent A: CHCN + 0.05% TFA Solvent B: CHCN + 0.05% TFA Solvent B: HO + 0.05% TFA
Gradient: 60 Gradient: Time composition Time composition 0.0 min A = 95%, B = 5.0% 0.0 min A = 10%, B = 90% 20.0 min A = 5%, B = 95% 20.0 min A = 90%, B = 10% 30.0 min A = 5%, B = 95% 65 30.0 min A = 90%, B = 10% US 9,630,949 B2
Method U Method Y
Column: Xbridge Phenyl 250 x 4 mm, 3 p.m. Column: Atlantis T3 150 x 4.6 mm, 5 Im UV detector: 190-420 mm UV detector: 190-420 mm Flow rate: 0.8 ml/min Flow rate: 0.3 ml/min Solvent A: CHCN + 5% THF + 0.02% TFA Solvent B: HO + 0.02% HCOOH Solvent A: CHCN + 0.05% TFA Solvent B: HO + 0.05% TFA Gradient: 10 Time composition Gradient: 0.0 min A = 2%, B = 98% 20.0 min A = 98%, B = 2% Time composition 30.0 min A = 98%, B = 2% 32.0 min A = 2%, B = 98% 15 40.0 min A = 2%, B = 98% 0.0 min A = 10%, B = 90% 20.0 min A = 90%, B = 10% Method Z 30.0 min A = 90%, B = 10% Column: Atlantis T3 150 x 2.1 mm, 3 um UV detector: 190-420 mm Method V Flow rate: 0.3 ml/min Solvent A: CHCN + 0.02% TFA Solvent B: HO + 0.02% TFA Column: Xbridge C18 250 x 4.5 mm, 5 m UV detector: 190-420 mm 25 Gradient: Flow rate: 1 ml/min Solvent A: CHCN + 0.05% TFA Time composition Solvent B: HO + 0.05% TFA 0.0 min A = 5%, B = 95% Gradient: 20.0 min A = 98%, B = 2% 30 30.0 min A = 98%, B = 2% Time composition
0.0 min A = 10%, B = 90% 25.0 min A = 90%, B = 10% EXAMPLE 1. 30.0 min A = 90%, B = 10% 35 N—(S)-1-(S)-2-(3-Butoxy-3-phenylazetidin-1-yl) Method W 1-(4-methoxybenzyl)-2-oxoethylcarbamoyl-2-(1H imidazol-4-yl)ethylbenzamide (compound No. 3; Table I) Column: Xbridge Phenyl 150 x 3 mm, 3 Lim 40 UV detector: 190-420 mm Flow rate: 1 ml/min 1-1 (S)-2-(S)-2-Benzoylamino-3-(1H-imidazol-4- Solvent A: CHCN + 0.05% TFA Solvent B: HO + 0.05% TFA yl)propionylamino-3-(4-methoxyphenyl)propanoic acid Gradient: 45 Time composition 5.07 g (15.8 mmol) of TBTU are added to a solution containing 4.05 g (15.6 mmol) of (S)-2-benzoylamino-3- 0.0 min A = 10%, B = 90% (1H-imidazol-4-yl)propanoic acid in 30 ml of DMF. The 25.0 min A = 95%, B = 10% reaction medium is left to stir for 15 minutes at ambient 30.0 min A = 95%, B = 10% 50 temperature. 3 g (14.3 mmol) of methyl (S)-2-amino-3-(4- methoxyphenyl)propanoate and 7.5 ml of DIEA in 20 ml of Method X DMF are added dropwise and stirred at ambient temperature for 4 hours. The reaction is stopped by adding water, and the organic products are extracted with dichloromethane. The Column: Atlantis 150 x 2.1 mm, 3 Lim 55 organic phase is dried in the presence of magnesium Sul UV detector: 190-420 mm phate. After filtration, the solvents are evaporated off. 6.56 Flow rate: 0.3 ml/min Solvent A: CHCN + 0.02% TFA g of a pale yellow solid are obtained and dissolved in 100 ml Solvent B: HO + 0.02% TFA of THF. 29 ml of a 1N solution of LiOH are added. The reaction medium is stirred at ambient temperature for 16 Gradient: 60 hours. 20 ml of a saturated solution of ammonium chloride are added, followed by extraction with diethyl ether. The Time composition aqueous phase is acidified to pH 5 with a 1N solution of HC1. 0.0 min A = 2%, B = 98% The white precipitate obtained is filtered off and oven-dried 20.0 min A = 98%, B = 2% under vacuum at 40° C. 5.6 g (12.8 mmol) of (S)-2-(S)-2- 30.0 min A = 98%, B = 2% 65 benzoylamino-3-(1H-imidazol-4-yl)propionylamino-3-(4- methoxyphenyl)propanoic acid are obtained with a yield of 88%. US 9,630,949 B2 29 30 1-2 N—(S)-1-(S)-2-(3-Butoxy-3-phenylazetidin-1- hydrogen carbonate. The organic phase is dried and evapo yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl-2- rated to dryness. The crude product obtained is purified by (1H-imidazol-4-yl)ethylbenzamide silica gel chromatography (eluent 9/1 dichloromethane/ methanol). 55 mg of N—(S)-1-(S)-2-(3-butoxy-3-phe nylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbam 1-2-1 3-Hydroxy-3-phenyl-1-(tert-butoxycarbonyl)- 5 oyl-2-(1H-imidazol-4-yl)ethylbenzamide are obtained in aZetidine the form of a white powder with a yield of 60%. HPLC: (method A); 2 peaks (mixtures of conformers): 3.9 ml (11.7 mmol) of a 3M solution of phenylmagnesium retention time: 16.44 min and 16.60 min, (34+57)%, M+H: bromide in diethyl ether are added dropwise to a solution, 624. immersed in a bath at -50° C., containing 500 mg (2.92 10 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 10 ml EXAMPLE 2 of THF. The medium is stirred for 1 hour at -50° C. and hydrolysed by adding a saturated Solution of ammonium 1-(S)-2-(S)-2-benzoylamino-3-(1H-imidazol-4-yl) chloride. After a return to ambient temperature, a 1N solu propionylamino-3-(4-methoxyphenyl)propionyl-3- tion of hydrochloric acid is added, followed by extraction 15 (4-fluorophenyl)azetidin-3-yl ester of butyric acid with ethyl acetate. The organic phase is dried and evaporated (compound No. 6; Table I) to dryness. The crude product obtained is purified on silica in a 7/3 heptane/ethyl acetate mixture. 253 mg in the form 2-1 3-(4-Fluorophenyl)-3-hydroxy-1-(tert-butoxy of a white powder are obtained with a yield of 35%. carbonyl)azetidine 1-2-2 3-Butoxy-3-phenyl-1-(tert-butoxycarbonyl)- 6 ml (11.7 mmol) of a 2M solution of 4-fluorophenyl aZetidine magnesium bromide in diethyl ether are added dropwise to a solution, immersed in a bath at -50° C., containing 500 mg (2.92 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in A solution of 1 g (4.0 mmol) of 3-hydroxy-3-phenyl-1- 10 ml of THF. The medium is stirred for 1 hour at -50° C. (tert-butoxycarbonyl)azetidine dissolved in 5 ml of DMF is 25 and hydrolysed by addition of a Saturated Solution of ammo added dropwise to a suspension of 300 mg of 60% NaH in nium chloride. After a return to ambient temperature, a 1N 3 ml of DMF, immersed in a bath at 0° C. 2.5 ml of solution of hydrochloric acid is added, followed by extrac n-iodobutane are added dropwise. The reaction medium is tion with ethyl acetate. The organic phase is dried and left to stir at 0° C. for 15 minutes and 72 hours at ambient evaporated to dryness. The crude product obtained is puri temperature. The medium is hydrolysed by addition of a 30 fied by silica gel chromatography (eluent 7/3 heptane/ethyl saturated solution of ammonium chloride, followed by acetate). 333 mg in the form of a white powder are obtained extraction with ethyl acetate. The organic phase is dried and with a yield of 43%. evaporated to dryness. The crude product obtained is puri fied on silica in a 7/3 heptane/ethyl acetate mixture. 500 mg 2-2 3-Butyryloxy-3-(4-fluorophenyl)-1-(tert-butoxy in the form of a light yellow oil are obtained with a yield of 35 carbonyl)azetidine 41%. 23 mg (0.188 mmol) of DMAP and 0.03 ml of pyridine 1-2-3 3-Butoxy-3-phenylazetidine trifluoroacetate are added to a solution containing 50 mg (0.187 mmol) of 3-butyryloxy-3-(4-fluorophenyl)-1-(tert-butoxy-carbonyl) 1 ml of trifluoroacetic acid is added to a solution con 40 azetidine in 1 ml of dichloromethane. After stirring at taining 500 mg (1.64 mmol) of 3-butoxy-3-phenyl-1-(tert ambient temperature for 10 minutes, 0.06 ml of butyric butoxycarbonyl)azetidine dissolved in 5 ml of dichlo anhydride are introduced. After 3 hours, a saturated solution romethane. The reaction medium is stirred at ambient of ammonium chloride is added, followed by extraction with temperature for 3 hours and then concentrated. The crude dichloromethane. The organic phase is dried and evaporated product obtained is purified by silica gel chromatography 45 to dryness. The crude product obtained is purified by silica (eluent 90/10 dichloromethane/methanol). 400 mg in the gel chromatography (eluent 773 heptane/ethyl acetate). 61 form of a pale yellow powder are obtained with a yield of mg in the form of a colourless oil are obtained with a yield 76%. of 97%.
1-3 N—(S)-1-(S)-2-(3-Butoxy-3-phenylazetidin-1- 50 2-3 3-(4-Fluorophenyl)azetidin-3-yl butyrate yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl-2- trifluoroacetate (1H-imidazol-4-yl)ethylbenzamide 2 ml of trifluoroacetic acid are added to a solution 1 ml of a 3/2 dichloromethane/trifluoroacetic acid solution containing 61 mg (0.181 mmol) of 3-hydroxy-3-(4-fluoro is added to 200 mg (0.343 mmol) of (S)-2-(S)-2-benzoy 55 phenyl)-1-(tert-butoxycarbonyl)azetidine dissolved in 8 ml lamino-3-(1H-imidazol-4-yl)propionylamino-3-(4- of dichloromethane. The reaction medium is stirred at ambi methoxyphenyl)propanoic acid. After stirring at ambient ent temperature for 3 hours and then concentrated. The crude temperature for 1 hour, the solvents are evaporated off. The product obtained is purified by silica gel chromatography residue obtained is dissolved in 5 ml of DMF, and 110 mg (eluent 90/10 dichloromethane/methanol). 40 mg in the form (0.343 mmol) of TBTU and 2.37 ml of DIEA are added. The 60 of a pale yellow oil are obtained with a yield of 63%. reaction medium is left to stir for 15 minutes at ambient temperature. 47 mg (0.147 mmol) of 3-butoxy-3-phenylaze 2-4 1-(S)-2-(S)-2-benzoylamino-3-(1H-imidazol-4- tidine trifluoroacetate dissolved in 5 ml of a 1/4 DCM/DMF yl)propionylamino-3-(4-methoxyphenyl)propionyl Solution are added dropwise and stirred at ambient tempera 3-(4-fluorophenyl)azetidin-3-yl ester of butyric acid ture for 16 hours. A 5% citric acid solution is added, 65 followed by extraction with dichloromethane. The organic 1 ml of a 3/2 dichloromethane?trifluoroacetic acid solution phase is washed with a saturated solution of potassium is added to 109 mg (0.252 mmol) of (S)-2-(S)-2-benzoy US 9,630,949 B2 31 32 lamino-3-(1H-imidazol-4-yl)propionylamino-3-(4- dropwise and stirred at ambient temperature for 2 hours. A methoxyphenyl)propanoic acid (cf. procedure 1-1). After saturated Solution of potassium hydrogen carbonate is stirring at ambient temperature for 1 hour, the solvents are added, followed by extraction with dichloromethane. The evaporated off. The residue obtained is dissolved in 5 ml of organic phase is washed with a saturated Solution of potas DMF and 81 mg (0.252 mmol) of TBTU and 1.74 ml of 5 sium hydrogen carbonate. The organic phase is dried and DIEA are added. The reaction medium is left to stir for 15 evaporated to dryness. The crude product obtained is puri minutes at ambient temperature. 40 mg (0.114 mmol) of fied by silica gel chromatography (eluent 85/15 dichloro 3-(4-fluorophenyl)azetidin-3-yl butyrate trifluoroacetate dis methane/methanol mixture). 35 mg of N (S)-1-(S)-2-(3- solved in 5 ml of a 1/4 dichloromethane/dimethylformamide cyclohexyl-3-hydroxyazetidin-1-yl)-1-(4-methoxybenzyl)- Solution are added dropwise and stirred at ambient tempera 10 2-oxoethylcarbamoyl-2-(1H-imidazol-4-yl)ethyl ture for 16 hours. A 5% citric acid solution is added, benzamide are obtained in the form of a yellow powder with followed by extraction with dichloromethane. The organic a yield of 32%. phase is washed with a saturated solution of potassium hydrogen carbonate. The organic phase is dried and evapo HPLC: (method B): 2 peaks (mixture of conformers): rated to dryness. The crude product obtained is purified by retention time: 10.68 min and 10.94 min, (36+62)%, M+H: silica gel chromatography (eluent 9/1 dichloromethane/ 574. methanol). 19 mg of 1-(S)-2-(S)-2-benzoylamino-3-(1H imidazol-4-yl)propionylamino-3-(4-methoxyphenyl)pro EXAMPLE 4 pionyl-3-(4-fluorophenyl)azetidin-3-yl ester of butyric acid are obtained in the form of a white powder with a yield of 20 N—(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-penty 25%. loxy-3-o-tolylazetidin-1-yl)ethyl-3-(1H-imidazol-4- HPLC: (method B): 2 peaks (mixtures of conformers): yl)propionamide (compound No. 24: Table I) retention time: 13.51 min and 13.72 min, (28+55)%, M+H: 656. 4-1 3-Pentyloxy-3-o-tolyl-1-(tert-butoxy-carbonyl) 25 aZetidine EXAMPLE 3 A solution of 3.53 g (13.4 mmol) of 3-hydroxy-3-phenyl N—(S)-1-(S)-2-(3-cyclohexyl-3-hydroxyazetidin 1-(tert-butoxycarbonyl)azetidine (cf. procedure 1-2-1) is 1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl-2- added dropwise to a suspension of 1.07 g (26.8 mmol) of (1H-imidazol-4-yl)ethylbenzamide (compound No. 30 60% NaH in 17 ml of DMF, immersed in a bath at 0°C. 9.0 7: Table I) ml of n-iodopentane are added dropwise. The reaction medium is left to stir at 0°C. for 15 minutes and 24 hours 3-1 3-Cyclohexyl-3-hydroxy-1-(tert-butoxy-carbo at ambient temperature. The medium is hydrolysed by nyl)aZetidine addition of a saturated Solution of ammonium chloride, 35 followed by extraction with ethyl acetate. The organic phase 0.5 ml of acetic acid and 40 mg of rhodium on alumina is dried and evaporated to dryness. The crude product 5% are added to a solution containing 117 mg (0.470 mmol) obtained is purified by silica gel chromatography (eluent 7/3 of 3-hydroxy-3-phenyl-1-(tert-butoxy-carbonyl)azetidine heptane/ethyl acetate). 3.41 g in the form of a light yellow (cf. procedure 1-2-1) dissolved in 4 ml of methanol. The oil are obtained with a yield of 76%. reaction medium is placed at 4 bar of hydrogen and heated 40 at 85°C. for 4 hours. The catalyst is filtered off and washed 4-2 3-pentoxy-3-phenylazetidine trifluoroacetate with methanol and the solvents are evaporated off. 120 mg in the form of a beige powder are obtained with a yield of 5.5 ml of trifluoroacetic acid are added to a solution 100%. containing 3.34 g (10 mmol) of 3-pentoxy-3-phenyl-1-(tert 45 butoxycarbonyl)azetidine dissolved in 10 ml of dichlo 3-2 3-Cyclohexylazetidin-3-ol trifluoroacetate romethane. The reaction medium is stirred at ambient tem perature for 2 hours 30 min and then concentrated. The crude 1 ml of trifluoroacetic acid is added to a solution con product obtained is purified by silica gel chromatography taining 120 mg (0.47 mmol) of 3-cyclohexyl-3-hydroxy-1- (eluent 90/10 dichloromethane/methanol). 3.5g in the form (tert-butoxycarbonyl)azetidine dissolved in 3 ml of dichlo- 50 of a pale yellow oil are obtained with a yield of 100%. romethane. The reaction medium is stirred at ambient temperature for 1 hour and then concentrated to dryness and 4-3 tert-butyl (R)-1-(4-methoxybenzyl)-2-oxo-2-(3- used without further purification. pentyloxy-3-o-tolylazetidin-1-yl)ethylcarbamate 3-3 N (S)-1-(S)-2-(3-Cyclohexyl-3-hydroxyazeti- 55 2.93 g (9.93 mmol) of (R)-2-tert-butoxycarbonylamino din-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbam 3-(4-methoxyphenyl)propionic acid are dissolved in 10 ml oyl-2-(1H-imidazol-4-yl)ethylbenzamide of DMF, 2.08 g (10.9 mmol) of EDC, 1.47 g (10.9 mmol) of HOBt and a solution of 3.45 g (9.93 mmol) of 3-pentoxy 1 ml of a 3/2 dichloromethane/trifluoroacetic acid solution 3-phenylazetidine trifluoroacetate in 15 ml of DMF are then is added to 84 mg (0.193 mmol) of (S)-2-(S)-2-benzoy- 60 added. 7 ml (40.2 mmol) of DIEA are added. The reaction lamino-3-(1H-imidazol-4-yl)propionylamino-3-(4- medium is stirred at ambient temperature for 2 h30 and then methoxyphenyl)propanoic acid (cf. procedure 1-1). After extracted with ethyl acetate. The organic phase is washed stirring at ambient temperature for 1 hour, the solvents are with 1N sodium hydroxide and then dried over magnesium evaporated off. The residue obtained is dissolved in 1 ml of sulphate, filtered and evaporated. The crude product DMF, and 79 mg (0.246 mmol) of TBTU and 15 drops of 65 obtained is purified by silica gel chromatography (eluent 6/4 DIEA are added. 0.235 mmol of 3-cyclohexylazetidin-3-ol heptane/ethyl acetate). 2.83 g in the form of a white powder trifluoroacetate dissolved in 1 ml of a DCM solution is added are obtained with a yield of 56%. US 9,630,949 B2 33 34 4-4 (R)-2-Amino-3-(4-methoxyphenyl)-1-(3-penty for 16 hours and then basified to pH-8-9 by introducing 1N loxy-3-o-tolylaZetidin-1-yl)propan-1-one trifluoroac Sodium hydroxide and a saturated Solution of Sodium hydro etate gen carbonate, followed by extraction with dichlorometh ane. The organic phase is dried over Sodium Sulphate, 2.81 g (5.5 mmol) of tert-butyl (R)-1-(4-methoxyben filtered and evaporated. The crude product obtained is Zyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethylcar purified by silica gel chromatography (eluent 85/15 dichlo bamate are solubilized in 10 ml of dichloromethane. The romethane/methanol). 11.0 g in the form of an orange oil are reaction medium is cooled to 0°C. 6.5 ml of trifluoroacetic obtained with a yield of 49%. acid are then introduced. After a return to ambient tempera ture, the reaction medium is stirred for 5 hours and then 10 5-3 (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3- concentrated to dryness. The crude product obtained is (4-methoxyphenyl)propanoic acid purified by silica gel chromatography (eluent 9/1 dichlo romethane/methanol). 2.81 g in the form of a white powder 40 ml of a 1N aqueous solution of lithium hydroxide are are obtained with a yield of 97%. added to a solution containing 11.0 g (33.3 mmol) of methyl 15 (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxy 4-5 N (R)-1-(4-Methoxybenzyl)-2-oxo-2-(3-pen tyloxy-3-o-tolylazetidin-1-yl)ethyl-3-(1H-imidazol phenyl)propanoate in 100 ml of THF. After stirring for 16 hours, the reaction medium is concentrated. The residue is 4-yl)propionamide purified by silica gel chromatography (eluent 70/30/1 670 mg (2.08 mmol) of TBTU, 0.8 ml of triethylamine dichloromethane/methanol/triethylamine). 8.4 g in the form and then 1.0 g (1.91 mmol) of (R)-2-amino-3-(4-methoxy of a white powder are obtained with a yield of 79%. phenyl)-1-(3-pentyloxy-3-o-tolylaZetidin-1-yl)propan-1- one trifluoroacetate are added to a solution containing 370 5-4-1 2-Phenylheptanenitrile mg (2.10 mmol) of desamino-histidine hydrochloride in 15 ml of dimethylformamide. The reaction medium is stirred at 25 5 g (42.7 mmol) of phenylacetonitrile are added dropwise ambient temperature for 21 hours. The reaction is stopped by to a suspension of 2 g of 60% NaH in 50 ml of DMF cooled adding a 1N solution of sodium hydroxide and then extrac to 0°C. After stirring for 30 minutes at 0°C., 5.32 ml (42.7 tion with dichloromethane is carried out. The organic phases mmol) of bromopentane are added dropwise. The reaction are combined and dried over sodium sulphate. After filtra medium is stirred for 16 hours at ambient temperature and tion, the solvents are evaporated off and the residue is then 30 then treated with ice and extracted with ethyl ether. The purified by silica gel chromatography (eluent 90/10 dichlo organic phase is washed with a saturated aqueous solution of romethane/methanol). 598 mg of N (R)-1-(4-methoxy sodium hydrogen carbonate, dried over sodium sulphate, benzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl filtered and evaporated under pressure. An orangey-yellow 3-(1H-imidazol-4-yl)propionamide are obtained in the form oil is obtained and purified by fractionated distillation under of a white powder with a yield of 59%. 35 reduced pressure (70-75° C. under 1x10 mbar). 5.14 g in HPLC: (method M); retention time: 18.20 min, 99%, the form of an orangey oil are obtained with a yield of 64%. M-H: 533. 5-4-2 2-Hydroxymethyl-2-phenylheptanenitrile EXAMPLE 5 40 5.14 g (27.4 mmol) of 2-phenylheptanenitrile are added to N—(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3- a suspension of 1.34g of 60% NaH in 50 ml of DMF cooled phenylazetidin-1-yl)ethyl-3-(1H-imidazol-4-yl)pro to 0°C. After stirring for 30 minutes, 7.6 g (220 mmol) of pionamide (compound No. 26: Table I) paraformaldehyde are added portionwise. The reaction medium is left to stir at ambient temperature for 6 hours and 5-1 Methyl 45 then hydrolysed with ice and extracted with diethyl ether. (R)-2-amino-3-(4-methoxyphenyl)propanoate The organic phase is washed with a saturated aqueous Solution of sodium hydrogen carbonate, dried over Sodium 20 ml of sulphuric acid are added, dropwise, over a period sulphate, filtered and evaporated under pressure. The crude of 30 minutes, to a solution containing 13 g (66.6 mmol) of product obtained is purified by silica gel chromatography (R)-2-amino-3-(4-methoxyphenyl)propionic acid in 150 ml 50 (eluent 8/2 heptane/ethyl acetate). 4.24 g in the form of a of methanol. After stirring for 24 hours at ambient tempera pale yellow oil are obtained with a yield of 71%. ture, the reaction medium is basified to pH 8-9 by introduc ing 10N sodium hydroxide and a saturated solution of 5-4-3 2-cyano-2-phenylheptyl ester of sodium hydrogen carbonate, followed by extraction with toluene-4-Sulphonic acid dichloromethane. The organic phase is dried over sodium 55 sulphate, filtered and evaporated. 12.8 g. in the form of a pale 4.1 g (21.5 mmol) of p-toluenesulphonyl chloride and 6 yellow oil are obtained with a yield of 92%. ml of triethylamine are added to a solution containing 4.24 g (19.5 mmol) of 2-hydroxymethyl-2-phenylheptanenitrile 5-2 Methyl (R)-2-(3-1H-imidazol-4-ylpropio in 25 ml of dichloromethane. The reaction medium is left to nylamino)-3-(4-methoxyphenyl)propanoate 60 stir for 15 hours at ambient temperature and then treated with a 1N solution of hydrochloric acid and extracted with 35.5 ml of DIEA are added to a solution containing 13.2 dichloromethane. The organic phase is dried over sodium g (74.7 mmol) of desamino-histidine hydrochloride and 24 sulphate, filtered and evaporated under pressure. A yellow g (74.7 mmol) of TBTU in 100 ml of DMF. After stirring for oil is obtained and precipitated from a 9/1 heptane/diiso 15 minutes at ambient temperature, 14.2 g (67.9 mmol) of 65 propyl ether mixture. The precipitate formed is filtered off methyl (R)-2-amino-3-(4-methoxyphenyl)-propanoate in and rinsed with diisopropyl ether. 5.26 g in the form of a 150 ml of DMF are added. The reaction medium is left to stir beige powder are obtained with a yield of 72%. US 9,630,949 B2 35 36 5-4-43-Pentyl-3-phenylazetidine and then dissolved in methanol, followed by evaporation of the solvents. 441 mg of (R)-2-amino-1-(3-butoxy-3-o-toly 600 mg (15.52 mmol) of powdered LiAlH4 are added laZetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one hydro carefully to a solution containing 5.26 g (14.15 mmol) of chloride are obtained in the form of a white powder with a 2-cyano-2-phenylheptyl ester of toluene-4-Sulphonic acid in 5 yield of 82%. 25 ml of THF under nitrogen. The reaction medium is left to stir for 1 hour at ambient temperature and then treated with 6-3 N (R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1- an aqueous solution of Sodium Sulphate. After stirring for 30 (4-methoxybenzyl)-2-oxoethyl-3-(1H1.2.3 triazol minute at ambient temperature, the salts formed are filtered 4-yl)propionamide off and the filtrate is evaporated under reduced pressure. The 10 residue is taken up in dichloromethane and washed with a 146 mg (0.34 mmol) of (R)-2-amino-1-(3-butoxy-3-o- 1N aqueous Solution of Sodium hydroxide. The organic tolylaZetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one phase is dried over Sodium Sulphate, filtered and evaporated hydrochloride in 2 ml of dimethylformamide are added to a under reduced pressure. 2.90 g in the form of a colourless oil solution of 47 mg (0.34 mmol) of 3-(1H12.3 triazol-4-yl) are obtained and used in the next stage without further 15 propanoic acid, 119 mg (0.37 mmol) of TBTU and 0.15 ml purification. (1.1 mmol) of triethylamine in 2 ml of dimethylformamide. The reaction mixture is stirred for 2 hours at ambient 5-4-5 N—(R)-1-(4-methoxybenzyl)-2-oxo-2-(3- temperature. The reaction is stopped by adding 10 ml of pentyl-3-phenylazetidin-1-yl)ethyl-3-(1H-imidazol water and then extracted with ethyl acetate. The organic 4-yl)propionamide phases are combined, washed with a 1N solution of sodium hydroxide and then a saturated solution of sodium chloride, 70 mg (0.345 mmol) of 3-pentyl-3-phenylazetidine and and dried over sodium sulphate. After filtration, the solvents 100 mg (0.315 mmol) of (R)-2-(3-1H-imidazol-4-ylpropio are evaporated off and the residue is then purified by silica nylamino)-3-(4-methoxyphenyl)propanoic acid are solubi gel chromatography (eluent 90/10 ethyl acetate/heptane). lized in 1 ml of DMF 67 mg (0.345 mmol) of EDC and 47 25 78.6 mg of N (R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1- mg (0.345 mmol) of HOBT are added to this solution. The (4-methoxybenzyl)-2-oxoethyl-3-(1H1.2.3 triazol-4-yl) whole is left to stir for 4 hours and is then treated with 1N propionamide are obtained in the form of a white powder sodium hydroxide and extracted with dichloromethane. The with a yield of 45%. organic phase is dried over Sodium Sulphate, filtered and HPLC: (method M); retention time: 19.03 min, 93%, evaporated under pressure. The crude product obtained is 30 M+H: 520. purified by silica gel chromatography (eluent 9/1 dichlo romethane/methanol). 85 mg of N (R)-1-(4-methoxyben EXAMPLE 7 Zyl)-2-oxo-2-(3-pentyl-3-phenylaZetidin-1-yl)ethyl-3-(1H imidazol-4-yl)propionamide are obtained in the form of a N—(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4- white powder with a yield of 49%. 35 methoxybenzyl)-2-oxoethyl-3-(5-methyl-3H-imida HPLC: (method L); retention time: 22.96 min, 97%, Zol-4-yl)propionamide (compound No. 41: Table I) M-H: 503. 7-13-(5-Methyl-3H-imidazol-4-yl)propanoic acid EXAMPLE 6 40 50 mg of palladium-on-charcoal at 10% are added to 500 N—(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4- mg (2.65 mmol) of 3-(5-methyl-3H-imidazol-4-yl)acrylic methoxybenzyl)-2-oxoethyl-3-(1H-1.2.3 triazol-4- acid chloride in 10 ml of a 0.5N solution of sodium yl)propionamide (compound No. 39: Table I) hydroxide. The reaction mixture is placed under 6 bar of hydrogen pressure and stirred at 80° C. for 72 hours. After 6-1 3-(1H-1.2.3 triazol-4-yl)propanoic acid 45 having filtered off the catalyst through celite, the residue is acidified to pH 2 with hydrochloric acid, concentrated to 39 mg of palladium-on-charcoal at 10% are added to a dryness and taken up in ethanol. The insoluble material is solution containing 390 mg (1.7 mmol) of 3-(1-benzyl-1H filtered off and the filtrate is concentrated to dryness. 102 mg 1.2.3 triazol-4-yl)propanoic acid in 3 ml of methanol. The of 3-(5-methyl-3H-imidazol-4-yl)propanoic acid chloride reaction mixture is placed under 10 bar of hydrogen pressure 50 are obtained in the form of a white powder with a yield of and stirred at 60° C. for 16 hours. After filtration through 16%. celite, the solvents are evaporated off and the residue is purified by silica gel chromatography (eluent 95/5 dichloro 7-2 N (R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1- methane/methanol). 159.8 mg of 3-(1H12.3 triazol-4-yl) (4-methoxybenzyl)-2-oxoethyl-3-(5-methyl-3H propanoic acid are obtained in the form of a white powder 55 imidazol-4-yl)propionamide with a yield of 67%. 146 mg (0.34 mmol) of (R)-2-amino-3-(4-methoxyphe 6-2 (R)-2-amino-3-(4-methoxyphenyl)-1-(3-buty nyl)-1-(3-butyloxy-3-o-tolylazetidin-1-yl)propan-1-one loxy-3-o-tolylaZetidin-1-yl)propan-1-one hydrochlo hydrochloride in solution in 2 ml of dimethylformamide are ride 60 added to a solution of 64 mg (0.34 mmol) of 3-(5-methyl 3H-imidazol-4-yl)propanoic acid chloride, 119 mg (2.34 6 ml of a 4N solution of hydrochloric acid in ethyl acetate mmol) of TBTU and 0.15 ml (1.1 mmol) of triethylamine in are added to 615 mg (1.24 mmol) of tert-butyl (R)-2-(3- 2 ml of dimethylformamide. The reaction mixture is stirred butoxy-3-o-tolylaZetidin-1-yl)-1-(4-methoxybenzyl)-2-oxo for 2 hours at ambient temperature. The reaction is stopped ethylcarbamate (procedure identical to 4-3). The reaction 65 by adding 10 ml of water and then extracted with ethyl mixture is stirred at ambient temperature for 2 hours. The acetate. The organic phases are combined, washed with a 1N precipitate obtained is filtered off, washed with diethyl ether Solution of sodium hydroxide and then a Saturated Solution US 9,630,949 B2 37 38 of sodium chloride, and dried over sodium sulphate. After Sulphate, filtered and evaporated under pressure. An filtration, the solvents are evaporated off and the residue is orangey-yellow oil is obtained and used as it is in the next then purified by silica gel chromatography (eluent 90/10 Stage. dichloromethane/methanol). 154 mg of N—(R)-2-(3-bu toxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxo 9-1-2 ethyl-3-(5-methyl-3H-imidazol-4-yl)propionamide a 2-Hydroxymethyl-2-(4-fluorophenyl)-heptanenitrile obtained in the form of a white powder with a yield of 86%. HPLC: (method M); retention time: 17.65 min, 96%, The crude (4-fluorophenyl)heptanenitrile obtained in M-H: 533. stage 9-1-1 is added to a suspension of 1.62 g of 60% NaH 10 in 50 ml of DMF cooled to 0° C. After stirring for 30 EXAMPLE 8 minutes, 8.9 g (296 mmol) of paraformaldehyde are added portionwise. The reaction medium is left to stir at ambient N—(S)-2-(3-Hydroxy-3-o-tolylazetidin-1-yl)-1-(4- temperature for 3 hours and then hydrolysed with ice and methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl) extracted with dichloromethane. The organic phase is dried propionamide (compound No. 11; Table I) 15 over sodium Sulphate, filtered and evaporated under pres sure. The crude product obtained is purified by silica gel 8-1 3-Hydroxy-3-phenylazetidine trifluoroacetate chromatography (eluent 8/2 heptane/ethyl acetate). 3.85g in the form of a pale yellow oil are obtained with a yield of 1 ml of trifluoroacetic acid is added to a solution con 44%. taining 50 mg (0.19 mmol) of tert-butyl 3-hydroxy-3-phe 9-1-3 2-cyano-2-(4-fluorophenyl)heptyl ester of nylazetidine-1-carboxylate dissolved in 4 ml of dichlo toluene-4-Sulphonic acid romethane. The reaction medium is stirred at ambient temperature for 3 hours and then concentrated. The crude 3.43 g (18.0 mmol) of p-toluenesulphonyl chloride and 5 product obtained is purified by silica gel chromatography 25 ml of triethylamine are added to a solution containing 3.85 (eluent 90/10 dichloromethane/methanol). 36 mg in the form g (16.4 mmol) of 2-hydroxymethyl-2-(4-fluorophenyl)hep of a white powder are obtained with a yield of 68%. tanenitrile in 40 ml of dichloromethane. The reaction medium is left to stir for 15 hours at ambient temperature 8-2 N (S)-2-(3-Hydroxy-3-o-tolylazetidin-1-yl)-1- and then treated with a 1N solution of hydrochloric acid and (4-methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4- 30 extracted with dichloromethane. The organic phase is dried yl)propionamide trifluoroacetate over sodium Sulphate, filtered and evaporated under pres sure. A yellow oil is obtained and precipitated from an 8/2 2 ml of DMF, 106 mg (0.33 mmol) of TBTU and 1 ml of dichloromethane/diisopropyl ether mixture. The precipitate DIEA are added to 105 mg (0.33 mmol) of (R)-2-(3-1H formed is filtered off. 4.4 g in the form of a beige powder are imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)pro 35 obtained with a yield of 65%. panoic acid. The reaction medium is left to stir for 15 minutes at ambient temperature. 36 mg (0.13 mmol) of 9-1-43-Pentyl-3-(4-fluorophenyl)azetidine 3-hydroxy-3-phenylazetidine trifluoroacetate dissolved in 5 ml of a 1/4 DCM/DMF solution are added dropwise and 471 mg (12.4 mmol) of powdered LiAlH4 are added stirred at ambient temperature for 16 hours. A 5% citric acid 40 carefully to a solution containing 4.4 g (11.3 mmol) of solution is added, followed by extraction with dichlorometh 2-cyano-2-(4-fluorophenyl)heptyl ester of toluene-4-Sul ane. The organic phase is washed with a saturated Solution phonic acid in 40 ml of THF under nitrogen. The reaction of potassium hydrogen carbonate. The organic phase is dried medium is left to stir for 1 hour at ambient temperature and and evaporated to dryness. The crude product obtained is then treated with an aqueous solution of Sodium Sulphate. purified by silica gel chromatography (eluent 9/1 dichlo 45 After stirring for 30 minutes at ambient temperature, the romethane/methanol). 6 mg of N (S)-2-(3-hydroxy-3-o- salts formed are filtered off and the filtrate is evaporated tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl-3- under reduced pressure. The residue is taken up in dichlo (1H-imidazol-4-yl)propionamide trifluoroacetate are romethane and washed with a 1N aqueous solution of obtained in the form of a white powder with a yield of 10%. Sodium hydroxide. The organic phase is dried over Sodium HPLC: (method D); retention time: 9.25 min, 89%, M+H: 50 Sulphate, filtered and evaporated under reduced pressure. 463. 2.02 g in the form of a yellow oil are obtained and used in the next stage without further purification. EXAMPLE 9 9-2 Tert-butyl (R)-1-(4-methoxybenzyl)-2-oxo-2- N—(R)-2-3-(4-Fluorophenyl)-3-pentylazetidin-1- 55 (3-pentyl-3-(4-fluorophenyl)azetidin-1-yl)ethylcar yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(1H-imida bamate zol-4-yl)propionamide (compound No. 38; Table I) 606 mg (2.05 mmol) of (R)-2-tert-butoxycarbonylamino 9-1-1 (4-Fluorophenyl)heptanenitrile 3-(4-methoxyphenyl)propionic acid and 500 mg (2.26 60 mmol) of 3-pentyl-3-(4-fluoro-phenyl)azetidine are dis 5 g (37.0 mmol) of (4-fluorophenyl)acetonitrile are added solved in 10 ml of DMF. 473 mg (2.46 mmol) of EDC, 333 dropwise to a suspension of 1.62 g of 60% NaH in 50 ml of mg (2.46 mmol) of HOBt and 0.6 ml (4.5 mmol) of DMF cooled to 0°C. After stirring for 30 minutes at 0°C., triethylamine are added to this solution. The reaction 4.62 mmol (37.0 mmol) of bromopentane are added drop medium is stirred at ambient temperature for 5 h and then wise. The reaction medium is stirred for 16 hours at ambient 65 extracted with dichloromethane. The organic phase is temperature and then treated with ice and extracted with washed with 1N sodium hydroxide and then dried over dichloromethane. The organic phase is dried over sodium magnesium Sulphate, filtered and evaporated. The crude US 9,630,949 B2 39 40 product obtained is purified by silica gel chromatography fied to pH-5 with an aqueous solution of citric acid at 5% (eluent 6/4 heptane/ethyl acetate). 780 mg in the form of a and then extracted with a 1/1 heptane/EtOAc mixture. The white powder are obtained with a yield of 76%. organic phase is dried over MgSO4, filtered and concen trated in a rotary evaporator. 0.58 g of 6-(1-trity1-1H 9-3 (R)-2-Amino-3-(4-methoxyphenyl)-1-(3-pentyl imidazol-4-yl)hex-5-enoic acid in the form of a beige pow 3-(4-fluorophenyl)aZetidin-1-yl)-propan-1-one der are obtained with a yield of 31%. 780 mg (1.56 mmol) of tert-butyl (R)-1-(4-methoxyben 10-1-2 6-(1H-imidazol-4-yl)hex-5-enoic acid Zyl)-2-oxo-2-(3-pentyl-3-(4-fluoro-phenyl)azetidin-1-yl) trifluoroacetate ethylcarbamate are solubilized in 10 ml of dichlorometh 10 ane. 4 ml of trifluoroacetic acid are introduced. The reaction 2 ml of trifluoroacetic acid are added to 0.58 g (1.37 medium is stirred for 1 hour and then concentrated to mmol) of 6-(1-trity1-1H-imidazol-4-yl)hex-5-enoic acid in dryness. The residue is taken up in a 1N aqueous solution of suspension in 8 ml of dichloromethane. After the solvents sodium hydroxide and extracted with dichloromethane and have been evaporated off, the oil obtained is purified on a then the resulting product is dried over magnesium Sulphate, 15 silica column (eluent 8/2 DCM/MeOH). 240 mg of 6-(1H filtered and evaporated. imidazol-4-yl)hex-5-enoic acid trifluoroacetate in the form 590 mg in the form of a colourless resin are obtained with of a yellow oil are isolated with a yield of 60%. a yield of 95%. 10-1-3 6-(1H-imidazol-4-yl)hexanoic acid 9-4 N—(R)-2-3-(4-Fluorophenyl)-3-pentylazeti trifluoroacetate din-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(1H imidazol-4-yl)propionamide 4 ml of acetic acid and 80 mg of palladium-on-charcoal at 10% are added to 218 mg (0.741 mmol) of 6-(1H-imidazol 600 mg (1.86 mmol) of TBTU and 0.45 ml of triethyl 4-yl)hex-5-enoic acid trifluoroacetate. The reaction medium amine are added to a solution containing 330 mg (1.86 25 is placed under a hydrogen atmosphere at atmospheric mmol) of desamino-histidine hydrochloride in 5 ml of pressure. After 13 hours, the reaction medium is filtered dimethylformamide. After stirring for 15 minutes, 590 mg through celite. After the solvents have been evaporated off, (1.55 mmol) of (R)-2-amino-3-(4-methoxyphenyl)-1-(3- 175 mg of 6-(1H-imidazol-4-yl)hexanoic acid trifluoroac pentyl-3-(4-fluorophenyl)aZetidin-1-yl)-propan-1-one dis etate in the form of a yellow oil are obtained with a yield of solved in 5 ml of dimethylformamide are added. The reac 30 80%. tion medium is stirred at ambient temperature for 3 days. The reaction is stopped by adding a 1N solution of sodium 10-2 N-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4- hydroxide and then extracted with a 1/1 heptane/ethyl methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl) acetate mixture. The organic phases are combined and dried hexyramide over sodium sulphate. After filtration, the solvents are 35 evaporated off and the residue is then purified by silica gel 60 mg (0.186 mmol) of TBTU, 0.1 ml (0.715 mmol) of chromatography (eluent 85/15 dichloromethane/methanol). triethylamine and a solution of 79 mg (0.155 mmol) of 490 mg of N (R)-2-3-(4-fluorophenyl)-3-pentylazetidin 2-amino-1-(3-butoxy-3-o-tolylaZetidin-1-yl)-3-(4-methoxy 1-yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4- phenyl)propan-1-one trifluoroacetate (cf. procedure 4-4) in 1 yl)-propionamide are obtained in the form of a white powder 40 ml of DMF are added to 55 mg (0.186 mmol) of 6-(1H with a yield of 61%. imidazol-4-yl)hexanoic acid trifluoroacetate dissolved in 1 HPLC: (method 0); retention time: 15.85 min, 99%, ml of DMF. The reaction medium is stirred for 66 hours and M+H: 521. is extracted with a 1/2 heptane/EtOAc mixture and then washed with 1N sodium hydroxide. The organic phase is EXAMPLE 10 45 dried over MgSO, filtered and concentrated. The crude product obtained is purified on a silica column (eluent 8/2 N-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4- DCM/MeOH). 40.8 mg of N-2-(3-butoxy-3-o-tolylazeti methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl) din-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(1H-imida hexyramide (compound No. 62; Table I) Zol-4-yl)hexyramide are obtained in the form of a white 50 powder with a yield of 47%. 10-1-1 6-(1-Trityl-1H-imidazol-4-yl)hex-5-enoic HPLC: (method V): retention time: 18.05 min, 99%, acid M+H: 561. 13.5 ml (14.3 mmol) of a solution of lithium hexameth EXAMPLE 11 yldisilazane at 1.06 M in THF are added to 3.27 g (7.38 55 mmol) of (4-carboxybutyl)triphenyl-phosphonium bromide N—(R)-1-(4-Methoxybenzyl)-2-oxo-2-(3-pentyl-3- in suspension in 45 ml of THF cooled to -75° C. The phenylazetidin-1-yl)ethyl-3-(3-methyl-3H-imidazol reaction medium is stirred at -75° C. for 20 minutes and then 4-yl)propionamide (compound No. 64; Table I) at 0° C. for 15 minutes. After a return to -75° C., 1.50 g (4.43 mmol) of 1-trity1-1H-imidazole-4-carbaldehyde in 60 11-1-1 5-(2-methoxycarbonylethyl)-1-methyl-3- suspension in 15 ml of THF are introduced. After a return to trityl-3H-imidazol-1-ium iodide ambient temperature, the reaction medium is stirred for 20 hours and then at 90° C. with microwave-heating for 5 720 mg (5.2 mmol) of potassium carbonate and 0.34 ml minutes. The reaction medium is filtered and concentrated in (5.72 mmol) of iodomethane are added to a solution of 1 g a rotary evaporator and then taken up in 1/1 heptane/EtOAc. 65 (2.6 mmol) of N-1-trityl-desamino-histidine in 10 ml of The organic phase is washed with a saturated aqueous DMF. The reaction medium is heated at 60° C. for 3 hours. solution of NaHCO. The aqueous phase obtained is acidi After a return to ambient temperature, the reaction medium US 9,630,949 B2 41 42 is treated with water and acetic acid (to pH 4-5) and in 13 ml of water and 6.5 ml of THF. The medium is placed extracted with dichloromethane. The organic phase is dried under a hydrogen atmosphere at 6 bar of pressure and heated over MgSO filtered and evaporated. The residue obtained at 80° C. After 23 hours, the reaction medium is filtered is purified by silica chromatography (eluent 8/2 DCM/ through celite and the solvents are evaporated off. 0.43 g of MeOH). 970 mg of 5-(2-methoxycarbonylethyl)-1-methyl- 5 3-cyclohexyl-3-pentylazetidine oxalate is obtained with a 3-trityl-3H-imidazol-1-ium iodide are obtained with a yield yield of 64%. of 69%. 11-1-2 Methyl 12-2 tert-Butyl (R)-2-(3-cyclohexyl-3-pentylazeti 3-(3-methyl-3H-imidazol-4-yl)propionate 10 din-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbam trifluoroacetate ate 0.5 ml of trifluoroacetic acid is added to a solution of 200 0.36 g (1.98 mmol) of EDC, 0.25 g (1.85 mmol) of HOBt mg (0.37 mmol) of 5-(2-methoxycarbonylethyl)-1-methyl and 0.51 g (1.73 mmol) of (R)-2-tert-butoxycarbonylamino 3-trityl-3H-imidazol-1-ium iodide in 2 ml of dichlorometh 3-(4-methoxyphenyl)propionic acid are added to 0.43 g ane. The reaction medium is left to stir overnight at ambient (1.69 mmol) of 3-cyclohexyl-3-pentylazetidine oxalate dis temperature and the solvents are evaporated off. The residue solved in 8 ml of DMF. After 5 minutes, 0.9 ml (6.5 mmol) is purified by silica chromatography (eluent 9/1 DCM/ of triethylamine is added. After 1 hour 30 minutes, the MeOH. 80 mg of methyl 3-(3-methyl-3H-imidazol-4-yl) reaction medium is extracted with a 1/1 EtOAc/heptane propionate trifluoroacetate are obtained with a yield of 76%. 20 mixture and washed with a solution of 1N hydrochloric acid, 11-1-33-(3-Methyl-1H-imidazol-4-yl)propionic of 1N sodium hydroxide and of water. The organic phase is acid hydrochloride dried over MgSO, filtered and concentrated. The residue is purified on a silica column (eluent 6/4 heptane/EtOAc). 0.48 2 ml of an aqueous solution of sodium hydroxide at 30% 25 g of tert-butyl (R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)- are added to a solution of 320 mg (1.13 mmol) of methyl 1-(4-methoxybenzyl)-2-oxoethylcarbamate in the form of a 3-(3-methyl-3H-imidazol-4-yl)propionate trifluoroacetate in colourless oil is obtained with a yield of 59%. 10 ml of THF. The reaction medium is stirred at ambient temperature for 16 hours and then cooled to 0° C., and 12-3 (R)-2-Amino-1-(3-cyclohexyl-3-pentylazetidin concentrated hydrochloric acid is added dropwise until pH 1 30 1-yl)-3-(4-methoxyphenyl)propan-1-one is obtained. After filtration, the filtrate is evaporated. 87 mg of 3-(3-methyl-1H-imidazol-4-yl)propionic acid hydrochlo ride are obtained with a yield of 39%. 2.5 ml of trifluoroacetic acid are added, at 0°C., to 0.48 g (0.99 mmol) of tert-butyl (R)-2-(3-cyclohexyl-3-penty 11-2 N—(R)-1-(4-Methoxybenzyl)-2-oxo-2-(3- 35 lazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamate pentyl-3-phenylazetidin-1-yl)ethyl-3-(3-methyl-3H dissolved in 10 ml of dichloromethane. After 2 hours, the imidazol-4-yl)propionamide solvents are evaporated off. The residue is taken up in dichloromethane and washed with 1N sodium hydroxide. 0.17 ml (1.23 mmol) of triethylamine is carefully added to The organic phases are combined, dried over MgSO, fil a solution containing 87 mg (0.45 mmol) of 3-(3-methyl- 40 tered and concentrated. 327 mg of (R)-2-amino-1-(3-cyclo 1H-imidazol-4-yl)propionic acid hydrochloride and 160 mg hexyl-3-pentylaZetidin-1-yl)-3-(4-methoxyphen-yl)propan (0.49 mmol) of TBTU in 1 ml of DMF. After stirring for 60 1-one are obtained with a yield of 86%. minutes at ambient temperature, 200 mg (0.32 mmol) of (R)-2-amino-3-(4-methoxyphenyl)-1-(3-pentyl-3-phe nylazetidin-1-yl)propan-1-one trifluoroacetate (cf. proce- 45 12-4 N (R)-2-(3-Cyclohexyl-3-pentylazetidin-1- dure 9-3) are added and the reaction medium is left to stir for yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(1H-imida three days. The reaction medium is treated with a 2 hep Zol-4-yl)propionamide tane/8 EtOAc mixture and a 1N aqueous solution of sodium hydroxide. The organic phase is dried over MgSO filtered and evaporated. The residue obtained is purified by silica 50 100 mg (0.311 mmol) of TBTU and 0.1 ml (0.715 mmol) chromatography (eluent 9 DCM/1 MeOH). 21 mg of of triethylamine are added to 55 mg (0.311 mmol) of N—(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phe 3-(1H-imidazol-4-yl)propionic acid hydrochloride in 1 ml of nylazetidin-1-yl)ethyl-3-(3-methyl-3H-imidazol-4-yl)pro DMF. After 10 minutes, 99 mg (0.256 mmol) of (R)-2- pionamide are obtained with a yield of 9%. amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4- HPLC: (method W); retention time: 18.04 min, 96%. 55 methoxyphenyl)propan-1-one dissolved in 1 ml of DMF are M-H: 517. added. After stirring for 118 hours at ambient temperature, the reaction medium is extracted with a 1/2 heptane/EtOAc EXAMPLE NO. 12 mixture and washed with 1N sodium hydroxide and a saturated Sodium chloride Solution. The organic phase is N—(R)-2-(3-Cyclohexyl-3-pentylazetidin-1-yl)-1- 60 dried over MgSO filtered and concentrated. The residue is (4-methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4- purified on a silica column (eluent 9/1 DCM/MeOH). 72 mg yl)propionamide (compound No. 66: Table I) of N (R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4- methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl)propio 12-13-Cyclohexyl-3-pentylaZetidine oxalate namide are obtained in the form of a white powder, with a 65 yield of 55%. 254 mg of rhodium-on-alumina at 5% are added to 652 HPLC: (method Y); retention time: 18.34 min, 98%, mg (2.62 mmol) of 3-pentyl-3-phenylaZetidine oxalate (cf.) M-H: 509. US 9,630,949 B2 43 44 EXAMPLE 13 utes, 0.2 ml (1.3 mmol) of triethylamine is added. The reaction medium is then stirred for 23 hours at ambient N—(R)-2-3-butoxy-3-(2-fluorophenyl)-azetidin-1- temperature and extracted with a 1/1 ethyl acetate?heptane yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(1H-imida mixture in the presence of a 1N aqueous Solution of Sodium Zol-4-yl)propionamide hydroxide. The organic phase is washed with a 1N aqueous solution of hydrochloric acid and then with water, dried over 13.1: 3-(2-Fluorophenyl)-3-hydroxy-1-(tert-butoxy magnesium Sulphate, filtered and evaporated. 94 mg of carbonyl)azetidine tert-butyl (R)-2-3-butoxy-3-(2-fluorophenyl)azetidin-1- yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamate a 3.1 ml (6.1 mmol) of a 2M solution of isopropylmagne 10 obtained in the form of a yellow oil with a yield of 58%. sium chloride in tetrahydrofuran are added to a solution of 1.1 g (6.2 mmol) of 1-bromo-2-fluorobenzene in 4 ml of 13.5: (R)-2-Amino-1-3-butoxy-3-(2-fluorophenyl)- tetrahydrofuran, cooled beforehand to -25°C. After stirring aZetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one for 30 minutes at -25°C., a solution of 0.65 g (3.7 mmol) trifluoroacetate of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 7.5 ml of tet 15 rahydrofuran is added. The reaction medium is stirred for 30 1 ml of trifluoroacetic acid is added to a solution of 94 mg min and then a saturated aqueous solution of ammonium (0.2 mmol) of tert-butyl (R)-2-3-butoxy-3-(2-fluorophe chloride is added. The organic compounds are extracted with nyl)azetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcar a 1/1 heptane/ethyl acetate mixture. The organic phase is bamate in 10 ml of dichloromethane, cooled beforehand to dried over magnesium Sulphate and then filtered and evapo 0° C. After stirring for 1 h 30 at ambient temperature, the rated. The crude product is purified by silica gel chroma reaction medium is evaporated off under a stream of nitro tography, elution being carried out with a 5/5 heptane/ethyl gen. 119 mg of (R)-2-amino-1-3-butoxy-3-(2-fluorophenyl) acetate mixture. 135 mg of 3-(2-fluorophenyl)-3-hydroxy aZetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one trifluoro 1-(tert-butoxycarbonyl)-azetidine are obtained in the form acetate are obtained in the form of a yellow oil with a yield of a white solid with a yield of 14%. 25 of 100%. 13.2:3-Butoxy-3-(2-fluorophenyl)-1-(tert-butoxy 13.6: N—(R)-2-3-Butoxy-3-(2-fluorophenyl)azeti carbonyl)azetidine din-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(1H imidazol-4-yl)propionamide 135 mg (0.4 mmol) of 3-(2-fluorophenyl)-3-hydroxy-1- 30 (tert-butoxycarbonyl)azetidine at 80% in 2 ml of dimethyl 81 mg (0.3 mmol) of TBTU and 0.1 ml (0.6 mmol) of formamide are added to a suspension of 65 mg (1.6 mmol) triethylamine are added to a solution of 42 mg (0.25 mmol) of sodium hydride at 60% in 1.5 ml of dimethylformamide, of desamino-histidine hydrochloride in 1 ml of dimethyl under nitrogen, at 0°C. After stirring for 20 minutes at 0°C., formamide. After stirring for 10 minutes, 119 mg (0.2 mmol) 0.2 ml (1.5 mmol) of iodobutane are added. The reaction 35 of (R)-2-amino-1-3-butoxy-3-(2-fluorophenyl)azetidin-1- medium is stirred at ambient temperature for 1 h 30 and is yl)-3-(4-methoxyphenyl)propan-1-one trifluoroacetate are then hydrolysed with water and with a saturated aqueous added and the reaction medium is stirred for 64 hat ambient solution of ammonium chloride and extracted with a 1/2 temperature. After extraction with a 1/2 heptane/ethyl heptane/ethyl acetate mixture. The organic phases are com acetate mixture, the organic phase is washed with 1N bined, washed with water, dried over magnesium Sulphate, 40 aqueous Solution of sodium hydroxide and a saturated filtered and evaporated. The crude product is purified by aqueous solution of sodium chloride, dried over magnesium silica gel chromatography, elution being carried out with an sulphate, filtered and evaporated. The crude product is 8/2 heptane/ethyl acetate mixture. 104 mg of 3-butoxy-3- purified by silica gel chromatography, elution being carried (2-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine a out with a 90/10 dichloromethane/methanol mixture. 59 mg obtained in the form of a yellow oil with a yield of 79%. 45 of N—(R)-2-3-butoxy-3-(2-fluoro-phenyl)azetidin-1-yl)- 1-(4-methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl)pro 13.3:3-Butoxy-3-(2-fluorophenyl)azetidine pionamide are obtained in the form of a white solid with a trifluoroacetate yield of 57%. 'HNMR/DMSO d100° C.: 8–0.78 (t, J=7.2-7.6 Hz,3H): 1 ml of trifluoroacetic acid is added to a solution con 50 1.23 (sext, J=6.8-7.2 Hz, 2H); 1.37 (quint, J=6.4-7.6 Hz, taining 104 mg (0.3 mmol) of 3-butoxy-3-(2-fluorophenyl)- 2H); 2.38-2.42 (m, 2H); 2.68–2.94 (m, 7H); 3.10 (bt, J=5.6- 1-(tert-butoxycarbonyl)azetidine in 3 ml of dichloromethane 6.4, 2H); 4.00-4.40 (m, 4H); 4.50 (q, J=7.2-7.6 Hz, 1H): at 0°C. After stirring for 30 minutes, the reaction medium 6.67-6.80 (m, 3H); 7.09-7.24 (m, 4H); 7.30-7.43 (m, 4H); is evaporated off under a stream of nitrogen. 126 mg of 7.70-7.90 (m, 1H). 3-butoxy-3-(2-fluorophenyl)azetidine trifluoroacetate are 55 obtained in the form of a pale yellow oil with a yield of EXAMPLE 1.4 100%. N—(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4- 13.4: tert-Butyl (R)-2-3-butoxy-3-(2-fluorophe methoxybenzyl)-2-oxoethyl-3-(1-methyl-1H-imida nyl)-azetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl 60 Zol-4-yl)propionamide carbamate 14.1 Methyl (E)-3-(1-methyl-1H-imidazol-4-yl) 68 mg of EDC (0.3 mmol), 45 mg (0.3 mmol) of HOBt acrylate and 100 mg (0.33 mmol) of Boc-D-methoxyphenylalanine are added successively to 126 mg (0.3 mmol) of 3-butoxy 65 1 ml (5.5 mmol) of methyl diethylphosphonoacetate are 3-(2-fluorophenyl)azetidine trifluoroacetate in 1.5 ml of added to a suspension of 220 mg (5.5 mmol) of sodium dimethylformamide under nitrogen. After stirring for 5 min hydride at 60% in 5 ml of tetrahydrofuran cooled to 0°C. US 9,630,949 B2 45 46 After stirring for 1 h, 500 mg (4.5 mmol) of 1-methyl-1H romethane. The organic phase is dried over magnesium imidazole-4-carbaldehyde are added and the mixture is sulphate, filtered and evaporated. The residue obtained is stirred for 4 hours at ambient temperature and then hydro precipitated from 1 heptane/ethyl acetate mixture (9575). lysed with water and extracted with ethyl acetate. The 2.75 g of 2-benzyloxy-4-methoxybenzaldehyde are obtained organic phase is washed with a saturated aqueous Solution of in the form of a white powder with a yield of 86%. Sodium hydrogen carbonate, dried over magnesium Sul phate, filtered and evaporated. The product obtained is 15.2: Methyl (E)-3-(2-benzyloxy-4-methoxyphe precipitated from heptane and filtered. 430 mg of methyl nyl)-2-(tert-butoxycarbonyl)aminoacrylate (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate are obtained in the form of a yellow powder with a yield of 57%. 10 1.8 g (5.4 mmol) of 1,8-diazabicyclo5.4.0]undec-7-ene are added to a solution of 1.8 g. (6.2 mmol) of (+)-Boc-C.- 14.2 3-(1-Methyl-1H-imidazol-4-yl)propanoic acid phosphonoglycine trimethyl ester in 10 ml of dichlorometh hydrochloride ane, cooled beforehand to 0°C. The mixture is stirred for 10 minutes at 0° C. and then a solution of 1 g (4.1 mmol) of 50 mg of palladium-on-charcoal at 10% are added to a 15 2-benzyloxy-4-methoxybenzaldehyde in 5 ml of dichlo solution of 100 mg (0.6 mmol) of methyl (E)-3-(1-methyl romethane is added and the reaction medium is then stirred 1H-imidazol-4-yl)acrylate in 5 ml of a 1N aqueous solution for 18 h at ambient temperature. After the dichloromethane of sodium hydroxide. The reaction medium is flushed with has been evaporated off, the residue is taken up in 50 ml of nitrogen and then stirred under a hydrogen atmosphere for ethyl acetate. The organic phase is washed with a saturated 24 h. After filtration through celite, the filtrate is brought aqueous Solution of ammonium chloride, and water, dried back to pH 2 with a concentrated aqueous Solution of over magnesium Sulphate, filtered and evaporated. The hydrochloric acid, toluene is added, and the medium is residue obtained is purified by silica gel chromatography concentrated to dryness. The residue obtained is taken up in (eluent: 70/30 heptane/ethyl acetate). 1.5 g of methyl (E)- acetone and the precipitated salts are filtered off. The filtrate 3-(2-benzyloxy-4-methoxyphenyl)-2-(tert-butoxycarbo is concentrated. 160 mg of 3-(1-methyl-1H-imidazol-4-yl) 25 nylamino)acrylate are obtained in the form of a beige propanoic acid hydrochloride are obtained in the form of a powder with a yield of 85%. solid with a yield of 32%. 15.3: Methyl 2-tert-butoxycarbonylamino-3-(2-hy 14.3 N (R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1- droxy-4-methoxyphenyl)propanoate (4-methoxybenzyl)-2-oxoethyl-3-(1-methyl-1H 30 imidazol-4-yl)propionamide 350 mg of palladium-on-charcoal at 10% are added to a solution containing 1.5 g (3.5 mmol) of methyl (E)-3-(2- 84 mg (0.3 mmol) of TBTU and 0.1 ml (0.5 mmol) of benzyloxy-4-methoxyphenyl)-2-(tert-butoxycarbo triethylamine are added to a solution of 50 mg (0.3 mmol) nylamino)acrylate in 15 ml of methanol. After stirring for of 3-(1-methyl-1H-imidazol-4-yl)propanoic acid hydrochlo 35 hours under a hydrogen atmosphere, the reaction medium is ride in 2 ml of dimethylformamide. After stirring for 1 h at filtered through celite and the filtrate is evaporated off. 850 ambient temperature, 90 mg (0.2 mmol) of (R)-2-amino-1- mg of methyl 2-tert-butoxycarbonylamino-3-(2-hydroxy-4- (3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)pro methoxyphenyl)-propanoate are obtained in the form of a pan-1-one hydrochloride (prepared as described in Example grey powder with a yield of 74%. 6.2) are added. The reaction medium is stirred at ambient 40 temperature for 72 h, extracted with a 2/8 heptane/ethyl 15.4: 2-tert-Butoxycarbonylamino-3-(2-hydroxy-4- acetate mixture and then washed with a 1N aqueous solution methoxyphenyl)propanoic acid of Sodium hydroxide. The organic phase is dried over magnesium Sulphate, filtered and evaporated. 5 ml of a 1N aqueous solution of sodium hydroxide are The crude product is purified by silica gel chromatogra 45 added to a solution of 850 mg (2.6 mmol) of methyl phy, elution being carried out with a 97/3 dichloromethane/ 2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphe methanol mixture. 22 mg of N—(R)-2-(3-butoxy-3-o-toly nyl)-propanoate in 10 ml of tetrahydrofuran. The reaction lazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(1- medium is stirred for 4 hours at ambient temperature and methyl-1H-imidazol-4-yl)propionamide are obtained in the then a 1N aqueous solution of hydrochloric acid is added form of a beige powder with a yield of 23%. 50 until the pH is 1, and the medium is extracted with dichlo HPLC: (Method U); retention time: 15.28 min, 96.5%, romethane. The organic phase is dried over magnesium M-H: 533 sulphate, filtered and evaporated. 820 mg of 2-tert-butoxy carbonylamino-3-(2-hydroxy-4-methoxyphenyl)propanoic EXAMPLE 1.5 acid are obtained in the form of a beige powder with a 55 quantitative yield. N-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(2-hy droxy-4-methoxybenzyl)-2-oxoethyl-3-(3H-imida 15.5: 3-butoxy-3-o-tolylazetidine trifluoroacetate Zol-4-yl)propionamide trifluoroacetate 1 ml of trifluoroacetic acid is added to a solution con 15.1: 2-Benzyloxy-4-methoxybenzaldehyde 60 taining 500 mg (1.65 mmol) of 3-butoxy-3-o-tolylazetidine 1-(tert-butoxycarbonyl)azetidine dissolved in 5 ml of 160 ml (1.3 mmol) of benzyl bromide and (1.3 mmol) of dichloromethane. The reaction medium is stirred at ambient potassium carbonate are added to a solution of 2 g (1.3 temperature for 3 hours and then concentrated. The crude mmol) of 2-hydroxy-4-methoxybenzaldehyde in 20 ml of product obtained is purified by silica gel chromatography acetone. The mixture is stirred at reflux for 6 hours and then 65 (eluent: 90/10 dichloromethane/methanol). 400 mg in the evaporated. 50 ml of 1 Naqueous solution of sodium hydrox form of a pale yellow powder are obtained with a yield of ide are added and the medium is extracted with dichlo 76%. US 9,630,949 B2 47 48 15.6: tert-Butyl 2-(3-butoxy-3-o-tolylazetidin-1-yl)- dazol-4-yl)propanoic acid and 100 mg (0.3 mmol) of TBTU 1-(2-hydroxy-4-methoxybenzyl)-2-oxoethylcarbam in 2 ml of dimethylformamide. After stirring for 1 hour at ate ambient temperature, 128 mg (0.3 mmol) of (R)-2-amino 1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl) 74 mg (0.4 mmol) of EDC and 52 mg (0.4 mmol) of HOBt 5 propan-1-one hydrochloride (described in Example 6.2) are are added to a solution of 100 mg (0.3 mmol) of 2-tert added and the mixture is stirred for 72 h at ambient tem butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)- perature. A 1N aqueous solution of sodium hydroxide is propanoic acid in 5 ml of dimethylformamide. The mixture added and the medium is extracted with a 20/80 heptane/ is stirred for 15 min and 107 mg (0.3 mmol) of 3-butoxy ethyl acetate mixture. The organic phase is dried over 3-o-tolylazetidine trifluoroacetate are added. After stirring magnesium Sulphate, filtered and concentrated. The crude for a further 15 minutes at ambient temperature, 0.3 ml (1.3 10 product is purified by preparative thin layer chromatography mmol) of diisopropylethylamine is added. The reaction (eluent: 90/10 dichloro-methane/methanol). 17 mg of (S)- medium is stirred for 2 h, and then 10 ml of a 1N aqueous N—(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxy solution of hydrochloric acid are added and the medium is benzyl)-2-oxoethyl-2-hydroxy-3-(1H-imidazol-4-yl)pro extracted with ethyl acetate. The organic phase is washed pionamide are obtained in the form of a white powder with with water and then dried over magnesium sulphate, filtered 15 a yield of 13%. and evaporated. The residue is filtered through silica gel "H NMR/DMSO d 100° C.: 8–0.78 (t, J=7.2 Hz, 3H): (eluent: 70/30 heptane/ethyl acetate). 220 mg of tert-butyl 1.23 (sext, J=7.3 Hz, 2H); 1.36 (quint, J=6.7 Hz, 2H); 2. 12 2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4- (s.3H); 2.55-2.75 (m. 1H); 2.86-2.98 (m, 7H); 3.68 (bs, 3H): methoxybenzyl)-2-oxoethylcarbamate are obtained in the 3.90-4.30 (m, 4H); 4.54 (bq, J–6.4 Hz, 1H); 5.25-5.45 (m, form of a yellow oil and are used crude in the next stage. 1H); 6.55-6.95 (m, 3H); 7.09-7.27 (m, 6H); 7.43 (bs, 1H): 15.7: 2-Amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)- 7.50-7.65 (m, 1H). 3-(2-hydroxy-4-methoxyphenyl)propan-1-one trif EXAMPLE 17 luoroacetate 25 N-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-hy 1 ml of trifluoroacetic acid is added to 220 mg (0.4 mmol) of tert-butyl 2-(3-butoxy-3-o-tolylaZetidin-1-yl)-1-(2-hy droxybenzyl)-2-oxoethyl-3-(3H-imidazol-4-yl)- droxy-4-methoxybenzyl)-2-oxoethylcarbamate in 2 ml of propionamide dichloromethane. After stirring for 1 hour at ambient tem perature, the reaction medium is concentrated under 17.1: tert-Butyl 2-(3-butoxy-3-o-tolylazetidin-1-yl)- vacuum. 250 mg of 2-amino-1-(3-butoxy-3-o-tolylazetidin 30 1-(4-hydroxybenzyl)-2-oxoethylcarbamate 1-yl)-3-(2-hydroxy-4-methoxyphenyl)propan-1-one trifluo roacetate are obtained in the form of a yellow oil with a 205 mg (1.1 mmol) of EDC and then 145 mg (1.1 mmol) quantitative yield. of HOBt are added to a solution of 250 mg (0.9 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-hydroxyphenyl)-pro 15.8: N-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2- 35 panoic acid in 5 ml of dimethylformamide. After stirring for hydroxy-4-methoxybenzyl)-2-oxoethyl-3-(3H-imi 15 minutes at ambient temperature, 300 mg (1.1 mmol) of dazol-4-yl)propionamide trifluoroacetate 3-butoxy-3-o-tolylazetidine trifluoroacetate (described in Example 15.5) and 0.5 ml (3.6 mmol) of triethylamine are 0.25 ml (0.6 mmol) of triethylamine is added to a solution added. The reaction medium is stirred for 2 h at ambient of 90 mg (0.6 mmol) of desamino-histidine and 207 mg (0.6 40 temperature and then a 1N aqueous Solution of hydrochloric mmol) of TBTU in 2 ml of dimethylformamide. After acid is added and the mixture is extracted with ethyl acetate. stirring for 1 h at ambient temperature, 250 mg (0.4 mmol) The organic phase is washed with water, and then dried over of 2-amino-1-(3-butoxy-3-o-tolylaZetidin-1-yl)-3-(3-hy magnesium Sulphate, filtered and evaporated. The residue is droxy-4-methoxyphenyl)propan-1-one trifluoroacetate are purified by silica gel chromatography, elution being carried added and the mixture is stirred for 72 h at ambient tem 45 out with a 60/40 heptane/ethyl acetate mixture. 410 mg of perature. 10 ml of a saturated aqueous solution of sodium 2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)- hydrogen carbonate are then poured into the reaction 2-oxoethyl-3-(3H-imidazol-4-yl)propionamide a medium, which is extracted with a 20/80 heptane/ethyl obtained with a yield of 90%. acetate mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. The product is purified 50 17.2: 2-Amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)- by preparative thin layer chromatography (eluent: 90/10 3-(4-hydroxyphenyl)propan-1-one trifluoroacetate dichloro-methane/methanol). 30 mg of N-2-(3-butoxy-3-o- tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxo 2 ml of trifluoroacetic acid are added to a solution of 410 ethyl-3-(3H-imidazol-4-yl)propionamide trifluoroacetate mg (0.8 mmol) of tert-butyl 2-(3-butoxy-3-o-tolylazetidin are obtained in the form of a beige powder with a yield of 55 1-yl)-1-(4-hydroxybenzyl)-2-oxoethylcarbamate in 5 ml of 11%. dichloromethane. After stirring for 1 hour at ambient tem HPLC: (Method A1): retention time: 14.39 min, 94.2%, perature, the solvent is evaporated off. 440 mg of 2-amino M-H: 535. 1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-hydroxyphenyl) propan-1-one trifluoroacetate are obtained with a EXAMPLE 16 60 quantitative yield. (S)- N (R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1- 17.3: N-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4- (4-methoxybenzyl)-2-oxoethyl-2-hydroxy-3-(1H hydroxybenzyl)-2-oxoethyl-3-(3H-imidazol-4-yl) imidazol-4-yl)propionamide propionamide 65 0.1 ml (0.8 mmol) of triethylamine is added to a solution 0.35 ml (2.6 mmol) of triethylamine are added to a containing 50 mg (0.3 mmol) of (S)-2-hydroxy-3-(1H-imi Solution containing 225 mg (1.3 mmol) of desamino-histi US 9,630,949 B2 49 50 dine hydrochloride and 410 mg (1.3 mmol) of TBTU in 5 ml butoxycarbonylamino-3-(4-methoxyphenyl)-3-oxopropano of DMF. After stirring for 1 hour at ambient temperature, ate in 40 ml of ethanol cooled to -78° C. After stirring for 440 mg (0.9 mmol) of 2-amino-1-(3-butoxy-3-o-tolylazeti 15 minutes, the reaction medium is hydrolysed with a din-1-yl)-3-(4-hydroxyphenyl)propan-1-one trifluoroacetate saturated aqueous Solution of ammonium chloride. The ethanol is evaporated off and the aqueous phase is extracted are added. After stirring for 72 hat ambient temperature, the with dichloromethane. The organic phase is dried over reaction medium is treated with a saturated aqueous Solution magnesium Sulphate, filtered and concentrated. The residue of Sodium hydrogen carbonate and then extracted with a is purified by silica gel chromatography, elution being 20/80 heptane/ethyl acetate mixture. The organic phase is carried out with a 70/30 heptane/ethyl acetate mixture. 3 g dried over magnesium Sulphate, filtered and concentrated. of ethyl 2-tert-butoxycarbonylamino-3-hydroxy-3-(4- The product is purified by preparative thin layer chroma 10 methoxyphenyl)propanoate are obtained in the form of a tography (eluent: 90/10 dichloro-methane/methanol). 205 yellow oil with a yield of 72%. mg of N-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxy 18.4: 2-tert-Butoxycarbonylamino-3-hydroxy-3-(4- benzyl)-2-oxoethyl-3-(3H-imidazol-4-yl)propionamide are methoxyphenyl)propanoic acid obtained in the form of a white powder with a yield of 47%. 15 H NMR/DMSO d 100° C.: 8–0.80 (t, J=7.6 Hz, 3H,); 15 ml of a 1N aqueous solution of sodium hydroxide are 1.22 (m. 2H); 1.36 (quint, J=6.4 Hz, 2H.); 2.23 (s.3H); 2.40 added to a solution containing 3 g (8.4 mmol) of 2-tert (t, J=8.8 Hz, 2H); 2.82-2.70 (m, 4H); 2.97 (t, J=6.4 Hz, 2H): butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)- 4.09 (d. J=10 Hz, 2H); 4.23 (d. J=7.6 Hz, 2H); 4.50 (q, J–7.6 propanoic acid in 40 ml of tetrahydrofuran. The mixture is HZ, 1H); 6.63 (m, 2H); 6.70 (s, 1H); 6.99 (m, 2H): 7.26-7.20 stirred for 4 hours at ambient temperature, treated with a 1N (m, 4H); 7.49 (s, 1H); 7.75 (s, 1H). aqueous Solution of hydrochloric acid until the pH is 1, and then extracted with dichloromethane. The organic phase is EXAMPLE 1.8 dried over magnesium Sulphate, filtered and concentrated. The residue is precipitated from a 1/1 diethyl ether/heptane N-1-(3-Butoxy-3-o-tolylazetidine-1-carbonyl)-2- mixture. 2.2 g of 2-tert-butoxycarbonylamino-3-hydroxy-3- hydroxy-2-(4-methoxyphenyl)ethyl-3-(1H-imida 25 (4-methoxyphenyl)-propanoic acid are obtained in the form Zol-4-yl)propionamide of a white powder with a yield of 84%. 18.5: tert-Butyl (1-(3-butoxy-3-o-tolylazetidine-1- 18.1: Ethyl carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate carbamate hydrochloride 30 740 mg (3.5 mmol) of EDC and 1.2 g (9.6 mmol) of 5 g (18.6 mmol) of ethyl N-(diphenylmethylene)glycinate 4-dimethylaminopyridine are added to a solution of 1 g (3.2 in solution in 20 ml of tetrahydrofuran are added to a mmol) of 2-tert-butoxycarbonylamino-3-hydroxy-3-(4- solution of 18.7 ml (18.6 mmol) of 1N potassium tert methoxyphenyl)propanoic acid, 1.1 g (3.5 mmol) of 3-bu butoxide in 20 ml of tetrahydrofuran cooled to -70° C. After 35 toxy-3-o-tolylazetidine trifluoroacetate and 480 mg (3.5 stirring for 30 minutes, this mixture is added to a solution mmol) of HOAT in 10 ml of dichloromethane cooled to 0° containing 3.2 g (18.6 mmol) of 4-methoxybenzoyl chloride C. After stirring for 24 hours at ambient temperature, the in 20 ml of tetrahydrofuran at -70° C. One hour after the reaction medium is treated with a 1N aqueous solution of addition, the reaction medium is hydrolysed with a 1N sodium hydroxide and then extracted with ethyl acetate. The aqueous solution of hydrochloric acid and concentrated. The 40 organic phase is washed Successively with a 1N aqueous residue is taken up in water and extracted with diethyl ether. solution of hydrochloric acid and water, and then dried over The organic phase is dried over magnesium Sulphate and the magnesium Sulphate, filtered and concentrated. The residue solvent is then evaporated off. 5.5 g of ethyl 2-amino-3-(4- obtained is purified by silica gel chromatography (eluent: methoxyphenyl)-3-oxopropanoate hydrochloride are 60/40 heptane/ethyl acetate). 1.4 g of tert-butyl (1-(3-bu obtained with a quantitative yield. 45 toxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4- methoxyphenyl)ethylcarbamate are obtained in the form of 18.2: Ethyl 2-tert-butoxycarbonylamino-3-(4- a colourless oil with a yield of 87%. methoxyphenyl)-3-oxopropanoate 18.6: 2-Amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)- 3-hydroxy-3-(4-methoxyphenyl)propan-1-one trif 4 g (18.3 mmol) of di-tert-butyl dicarbonate and 2.6 ml 50 (18.3 mmol) of triethylamine are added to 5 g (18.3 mmol) luoroacetate of ethyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate 10 ml of trifluoroacetic acid are added to a solution hydrochloride dissolved in 60 ml of tetrahydrofuran at 0°C. containing 1.4 g (2.8 mmol) of tert-butyl (1-(3-butoxy-3-o- After stirring for 3 hours at ambient temperature, the mixture tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl) is treated with water and extracted with ethyl acetate. The 55 ethylcarbamate in 20 ml of dichloromethane. After stirring organic phase is washed with a 1N aqueous solution of for 1 hour at ambient temperature, the reaction medium is Sodium hydrogen Sulphate, and water and then dried over concentrated. 1.5 g of 2-amino-1-(3-butoxy-3-o-tolylazeti magnesium Sulphate, filtered and concentrated. 4.1 g of din-1-yl)-3-hydroxy-3-(4-methoxyphenyl)propan-1-one tri ethyl 2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-3- fluoroacetate are obtained in the form of a beige powder with oxopropanoate are obtained in the form of a yellow oil with 60 a quantitative yield. a yield of 66%. 18.7: N-1-(3-Butoxy-3-o-tolylazetidine-1-carbo 18.3: Ethyl 2-tert-butoxycarbonylamino-3-hydroxy nyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl-3-(1H 3-(4-methoxyphenyl)propanoate imidazol-4-yl)propionamide 65 461 mg (0.7 mmol) of sodium borohydride are carefully 0.2 ml (1.5 mmol) of triethylamine is added to a solution added to a solution of 4.1 mg (12.2 mmol) of ethyl 2-tert containing 100 mg (0.6 mmol) of desamino-histidine hydro US 9,630,949 B2 51 52 chloride and 180 mg (0.6 mmol) of TBTU in 5 ml of yl)propanoic acid and 1.0 g (3 mmol) of TBTU in 2 ml of dimethylformamide. After stirring for 1 h at ambient tem dimethylformamide. After stirring for 1 h at ambient tem perature, 200 mg (0.4 mmol) of 2-amino-1-(3-butoxy-3-o- perature, 1.5 g (3 mmol) of (R)-2-amino-1-(3-butoxy-3-o- tolylaZetidin-1-yl)-3-hydroxy-3-(4-methoxyphenyl)propan tolylaZetidin-1-yl)-3-(4-methoxyphenyl)-propan-1-one 1-one trifluoroacetate are added. The reaction medium is hydrochloride (prepared as described in Example 6.2) are added. The reaction medium is stirred for 24 h at ambient stirred for 48 h at ambient temperature and then treated with temperature, treated with a 1N aqueous solution of Sodium a 1N aqueous Solution of Sodium hydroxide and extracted hydroxide and extracted with a 20/80 heptane/ethyl acetate with a 20/80 heptane/ethyl acetate mixture. The organic mixture. The organic phase is dried over magnesium Sul phase is dried over magnesium Sulphate, filtered and con phate, filtered and concentrated. The product is purified by centrated. The residue is purified by preparative thin layer 10 silica gel chromatography, elution being carried out with a chromatography (eluent: 90/10 dichloromethane/methanol). 97/3 dichloromethane/methanol mixture. 72 mg of N (R)- 80 mg of N-1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2- 2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)- hydroxy-2-(4-methoxyphenyl)ethyl-3-(1H-imidazol-4-yl) 2-oxoethyl-3-hydroxy-3-(1H-imidazol-4-yl)propionamide propionamide are obtained in the form of a beige powder are obtained in the form of a beige powder with a yield of with a yield of 39%. 15 5%. "H NMR/DMSO d 100° C.: 8–0.78 (t, J=7.6 Hz, 3H): "H NMR/DMSO d 100° C.: 8–0.78 (t, J=7.2 Hz, 3H): 1.23 (sext, J=7.3 Hz, 2H); 1.37 (quint, J=6.7 Hz, 2H); 2.25 1.23 (sext, J=7.3 Hz, 2H); 1.36 (quint, J=6.7 Hz, 2H); 2.21 (s, 3H); 2.40-2.50 (m, 2H); 2.75 (m, 2H); 3.01 (t, (s.3H); 2.55-2.65 (m, 2H); 2.70-2.90 (m, 3H); 2.90-3.00 (m, J=12 Hz, 2H); 3.70-3.80 (bs, 3H); 4.10-4.50 (m, 6H); 4.55 2H); 3.68 (bs, 3H); 3.90-4.40 (m, 5H); 4.54 (bq, J–7.2 Hz, (m. 1H); 4.73 (m, 1H); 6.82 (m, 2H); 7.10-7.40 (m, 8H): 1H); 4.92 (bs, 1H); 6.60-6.80 (m, 3H); 7.00-7.30 (m, 6H): 7.86 (m, 1H). 7.46 (bs, 1H); 7.81 (bs, 1H). EXAMPLE 19 EXAMPLE 20 N—(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1-yl)- N—(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4- 25 methoxybenzyl)-2-oxoethyl-3-hydroxy-3-(1H-imi 1-(4-methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4- dazol-4-yl)propionamide yl)propionamide 20.1: tert-Butyl 19.1: tert-Butyl 3-hydroxy-3-(1-trityl-1H-imidazol 3-hydroxy-3-o-tolylazetidine-1-carboxylate 4-yl)propanoate 30 60 ml (60 mmol) of 1M ortho-tolylmagnesium chloride in 2.15 ml (14.5 mmol) of tert-butyl bromoacetate are added THF are added dropwise to a solution of 7.4 g (43 mmol) of dropwise to a solution of 1 g (15.3 mmol) of zinc 20 mesh tert-butyl 3-oxoazetidine-1-carboxylate in 60 ml of tetrahy in 20 ml of tetrahydrofuran, stirred for 15 min with a few drofuran cooled to -78°C. After stirring for 1 h at ambient drops of trimethylsilane chloride. After stirring for 15 min 35 temperature, the mixture is hydrolysed with a saturated utes at ambient temperature, the temperature of the mixture aqueous solution of ammonium chloride and then extracted is kept at 50° C. for 1 hour. After a return to ambient with ethyl acetate. The organic phase is dried over sodium temperature, a solution containing 1.2 g (3.6 mmol) of sulphate, filtered and concentrated. The beige solid obtained 1-trityl-1H-imidazole-4-carbaldehyde in 10 ml of THF is is purified by silica gel chromatography, elution being added. The reaction medium is stirred for 6 h at ambient 40 carried out with a 50/50 heptane/ethyl acetate mixture. 8.9 g, temperature, and then treated with a 1N aqueous Solution of of tert-butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate are hydrochloric acid and extracted with ethyl acetate. The obtained in the form of a white solid with a yield of 79%. organic phase is washed Successively with a saturated aque ous solution of sodium hydrogen carbonate and then with 20.2: tert-Butyl water. After drying over magnesium Sulphate and filtration, 45 3-but-2-ynyloxy-3-o-tolylazetidine-1-carboxylate the solvent is evaporated off. The residue obtained is pre cipitated from diisopropyl ether and filtered off. 1.4 g of 1 ml (11.4 mmol) of 1-bromo-2-butyne is added to a tert-butyl 3-hydroxy-3-(1-trity1-1H-imidazol-4-yl)propano suspension of 1.4 g (34.2 mmol) of sodium hydride at 60% ate are obtained in the form of a white powder with a yield in 14 ml of dimethylformamide cooled beforehand to 0°C. of 84%. 50 After stirring for 1 h, 3 g (11.4 mmol) of tert-butyl 3-hy droxy-3-o-tolylazetidine-1-carboxylate in 20 ml of dimeth 19.2: 3-Hydroxy-3-(1H-imidazol-4-yl)propanoic ylformamide are added dropwise and the reaction mixture is acid then stirred for 1 h 30. After hydrolysis with water and with a Saturated aqueous solution of ammonium chloride, the 3 ml of trifluoroacetic acid are added to a solution of 1.4 55 reaction medium is extracted with a 1/1 heptane/ethyl g (3 mmol) of tert-butyl 3-hydroxy-3-(1-trity1-1H-imidazol acetate mixture. The organic phase is dried over sodium 4-yl)propanoate in 7 ml of dichloromethane. After stirring sulphate, filtered and concentrated. The residue obtained is for 4 hours at ambient temperature, the reaction medium is purified by silica gel chromatography, elution being carried concentrated. 0.5g of crude product is used directly in the out with a 80/20 heptane/ethyl acetate mixture. 2.9 g of neXt Stage. 60 tert-butyl 3-but-2-ynyloxy-3-o-tolylazetidine-1-carboxylate are obtained in the form of a yellow oil with a yield of 81%. 19.3: N (R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)- 1-(4-methoxybenzyl)-2-oxoethyl-3-hydroxy-3-(1H 20.3: 3-But-2-ynyloxy-3-o-tolylazetidine imidazol-4-yl)propionamide hydrochloride 65 0.5 ml (3 mmol) of triethylamine are added to a solution 2.8 g. (9 mmol) of tert-butyl 3-but-2-ynyloxy-3-o-toly containing 0.5 g (3 mmol) of 3-hydroxy-3-(1H-imidazol-4- lazetidine-1-carboxylate are solubilised in 40 ml (120 mmol) US 9,630,949 B2 53 54 of a 3M solution of hydrochloric acid in ethyl acetate. After 4.10-440 (m, 4H); 4.52(q, J–7.2-8.0 Hz, 1H); 6.67-6.85 (m, stirring for 1 hour 30 minutes at ambient temperature, the 3H): 705-7.15 (m, 2H); 7.18-7.29 (m, 4H); 7.41 (s, 1H): reaction medium is concentrated under vacuum. 2.2 g of 7.75-7.85 (m, 1H). 3-but-2-ynyloxy-3-o-tolylazetidine hydrochloride are obtained in the form of a beige solid with a yield of 96%. 5 EXAMPLE 21 N—(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1-yl)- 20.4: tert-Butyl (R)-2-(3-but-2-ynyloxy-3-o-toly 1-(4-methoxybenzyl)-2-oxoethyl-3-(5-methyl-1H lazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl 10 imidazol-4-yl)propionamide carbamate 1.9 g (10.2 mmol) of EDC, 1.4 g (10.2 mmol) of HOBt 21.1: 3-(5-Methyl-1H-imidazol-4-yl)propanoic acid and 3.8 ml (27.2 mmol) of triethylamine are added to a hydrochloride Solution containing 2.7 g (9.2 mmol) of Boc-D-methoxy phenylalanine in 55 ml of dimethylformamide. After stirring 60 mg of palladium-on-charcoal at 10% are added to a solution of 387 mg (1.1 mmol) of (E)-3-(5-methyl-1H for 1 h, a solution of 2.2 g (8.7 mmol) of 3-but-2-ynyloxy imidazol-4-yl)acrylic acid hydrochloride in a 1/1 tetrahy 3-o-tolylazetidine hydrochloride in 35 ml of dimethylfor drofuran/water mixture. The reaction medium is placed mamide is added to the mixture. The reaction medium is under a hydrogen atmosphere and stirred for 19 h, and then then stirred for 38 hours at ambient temperature. It is filtered through celite. The filtrate is concentrated under subsequently extracted with a 1/1 heptane/ethyl acetate vacuum. The residue obtained is taken up in a heptane/ mixture. The organic phase is washed Successively with a diisopropyl ether mixture with stirring for 2 h. The white 1N aqueous solution of sodium hydroxide and then with a precipitate formed is filtered off and then dried. 326 mg of 1Naqueous solution of hydrochloric acid, dried over sodium 3-(5-methyl-1H-imidazol-4-yl)propanoic acid hydrochlo sulphate, filtered and concentrated. The residue obtained is 25 ride are obtained in the form of a white solid with a yield of purified by silica gel chromatography, elution being carried 83%. out with a 60/40 heptane/ethyl acetate mixture. 1.8 g of tert-butyl (R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)- 21.2: N (R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin 30 1-yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(5-methyl 1-(4-methoxybenzyl)-2-oxoethylcarbamate are obtained in 1H-imidazol-4-yl)propionamide the form of a white solid with a yield of 41%. 20.5: (R)-2-Amino-1-(3-but-2-ynyloxy-3-o-tolylaze 389 mg (1.2 mmol) of TBTU and 0.5 ml (3.7 mmol) of tidin-1-yl)-3-(4-methoxyphenyl)propan-1-one triethylamine are added to a solution containing 229 mg (1.2 35 mmol) of 3-(5-methyl-1H-imidazol-4-yl)propanoic acid 1.7 g (3.5 mmol) of tert-butyl (R)-2-(3-but-2-ynyloxy hydrochloride in 4 ml of dimethylformamide. After 5 min, 3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl 402 mg (0.9 mmol) of (R)-2-amino-1-(3-but-2-ynyloxy-3- carbamate are solubilised in 45 ml (135 mmol) of a 3M o-tolylaZetidin-1-yl)-3-(4-methoxyphenyl)-propan-1-one solution of hydrochloric acid in ethyl acetate. After stirring dissolved in 4 ml of dimethylformamide are added. The for 3 hat ambient temperature, the mixture is concentrated. 40 reaction medium is then stirred for 90 h at ambient tem 1.6 g of (R)-2-amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin perature, and then a 1N aqueous solution of sodium hydrox 1-yl)-3-(4-methoxyphenyl)-propan-1-one are obtained in ide is added and the medium is extracted with a 1/1 the form of a beige solid with a quantitative yield. heptane/ethyl acetate mixture. The organic phase is washed with a saturated aqueous solution of Sodium chloride and 20.6: N (R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin 45 then dried over sodium sulphate, filtered and concentrated. 1-yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(1H-imi The residue obtained is purified by Silica gel chromatogra dazol-4-yl)propionamide phy, elution being carried out with an 88/12 dichlorometh ane/methanol mixture. 45 mg of N—(R)-2-(3-but-2-yny 732 mg (2.3 mmol) of TBTU and 1 ml (7 mmol) of loxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2- triethylamine are added to a solution of 408 mg (2.3 mmol) so oxoethyl-3-(5-methyl-1H-imidazol-4-yl)propionamide are of desamino-histidine hydrochloride in 6 ml of dimethyl obtained in the form of a white solid with a yield of 9%. formamide. After stirring for 10 min, 751 mg (1.8 mmol) of H NMR/DMSO d100° C.: 8=1.74 (s.3H); 2.06 (s.3H): (R)-2-amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-3- 2.21 (s, 3H); 2.30-2.45 (m, 2H); 2.55-2.70 (m, 2H); 2.74 (4-methoxyphenyl)propan-1-one in 6 ml of dimethylforma 3.10 (m, 2H); 3.55-3.80 (m, 5H); 4.00-4.45 (m, 4H); 4.50 mide are added. The reaction medium is stirred for 115 hours 55 (bq, J=8.0 Hz, 1H); 6.65-6.85 (m, 2H); 7.00-7.15 (m, 2H): at ambient temperature and then a 1N aqueous Solution of 7.15-7.35 (m, 5H); 7.75-7.90 (m, 1H). sodium hydroxide is added and the medium is extracted with Table I illustrates the examples of compounds according a 1/1 heptane/ethyl acetate mixture. The organic phase is to the invention. dried over sodium sulphate, filtered and concentrated. The In this table: residue obtained is purified by Silica gel chromatography, 60 elution being carried out with a 90/10 dichloro-methane/ in the “salt’ column, TFA represents a compound in methanol mixture. 362 mg of N (R)-2-(3-but-2-ynyloxy trifluoroacetate form, 3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl-3- purity (%) represents the purity of the product, obtained (1H-imidazol-4-yl)propionamide are obtained in the form of by HPLC, a white solid with a yield of 40%. 65 mass (M--H) represents the mass+1 (hydrogen) derived H NMR/DMSO d 100° C.: 8=1.74 (bs, 3H); 2.21 (s, from the mass spectrum, associated with the HPLC 3H); 2.39-2.43 (m, 2H); 2.69-3.10 (m, 4H); 3.68 (m, 5H): peak of the expected product.
US 9,630,949 B2 63 64 TABLE I-continued 1H); 6.70-6.85 (m, 2H); 7.05-7.15 (m, 2H): 7.18-7.28 (m, 5H); 7.75-7.85 (m, 1H). 80 8 = 1.43 (s, 3H); 1.63 (s, 3H); 2.06 (s, 3H); 2.22 (s, 3H): 2.36 (bt, J = 6.8-7.2 Hz, 2H); 2.62 (bt, J = 7.2 Hz, 2H): 2.76-3.10 (m, 2H); 3.52 (d, J = 6.8 Hz, 2H); 3.68 (bs, 3H): 4.00-445 (m, 4H); 4.52 (q, J = 7.2-7.6 Hz, 1H); 5.12 (bt, J = 6.8-8.0 Hz, 1H); 6.65-6.90 (m, 2H); 7.09-7.18 (m, 2H): 7.19-7.27 (m, 4H); 7.30 (s, 1H); 7.70-7.85 (m, 1H). (mixture of conformers)
EXAMPLE 22 -continued
Example No. EC50 hMC1R (nM) EC50 hMC4R (nM) Transactivation Test: Melanocortin Receptors 15 2O 120 4OOO Cells: 21 4OOO IA HEK293 lines are transfected with the pCRE-Luc and 22 120 1OOOO 23 60 1OOO hMC1R, hMC3R, hMC4R or hMC5R vectors. The cells are 24 250 4OOO cultured at 37° C., 5% CO, in DMEM medium supple 25 1OOO 8000 mented with 10% of foetal calf serum. 26 500 4OOO 27 500 8000 Principle of the Test: 28 1OOO 8000 In the presence of an activator (agonist), the melanocortin 29 1OOO IA receptor will activate the cAMP pathway which, via the 31 500 4OOO 25 32 1OOO 4OOO CRE-Luc vector, will result in the synthesis of luciferase. 33 500 2OOO After the addition of a lysis buffer containing a luminescent 34 1OOO 2OOO substrate for luciferase, it will be possible to measure the 35 500 2OOO luminescence proportional to the degree of activation or of 36 1OOO 3OOO inhibition of the receptor. 37 250 2OOO Product Test: 38 250 NT 30 39 8000 2OOO The products are solubilized at 10 mM in DMSO. They 40 8000 500 are tested in the form of dose-response at a final DMSO 41 120 1OOO concentration of 0.1%. The range comprising 10 points and 42 60 30 one Zero begins at 10 uM with 4-fold dilutions. For testing 43 30 NT agonists, the products are tested alone. For determining the 44 30 NT 35 45 2OOO 2OOO behaviour of antagonists, the products of interest are tested 46 1OOO 4OOO in the presence of 1 nM NDP-MSH (reference agonist). The 47 500 4OOO cells are seeded at a rate of 5000 cells per well (384 well 48 4OOO 500 plate) in serum-free DMEM medium, and incubated over 49 15 2OOO night at 37° C., 5% CO. 50 1OOO 500 40 51 1OOO IA The products and the reference ligand (NDP-MSH) are 52 2OOO 250 added the following day, and the plates are again incubated 53 1OOO 4OOO for 6 hat 37° C., 5% CO. After the addition of lysis buffer S4 250 NT containing luciferin, the plates are read on a Top-Count 55 120 1OOO instrument. The results are standardized as % activity using 56 4OOO 8000 45 57 1OOO 4OOO the 100% (cells+NDP-MSH at 10 nM) and 0% (cells alone) 58 2OOO 500 controls. An EC50 is calculated for each product using the 59 NT IA XLFit software. The results are given in nM. 60 120 100 61 120 100 62 4OOO 500 63 500 500 Example No. EC50 hMC1R (nM) EC50 hMC4R (nM) 50 64 2OOO 500 65 LA 100 1 500 NT 66 250 250 2 30 8000 67 500 500 3 60 4OOO 68 60 2OOO 4 250 4OOO 69 1OOO 8000 5 4000 8000 55 70 4OOO IA 6 2OOO 8000 71 60 4OOO 7 500 4OOO 72 2OOO IA 8 120 4OOO 73 500 8000 9 120 1OOO 74 250 8000 10 8OOO IA 75 60 4OOO 11 4000 8000 12 8OOO IA 60 76 30 4OOO 13 2OOO 1SOOO 77 120 2OOO 14 2OOO 1SOOO 78 120 2OOO 15 120 4OOO 79 15 1OOO 16 2OOO 1SOOO 8O 15 4OOO 17 250 8000 18 8OOO 8000 65 LA: inactive 1 9 2OOO 120 NT: not tested US 9,630,949 B2 65 66 What is claimed is: marins, halogenated Salicylanilides, local Sulphamides, 1. A method for treating a disorder, disease, or dysfunction psoralens, tetracyclines, systemic Sulphamides, phe selected from the group consisting of: nothiazines, nalidixic acid, and tricyclic antidepres an inflammatory disease of the digestive tract selected Sants, from the group consisting of irritable bowel syndrome, 5 or for inhibiting a dermatosis attack with photosensitivity ulcerative colitis, Crohn's disease, pancreatitis, hepa which is: titis, an inflammatory pathological condition of the a photoaggravated dermatosis selected from the group bladder and gastritis; consisting of lupus erythematosus, recurrent herpes, an inflammatory disease of the locomotor system selected congenital poikilodermal and telangiectasic conditions from the group consisting of rheumatoid arthritis, 10 with photosensitivity selected from the group consist osteoarthritis, osteoporosis, traumatic arthritis, post ing of Bloom syndrome, Cockayne syndrome and infectious arthritis, muscle degeneration and dermato Rothmund-Thomson syndrome, actinic lichen planus, myositis; actinic granuloma, disseminated Superficial actinic glomerulonephritis; porokeratosis, acne rosacea, juvenile acne, bullous der an inflammatory disease of the cardiac system selected 15 matosis, Darier's disease, cutaneous lymphoma, pso from the group consisting of pericarditis, myocarditis, riasis, atopic dermatitis, contact eczema, follicular atherosclerosis, transplant atherosclerosis, peripheral mucinosis, erythema multiforme, fixed drug erythema, vascular disease, inflammatory vasculardisease, inter lymphocytoma cutis, reticular erythema with mucino mittent claudication, restenosis, stroke, transient sis and melasma, ischaemic attack, myocardial ischaemia, myocardial a dermatosis with photosensitivity caused by deficiency of infarction, hypertension, hyperlipidaemia, coronary the protection system with melanin formation or dis artery disease, unstable angina, thrombosis, platelet tribution anomalies selected from the group consisting aggregation induced by thrombin and atheroma plaque of oculocutaneous albinism, phenylketonuria, anterior formation; hypophyseal insufficiency, vitiligo, and piebaldism and an inflammatory disease of the respiratory and ENT 25 with DNA repair system deficiency selected from the system selected from the group consisting of asthma, group consisting of Xeroderma pigmentosum and Coc acute respiratory distress syndrome, hayfever, allergic kayne syndrome, rhinitis, chronic obstructive pulmonary disease and a dermatosis with photosensitivity caused by metabolic allergies; anomalies which is a cutaneous porphyria selected from the an inflammatory disease of the central nervous system 30 group consisting of late cutaneous porphyria, mixed por Selected from the group consisting of Alzheimer's phyria, erythropoietic protoporphyria, congenital erythro disease, other form of dementia, Parkinson's disease, poietic porphyria Günther's disease and erythropoietic Creutzfeldt Jacob disease, multiple sclerosis and men coproporphyria, or which is pellagra or a pellagroid ery ingitis; thema or a tryptophan metabolism disorder; an inflammatory skin disease selected from the group 35 an idiopathic photodermatosis attack selected from the consisting of urticaria, Scleroderma, contact dermatitis, group consisting of polymorphous light eruption, atopic dermatitis, psoriasis, ichthyosis, acne and other benign Summer light eruption, actinic prurigo, persis forms of folliculitis, rosacea and alopecia; tent photosensitization selected from the group consist an autoimmune disease selected from the group consisting ing of actino-reticulosis, chronic actinic dermatosis, of lupus erythematosus, a thyroid condition, an auto 40 and photosensitive eczema, Solar urticaria, hydroa vac immune disease of the adrenal gland, autoimmune ciniforme, juvenile spring eruption and Solar pruritus, gastritis, vitiligo and alopecia areata; or for modulating the color of the skin or of the hair and an inflammation accompanying bacterial, viral or fungal of body hairs by causing the skin to tan by increasing infections selected from the group consisting of tuber melanin synthesis or causing it to bleach by interfering culosis, septicaemia, fever, HIV, herpes, cytomegalo 45 with melanin synthesis, by preventing hair and body virus, hepatitis A, hepatitis B and hepatitis C; hair from turning white or grey; or for modifying the a transplant or graft rejection selected from the group color of the hair and body hairs in cosmetic indications; consisting of kidney, liver, heart, lung, pancreas, bone or for modulating sebaceous function in treating: marrow, cornea, intestine and skin; a condition with hyperseborrhoea selected from the group pain selected from the group consisting of post-operative 50 consisting of acne, Seborrhoeic dermatitis, greasy skin pain, neuromuscular pain, headache, cancer-related and greasy hair, hyperseborrhoea in Parkinson's and pain, dental pain and osteoarticular pain; epilepsy, and hyperandrogenism; a disease with a pigmentation disorder selected from the a condition with decreasing sebaceous secretion selected group consisting of a benign dermatosis selected from from the group consisting of Xerosis and dry skin; the group consisting of vitiligo, albinism, melasma, 55 benign and malignant sebocyte and sebaceous gland pro lentigines, freckles, melanocytic naevi and post inflam liferation; matory pigmentation; and a pigmented tumor selected an inflammatory condition of the pilosebaceous follicle from the group consisting of melanoma and local selected from the group consisting of acne, boils, carbuncles metastases, regional metastases and systemic metasta and folliculitis; ses thereof 60 a neurodegenerative disorder selected from the group or a method for inhibiting: consisting of depression, anxiety, an obsessive-com actinic erythema, skin ageing, a skincancer, and a disease pulsive disorder, a neurosis, a psychosis, insomnia, in which Sunlight accelerates onset selected from the sleep apnea, and drug abuse; group consisting of Xeroderma pigmentosum, basal cell a male sexual dysfunction selected from the group con naevus syndrome and familial melanoma; 65 sisting of impotence, loss of libido, and erectile dys a photodermatosis due to an exogenous photosensitizing function; a female sexual dysfunction selected from the agent selected from the group consisting of furocou group consisting of sexual stimulation disorders, or
US 9,630,949 B2 69 70 N-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxyben culosis, septicaemia, fever, HIV, herpes, cytomegalo Zyl)-2-oxoethyl-3-(3H-imidazol-4-yl)propionamide: virus, hepatitis A, hepatitis B and hepatitis C; N—(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- a transplant or graft rejection selected from the group methoxybenzyl)-2-oxoethyl-3-hydroxy-3-(1H-imida consisting of kidney, liver, heart, lung, pancreas, bone Zol-4-yl)propionamide: marrow, cornea, intestine and skin; N—(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1- pain selected from the group consisting of post-operative (4-methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl) pain, neuromuscular pain, headache, cancer-related propionamide; pain, dental pain and osteoarticular pain; N—(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1- a disease with a pigmentation disorder selected from the (4-methoxybenzyl)-2-oxoethyl-3-(5-methyl-1H-imi 10 group consisting of a benign dermatosis selected from the dazol-4-yl)propionamide; group consisting of vitiligo, albinism, melasma, lentigines, N—(R)-2-(3-cyclohexylmethoxy-3-o-tolylazetidin-1- freckles, melanocytic naevi and post inflammatory pigmen yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(1H-imidazol tation; and a pigmented tumor selected from the group 4-yl)propionamide; consisting of melanoma and local metastases, regional 3-(1H-imidazol-4-yl)-N-((R)-1-(4-methoxybenzyl)-2- 15 metastases and systemic metastases thereof; oxo-2-3-o-tolyl-3-(4,4,4-trifluorobutoxy)azetidin-1- or a method for inhibiting: ylethylpropionamide; actinic erythema, skin ageing, a skincancer, and a disease in N—(R)-2-(3-cyclobutylmethoxy-3-o-tolylaZetidin-1- which Sunlight accelerates onset selected from the group yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(5-methyl-1H consisting of Xeroderma pigmentosum, basal cell naevus imidazol-4-yl)propionamide; and syndrome and familial melanoma; N—{(R)-1-(4-methoxybenzyl)-2-3-(3-methylbut-2-eny a photodermatosis due to an exogenous photosensitizing loxy)-3-o-tolylazetidin-1-yl)-2-oxoethyl-3-(5-methyl agent selected from the group consisting of furocou 1H-imidazol-4-ylpropionamide; marins, halogenated Salicylanilides, local Sulphamides, and the salts and enantiomers thereof. psoralens, tetracyclines, systemic Sulphamides, phe 2. A method for treating a disorder, disease, or dysfunction 25 nothiazines, nalidixic acid, and tricyclic antidepres selected from the group consisting of: Sants, an inflammatory disease of the digestive tract selected or for inhibiting a dermatosis attack with photosensitivity from the group consisting of irritable bowel syndrome, which is: ulcerative colitis, Crohn's disease, pancreatitis, hepa a photoaggravated dermatosis selected from the group titis, an inflammatory pathological condition of the 30 consisting of lupus erythematosus, recurrent herpes, bladder and gastritis; congenital poikilodermal and telangiectasic conditions an inflammatory disease of the locomotor system selected with photosensitivity selected from the group consist from the group consisting of rheumatoid arthritis, ing of Bloom syndrome, Cockayne syndrome and osteoarthritis, osteoporosis, traumatic arthritis, post Rothmund-Thomson syndrome, actinic lichen planus, infectious arthritis, muscle degeneration and dermato 35 actinic granuloma, disseminated Superficial actinic myositis; porokeratosis, acne rosacea, juvenile acne, bullous der glomerulonephritis; matosis, Darier's disease, cutaneous lymphoma, pso an inflammatory disease of the cardiac system selected riasis, atopic dermatitis, contact eczema, follicular from the group consisting of pericarditis, myocarditis, mucinosis, erythema multiforme, fixed drug erythema, atherosclerosis, transplant atherosclerosis, peripheral 40 lymphocytoma cutis, reticular erythema with mucino vascular disease, inflammatory vasculardisease, inter sis and melasma, mittent claudication restenosis, stroke, transient ischae a dermatosis with photosensitivity caused by deficiency of mic attack, myocardial ischaemia, myocardial infarc the protection system with melanin formation or dis tion, hypertension, hyperlipidaemia, coronary artery tribution anomalies selected from the group consisting disease, unstable angina, thrombosis, platelet aggrega 45 of oculocutaneous albinism, phenylketonuria, anterior tion induced by thrombin and atheroma plaque forma hypophyseal insufficiency, vitiligo, and piebaldism and tion; with DNA repair system deficiency selected from the an inflammatory disease of the respiratory and ENT group consisting of Xeroderma pigmentosum and Coc system selected from the group consisting of asthma, kayne syndrome, acute respiratory distress syndrome, hayfever, allergic 50 a dermatosis with photosensitivity caused by metabolic rhinitis, chronic obstructive pulmonary disease and anomalies which is a cutaneous porphyria selected allergies; from the group consisting of late cutaneous porphyria, an inflammatory disease of the central nervous system mixed porphyria, erythropoietic protoporphyria, con Selected from the group consisting of Alzheimer's genital erythropoietic porphyria Günther's disease and disease, other form of dementia, Parkinson's disease, 55 erythropoietic coproporphyria, or which is pellagra or Creutzfeldt Jacob disease, multiple sclerosis and men a pellagroid erythema or a tryptophan metabolism ingitis; disorder; an inflammatory skin disease selected from the group an idiopathic photodermatosis attack selected from the consisting of urticaria, Scleroderma, contact dermatitis, group consisting of polymorphous light eruption, atopic dermatitis, psoriasis, ichthyosis, acne and other 60 benign Summer light eruption, actinic prurigo, persis forms of folliculitis, rosacea and alopecia; tent photosensitization selected from the group consist an autoimmune disease selected from the group consisting ing of actino-reticulosis, chronic actinic dermatosis, of lupus erythematosus, a thyroid condition, an auto and photosensitive eczema, Solar urticaria, hydroa vac immune disease of the adrenal gland, autoimmune ciniforme, juvenile spring eruption and Solar pruritus, gastritis, vitiligo and alopecia areata; 65 or for modulating the color of the skin or of the hair and an inflammation accompanying bacterial, viral or fungal of body hairs by causing the skin to tan by increasing infections selected from the group consisting of tuber melanin synthesis or causing it to bleach by interfering
US 9,630,949 B2 73 74 N—{(R)-1-(4-methoxybenzyl)-2-3-(3-methylbut-2-eny group consisting of Xeroderma pigmentosum, basal cell loxy)-3-o-tolylazetidin-1-yl)-2-oxoethyl-3-(5-methyl naevus syndrome and familial melanoma; 1H-imidazol-4-yl)propionamide; a photodermatosis due to an exogenous photosensitizing and the salts and enantiomers thereof. agent selected from the group consisting of furocou 3. A method for treating a disorder, disease, of dysfunction 5 marins, halogenated Salicylanilides, local Sulphamides, selected from the group consisting of: psoralens, tetracyclines, systemic Sulphamides, phe an inflammatory disease of the digestive tract selected nothiazines, nalidixic acid, and tricyclic antidepres from the group consisting of irritable bowel syndrome, Sants, ulcerative colitis, Crohn's disease, pancreatitis, hepa or for inhibiting a dermatosis attack with photosensitivity 10 which is: titis, an inflammatory pathological condition of the a photoaggravated dermatosis selected from the group bladder and gastritis; consisting of lupus erythematosus, recurrent herpes, an inflammatory disease of the locomotor system selected congenital poikilodermal and telangiectasic conditions from the group consisting of rheumatoid arthritis, with photosensitivity selected from the group consist osteoarthritis, osteoporosis, traumatic arthritis, post 15 ing of Bloom syndrome, Cockayne syndrome and infectious arthritis, muscle degeneration and dermato Rothmund-Thomson syndrome, actinic lichen planus, myositis; actinic granuloma, disseminated Superficial actinic glomerulonephritis; porokeratosis, acne rosacea, juvenile acne, bullous der an inflammatory disease of the cardiac system selected matosis, Darier's disease, cutaneous lymphoma, pso from the group consisting of pericarditis, myocarditis, riasis, atopic dermatitis, contact eczema, follicular atherosclerosis, transplant atherosclerosis, peripheral mucinosis, erythema multiforme, fixed drug erythema, vascular disease, inflammatory vasculardisease, inter lymphocytoma cutis, reticular erythema with mucino mittent claudication restenosis, stroke, transient ischae sis and melasma, mic attack, myocardial ischaemia, myocardial infarc a dermatosis with photosensitivity caused by deficiency of tion, hypertension, hyperlipidaemia, coronary artery 25 the protection system with melanin formation or dis disease, unstable angina, thrombosis, platelet aggrega tribution anomalies selected from the group consisting tion induced by thrombin and atheroma plaque forma of oculocutaneous albinism, phenylketonuria, anterior tion; hypophyseal insufficiency, vitiligo, and piebaldism and an inflammatory disease of the respiratory and ENT with DNA repair system deficiency selected from the system selected from the group consisting of asthma, 30 group consisting of Xeroderma pigmentosum and Coc acute respiratory distress syndrome, hayfever, allergic kayne syndrome, rhinitis, chronic obstructive pulmonary disease and a dermatosis with photosensitivity caused by metabolic allergies; anomalies which is a cutaneous porphyria selected an inflammatory disease of the central nervous system from the group consisting of late cutaneous porphyria, Selected from the group consisting of Alzheimer's 35 mixed porphyria, erythropoietic protoporphyria, con disease, other form of dementia, Parkinson's disease, genital erythropoietic porphyria Günther's disease and Creutzfeldt Jacob disease, multiple sclerosis and men erythropoietic coproporphyria, or which is pellagra or ingitis; a pellagroid erythema or a tryptophan metabolism an inflammatory skin disease selected from the group disorder; consisting of urticaria, Scleroderma, contact dermatitis, 40 an idiopathic photodermatosis attack selected from the atopic dermatitis, psoriasis, ichthyosis, acne and other group consisting of PMLE (polymorphous light erup forms of folliculitis, rosacea and alopecia; tion), benign Summer light eruption, actinic prurigo, an autoimmune disease selected from the group consisting persistent photosensitization selected from the group of lupus erythematosus, a thyroid condition, an auto consisting of actino-reticulosis, chronic actinic derma immune disease of the adrenal gland, autoimmune 45 tosis, and photosensitive eczema, Solar urticaria, gastritis, vitiligo and alopecia areata; hydroa vacciniforme, juvenile spring eruption and Solar an inflammation accompanying bacterial, viral or fungal pruritus, infections selected from the group consisting of tuber or for modulating the color of the skin or of the hair and culosis, septicaemia, fever, HIV, herpes, cytomegalo of body hairs by causing the skin to tan by increasing virus, hepatitis A, hepatitis B and hepatitis C; 50 melanin synthesis or causing it to bleach by interfering a transplant or graft rejection selected from the group with melanin synthesis, by preventing hair and body consisting of kidney, liver, heart, lung, pancreas, bone hair from turning white or grey; or for modifying the marrow, cornea, intestine and skin; color of the hair and body hairs in cosmetic indications; pain selected from the group consisting of post-operative or for modulating sebaceous function in treating: pain, neuromuscular pain, headache, cancer-related 55 a condition with hyperseborrhoea selected from the group pain, dental pain and osteoarticular pain; consisting of acne, Seborrhoeic dermatitis, greasy skin a disease with a pigmentation disorder selected from the and greasy hair, hyperseborrhoea in Parkinson's and group consisting of a benign dermatosis selected from epilepsy, and hyperandrogenism; the group consisting of vitiligo, albinism, melasma, a condition with decreasing sebaceous secretion selected lentigines, freckles, melanocytic naevi and post inflam 60 from the group consisting of Xerosis and dry skin; matory pigmentation; and a pigmented tumor selected benign and malignant sebocyte and sebaceous gland pro from the group consisting of melanoma and local liferation; metastases, regional metastases and systemic metasta an inflammatory condition of the pilosebaceous follicle ses thereof Selected from the group consisting of acne, boils, or a method for inhibiting: 65 carbuncles and folliculitis; actinic erythema, skin ageing, a skincancer, and a disease a neurodegenerative disorder selected from the group in which Sunlight accelerates onset selected from the consisting of depression, anxiety, an obsessive-com US 9,630,949 B2 75 76 pulsive disorder, a neurosis, a psychosis, insomnia, protection system with melanin formation or distri sleep apnea, and drug abuse; bution anomalies selected from the group consisting a male sexual dysfunction selected from the group con of oculocutaneous albinism, phenylketonuria, ante sisting of impotence, loss of libido, and erectile dys rior hypophyseal insufficiency, vitiligo and piebald function; a female sexual dysfunction selected from the ism) and with DNA repair system deficiency selected group consisting of sexual stimulation disorders, or from the group consisting of Xeroderma pigmento disorders related to desire, sexual receptivity, orgasm, Sum and Cockayne syndrome, and disturbances of the major points of sexual function; a dermatosis with photosensitivity caused by metabolic pain, preterm labor, dysmenorrhoea, excessive menstrua anomalies which is a cutaneous porphyria selected tion, and endometriosis: 10 from the group consisting of late cutaneous porphy a disorder related to weight selected from the group ria, mixed porphyrias, erythropoietic protoporphyria, consisting of obesity, anorexia, modification and congenital erythropoietic porphyria, Günther's dis impairment of appetite, spleen metabolism, innocent ease and erythropoietic coproporphyria, or which is intake of fats and carbohydrates; diabetes mellitus: pellagra or a pelagroid erythema or a tryptophan cancer selected from the group consisting of lung cancer, 15 metabolism disorder; prostate cancer, colon cancer, breast cancer, ovarian an idiopathic photodermatosis attack selected from the cancer and bone cancer, an angiogenesis disorder, and group consisting of polymorphous light eruption, the formation or growth of a solid tumor, benign Summer light eruption, actinic prurigo, persis said method comprising administering to a Subject in need tent photosensitization selected from the group consist of such treatment the compound N-2-(3-butoxy-3-o- ing of actino-reticulosis, chronic actinic dermatosis, tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2- and photosensitive eczema, Solar urticaria, hydroa vac oxoethyl-3-(3H-imidazol-4-yl)propionamide trifluo ciniforme, juvenile spring eruption and Solar pruritus; rOacetate. or wherein the method is for modulating the color of the 4. The method according to claim 1, wherein the disorder, skin or of the hair and of body hairs by causing the skin disease, or dysfunction is selected from the group consisting 25 to tan by increasing melanin synthesis or causing it to of: bleach by interfering with melanin synthesis, by inhib a skin disease selected from the group consisting of iting hair and body hair turning white or grey; urticaria, Scleroderma, contact dermatitis, atopic der or for modifying the color of the hair and body hairs in matitis, psoriasis, ichthyosis, acne and other forms of cosmetic indications. folliculitis, rosacea and alopecia; 30 5. The method according to claim 2, wherein the disorder, an autoimmune disease selected from the group consisting disease, of dysfunction is selected from the group consisting of lupus erythematosus, a thyroid condition, an auto of: immune disease of the adrenal gland, autoimmune a skin disease selected from the group consisting of gastritis, vitiligo and alopecia areata; urticaria, Scleroderma, contact dermatitis, atopic der a disease with a pigmentation disorder selected from the 35 matitis, psoriasis, ichthyosis, acne and other forms of group consisting of a benign dermatosis selected from folliculitis, rosacea and alopecia; the group consisting of vitiligo, albinism, melasma, an autoimmune disease selected from the group consisting lentigines, freckles, melanocytic naevi and a post of lupus erythematosus, a thyroid condition, an auto inflammatory pigmentation disorder; and a pigmented immune disease of the adrenal gland, autoimmune tumor selected from the group consisting of melanoma 40 gastritis, vitiligo and alopecia areata; and local metastases, regional metastases and systemic a disease with a pigmentation disorder selected from the metastases thereof; group consisting of a benign dermatosis selected from actinic erythema, skin ageing, a skin cancer, and a disease the group consisting of vitiligo, albinism, melasma, in which Sunlight accelerates onset selected from the lentigines, freckles, melanocytic naevi and a post group consisting of Xeroderma pigmentosum, basal cell 45 inflammatory pigmentation disorder; and a pigmented naevus syndrome and familial melanoma; tumor selected from the group consisting of melanoma a photodermatosis due to an exogenous photosensitizing and local metastases, regional metastases and systemic agent selected from the group consisting of furocou metastases thereof; marins, halogenated Salicylanilides, local Sulphamides, actinic erythema, skin ageing, a skin cancer, and a disease psoralens, tetracyclines, systemic Sulphamides, phe 50 in which Sunlight accelerates onset selected from the nothiazines, nalidixic acid, and tricyclic antidepres group consisting of Xeroderma pigmentosum, basal cell Sants, naevus syndrome and familial melanoma; a dermatosis attack with photosensitivity which is: a photodermatosis due to an exogenous photosensitizing a photoaggravated dermatosis selected from the group agent selected from the group consisting of furocou consisting of lupus erythematosus, recurrent herpes, 55 marins, halogenated Salicylanilides, local Sulphamides, congenital poikilodermal and a telangiectasic condi psoralens, tetracyclines, systemic Sulphamides, phe tion with photosensitivity selected from the group nothiazines, nalidixic acid, and tricyclic antidepres consisting of Bloom syndrome, Cockayne syndrome Sants, and Rothmund-Thomson syndrome, actinic lichen a dermatosis attack with photosensitivity which is: planus, actinic granuloma, disseminated Superficial 60 a photoaggravated dermatosis selected from the group actinic porokeratosis, acne rosacea, juvenile acne, consisting of lupus erythematosus, recurrent herpes, bullous dermatosis, Darier's disease, cutaneous lym congenital poikilodermal and a telangiectasic condi phoma, psoriasis, atopic dermatitis, contact eczema, tion with photosensitivity selected from the group follicular mucinosis, erythema multiforme, fixed consisting of Bloom syndrome, Cockayne syndrome drug erythema, lymphocytoma cutis, reticular ery 65 and Rothmund-Thomson syndrome, actinic lichen thema with mucinosis and melasma, a dermatosis planus, actinic granuloma, disseminated Superficial with photosensitivity caused by deficiency of the actinic porokeratosis, acne rosacea, juvenile acne, US 9,630,949 B2 77 78 bullous dermatosis, Darier's disease, cutaneous lym congenital poikilodermal and a telangiectasic condi phoma, psoriasis, atopic dermatitis, contact eczema, tion with photosensitivity selected from the group follicular mucinosis, erythema multiforme, fixed consisting of Bloom syndrome, Cockayne syndrome drug erythema, lymphocytoma cutis, reticular ery and Rothmund-Thomson syndrome, actinic lichen thema with mucinosis and melasma, planus, actinic granuloma, disseminated Superficial a dermatosis with photosensitivity caused by deficiency actinic porokeratosis, acne rosacea, juvenile acne, of the protection system with melanin formation or bullous dermatosis, Darier's disease, cutaneous lym distribution anomalies selected from the group con phoma, psoriasis, atopic dermatitis, contact eczema, sisting of oculocutaneous albinism, phenylketonuria, follicular mucinosis, erythema multiforme, fixed anterior hypophyseal insufficiency, vitiligo and pie 10 baldism) and with DNA repair system deficiency drug erythema, lymphocytoma cutis, reticular ery selected from the group consisting of Xeroderma thema with mucinosis and melasma, pigmentosum and Cockayne syndrome, a dermatosis with photosensitivity caused by deficiency a dermatosis with photosensitivity caused by metabolic of the protection system with melanin formation or anomalies which is a cutaneous porphyria selected 15 distribution anomalies selected from the group con from the group consisting of late cutaneous porphy sisting of oculocutaneous albinism, phenylketonuria, ria, mixed porphyrias, erythropoietic protoporphyria, anterior hypophyseal insufficiency, vitiligo and pie congenital erythropoietic porphyria, Günther's dis baldism and with DNA repair system deficiency ease and erythropoietic coproporphyria, or which is selected from the group consisting of Xeroderma pellagra or a pelagroid erythema or a tryptophan pigmentosum and Cockayne syndrome, metabolism disorder; a dermatosis with photosensitivity caused by metabolic an idiopathic photodermatosis attack selected from the anomalies which is a cutaneous porphyria selected group consisting of polymorphous light eruption, from the group consisting of late cutaneous porphy benign Summer light eruption, actinic prurigo, persis ria, mixed porphyrias, erythropoietic protoporphyria, tent photosensitization selected from the group consist 25 congenital erythropoietic porphyria, Günther's dis ing of actino-reticulosis, chronic actinic dermatosis, ease and erythropoietic coproporphyria, or which is and photosensitive eczema, Solar urticaria, hydroa vac pellagra or a pelagroid erythema or a tryptophan ciniforme, juvenile spring eruption and Solar pruritus; metabolism disorder; or wherein the method is for modulating the color of the an idiopathic photodermatosis attack selected from the skin or of the hair and of body hairs by causing the skin 30 group consisting of polymorphous light eruption, to tanby increasing melanin synthesis or causing it to benign Summer light eruption, actinic prurigo, persis bleach by interfering with melanin synthesis, by inhib tent photosensitization selected from the group consist iting hair and body hair turning white or grey; ing of actino-reticulosis, chronic actinic dermatosis, or for modifying the color of the hair and body hairs in and photosensitive eczema, Solar urticaria, hydroa vac cosmetic indications. 35 ciniforme, juvenile spring eruption and Solar pruritus; 6. The method according to claim3, wherein the disorder, or wherein the method is for modulating the color of the disease, or dysfunction is selected from the group consisting skin or of the hair and of body hairs by causing the skin of: to tan by increasing melanin synthesis or causing it to a skin disease selected from the group consisting of bleach by interfering with melanin synthesis, by inhib urticaria, Scleroderma, contact dermatitis, atopic der 40 iting hair and body hair turning white or grey; matitis, psoriasis, ichthyosis, acne and other forms of or for modifying the color of the hair and body hairs in folliculitis, rosacea and alopecia; cosmetic indications. an autoimmune disease selected from the group consisting 7. The method according to claim 1, wherein the disease, of lupus erythematosus, a thyroid condition, an auto disorder, or dysfunction is selected from the group consist immune disease of the adrenal gland, autoimmune 45 ing of gastritis, vitiligo and alopecia areata; a condition with hyperseborrhoea selected from the group a disease with a pigmentation disorder selected from the consisting of acne, Seborrhoeic dermatitis, greasy skin group consisting of a benign dermatosis selected from and greasy hair, hyperseborrhoea in Parkinson's and the group consisting of vitiligo, albinism, melasma, epilepsy, and hyperandrogenism; lentigines, freckles, melanocytic naevi and a post 50 a condition with decreased sebaceous secretion selected inflammatory pigmentation disorder; and a pigmented from the group consisting of Xerosis and dry skin; tumor selected from the group consisting of melanoma benign and malignant sebocyte and sebaceous gland pro and local metastases, regional metastases and systemic liferation; metastases thereof; an inflammatory condition of the pilosebaceous follicle actinic erythema, skin ageing, a skin cancer, and a disease 55 Selected from the group consisting of acne, boils, in which Sunlight accelerates onset selected from the carbuncles and folliculitis. group consisting of Xeroderma pigmentosum, basal cell 8. The method according to claim 2, wherein the disease, naevus syndrome and familial melanoma; disorder, or dysfunction is selected from the group consist a photodermatosis due to an exogenous photosensitizing ing of agent selected from the group consisting of furocou 60 a condition with hyperseborrhoea selected from the group marins, halogenated Salicylanilides, local Sulphamides, consisting of acne, Seborrhoeic dermatitis, greasy skin psoralens, tetracyclines, systemic Sulphamides, phe and greasy hair, hyperseborrhoea in Parkinson's and nothiazines, nalidixic acid, and tricyclic antidepres epilepsy, and hyperandrogenism; Sants, a condition with decreased sebaceous secretion selected a dermatosis attack with photosensitivity which is: 65 from the group consisting of Xerosis and dry skin; a photoaggravated dermatosis selected from the group benign and malignant sebocyte and sebaceous gland pro consisting of lupus erythematosus, recurrent herpes, liferation; US 9,630,949 B2 79 80 an inflammatory condition of the pilosebaceous follicle 14. The method as defined by claim 1 wherein the method Selected from the group consisting of acne, boils, is for treating signs of ageing skin, said method comprising carbuncles and folliculitis. applying the composition as defined in claim 1 to the skin of 9. The method according to claim 3, wherein the disease, a Subject in need of Such treatment and the compound is disorder, or dysfunction is selected from the group consist N-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4- ing of methoxybenzyl)-2-oxoethyl-3-(3H-imidazol-4-yl)propio a condition with hyperseborrhoea selected from the group namide trifluoroacetate. consisting of acne, Seborrhoeic dermatitis, greasy skin 15. The method as defined by claim 1 wherein the method and greasy hair, hyperseborrhoea in Parkinson's and is for body or hair hygiene, said method comprising apply epilepsy, and hyperandrogenism; 10 ing to the body or the hair of a subject in need of such a condition with decreased sebaceous secretion selected treatment for body or hair hygiene, a composition as defined from the group consisting of Xerosis and dry skin; in claim 1. benign and malignant sebocyte and sebaceous gland pro 16. The method as defined by claim 1, for body or hair liferation; 15 hygiene, said method comprising applying to the body or the an inflammatory condition of the pilosebaceous follicle hair of a subject in need of such treatment for body or hair Selected from the group consisting of acne, boils, hygiene and the compound is N-2-(3-butoxy-3-o-tolylaze carbuncles and folliculitis. tidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl-3- 10. The method according to claim 4, wherein the disor (3H-imidazol-4-yl)propionamide trifluoroacetate; a compo der, disease, or dysfunction is selected from the group sition as defined in claim 1. consisting of: 17. A method for modulating a melanocortin receptor a skin disease selected from the group consisting of MC1R or MC4R in a cell, said method comprising contact urticaria, Scleroderma, contact dermatitis, atopic der ing the cell with a melanocortin receptor MC1R or MC4R matitis, psoriasis, ichthyosis, acne and other forms of modulating amount of a compound selected from the group folliculitis, rosacea and alopecia; and 25 consisting of: a disease with a pigmentation disorder selected from the N—(S)-1-(S)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- group consisting of a benign dermatosis selected from methoxybenzyl)-2-oxoethylcarbamoyl-2-(1H-imida the group consisting of vitiligo, albinism, melasma, zol-4-yl)ethylbenzamide: lentigines, freckles, melanocytic naevi and a post N—(S)-1-(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4- inflammatory pigmentation disorder and a pigmented 30 methoxybenzyl)-2-oxoethylcarbamoyl-2-(1H-imida tumor selected from the group consisting of melanoma zol-4-yl)ethylbenzamide: and local metastases, regional metastases and Systemic N-(S)-1-(S)-2-3-butoxy-3-(4-fluorophenyl)azetidin metastases thereof. 1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl-2- 11. The method according to claim 5, wherein the disor (1H-imidazol-4-yl)ethylbenzamide: der, disease, or dysfunction is selected from the group 35 N—(S)-1-(S)-2-3-butoxy-3-(3-fluorophenyl)azetidin consisting of: 1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl-2- a skin disease selected from the group consisting of (1H-imidazol-4-yl)ethylbenzamide: urticaria, Scleroderma, contact dermatitis, atopic der N—(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- matitis, psoriasis, ichthyosis, acne and other forms of methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl)pro folliculitis, rosacea and alopecia; and 40 pionamide; a disease with a pigmentation disorder selected from the N—(R)-2-(3-ethoxy-3-o-tolylaZetidin-1-yl)-1-(4- group consisting of a benign dermatosis selected from methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl)pro the group consisting of vitiligo, albinism, melasma, pionamide; lentigines, freckles, melanocytic naevi and a post N—(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(2,4-di inflammatory pigmentation disorder and a pigmented 45 chlorobenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl)pro tumor selected from the group consisting of melanoma pionamide; and local metastases, regional metastases and systemic N—(R)-2-(3-cyclopropyl methoxy-3-o-tolylazetidin-1- metastases thereof. yl)-1-(4-methoxybenzyl)-2-oxoethyl-3-(1H-imidazol 12. The method according to claim 6, wherein the disor 4-yl)propionamide; der, disease, or dysfunction is selected from the group 50 N—(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o- consisting of: tolylazetidin-1-yl)ethyl-3-(1H-imidazol-4-yl)propio a skin disease selected from the group consisting of namide: urticaria, Scleroderma, contact dermatitis, atopic der N—(R)-2-3-butoxy-3-(4-fluorophenyl)azetidin-1-yl)-1- matitis, psoriasis, ichthyosis, acne and other forms of (4-methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl) folliculitis, rosacea and alopecia; and 55 propionamide; a disease with a pigmentation disorder selected from the N—(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3- group consisting of a benign dermatosis selected from o-tolylazetidin-1-yl)ethyl-3-(1H-imidazol-4-yl)pro the group consisting of vitiligo, albinism, melasma, pionamide; lentigines, freckles, melanocytic naevi and a post N—(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phe inflammatory pigmentation disorder and a pigmented 60 nylazetidin-1-yl)ethyl-3-(1H-imidazol-4-yl)propiona tumor selected from the group consisting of melanoma mide; and local metastases, regional metastases and systemic N—(R)-2-(3-butyl-3-phenylazetidin-1-yl)-1-(4- metastases thereof. methoxybenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl)pro 13. The method as defined in claim 1, wherein the method pionamide; is for treating signs of ageing skin, said method comprising 65 N—(R)-2-3-butoxy-3-(4-fluorophenyl)azetidin-1-yl)-1- applying the composition as defined in claim 1 to the skin of (3-fluorobenzyl)-2-oxoethyl-3-(1H-imidazol-4-yl) a Subject in need of Such treatment. propionamide;