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WO2012131090A1 - Method for treatment of xeroderma pigmentosum - Google Patents

Method for treatment of xeroderma pigmentosum Download PDF

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Publication number
WO2012131090A1
WO2012131090A1 PCT/EP2012/055955 EP2012055955W WO2012131090A1 WO 2012131090 A1 WO2012131090 A1 WO 2012131090A1 EP 2012055955 W EP2012055955 W EP 2012055955W WO 2012131090 A1 WO2012131090 A1 WO 2012131090A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
imidazol
cyclohexyl
propionyl
ureido
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PCT/EP2012/055955
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French (fr)
Inventor
Philippe Andres
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Galderma Research & Development
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Publication of WO2012131090A1 publication Critical patent/WO2012131090A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/0616—Skin treatment other than tanning
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/065—Light sources therefor
    • A61N2005/0651—Diodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/065—Light sources therefor
    • A61N2005/0657—Natural light sources, e.g. captured sunlight
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0662—Visible light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent

Definitions

  • This invention relates to a method of treating xeroderma pigmentosum and related symptoms in patients by administering a MC1 R before or after exposing them to visible light.
  • Xeroderma pigmentosum which is commonly known as XP, is an inherited condition characterized by an extreme sensitivity to ultraviolet (UV) rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun. Some affected individuals also have problems involving the nervous system.
  • UV ultraviolet
  • xeroderma pigmentosum The signs of xeroderma pigmentosum usually appear in infancy or early childhood. Many affected children develop a severe sunburn after spending just a few minutes in the sun. The sunburn causes redness and blistering that can last for weeks. Other affected children do not get sunburned with minimal sun exposure, but instead tan normally. By age 2, almost all children with xeroderma pigmentosum develop freckling of the skin in sun-exposed areas (such as the face, arms, and lips); this type of freckling rarely occurs in young children without the disorder. In affected individuals, exposure to sunlight often causes dry skin (xeroderma) and changes in skin coloring (pigmentation). This combination of features gives the condition its name, xeroderma pigmentosum.
  • the eyes of people with xeroderma pigmentosum may be painfully sensitive to UV rays from the sun. If the eyes are not protected from the sun, they may become bloodshot and irritated, and the clear front covering of the eyes (the cornea) may become cloudy. In some people, the eyelashes fall out and the eyelids may be thin and turn abnormally inward or outward. In addition to an increased risk of eye cancer, xeroderma pigmentosum is associated with noncancerous growths on the eye. Many of these eye abnormalities can impair vision.
  • complementation group A (XP-A) through complementation group G (XP-G) plus a variant type (XP-V).
  • the types are distinguished by their genetic cause. All of the types increase skin cancer risk, although some are more likely than others to be associated with neurological abnormalities.
  • Xeroderma pigmentosum is a rare disorder; it is estimated to affect about 1 in 1 million people in the United States and Europe. The condition is more common in Japan, North Africa, and the Middle East.
  • Xeroderma pigmentosum is caused by mutations in genes that are involved in repairing damaged DNA.
  • DNA can be damaged by UV rays from the sun and by toxic chemicals such as those found in cigarette smoke. Normal cells are usually able to fix DNA damage before it causes problems. However, in people with xeroderma pigmentosum, DNA damage is not repaired normally. As more abnormalities form in DNA, cells malfunction and eventually become cancerous or die.
  • NER nucleotide excision repair
  • xeroderma pigmentosum The major features of xeroderma pigmentosum result from a buildup of unrepaired DNA damage.
  • UV rays damage genes that control cell growth and division, cells can either die or grow too fast and in an uncontrolled way. Unregulated cell growth can lead to the development of cancerous tumors.
  • Neurological abnormalities are also thought to result from an accumulation of DNA damage, although the brain is not exposed to UV rays.
  • pigmentosum More than half of all cases in the United States result from mutations in the XPC, ERCC2, or POLH genes. Mutations in the other genes generally account for a smaller percentage of cases.
  • MCRs Melanocortin receptors
  • MCRs melanocyte-stimulating hormones
  • ACTH adrenocorticotropic hormone
  • Agouti proteins and derivatives thereof for instance the melanocyte-stimulating hormones (MSH), adrenocorticotropic hormone (ACTH), and the Agouti proteins and derivatives thereof.
  • MCRs have varied physiological roles.
  • MC1 R regulates the formation of melanin in the skin, and has a role in regulating the immune system.
  • MC2R regulates the production of corticosteroids in the adrenal glands.
  • MC4R play a role in controlling food intake and sexual behaviour.
  • MC5R is involved in regulating the exocrine glands (Wikberg, Jarl E. S., Melanocortin receptors: perspectives for novel drugs.
  • MCRs as targets for medicaments for treating major pathologies such as obesity, diabetes, inflammatory conditions and sexual dysfunction raises the need for compounds that show high specificity towards a particular subtype.
  • MC1 -R is expressed in the melanocytes and is involved in skin pigmentation, the coloration of animal fur and the functions of the melanocyte.
  • Polymorphism data for the MC1 -R gene have been associated with the ginger hair phenotype and with malignant and non-malignant skin cancers (Xu X. et al., Nat. Genet.
  • MC1 -R is also expressed in macrophages and monocytes (Star et al., Proc. Natl. Acad. Sci. USA 92; 8016-8020; Hartmeyer et al., J. Immunol. 159; 1930-1937), neutrophils (Catania et al., Peptides 17; 675-679), endothelial cells (Hartmeyer et al., J. Immunol.
  • gliomal cells and astrocytes Wong et al., Neuroimmunomodulation 4, 37-41
  • fibroblasts Boston and Cone, Endocrinology 137, 2043-2050
  • keratinocytes Localization of MC1 -R in these cells is associated with the capacity of MSH-based peptides to inhibit inflammatory processes.
  • . alpha. -MSH has shown strong inhibition of inflammation in chronic models of intestinal inflammation, arthritis, ischaemia, contact hypersensitivity and dermatitis, and is also capable of inducing tolerance to haptenes (Ceriana et al., Neuroimmunomodulation, 1 , 28-32; Chiao et al., Clin. Invest. 99, 1 165-1 172; Huh and Lipton, Neurosurgery, 40, 132- 139; Luger et al J. Invest. Dermatol. Symp. Proc. 2, 87-93; Rajora et al., Peptides 18, 381 - 385; J. Neurosci. 17,2181 -2196; Lipton et al., Neuroimmunomodulation, 5, 178-183).
  • Melanocortins may thus be used for treating inflammatory disorders and immune disorders. It has been suggested that the MC1 -R signalling pathway plays a role in the perception of pain and that functional variations of MC1 -R are linked to a high tolerance to pain (Mogil et al., J. Med. Genet. 2005 Jul; 42(7): 583-7).
  • Patents WO 96/35713, WO 96/38471 and WO 99/58501 disclose certain dipeptides and their use for stimulating the synthesis of growth hormone.
  • Patents WO 02/070 51 1 , WO 02/079 146 and WO 02/069 905 claim the use of compounds as modulators of melanocortin receptors, more particularly MC1 -R and MC4-R.
  • Patent WO 05/047 253 describes compounds and their use as melanocortin receptor agonists.
  • WO2010052255 discloses MC1 R agonists including those of the formula (I):
  • a-Melanotropin 4-L-norleucine-7-D-phenylalanine- (Afamelanotide) is a product sold by Clinuvel® as a Alpha-Melanocyte Stimulating Hormone (a-MSH) having MC-1 R agonist properties under the tradename SCENESSE®
  • the present invention relates to method of treating patients suffering from xeroderma pigmentosum or from a symptom associated therewith, comprising the steps:
  • Administering a MC1 R agonist MC1 R agonist could be of any type but are preferably compounds of general formula (I) below:
  • R1 represents a hydrogen atom, an aryl, a substituted aryl, an alkyl, a cycloalkyi, a cycloalkylalkyl or a cycloalkylalkylalkyl,
  • R2 represents a hydrogen atom, a hydroxyl, a lower alkyl, a substituted lower alkyl, a higher alkyl, a substituted higher alkyl, a cycloalkyi, a cycloalkylalkyl, a lower alkoxy, a substituted lower alkoxy, a higher alkoxy, a substituted higher alkoxy, a cycloalkylalkoxy, an acyloxy, an acyl, an alkoxycarbonyl, a carboxamide, a carboxylic acid, a cyano, or an amino disubstituted with an acyl and an aryl or alkyl, R3 represents an aralkyl or a substituted aralkyl, R4 represents a heteroaralkyl or a substituted heteroaralkyl, R5 represents a hydrogen atom or an alkyl, X represents an oxygen atom or a sulfur atom, n, m may be equal to 1 or
  • the light source used for exposing patients to visible light coud be either sunlight or artificial light like LED lamps.
  • Visible light is defined as the portion of electromagnetic radiation that is visible to the human eye, responsible for the sense of sight. Visible light has a wavelength in a range from about 380 or 400 nanometres to about 760 or 780 nm, with a frequency range of about 405 THz to 790 THz. Preferably from 400nm to 700nm
  • Exposure time is also a key factor. Exposure time may vary to achieve sufficient tanning and is linked to the source of visible light and/or the intensity of the light source.
  • the exposure time is at leat 5 min but preferably at least 1 hour.
  • a sunscreen may help to achieve the visible light only exposure within the acceptable range of wavelenght.
  • the method of treatment is particularly effective for patients having skin type IV to VI.
  • skin type it is means that a skin type according to the Fitzpatrick Scale (aka Fitzpatrick skin typing test or Fitzpatrick phototyping scale).
  • This scale is a numerical classification schema for the color of skin. It was developed in 1975 by T.B. Fitzpatrick, a Harvard dermatologist, as a way to classify the response of different types of skin to UV light. It remains a recognized tool for dermatologic research into the color of skin.
  • Type I (scores 0-7) White; very fair; freckles. Always burns, never tans
  • Type II (scores 8-16) White; fair. Usually burns, tans with difficulty
  • Type III (scores 17-25) Beige; very common. Sometimes mild burn, gradually tans
  • Type IV (scores 25-30) Beige with a brown tint; typical Mediterranean Caucasian skin. Rarely burns, tans with ease
  • Type V (scores over 30) Dark brown. Very rarely burns, tans very easily
  • the skin type is from type IV to VI.
  • Example 1 4-Cyclohexyl-1-[2- ⁇ 3-[2-(1 H-imidazol-4-yl)ethyl]ureido ⁇ -3-(4- methoxyphenyl)propionyl]piperidine-4-tert-butylcarbamoyl
  • reaction medium After stirring for 4 hours, the reaction medium is washed with aqueous 1 N hydrochloric acid solution and then with aqueous sodium hydroxide solution, adjusting the pH to 10.
  • reaction medium is immersed in a bath of cold water. 7.34 g (36.4 mmol) of 4- nitrophenyl chloroformate are added, followed by 6.33 ml of diisopropylethylamine.
  • the reaction is stopped by adding water, followed byextraction with dichloromethane.
  • the reaction medium is placed in a microwave reactor with stirring, at 100(0)C for 10 minutes.
  • the crude product obtained is purified by filtration on a pad of silica (eluent: 1/1
  • Example 2 1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxy- benzyl)-2- oxoethyl]-3-[2-(1 -methyl-1 H-imidazol-4-yl)ethyl]urea 2-1-1 4-Phenyl-1-(toluene-4-sulfonyl)pipe dine-4-carbonit le
  • dichloromethane are added to a solution of 20 g (89.8 mmol) of 4-phenylpiperidine-4- carbonitrile and 28 ml of triethylamine in 200 ml of dichloromethane.
  • the reaction mixture is stirred for 1 hour at room temperature.
  • the reaction mixture is stirred for 6 hours at 65-70(0)C and then overnight at room temperature.
  • reaction is stopped by adding 100 ml of tetrahydrofuran, and is then hydrolysed with 1 N hydrochloric acid solution and extracted with ethyl acetate.
  • the reaction mixture is stirred at reflux for 48 hours.
  • reaction is monitored by HPLC. 50 ml of ethanol are added to homogenize the reaction medium, followed by 40 ml of sulfuric acid, and heating is continued for 24 hours.
  • reaction is stopped by addition to ice and basified with sodium hydroxide solution, and then extracted with ethyl acetate.
  • the reaction medium is heated at 80(0)C for 12 hours.
  • reaction is stopped and then filtered through Celite andwashed with dichloromethane.
  • the solvents are evaporated off and the residue is taken up in water, basified with 1 N sodium hydroxide solution and extracted with ethyl acetate.
  • the organic phases are dried over sodium sulfate.
  • the solution is washed with aqueous 2.5% citric acid solution and extracted with ethyl acetate, and the organic phase is then washed with aqueous 10N sodium hydroxide solution. It is dried over sodium sulfate, filtered and concentrated.
  • the solution is stirred for 1 hour 30 minutes at room temperature and then poured into 1 N sodium hydroxide solution and extracted with dichloromethane.
  • the oil obtained is diluted in 5 ml of DMF, the mixture is heated to 80(0)C and 39 mg (0.2 mmol) of 1 - methylhistamine and 0.05 ml (0.36 mmol) of triethylamine are then added, and the solution is stirred for 5 minutes at 80(0)C and for 10 minutes at room temperature.
  • reaction is stopped by adding aqueous 1 N sodium hydroxide solution and then extracted with DCM.
  • organic phase is washed with water and then dried over sulfate, filtered and concentrated.
  • Example 3 1 -[(/?)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxy- benzyl)-2- oxoethyl]-3-[2-(1 H-[1 ,2,3]triazol-4-yl)ethyl]urea
  • reaction medium After stirring for 2 hours, the reaction medium is extracted with DCM. The aqueous phase is concentrated.
  • the solid obtained is taken up in ethanol and, after filtration, the solvents are evaporated off.
  • the crude product is purified in a column of silica (7/3 DCM/MeOH). 558 mg of a white solid are obtained and dissolved in 15 ml of THF and 6 ml of water, to which are added 720 mg of lithium hydroxide.
  • the reaction medium is placed at 160(0)C in a microwave reactor for 45 minutes.
  • reaction medium is filtered and then extracted with DCM.
  • reaction is stopped by adding aqueous NH[4]OH solution and the organic compounds are extracted with DCM. The organic phase is then washed with water and dried over MgSO[4], filtered and concentrated.
  • the reaction mixture is stirred at 80.deg.C for 10 minutes.
  • the medium is stirred in a microwave reactor for 10 minutes at 120(0)C.
  • Dichloromethane is added to the reaction medium and the organic phase is washed with a saturated aqueous NaHC03 solution.
  • reaction medium After warming to room temperature, the reaction medium is stirred for 2 hours and 30 minutes.
  • the reaction is stopped by adding aqueous ammonia solution.
  • the oil obtained is dissolved in 4 ml of DMF at 80(0)C, and 110 mg (0.31 mmol) of 3-(1 H- imidazol-4-yl)propylamine bis(thfluoroacetate), 0.05 ml of thethylamine are then added.
  • the reaction mixture is left stirring at 80(0)C for 15 minutes.
  • the reaction is stopped by addition of an aqueous 5% citric acid solution.
  • the organic compounds are extracted with ethyl acetate, then the organic phase is washed with aqueous 1 N sodium hydroxide solution and then with water.
  • the colourless oil obtained is diluted in 5 ml of dimethylformamide, the mixture is heated to 80(0)C, and 18 mg (0.12 mmol) of histamine are added and the solution is stirred for 5 minutes at 80(0)C and overnight at room temperature.
  • the reaction is stopped by adding aqueous 1 N sodium hydroxide solution and the organic compounds are extracted with dichloromethane.
  • Example 7 Ethyl 4-cyclohexyl-1 -[(/?)-2- ⁇ 3-[3-(1 H-imidazol-4-yl)propyl]- thioureido ⁇ -3-(4- methoxyphenyl)propionyl]piperidine-4-carboxylate 7- 1 Ethyl i-KR A -amino-S-ft-methoxyphenyljpropionyl A -cyclohexylpiperidine- A carboxylate trifluoroacetate
  • dichloromethane are added 20 ml of trifluoroacetic acid.
  • the reaction medium is stirred for 2 hours at room temperature.
  • reaction medium is stirred for 2 hours and then hydrolysed by adding aqueous 5% citric acid solution.
  • the organic compounds are extracted with dichloromethane.
  • Example 8 Ethyl 4-cyclohexyl-1-((R)-3-(4-methoxyphenyl)-2- ⁇ 3-[2-(1- methyl- 1 H-imidazol-4- yl)ethyl]thioureido ⁇ propionyl)piperidine-4- carboxylate
  • the reaction medium is refluxed for 18 hours.
  • the reaction is stopped by adding aqueous 5% citric acid solution and the organic compounds are extracted with CH[2]CI[2].
  • the organic phase is dried over MgSO[4], filtered and concentrated.
  • reaction medium is stirred at room temperature under a hydrogen pressure of 5 bar. After 4 hours, the reaction medium is filtered through Celite and concentrated.
  • the crude product obtained is purified by preparative HPLC. 4 ml of dichloromethane and 0.5 ml of trifluoroacetic acid are added to the residue obtained.
  • the reaction medium is stirred at room temperature for 18 hours.
  • chloroformate are added to 25 mg (47 .micro. mol) of 1 - ⁇ 1 -[(R)-2-amino-3-(4- methoxyphenyl)propionyl]-4- cyclohexylpiperidin-4-yl ⁇ butan-1 -one (cf. preparation 4.4) dissolved in 5 ml of DCM.
  • the reaction mixture is stirred for 2 hours at room temperature.
  • reaction is stopped by adding water and the organic compounds are extracted with DCM.
  • organic phase is then dried over MgSO[4], filtered and concentrated.
  • the oil obtained is dissolved in 5 ml of DMF at 80(0)C, and 14 mg of 5-(1 H-imidazol-4- yl)pentylamine bis(thfluoroacetate) are added.
  • reaction mixture is stirred at 80(0)C for 5 minutesand for 18 hours at room temperature.
  • organic phase is washed with 1 N sodium hydroxide, extracted with dichloromethane and then dried over MgSO[4], filtered and concentrated.

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Abstract

This invention relates to a method of treating xeroderma pigmentosum and related symptoms in patients by administering a MC1R before or after exposing them to visible light.

Description

METHOD FOR TREATMENT OF XERODERMA PIGMENTOSUM
BACKGROUND OF THE INVENTION This invention relates to a method of treating xeroderma pigmentosum and related symptoms in patients by administering a MC1 R before or after exposing them to visible light.
Xeroderma pigmentosum, which is commonly known as XP, is an inherited condition characterized by an extreme sensitivity to ultraviolet (UV) rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun. Some affected individuals also have problems involving the nervous system.
The signs of xeroderma pigmentosum usually appear in infancy or early childhood. Many affected children develop a severe sunburn after spending just a few minutes in the sun. The sunburn causes redness and blistering that can last for weeks. Other affected children do not get sunburned with minimal sun exposure, but instead tan normally. By age 2, almost all children with xeroderma pigmentosum develop freckling of the skin in sun-exposed areas (such as the face, arms, and lips); this type of freckling rarely occurs in young children without the disorder. In affected individuals, exposure to sunlight often causes dry skin (xeroderma) and changes in skin coloring (pigmentation). This combination of features gives the condition its name, xeroderma pigmentosum.
People with xeroderma pigmentosum have a greatly increased risk of developing skin cancer. Without sun protection, about half of children with this condition develop their first skin cancer by age 10. Most people with xeroderma pigmentosum develop multiple skin cancers during their lifetime. These cancers occur most often on the face, lips, and eyelids. Cancer can also develop on the scalp, in the eyes, and on the tip of the tongue. Studies suggest that people with xeroderma pigmentosum may also have an increased risk of other types of cancer, including brain tumors. Additionally, affected individuals who smoke cigarettes have a significantly increased risk of lung cancer.
The eyes of people with xeroderma pigmentosum may be painfully sensitive to UV rays from the sun. If the eyes are not protected from the sun, they may become bloodshot and irritated, and the clear front covering of the eyes (the cornea) may become cloudy. In some people, the eyelashes fall out and the eyelids may be thin and turn abnormally inward or outward. In addition to an increased risk of eye cancer, xeroderma pigmentosum is associated with noncancerous growths on the eye. Many of these eye abnormalities can impair vision.
About 30 percent of people with xeroderma pigmentosum develop progressive neurological abnormalities in addition to problems involving the skin and eyes. These abnormalities can include hearing loss, poor coordination, difficulty walking, movement problems, loss of intellectual function, difficulty swallowing and talking, and seizures. When these neurological problems occur, they tend to worsen with time.
Researchers have identified at least eight inherited forms of xeroderma pigmentosum:
complementation group A (XP-A) through complementation group G (XP-G) plus a variant type (XP-V). The types are distinguished by their genetic cause. All of the types increase skin cancer risk, although some are more likely than others to be associated with neurological abnormalities.
Xeroderma pigmentosum is a rare disorder; it is estimated to affect about 1 in 1 million people in the United States and Europe. The condition is more common in Japan, North Africa, and the Middle East.
Xeroderma pigmentosum is caused by mutations in genes that are involved in repairing damaged DNA. DNA can be damaged by UV rays from the sun and by toxic chemicals such as those found in cigarette smoke. Normal cells are usually able to fix DNA damage before it causes problems. However, in people with xeroderma pigmentosum, DNA damage is not repaired normally. As more abnormalities form in DNA, cells malfunction and eventually become cancerous or die.
Many of the genes related to xeroderma pigmentosum are part of a DNA-repair process known as nucleotide excision repair (NER). The proteins produced from these genes play a variety of roles in this process. They recognize DNA damage, unwind regions of DNA where the damage has occurred, snip out (excise) the abnormal sections, and replace the damaged areas with the correct DNA. Inherited abnormalities in the NER-related genes prevent cells from carrying out one or more of these steps. The POLH gene also plays a role in protecting cells from UV-induced DNA damage, although it is not involved in NER; mutations in this gene cause the variant type of xeroderma pigmentosum.
The major features of xeroderma pigmentosum result from a buildup of unrepaired DNA damage. When UV rays damage genes that control cell growth and division, cells can either die or grow too fast and in an uncontrolled way. Unregulated cell growth can lead to the development of cancerous tumors. Neurological abnormalities are also thought to result from an accumulation of DNA damage, although the brain is not exposed to UV rays. Researchers suspect that other factors damage DNA in nerve cells. It is unclear why some people with xeroderma pigmentosum develop neurological abnormalities and others do not.
Inherited mutations in at least eight genes have been found to cause xeroderma
pigmentosum. More than half of all cases in the United States result from mutations in the XPC, ERCC2, or POLH genes. Mutations in the other genes generally account for a smaller percentage of cases.
Melanocortin receptors (MCRs) form part of the superfamily of GPCRs with seven transmembrane domains.
To date, five subtypes of receptor, MC1 -5R, have been identified in mammals.
An endogenous group of peptides binds to MCRs with agonist or antagonist effects, for instance the melanocyte-stimulating hormones (MSH), adrenocorticotropic hormone (ACTH), and the Agouti proteins and derivatives thereof.
However, an exception is the MC2R receptor, which binds only with ACTH (Major pharmacological distinction of the ACTH receptor from other melanocortin receptors, Schioth et al., Life Sciences (1996), 59(10), 797-801 ).
MCRs have varied physiological roles.
MC1 R regulates the formation of melanin in the skin, and has a role in regulating the immune system.
MC2R regulates the production of corticosteroids in the adrenal glands.
The receptors MC3R and
MC4R play a role in controlling food intake and sexual behaviour.
MC5R is involved in regulating the exocrine glands (Wikberg, Jarl E. S., Melanocortin receptors: perspectives for novel drugs.
European Journal of Pharmacology (1999), 375(1 -3), 295-310. Wikberg, Jarl E. S.,
Melanocortin receptors: new opportunities in drug discovery.
Expert Opinion on Therapeutic Patents (2001 ), 1 1 (1 ), 61-76).
The potential use of MCRs as targets for medicaments for treating major pathologies such as obesity, diabetes, inflammatory conditions and sexual dysfunction raises the need for compounds that show high specificity towards a particular subtype.
However, the modelling of selective medicaments, for slightlydifferent receptor subtypes, is a difficult task that would be simplified in the light of detailed knowledge regarding the determinants of the ligand-receptor interaction.
MC1 -R is expressed in the melanocytes and is involved in skin pigmentation, the coloration of animal fur and the functions of the melanocyte. Polymorphism data for the MC1 -R gene have been associated with the ginger hair phenotype and with malignant and non-malignant skin cancers (Xu X. et al., Nat. Genet.
1996; 14: 384; Van Der Velden P. A. et al., Am. J. Hum. Genet. 2001 ; 69; 774- 779;
Valverde P. et al., Hum. Mol. Genet. 1996; 5; 1663-1666; Schioth H. B., Biochem. Biophys. Res. Commun. 1999; 260: 488-491 ; Scott M. C. et al., J. Cell Sci. 2002; 1 15; 2349-2355). Thus, a connection exists between MC1 -R and melanoma, and as a result MC1 -R may be important in preventing and treating certain forms of skin cancer (Stockfleth E. et al., Recent Results in Cancer Res. 2002; 160; 259-268; Stander et al., Exp. Dermatol. 2002; 1 1 :42-51 ). MC1 -R is also expressed in macrophages and monocytes (Star et al., Proc. Natl. Acad. Sci. USA 92; 8016-8020; Hartmeyer et al., J. Immunol. 159; 1930-1937), neutrophils (Catania et al., Peptides 17; 675-679), endothelial cells (Hartmeyer et al., J. Immunol. 159; 1930-1937), gliomal cells and astrocytes (Wong et al., Neuroimmunomodulation 4, 37-41 ), fibroblasts (Boston and Cone, Endocrinology 137, 2043-2050) and keratinocytes (Luger et al., J. Invest. Dermatol. Symp. Proc. 2, 87-93). Localization of MC1 -R in these cells is associated with the capacity of MSH-based peptides to inhibit inflammatory processes.
Specifically, . alpha. -MSH has shown strong inhibition of inflammation in chronic models of intestinal inflammation, arthritis, ischaemia, contact hypersensitivity and dermatitis, and is also capable of inducing tolerance to haptenes (Ceriana et al., Neuroimmunomodulation, 1 , 28-32; Chiao et al., Clin. Invest. 99, 1 165-1 172; Huh and Lipton, Neurosurgery, 40, 132- 139; Luger et al J. Invest. Dermatol. Symp. Proc. 2, 87-93; Rajora et al., Peptides 18, 381 - 385; J. Neurosci. 17,2181 -2196; Lipton et al., Neuroimmunomodulation, 5, 178-183).
Melanocortins may thus be used for treating inflammatory disorders and immune disorders. It has been suggested that the MC1 -R signalling pathway plays a role in the perception of pain and that functional variations of MC1 -R are linked to a high tolerance to pain (Mogil et al., J. Med. Genet. 2005 Jul; 42(7): 583-7).
There is a strong correlation between the colour of human hair and the variants of MC1 -R (Valverde et al., Nat. Genet. 1995 Nov; 1 1 (3): 328-30). Functional variations of MC1 -R are associated with the ginger hair colour.
It is also known that the sebaceous gland expresses both MC1 -R (Ganceviciene et al., Exp. Dermatol. 2007 Jul; 16(7): 547-52) and MC5-R (Zhang et al., Peptides, 2006 Feb; 27(2):413- 20). It has also been reported that MC1 -R is overexpressed in the sebaceous gland in the case of acne.
Thus, the compounds according to the present invention find applications in human medicine, especially in dermatology, and in the field of cosmetics. Patents WO 96/35713, WO 96/38471 and WO 99/58501 disclose certain dipeptides and their use for stimulating the synthesis of growth hormone.
The publication in the Journal of Medicinal Chemistry (2003), 46, 1 123-1 126 describes the 'discovery of small, powerful and selective tyrosine-based agonist molecules of the MC1 -R receptor that have anti-inflammatory properties'.
Patents WO 02/070 51 1 , WO 02/079 146 and WO 02/069 905 claim the use of compounds as modulators of melanocortin receptors, more particularly MC1 -R and MC4-R.
Patent WO 05/047 253 describes compounds and their use as melanocortin receptor agonists.
Bouix-Peter and al., WO2010052255 discloses MC1 R agonists including those of the formula (I):
Figure imgf000006_0001
Mahmoud and al., J. Invest. Dermatol. (2010) 130, 2092-2097 discloses the impact of visible light on melanocompetent skin. a-Melanotropin , 4-L-norleucine-7-D-phenylalanine- (Afamelanotide) is a product sold by Clinuvel® as a Alpha-Melanocyte Stimulating Hormone (a-MSH) having MC-1 R agonist properties under the tradename SCENESSE®
It has been found that obtaining a tanning through visible light exposure enhance MC1 R agonist properties and thus achieve an unexpected efficacy for treating xeroderma pigmentosum and symptoms related. SUMMARY OF THE INVENTION
Accordingly it is one object of the invention to provide a method of treating patients suffering from xeroderma pigmentosum or from a symptom associated therewith, comprising the steps : Administering either topically or orally a MC1 R agonist allowing sufficient time to be absorbed by the skin of the subject
Exposing skin areas to visible light.
Wherein the sequence of these steps could simultaneous or in any order provided visible light is filtered out from UV rays.
DETAILLED DESCRIPTION OF THE PREFRERRED EMBODIMENTS Thus, the present invention relates to method of treating patients suffering from xeroderma pigmentosum or from a symptom associated therewith, comprising the steps:
Exposing skin area to visible light
Administering a MC1 R agonist MC1 R agonist could be of any type but are preferably compounds of general formula (I) below:
Figure imgf000007_0001
in which: R1 represents a hydrogen atom, an aryl, a substituted aryl, an alkyl, a cycloalkyi, a cycloalkylalkyl or a cycloalkylalkylalkyl,
R2 represents a hydrogen atom, a hydroxyl, a lower alkyl, a substituted lower alkyl, a higher alkyl, a substituted higher alkyl, a cycloalkyi, a cycloalkylalkyl, a lower alkoxy, a substituted lower alkoxy, a higher alkoxy, a substituted higher alkoxy, a cycloalkylalkoxy, an acyloxy, an acyl, an alkoxycarbonyl, a carboxamide, a carboxylic acid, a cyano, or an amino disubstituted with an acyl and an aryl or alkyl, R3 represents an aralkyl or a substituted aralkyl, R4 represents a heteroaralkyl or a substituted heteroaralkyl, R5 represents a hydrogen atom or an alkyl, X represents an oxygen atom or a sulfur atom, n, m may be equal to 1 or 2; and also the corresponding salts and enantiomers.
They could be administered in amounts from 0.001 to 20%, particularly, from 0.01 to 15% Among the compounds of general formula (I) included in the context of the present invention, mention may be made especially of the following:
1 -[(S)-2-(4-Butyryl-4-phenylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea
1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-[1 -(4-methoxybenzyl)-2-oxo-2-(4-oxo-1 -phenyl-1 ,3,8- triazaspiro[4.5]dec-8-yl)ethyl]urea 1 -[2-(4-Cyano-4-phenylpiperidin-1 -yl)-1 -(4- methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea
1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-[1 -(4-methoxybenzyl)-2-oxo-2-(4-phenylpiperidin-1 - yl)ethyl]urea 1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-[1 -(4-methoxybenzyl)-2-oxo-2-piperidin-1 -yl-ethyl]urea Ethyl 4-cyclohexyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate
N-{1 -[2-{3-[2-(1 H-lmidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]piperidin- 4-yl}- N-phenylpropionamide
1 -[2-{3-[2-(1 H-lmidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]-3-phenyl- azetidin- 3-yl butyrate Ethyl 1-[2-{3-[2-(1 H-lmidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]piper- idine-4- carboxylate
1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-{1 -(4-methoxybenzyl)-2-[4-(2-methoxyphenyl)- piperidin-1 - yl]-2-oxoethyl}urea 1 -[2-(3-Butoxy-3-phenylazetidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]- 3-[2-(1 H- imidazol-4-yl)ethyl]urea
Methyl 4-cyclohexyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylamide 1 -A-(S-Cyclohexanecarbonylazetidin-l -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]ureaEthyl 4-cyclohexyl-1 -[2-{3-ethyl-3-[2-(1 H-imidazol-4-yl)ethyl]ureido}- 3-(4-methoxy- phenyl)propionyl]piperidine-4-carboxylate N-Cyclopropyl-N-{1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-nnethoxyphenyl)- propionyl]piperidin-4-yl}propionamide Ethyl 4-cyclohexyl-1 -(2-{3-[2-(1 H-imidazol-4- yl)ethyl]ureido}-3-phenylpropionyl)- piperidine-4-carboxylate
1 -[2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2-(3H- imidazol-4-yl)ethyl]urea
1 -[2-(4-Butoxy-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea Ethyl 4-cyclohexyl-1 -(2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-2-phenylacetyl)- piperidine-4- carboxylate
Methyl 4-cyclohexyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate 1 -[2-(4-Cyclohexyl-4-ethoxypiperidin-1 -yl)-1 -(4- methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea
1 -[2-(4-Acetyl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea Methyl 4-cyclohexyl-1 -(2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-2-phenylacetyl)- piperidine-4- carboxylate
Ethyl 4-ethyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate
1 -[2-(4-Cyclohexyl-4-propoxypiperidin-1 -yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-
(1 H-imidazol-4-yl)ethyl]urea 4-Cyclohexyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4- methoxyphenyl)- propionyl]piperidine-4-carboxylic acid
1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-{1 -(4-methoxybenzyl)-2-[3-(2-nnethylcyclohexyl)-3- propoxyazetidin-1 -yl]-2-oxoethyl}urea Propyl 4-cyclohexyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate 1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-[1 -(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenyl- azetidin-1 -yl)ethyl]urea
Ethyl 1 -((R)-3-(4-chlorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}propionyl)-4- cyclohexylpiperidine-4-carboxylate
Ethyl 1 -((S)-3-(4-chlorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}propionyl)-4- cyclohexylpiperidine-4-carboxylate
1 -[2-(4-Cyclohexyl-4-propionylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]urea
1 -[2-(4-Cyclohexyl-4-propionylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-(1 H- imidazol-4-ylmethyl)urea Ethyl 4-cyclohexyl-1 -[(R)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3- (4-methoxyphenyl)- propionyl]piperidine-4-carboxylate
Ethyl 4-cyclopropylmethyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxy- phenyl)propionyl]piperidine-4-carboxylate
Propyl 4-cyclohexyl-1 -(2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-phenylpropionyl)- piperidine-4-carboxylate
Ethyl 4-cyclopentyl-1 -(2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-phenylpropionyl)- piperidine- 4-carboxylate Ethyl 4-cyclopentyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate Ethyl 4-cyclohexyl-1 -[(S)-2-{3-[2-(1 H-imidazol-4- yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate
1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]urea 1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-fluorobenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea
1 -[(R)-1 -Benzyl-2-(4-butyryl-4-cyclohexylpiperidin-1 -yl)-2-oxoethyl]-3-[2-(1 H-imidazol- 4- yl)ethyl]urea
1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3- [2- (3- methyl-3H-imidazol-4-yl)ethyl]urea 1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-chlorobenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]urea
Ethyl 4-cyclohexyl-1 -((R)-3-(3,4-dichlorophenyl)-2-{3-[3-(1 H-imidazol-4-yl)propyl]- ureido}propionyl)piperidine-4-carboxylate
Ethyl 4-cyclohexyl-1 -((R)-3-(4-methoxyphenyl)-2-{3-[2-(3-methyl-3H-innidazol-4- yl)ethyl]ureido}propionyl)piperidine-4-carboxylate Ethyl 4-cyclohexyl-1 -[(R)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]thioureido}-3-(4-methoxy- phenyl)propionyl]piperidine-4-carboxylate
1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]thiourea
1 -[(R)-2-(4-Cyclohexyl-4-propoxypiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]thiourea
1 -[(R)-1 -Benzyl-2-(4-cyclohexyl-4-propoxypiperidin-1 -yl)-2-oxoethyl]-3-[2-(1 H- imidazol-4- yl)ethyl]thiourea
1 -[(R)- 1 -Benzyl-2-(4-cyclohexyl-4-propoxypiperidin-1 -yl)-2-oxoethyl]-3-[2-(1 H- imidazol-4- yl)ethyl]urea Ethyl 4-cyclohexyl-1 -((R)-3-(4-methoxyphenyl)-2-{3-[2-(3-methyl-3H-imidazol-4- yl)ethyl]thioureido}propionyl)piperidine-4-carboxylate Ethyl 4-cyclohexyl-1 -((R)-2-{3-[2-(3-methyl-3H-imidazol-4-yl)ethyl]ureido}-3-phenyl- propionyl)piperidine-4-carboxylate
1 -[(R)-2-(4-Cyclohexyl-4-propoxypiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2- (3- methyl-3H-imidazol-4-yl)ethyl]urea
Ethyl 1 -((R)-3-(4-chlorophenyl)-2-{3-[2-(3-methyl-3H-imidazol-4-yl)ethyl]ureido}- propionyl)- 4-cyclohexylpiperidine-4-carboxylate Ethyl 4-cyclohexyl-1 -((R)-3-(4-fluorophenyl)-2-{3-[2-(3-methyl-3H-imidazol-4-yl)ethyl]- ureido}propionyl)piperidine-4-carboxylate
Ethyl 4-cyclohexyl-1 -((R)-3-(4-fluorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}- propionyl)piperidine-4-carboxylate
Ethyl 4-cyclohexyl-1 -((R)-3-(4-fluorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]thio- ureido}propionyl)piperidine-4-carboxylate
Ethyl 1 -((R)-3-(4-chlorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]thioureido}propionyl)-4- cyclohexylpiperidineA-carboxylate
Ethyl 1-((R)-3-(4-chlorophenyl)-2-{3-[2-(3-methyl-3H-imidazol-4-yl)ethyl]thioureido}- propionyl)-4-cyclohexylpiperidine-4-carboxylate 1 -[(R)-2-(4-Cyclohexyl-4-propoxypiperidin-1 -yl)-1 -(4-fluorobenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]urea a-Melanotropin , 4-L-norleucine-7-D-phenylalanine- 1 -[(R)-1 -(4-Chlorobenzyl)-2-(4-cyclohexyl-4-propoxypiperidin-1 -yl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]urea and also the respective salts and enantiomers thereof.
The light source used for exposing patients to visible light coud be either sunlight or artificial light like LED lamps.
'Visible light' is defined as the portion of electromagnetic radiation that is visible to the human eye, responsible for the sense of sight. Visible light has a wavelength in a range from about 380 or 400 nanometres to about 760 or 780 nm, with a frequency range of about 405 THz to 790 THz. Preferably from 400nm to 700nm
The exposure time is also a key factor. Exposure time may vary to achieve sufficient tanning and is linked to the source of visible light and/or the intensity of the light source.
The exposure time is at leat 5 min but preferably at least 1 hour.
In order to avoid UV exposure which is painful and dangerous for patients suffering from xeroderma pigmentosum, the use of a sunscreen may help to achieve the visible light only exposure within the acceptable range of wavelenght.
The method of treatment is particularly effective for patients having skin type IV to VI. By skin type it is means that a skin type according to the Fitzpatrick Scale (aka Fitzpatrick skin typing test or Fitzpatrick phototyping scale).
This scale is a numerical classification schema for the color of skin. It was developed in 1975 by T.B. Fitzpatrick, a Harvard dermatologist, as a way to classify the response of different types of skin to UV light. It remains a recognized tool for dermatologic research into the color of skin.
It measures several components: Genetic Disposition, Reaction to Sun Exposure and Tanning Habits
The Fitzpatrick Scale:
Type I (scores 0-7) White; very fair; freckles. Always burns, never tans
Type II (scores 8-16) White; fair. Usually burns, tans with difficulty
Type III (scores 17-25) Beige; very common. Sometimes mild burn, gradually tans
Type IV (scores 25-30) Beige with a brown tint; typical Mediterranean Caucasian skin. Rarely burns, tans with ease
Type V (scores over 30) Dark brown. Very rarely burns, tans very easily
Type VI Black. Never burns, tans very easily
Preferably the skin type is from type IV to VI. EXAMPLES
These examples are intended to be illustrative only, and are not to be construed as limiting the scope of the appended claims: Example 1 : 4-Cyclohexyl-1-[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4- methoxyphenyl)propionyl]piperidine-4-tert-butylcarbamoyl
1-1-1 4-tert-Butylcarbamoyl-4-cyclohexylpiperidine-1-tert-butoxycarbonyl
0.53 ml (1.06 mmol) of a 2M solution of oxalic acid in dichloromethane and 0.04 ml of dimethylformamide are added to 300 mg (0.96 mmol) of piperidine-1 -tert-butoxycarbonyl-4- cyclohexyl-4'-carboxylic acid in 3.5 ml of dichloromethane at 0(0)C. After 1 hour, the solvents are evaporated off. 3.5 ml of tert-butylamine are added and the medium is stirred at room temperature for 6 hours.
After evaporating off the solvents, the crude product obtained is chromatographed on silica gel (eluent: 1/1 heptane/ethyl acetate). 285 mg of a white solid are obtained in a yield of 81 %.
1-1-24-tert-Butylcarbamoyl-4-cyclohexylpiperidine
5 ml of a 4M solution of hydrogen chloride in ethyl acetate are added to 280 mg (1.86 mmol) of 4-tert-butylcarbamoyl-4-cyclohexylpiperidine-1 -tert-butoxycarbonyl.
After stirring for 4 hours, the reaction medium is washed with aqueous 1 N hydrochloric acid solution and then with aqueous sodium hydroxide solution, adjusting the pH to 10.
The organic products are extracted with ethyl acetate.
After evaporating off the solvents, 172 mg of a white powder are obtained in a yield of 72%. 1 H NMR CDCh: .delta. = 0.80-1.06 (m, 7H); 1.16 (s, 9H); 1.52-1.60 (m, 6H); 1.78-1.85 (m, 2H); 2.62 (bt, 2H, J = 12.8 Hz); 2.98 (bd, 2H, J = 12.8 Hz) 1-2-1 Methyl (S)-2-amino-3-(4-methoxyphenyl)propionate
To 10 g (33.8 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid are added 75 ml of methanol and then 10 ml of sulfuric acid dropwise over 30 minutes. After 30 hours, the reaction medium is basified to pH 8-9 by adding aqueous 10N sodium hydroxide solution followed by saturated sodium hydrogen carbonate solution.
The organic products are extracted with dichloromethane.
The organic phase is dried over magnesium sulfate and then filtered, and the solvents are evaporated off. 6.36 g of methyl (S)-2-amino-3-(4-methoxyphenyl)propionate in the form of a brown oil are obtained in a yield of 90%.
1-2-2 Methyl (S)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propanoate
To 5.08 g (24.3 mmol) of methyl (S)-2-amino-3-(4-methoxyphenyl)propionate are added 15 ml of dichloromethane.
The reaction medium is immersed in a bath of cold water. 7.34 g (36.4 mmol) of 4- nitrophenyl chloroformate are added, followed by 6.33 ml of diisopropylethylamine.
After warming to room temperature, the reaction medium is stirred for 2 hours.
The reaction is stopped by adding water, followed byextraction with dichloromethane.
The organic phase is dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. 12 g of a yellow oil are obtained.
To these 12 g are added 10 ml of dimethylformamide and the mixture is then heated to 80(0)C. 8.95 g (48.6 mmol) of histamine dihydrochloride are added, followed by dropwise addition of 14.8 ml (85.1 mmol) of diisopropylethylamine.
After cooling to room temperature, the solvents are evaporated off and the crude product is chromatographed on a silica column (eluent: 85/15 dichloromethane/methanol). 5.6 g of methyl (S)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propanoate in the form of a yellow oil are obtained in a yield of 67%. 1 H NMR/CDsOD: .delta.= 2.72 (t, 2H J= 6.36Hz); 2.90 (dd, 1 H, J=13.7, 5.88 Hz); 3.04 (dd, 1 H, J=13.7, 5.60 Hz); 3.22 (q, 2H, J=7.4Hz); 3.67 (s, 3H), 3.75 (s, 3H); 4.48 (q, 1 H, J= 5.76Hz); 6.81 (d, 2H, J=8.6Hz); 6.87 (s, 1 H); 7.05 (d, 2H, J=8.6Hz); 7.75 (s, 1 H)
1-2-3 2-{3-[2-(1 H-lmidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propanoic acid
To 500 mg (1.44 mmol) of methyl (S)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4- methoxyphenyl)propanoate are added 500 mg of lithium hydroxide, 7 ml of tetrahydrofuran and 2 ml of water.
The reaction medium is placed in a microwave reactor with stirring, at 100(0)C for 10 minutes.
Seven other identical tests are performed.
The various tests are combined and concentrated to dryness.
The crude product obtained is purified by filtration on a pad of silica (eluent: 1/1
dichloromethane/methanol). 2.73 g of 2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4- methoxyphenyl)propanoic acid in the form of a pale yellow powder are obtained in a yield of
70%. 1 H NMR/CDsOD : .delta.= 2.71 (t, 2H J= 6.94Hz); 2.89 (dd, 1 H, J=13.6, 6.67 Hz); 3.05
(dd, 1 H, J=13.6, 4.97 Hz); 3.22 (q, 2H, J=7.4Hz); 3.72 (s, 3H); 4.31 (tl, 1 H, J= 5.97Hz); 6.76
(d, 2H, J=8.5Hz); 6.84 (s, 1 H); 7.10 (d, 2H, J=8.5Hz); 7.68 (s, 1 H) 1 -3 4-tert-Butylcarbamoyl 4-cyclohexyl- 1 -[2-{3-[2-(1 H-imidazol-4-yl) ethyl]ureido}-3-(4- methoxyphenyl)propionyl]piperidine
To 150 mg (0.45 mmol) of 2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxy- phenyl)propanoic acid dissolved in 3 ml of dichloromethane and 0.5 ml of dimethylformamide are added 0.16 ml (0.90 mmol) of diisopropylethylamine, 161 mg (0.50 mmol) of TBTU and 133 mg (0.50 mmol) of 4-tert-butylcarbamoyl-4-cyclohexyl-piperidine.
After 3 hours, the solution is washed with 1 N sodium hydroxide solution and the organic products are extracted with dichloromethane.
The organic phase is dried over magnesium sulfate, filtered and concentrated.
The crude product obtained is purified by preparative TLC (eluent:
dichloromethane/methanol 85/15). 29 mg of 4- tert-butylcarbamoyl 4-cyclohexyl- 1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4- methoxyphenyl)propionyl]-pipehdine in the form of a white powder are obtained in a yield of 11 %.
(1)1-1 NMR/DMSOn[fi] 100.deg.C: .delta. = 0.89-1.17 (m, 7H); 1.29 (s, 9H); 1.34-1.99 (m, 9H); 2.62 (t, J = 7.2 Hz, 2H); 2.73-2.89 (m, 4H); 3.24 (ql, J = 6 - 7.6 Hz, 2H); 3.73 (s, 3H); 4.81 (ql, J = 6 Hz, 1 H); 5.93 (tl, 1 H); 6.00 (d, J = 8.8 Hz, 1 H); 6.23 (s, 1 H); 6.74 (s, 1 H); 6.81 (d, J = 8.4 Hz, 2H); 7.08 (d, J = 8 Hz, 2H); 7.47 (s, 1 H).
Example 2: 1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxy- benzyl)-2- oxoethyl]-3-[2-(1 -methyl-1 H-imidazol-4-yl)ethyl]urea 2-1-1 4-Phenyl-1-(toluene-4-sulfonyl)pipe dine-4-carbonit le
17.2 g (89.8 mmol) of 4-methylbenzenesulfonyl chloride dissolved in 150 ml of
dichloromethane are added to a solution of 20 g (89.8 mmol) of 4-phenylpiperidine-4- carbonitrile and 28 ml of triethylamine in 200 ml of dichloromethane.
The reaction mixture is stirred for 1 hour at room temperature.
The reaction is stopped by adding
200 ml of water, and is then extracted with dichloromethane.
The organic phases are combined and dried over sodium sulfate.
The solvents are evaporated off and the residue is then taken up in diethyl ether and filtered off. 30.3 g of 4-phenyl-1-(toluene- 4-sulfonyl)piperidin-4-carbonitrile in the form of a white powder are obtained in a yield of 99%. (1)H NMRZCDCI[3]: .delta.=0.60 (t, 3H, J=7.36Hz); 1.35 (hex, 2H, J=7.36Hz); 2.09 (t, 2H, J=7.36Hz); 2.15 (m, 2H); 2.46 (s, 3H); 2.57-2.66 (4H, m); 3.57-3.62 (2H, m); 7.22 (d, 2H, J=8.2Hz); 7.23-7.46 (m, 5H); 7.71 (d, J=8.2Hz)
2-1-2 1-[4-Phenyl-1-(toluene-4-sulfonyl)piperidin-4-yl]-butan-1-one 88 ml (176 mmol) of n-propylmagnesium chloride are added to a solution of 30 g (88 mmol) of 4-phenyl-1 -(toluene-4-sulfonyl)piperidine-4-carbonithle in 500 ml oftoluene.
The reaction mixture is stirred for 6 hours at 65-70(0)C and then overnight at room temperature.
The reaction is stopped by adding 100 ml of tetrahydrofuran, and is then hydrolysed with 1 N hydrochloric acid solution and extracted with ethyl acetate.
The organic phases are combined and dried over sodium sulfate.
The solvents are evaporated off and the residue is then taken up in diethyl ether and filtered off. 1.38 g of starting material are recovered.
The filtrate is concentrated to dryness and then chromatographed on silica gel (eluent: 80/20 heptane/ethyl acetate). 17.8 g of 1 -[4-phenyl-1-(toluene-4-sulfonyl)piperidin-4-yl]-butan-1 - one in the form of a white powder are obtained in a yield of 50%. 1 H
NMRZCDCI[3]: .delta.=0.60 (t, 3H, J=7.36Hz); 1.35 (hex, 2H, J=7.36Hz); 2.09 (t, 2H, J=7.36Hz); 2.15 (m, 2H); 2.46 (s, 3H); 2.57-2.66 (4H, m); 3.57-3.62 (2H, m); 7.22 (d, 2H, J=8.2Hz); 7.23-7.46 (m, 5H); 7.71 (d, J=8.2Hz) 2-1-34-Butyryl-4-phenylpiperidine hydrochloride
10 g (26 mmol) of 1 -[4-phenyl-1-(toluene-4-sulfonyl)piperidin-4-yl]-butan-1 -one are suspended in 64 ml of sulfuric acid and 32 ml of water.
The reaction mixture is stirred at reflux for 48 hours.
The reaction is monitored by HPLC. 50 ml of ethanol are added to homogenize the reaction medium, followed by 40 ml of sulfuric acid, and heating is continued for 24 hours.
The reaction is stopped by addition to ice and basified with sodium hydroxide solution, and then extracted with ethyl acetate.
The organic phases are combined and dried over sodium sulfate.
The solvents are evaporated off and the residue is then taken up in diethyl ether and precipitated with a 4N solution of hydrogen chloride in ethyl acetate. 3.8 g of 4-butyryl-4- phenylpiperidine hydrochloride in the form of a white powder are obtained in a yield of 55%. (1)H NMR/DMSO: .delta.=0.56 (t, 3H, J=7.36Hz); 1.31 (hex, 2H, J=7.36Hz); 2.21 (m, 2H); 2.27 (t, 2H, J=7.36Hz); 2.55 (m, 2H); 2.94-2.99 (m, 2H); 3.09-3.12 (m, 2H); 7.32-7.37 (m, 3H); 7.42-7.46 (m, 2H); 8.99 (si, 1 H).
2-1-4 1 -(4-Cyclohexylpiperidin-4-yl)butan-1 -one In a Parr bomb under a hydrogen pressure of 6 bar, 100 mg of rhodium on alumina and 0.2 ml of acetic acid are added to a solution of 100 mg (0.5 mmol) of 4-butyryl-4- phenylpiperidine hydrochloride in 10 ml of dioxane.
The reaction medium is heated at 80(0)C for 12 hours.
The reaction is stopped and then filtered through Celite andwashed with dichloromethane. The solvents are evaporated off and the residue is taken up in water, basified with 1 N sodium hydroxide solution and extracted with ethyl acetate.
The organic phases are dried over sodium sulfate.
The solvents are evaporated off and the residue is chromatographed on silica gel (eluent: 9/1 dichloromethane/methanol). 51.2 mg of 1 -(4-cyclohexylpiperidin-4-yl)-butan-1-one in the form of a white powder are obtained in a yield of 61 %.
(1)1-1 NMRZCDCI[3]: .delta.=0.92 (t, 2H, J=7.36Hz); 0.98 (m, 2H); 1.07-1.27 (m, 3H), 1.34- 1.42 (m, 1 H); 1.49-1.68 (m, 5H), 1.62 (hex, 2H, J=7.36Hz); 1.72-1.82 (m, 2H); 2.02 (ddl, 2H, J=2.28; 13.7Hz); 2.40 (t, 2H, J=7.36Hz); 2.55 (td, 2H, J=2.28; 12.4Hz); 2.95 (dtl, 2H, J=2.96, 12.4Hz). 2-2 tert-Butyl [(R)-2-(4-butyry\-4-cyc\ohexy\p\per\ \n-1-y\)-1-(4-methoxybenzy\)-2- oxoethyljcarbamate
0.44 g (1.9 mmol) of 1 -(4-cyclohexylpiperidin-4-yl)butan-1 -one, 0.56 g of (R)-2-tert- butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid (1.9 mmol), 0.4 g (2.1 mmol) of EDC and 0.282 g (2.1 mmol) of HOBt are dissolved in 4 ml of DMF. The mixture is stirred at room temperature for 2 hours.
The solution is washed with aqueous 2.5% citric acid solution and extracted with ethyl acetate, and the organic phase is then washed with aqueous 10N sodium hydroxide solution. It is dried over sodium sulfate, filtered and concentrated.
The crude product obtained is chromatographed on silica gel (eluent: 7/3 heptane/ethyl acetate). 0.43 g is obtained in the form of a colourless oil in a yield of 44%.
(1)H NMR CDCh: results given in figure 2a (mixture of conformers) 2-3 1-{1-[(R)-2-Amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidin-4-yl}- butan-1- one
0.43 g (0.84 mmol) of tert-butyl [(R)-2-(4-butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4- methoxybenzyl)-2-oxoethyl]carbamate is diluted in 8 ml of DCM and 2 ml of trifluoroacetic acid.
The solution is stirred for 1 hour 30 minutes at room temperature and then poured into 1 N sodium hydroxide solution and extracted with dichloromethane.
The organic phase is dried, filtered and then concentrated. 300 mg of 1 -{1 - [(RA-amino-SA- methoxyphenylJpropionyllA-cyclohexylpiperidinA-ylJbutan-i-one in the form of a colourless oil are obtained in a yield of 86%.(1)H NMR CDCh: results given in figure 2b (mixture of conformers)
2-4 i-KRA-ft-ButyrylA-cyclohexylpiperidin-i-yty-i-A-methoxybenzytyA-oxoethyl]- 3-[2-(1 -methyl- 1 H-imidazol-4-yl)ethyl]urea
75 mg (0.18 mmol) of 1-{1 -[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexyl- piperidin-4-yl}butan-1 -one and 40 mg (0.2 mmol) of para-nitrophenyl chloroformate are dissolved in 5 ml of dichloromethane.
The mixture is stirred for 1 hour at room temperature and the solution is then stopped by adding 20% aqueous ammonia and extracted with dichloromethane.
The organic phase is washed with water and then dried over sodium sulfate, filtered and concentrated to dryness.
The oil obtained is diluted in 5 ml of DMF, the mixture is heated to 80(0)C and 39 mg (0.2 mmol) of 1 - methylhistamine and 0.05 ml (0.36 mmol) of triethylamine are then added, and the solution is stirred for 5 minutes at 80(0)C and for 10 minutes at room temperature.
The reaction is stopped by adding aqueous 1 N sodium hydroxide solution and then extracted with DCM. The organic phase is washed with water and then dried over sulfate, filtered and concentrated.
The oil obtained is chromatographed on silica gel (eluent: 90/10 DCM/MeOH). 40 mg of 1 - [(R)-2-(4-butyryl-4-cyclohexylpiperidin-1-yl)- 1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1-methyl- 1 H-imidazol-4-yl)ethyl]urea in the form of a colourless oil are obtained in a yield of 39%. (1)1-1 NMR DMSOnfi 100.deg.C: 0.80-0.90 (m, 5H); 1.04-1.22 (m, 4H); 1.32-1.54 (m, 6H); 1.59-1.62 (m, 1 H); 1.72 (bd, 2H, J=13.2Hz); 1.89 (bt, 2H, J=13.2Hz); 2.40 (t, 2H, J=7.2Hz); 2.54 (t, 2H, J=7.2Hz); 2.71 (dd, 1 H, J=8.0, 13.6Hz); 2.79 (dd, 1 H, J=13.6, 5.6Hz); 3.2 (m, 4H); 3.22 (q, 2H, J=7.2Hz); 3.59 (s, 3H); 3.73 (s, 3H); 4.79 (q, 1 H, J=4.3Hz); 5.89 (vs, 1 H); 5.98 (bd, J= 7.2Hz); 6.76 (s, 1 H); 6.81 (d, 2H, J=8.0Hz); 7.07 (d, 2H, J=8.0Hz); 7.39 (s, 1 H). Example 3: 1 -[(/?)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxy- benzyl)-2- oxoethyl]-3-[2-(1 H-[1 ,2,3]triazol-4-yl)ethyl]urea
3-1-1 2,2-Dimethylpropionic acid 4-[2-(1 ,3-dioxo-1 ,3-dihydroisoindol-2-yl)ethyl]- [1 ,2,3]triazol- 1-ylmethyl ester 702 mg (3.52 mmol) of N-(3-butynyl)phthalimide and 552 mg (3.51 mmol) of 2,2- dimethylpropionic acid azidomethyl ester are suspended in a water/f-butanol mixture (1/1 , 10.5 ml). 0.18 ml of a 1 M CuSO[4] solution is added. 206 mg (1.04 mmol) of sodium ascorbate are then added.
After 4 hours, the reaction is stopped by adding aqueous ammonia solution, and the reaction medium is extracted with EtOAc. The organic phase is then washed with brine and dried over MgSO[4], filtered and concentrated. 1.1 1 g of 2,2-dimethylpropionic acid 4-[2-(1 ,3-dioxo-1 ,3- dihydro- isoindol-2-yl)ethyl]-[1 ,2,3]thazol-1 -ylmethyl ester in the form of a yellow oil are obtained in a yield of 88%.
3-1-2 2-(1 H-[1 ,2,3]Triazol-4-yl)ethylamine dihydrochloride 1.08 g (3.03 mmol) of 2,2-dimethylpropionic acid 4-[2-(1 ,3-dioxo-1 ,3-dihydroisoindol- 2- yl)ethyl]-[1 ,2,3]thazol-1 -ylmethyl ester are dissolved in 7 ml of MeOH, to which 7 ml of aqueous 1 N sodium hydroxide solution are added.
After stirring for 2 hours, the reaction medium is extracted with DCM. The aqueous phase is concentrated.
The solid obtained is taken up in ethanol and, after filtration, the solvents are evaporated off. The crude product is purified in a column of silica (7/3 DCM/MeOH). 558 mg of a white solid are obtained and dissolved in 15 ml of THF and 6 ml of water, to which are added 720 mg of lithium hydroxide.
The reaction medium is placed at 160(0)C in a microwave reactor for 45 minutes.
The reaction medium is filtered and then extracted with DCM. The aqueous phase is then acidified with hydrochloric acid (pH = 1 ) and is then concentrated.
The crude product obtained is chromatographed on silica gel (eluent: 7/3 DCM/MeOH). 430 mg of 2-(1 H-[1 ,2,3]thazol-4-yl)ethylamine dihydrochloride are obtained in the form of a white powder in a yield of 14%. 1 H NMR DMSO: 2.93 (m, 2H); 3.02 (m, 2H); 7.76 (s, 1 H)3-2 i-tfRA- AButyryl-Acyclohexylpiperidin-i-yty-i-AmethoxybenzylA-oxoethylJ-S- [2-(1 H-[l[1]2, 3]triazol-4- yl)ethyl]urea
30 mg (0.15 mmol) of 4-nitrophenyl chloroformate are added, at 0(0)C, to 57 mg (0.14 mmol) of 1 -{1 -[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexyl- piperidin-4-yl}butan-1 - one (cf. preparation 2-3) dissolved in 2 ml of DCM. The reaction mixture is stirred for 4 hours at room temperature.
The reaction is stopped by adding aqueous NH[4]OH solution and the organic compounds are extracted with DCM. The organic phase is then washed with water and dried over MgSO[4], filtered and concentrated.
The oil obtained is dissolved in DMF at 80(0)C, and 52 mg (0.28 mmol) of 2-(1 H- [1 ,2,3]triazol-4-yl)ethylamine dihydrochloride and 0.1 ml (0.72 mmol) of thethylamine are then added.
The reaction mixture is stirred at 80.deg.C for 10 minutes.
After cooling to room temperature, dichloromethane is added and the organic phase is washed with 1 N sodium hydroxide.
The organic phase is dried over MgSO[4], filtered and concentrated.
The crude product obtained is chromatographed on silica gel (eluent: 93/7 DCM/MeOH). 25 mg of 1 -[(R)-2-(4-butyryl-4-cyclohexyl- piperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2- (1 H-[1 ,2,3]thazol-4-yl)ethyl]urea are obtained in the form of a white solid in a yield of 32%.
HPLC:
Atlantis T3 150 x 4.6 mm, 5 . micro. m column UV detector: 190-450 nm Flow rate: 0.3 ml/min Solvent A: H2O+0.05TFA Solvent B: CH3CN+0.05TFA Gradient: Time composition 0.0 min A=95%, B=5%
20.0 min A=5%, B=95% 30.0 min A=5%, B=95% Retention time: 17.44 min, 97%, M+H: 553. Example 4: Ethyl 4-cyclohexyl-1-[(/?)-2-{3-[3- (3H-imidazol-4-yl)propyl]- ureido}-3-(4-methoxyphenyl)propionyl]piperidine-4-carboxylate
4-1-1 Ethyl piperidine-1-tert-butoxycarbonyl-4-cyclohexyl-4'-carboxylate 1.92 ml (12.8 mmol) of DBU and 1.04 ml (12.8 mmol) of iodoethane are added to 2.00 g (6.42 mmol) of piperidine-1 -tert-butoxycarbonyl-4-cyclohexyl-4'-carboxylic acid in 10 ml of toluene.
The medium is stirred in a microwave reactor for 10 minutes at 120(0)C. Dichloromethane is added to the reaction medium and the organic phase is washed with a saturated aqueous NaHC03 solution.
The organic phase is dried over MgSO[4], filtered and concentrated.
The crude product obtained is chromatographed on silica gel (eluent: 9/1 heptane/ethyl acetate). 1.92 g of ethyl piperidine-1 -tert- butoxycarbonyl-4-cyclohexyl-4'-carboxylate in the form of a colourless oil are obtained in a yield of 88%.
4-1-2 Ethyl piperidine-4-cyclohexyl-4'-carboxylate
6 ml of trifluoroacetic acid are introduced at 0(0)C into 1.90 g (5.60 mmol) dissolved in 8 ml of dichloromethane.
After 4 hours, the solvents are evaporated off and the reaction medium is taken off in EtOAc and then washed with 1 N sodium hydroxide.
The organic phase is dried over MgSO[4], filtered and evaporated. 1.21 g of ethyl piperidine- 4-cyclohexyl-4'-carboxylate in the form of a white solid are obtained in a yield of 90%.
(1)1-1 NMR CDCh: 1.07-1.17 (m, 6H) ; 1.21 (t, 3H, J=7.2Hz); 1.25-1.33 (m, 1 H); 1.45 (dt, 2H, J=13.4, 4.16Hz); 1.56-1.71 (m, 5H); 2.09 (bd, 2H, J=13.6Hz); 2.61 (bt, 2H, J=12.8Hz), 3.03 (bd, 2H, J=12.8Hz); 4.12 (q, 2H, J=7.12Hz)
4-2 3-(1 H-lmidazol-4-yl)propylamine bis(trifluoroacetate)
2 ml of trifluoroacetic acid are added to 195 mg (0.53 mmol) of 3-(1 -trityl-1 H-imidazol- 4-yl) propylamine dissolved in 8 ml of DCM and then immersed in an ice bath.
After warming to room temperature, the reaction medium is stirred for 2 hours and the solvents are then evaporated off.
The solid obtained is taken up in EtOAc and water.
The aqueous phase is then concentrated and 110 mg of a white powder are obtained and used in the next step without further purification. (1)H NMR DMSO: 2.09 (pent, 2H, J=6.9Hz); 2.77-2.82 (m, 2H); 4.28 (t, 2H, J=6.8Hz); 7.71 (s, 1 H); 7.77 (s, 1 H); 9.1 1 (s, 1 H) 4-3 Ethyl 1-[(R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionyl]-4- cyclohexylpiperidine-4-carboxylate
To 3.22 g (10.9 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)- propionic acid dissolved in 20 ml of DMF are added 2.29 g (12.0 mmol) of EDC, 1.62 g (12.0 mmol) of HOBt, 2.62 g (10.9 mmol) of ethyl 4-cyclohexylpiperidine-4- carboxylate and 4.6 ml (32.7 mmol) of triethylamine.
After stirring for 2 hours 30 minutes, the reaction is stopped by adding aqueous 1 N sodium hydroxide solution and the organic products are extracted with dichloromethane.
The organic phase is dried over MgSO[4], filtered and evaporated.
The crude product obtained is chromatographed on silica gel (eluent: 7/3 heptane/EtOAc). 3.70 g of ethyl 1 -[(R)-2- tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionyl]-4- cyclohexylpiperidine-4- carboxylate in the form of a white powder are obtained in a yield of 66%. 1 H NMR/CDCh: results presented in figure 3a (mixture of conformers)
4-4 Ethyl i-KRA-amino-S-ft-methoxyphenyljpropionylA-cyclohexylpiperidineA- carboxylate To 3.7 g (7.16 mmol) of ethyl 1 -[(R)-2-tert-butoxycarbonylamino-3-(4-methoxy- phenylJpropionylH-cyclohexylpipehdineA-carboxylate dissolved in 30 ml of DCM immersed in a bath at 0(0)C are added 10 ml of trifluoroacetic acid.
After stirring for 1 hour 30 minutes, the solvents are evaporated off.
The reaction medium is washed with aqueous 1 N sodium hydroxide solution and extracted with DCM. The organic phase is then washed with water and then dried over MgSO[4], filtered and concentrated. 2.74 g of ethyl 1 -[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4- cyclohexylpiperidine-4-carboxylate in the form of a white powder are obtained in a yield of
92%.
(1)H NMR/CDCh: results presented in figure 3b (mixture of conformers)4-5 Ethyl 4- cyclohexyl-1-[(R)-2-{3-[3-(3H-imidazol-4-yl)propyl]ureido}-3-(4-methoxy- phenyl)propionyl]piperidine-4-carboxylate
To 100 mg (0.24 mmol) of ethyl 1 -[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4- cyclohexylpiperidineA-carboxylate dissolved in 2 ml of DCM immersed in a bath of cold water are added 53 mg (0.26 mmol) of 4-nitrophenyl chloroform ate.
After warming to room temperature, the reaction medium is stirred for 2 hours and 30 minutes.
The reaction is stopped by adding aqueous ammonia solution.
The organic phase is then washed with water and then dried over MgSO[4], filtered and concentrated.
The oil obtained is dissolved in 4 ml of DMF at 80(0)C, and 110 mg (0.31 mmol) of 3-(1 H- imidazol-4-yl)propylamine bis(thfluoroacetate), 0.05 ml of thethylamine are then added. The reaction mixture is left stirring at 80(0)C for 15 minutes.
After returning to room temperature, dichloromethane is added and the organic phase is washed with 1 N sodium hydroxide solution.
The organic phase is dried over MgSO[4], filtered and concentrated.
The crude product obtained is chromatographed on silica gel (eluent: 9/1 DCM/MeOH). 26 mg of ethyl 4-cyclohexyl- 1 -[(R)-2-{3-[3-(3H-imidazol-4-yl)propyl]ureido}-3-(4- methoxyphenyl)propionyl]- piperidine-4-carboxylate in the form of a colourless oil are obtained in a yield of 11 %. (1)H NMR: results presented in figure 3c (mixture of conformers)
Example 5: Ethyl 4-cyclohexyl-1-((R)-3-(3,4-dichlorophenyl)-2-{3-[2-(1 H- imidazol-4- yl)ethyl]ureido}propionyl)piperidine-4-carboxylate:
5-1 Ethyl 1-[(R)-2-tert-butoxycarbonylamino-3-(3,4-dichlorophenyl)propionyl]-4- cyclohexylpiperidineA-carboxylate
0.5 g (2.1 mmol) of ethyl pipehdine-4-cyclohexyl-4'-carboxylate (cf. preparation 4-1- 2), 0.7 g
(2.1 mmol) of (R)-2-tert-butoxycarbonylamino-3-(3,4-dichlorophenyl)- propionic, 0.31 g (2.3 mmol) of HOBT, 0.44 g (2.3 mmol) of EDC and 0.73 ml (4.2 mmol) of diisopropylethylamine are placed in 5 ml of DMF. The mixture is stirred for 2 hours at room temperature.
The reaction is stopped by addition of an aqueous 5% citric acid solution.
The organic compounds are extracted with ethyl acetate, then the organic phase is washed with aqueous 1 N sodium hydroxide solution and then with water.
The organic phase is dried over sodium sulfate, filtered and concentrated.
The oil obtained is chromatographed on silica gel (eluent: 1/1 heptane/ethyl acetate).300 mg of ethyl 1 -[(R)-2-tert-butoxycarbonylamino-3-(3,4-dichlorophenyl)propionyl]-4- cyclohexylpiperidine-4-carboxylate are obtained in a yield of 26%. 1 H NMR CDCh: results given in figure 4 (mixture of conformers)
5-2 Ethyl 1-[(R)-2-amino-3-(3,4-dichlorophenyl)propionyl]-4-cyclohexylpiperidine-4- carboxylate 300 mg (0.54 mmol) of ethyl 1 -[(R)-2-tert-butoxycarbonylamino-3-(3,4-dichloro- phenylJpropionylH-cyclohexylpipehdineA-carboxylate are diluted in 5 ml of a 4/1
dichloromethane/trifluoroacetic acid solution.
After stirring for 2 hours, the mixture is poured into aqueous 1 N sodium hydroxide solution and then extracted with dichloromethane.
The organic phase is dried over sodium sulfate, filtered and concentrated. 210 mg of ethyl 1 - [(R)-2-amino-3-(3,4-dichlorophenyl)propionyl]-4- cyclohexylpiperidine-4-carboxylate in the form of a white powder are obtained in a yield of 86%. 5-3 Ethyl 4-cyclohexyl-1-((R)-3-(3,4-dichlorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]- ureido}propionyl)piperidine-4-carboxylate
60 mg (11 mmol) of ethyl 1 -[(R)-2-amino-3-(3,4-dichlorophenyl)propionyl]-4- cyclohexylpiperidine-4-carboxylate and 29 mg (0.12 mmol) of para-nitrophenyl chloroformate are dissolved in 5 ml of dichloromethane.
The mixture is stirred for 1 hour at room temperature and the solution is then poured into water and extracted with dichloromethane.
The organic phase is dried over sodium sulfate, filtered and concentrated.
The colourless oil obtained is diluted in 5 ml of dimethylformamide, the mixture is heated to 80(0)C, and 18 mg (0.12 mmol) of histamine are added and the solution is stirred for 5 minutes at 80(0)C and overnight at room temperature.
The reaction is stopped by adding aqueous 1 N sodium hydroxide solution and the organic compounds are extracted with dichloromethane.
The organic phase is washed with water and then dried over sodium sulfate, filtered and concentrated.
The oil obtained is chromatographed on silica gel (eluent: 90/10 DCM/MeOH). 25 mg of ethyl 4- cyclohexyl-1 -((R)-3-(3,4-dichlorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}- propionyl)piperidine-4-carboxylate in the form of a colourless oil are obtained in a yield of 38%. 1 H NMR/DMSO lOO.deg.C: 0.89(m, 4H); 1.1 1 (m,4H); 1.22(t,3H,6Hz); 1.28(s,2H); 1.61 (d,3H,8Hz); 1.73(d,2H, 12Hz); 1.97(t,2H,8Hz); 2.62(t,2H,6Hz); 2.87(m,6H);3.24(qua,2H,6Hz); 4.13(qua,2H,8Hz); 4.85(qua,2H8Hz); 5.94(m,1 H) ;
6.09(d, 1 H,8Hz); 6.76(d, 1 H,8Hz); 7.18(d, 1 H,8Hz); 7.40(s,1 H); 7.47(d,1 H,8Hz) ; 7.53(s,1 H)
Example 6: Ethyl 4-cyclohexyl-1 -((/?)-3-(3,4-dichlorophenyl)-2-{3-[2-(3- methyl-3H-imidazol- 4-yl)ethyl]ureido}propionyl)piperidine-4-carboxylate
Synthetic route identical to that of Example 5. (1)H NMRZDMSO 100(0)C: 0.89 (m, 3H); 1.05-1.45 (m,8H); 1.22 (t,3H,6Hz); 1.61 (m,3H); 1.75 (m,2H); 1.97 (m,2H); 2.64 (m,2H); 2.78 (m, 2H); 2.80-3.10 (m,4H); 3.24 (m,2H); 3.56 (s, 3H); 4.15 (qua,2H,8Hz); 4.87 (qua,2H8Hz); 6.02 (m, 1 H); 6.14 (d, 1 H,8Hz); 6.78 (d, 1 H,8Hz); 7.18 (d, 1 H,8Hz); 7.40 (s, 1 H); 7.48 (d, 1 H,8Hz); 7.66 (s, 1 H)
Example 7: Ethyl 4-cyclohexyl-1 -[(/?)-2-{3-[3-(1 H-imidazol-4-yl)propyl]- thioureido}-3-(4- methoxyphenyl)propionyl]piperidine-4-carboxylate 7- 1 Ethyl i-KRA-amino-S-ft-methoxyphenyljpropionylA-cyclohexylpiperidine-A carboxylate trifluoroacetate
To 10 g (19.4 mmol) of ethyl 1 -[(R)-2-tert-butoxycarbonylamino-3-(4-nnethoxyphenyl)- propionyl]-4-cyclohexylpipehdine-4-carboxylate (cf. preparation 4-3) in 80 ml of
dichloromethane are added 20 ml of trifluoroacetic acid.
The reaction medium is stirred for 2 hours at room temperature.
The solvents are evaporated off and diethyl ether is added in the presence of a few drops of dichloromethane.
The precipitate obtained is filtered off and then dried under vacuum at 40(0)C. 8 g of ethyl 1 - [(R)-2- amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpipehdine-4-carboxylate trifluoroacetate in the form of a white powder are obtained in a yield of 78%. 1 H
NMR/CD30D: results presented in figure 5a (mixture of conform ers)
7-2 Ethyl Acyclohexyl-i-KfyA-isothiocyanato-S-A-methoxyphenytypropionyl]- piperidine-4- carboxylate
To 1 g (1.88 mmol) of ethyl 1 -[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4- cyclohexylpiperidineA-carboxylate trifluoroacetate dissolved in 10 ml of CH[2]CA andl ml (5.66 mmol) of diisopropylethylamine are added 438 mg (1.88 mmol) of thiocarbonic acid 0,0-bis(2-pyridyl) ester.
After stirring the reaction medium for 2 hours at room temperature, the solvents are evaporated off and the crude product obtained is chromatographed on silica gel (eluent: 6/4 heptane/EtOAc). 763 mg of ethyl 4-cyclohexyl-1 -[(R)-2-isothiocyanato-3-(4- methoxyphenyl)propionyl]piperidine- 4-carboxylate in the form of a colourless oil are obtained in a yield of 88%. 1 H NMR/CDCh: results presented in figure 5b (mixture of conformers)
7-3 Ethyl 4-cyclohexyl-1-[(R)-2-{3-[3-(1 H-imidazol-4-yl)propyl]thioureido}-3-(4- methoxyphenyl)propionyl]piperidine-4-carboxylate To 65 mg (0.141 mmol) of ethyl 4-cyclohexyl-1-[(R)-2-isothiocyanato-3-(4-methoxy- phenyl)propionyl]piperidine-4-carboxylate in 5 ml of DMF are added 50 mg (0.141 mmol) of 3-(1 H-imidazol-4-yl)propylamine bis(trifluoroacetate) (cf. preparation 4-2) and then 0.063 ml (0.425 mmol) of 1 ,8-diazabicyclo[5.4.0]undec-7-ene.
The reaction medium is stirred for 2 hours and then hydrolysed by adding aqueous 5% citric acid solution.
The organic compounds are extracted with dichloromethane.
The organic phase is dried over MgSO[4], filtered and concentrated.
The crude product obtained is chromatographed on silica gel (eluent: 80/20 CH[2]CbZMeOH). 22 mg of ethyl 4-cyclohexyl-1 -[(R)-2-{3-[2-(1 H-imidazol-4-yl)propyl]thioureido}-3-(4- methoxy- phenyl)propionyl]piperidine-4-carboxylate in the form of a pale yellow powder are obtained in a yield of 26%. 1 H NMR: results presented in figure 5c (mixture of conformers). Example 8 : Ethyl 4-cyclohexyl-1-((R)-3-(4-methoxyphenyl)-2-{3-[2-(1- methyl- 1 H-imidazol-4- yl)ethyl]thioureido}propionyl)piperidine-4- carboxylate
Synthetic route identical to that of Example 7. 1 H NMR: results presented in figure 6 (mixture of conformers).
Example 9 : Ethyl 4-cyclohexyl-1-((/?)-3-(2,4-dichlorophenyl)-2-{3-[2-(1 H- imidazol-4- yl)ethylureido}propionyl)piperidine-4-carboxylate
Synthetic route identical to that of Example 5. 1 H NMR/DMSO 100(0)C: 0.90(m,3H) ; 1.07- 1.27(m,8H); 1.60(m,3H); 1.74(m,2H); 1.96(dd,2H,2.4Hz,1 1.2Hz); 2.60(t,2H,7.2Hz);
2.76(m,2H) ; 2.96(m,4H) ; 3.21 (qua, 2H,7.2Hz) ; 4.12(qua,2H,7.2Hz) ; 4.99(qua,1 H) ;
5.93(s, 1 H) ; 6.1 1 (0,1 HAeHz) ; 6.74(s, 1 H) ; 7.28(s,2H) ; 7.49(d,2H, 11.2Hz) ; 7.97(s, 1 H) Example 10 : Ethyl 4-cyclohexyl-1-[(/?)-2-{3-[5-(1 H-imidazol-4-yl)pentyl]- ureido}-3-(4- methoxyphenyl)propionyl]piperidine-4-carboxylate
10-1-1 1-Trityl- 1 H-imidazole-4-carbaldehyde:
To a solution containing 1 g (10.4 mmol) of 1 H-imidazole-4-carbaldehyde and 3.18 g (11.4 mmol) of trityl chloride suspended in 28 ml of acetonitrile are added dropwise 2.5 ml (17.7 mmol) of triethylamine.
After stirring for 2 hours at room temperature, 30 ml of water are added and the crude reaction product is filtered. 3.2 g in the form of a beige-coloured powder are obtained and used in the following step without further purification.
10-1-2 2-[5-(1-Trityl-1 H-imidazol-4-yl)pent-4-enyl]isoindole-1 ,3-dione 0.663 ml (4.43 mmol) of DBU and 1.0 g (2.96 mmol) of 1 -trityl- 1 H-imidazole-4- carbaldehyde are added to 2.41 g (4.43 mmol) of [4-(1 ,3-dioxo-1 ,3-dihydroisoindol-2- yl)butyl]thphenylphosphonium bromide.
The reaction medium is refluxed for 18 hours.
The reaction is stopped by adding aqueous 5% citric acid solution and the organic compounds are extracted with CH[2]CI[2]. The organic phase is dried over MgSO[4], filtered and concentrated.
The residue obtained is chromatographed on silica gel (eluent: heptane/EtOAc (6/4)). 785 mg of 2-[5-(1 -trityl-1 H-imidazol-4-yl)pent-4- enyl]isoindole-1 ,3-dione are obtained in a yield of 51 %.10-1-3 2-[5-(1 -Trityl-1 H-imidazol-4-yl)pentyl]isoindole-1 ,3-dione
785 mg (1.5 mmol) of 2-[5-(1 -trityl-1 H-imidazol-4-yl)pent-4-enyl]isoindole-1 ,3-dione, 10 ml of a MeOH/THF mixture (6/4) and 392 mg of 10% Pd/C are introduced into a Parr bomb.
The reaction medium is stirred at room temperature under a hydrogen pressure of 5 bar. After 4 hours, the reaction medium is filtered through Celite and concentrated.
The crude product obtained is chromatographed on silica gel (eluent: heptane/EtOAc (5/5) and then CH[2]CI[2]/MeOH (9/1 )). 380 mg of 2-[5-(1 -trityl-1 H- imidazol-4- yl)pentyl]isoindole-1 ,3-dione in the form of a white powder are obtained in a yield of 48%.
(1)1-1 NMR CDCh: 1.30 (pent, 2H, J = 6.6 Hz); 1.55-1.64 (m, 4H); 2.45 (t, 2H, J = 7.5 Hz); 3.58 (t, 2H, J = 7.3 Hz); 6.43 (s, 1 H); 7.09 (m, 6H); 7.27 (m, 7H); 7.62 (m, 2H); 7.77 (m, 2H).
10-1-4 5-(1 H-imidazol-4-yl)pentylamine bis(trifluoroacetate) 0.10 ml of hydrazine hydrate is added to 380 mg (0.72 mmol) of 2-[5-(1 -trityl-1 H- imidazol-4- yl)pentyl]isoindole-1 ,3-dione dissolved in 10 ml of MeOH. The reaction medium is refluxed for 4 hours.
After cooling to room temperature, the mixture is filtered and the filtrate concentrated.
The crude product obtained is purified by preparative HPLC. 4 ml of dichloromethane and 0.5 ml of trifluoroacetic acid are added to the residue obtained.
The reaction medium is stirred at room temperature for 18 hours.
The solvents are evaporated off. 14 mg of a powder are obtained, and are used in the next step without further purification.
10-2 Ethyl 4-cyclohexyl-1-[(R)-2-{3-[5-(1 H-imidazol-4-yl)pentyl]ureido}-3-(4-methoxy- phenyl)propionyl]piperidine-4-carboxylate
16 .micro. I- of diisopropylethylamine and 10 mg (51 . micro. mol) of 4-nitrophenyl
chloroformate are added to 25 mg (47 .micro. mol) of 1 -{1 -[(R)-2-amino-3-(4- methoxyphenyl)propionyl]-4- cyclohexylpiperidin-4-yl}butan-1 -one (cf. preparation 4.4) dissolved in 5 ml of DCM.
The reaction mixture is stirred for 2 hours at room temperature.
The reaction is stopped by adding water and the organic compounds are extracted with DCM. The organic phase is then dried over MgSO[4], filtered and concentrated.
The oil obtained is dissolved in 5 ml of DMF at 80(0)C, and 14 mg of 5-(1 H-imidazol-4- yl)pentylamine bis(thfluoroacetate) are added.
The reaction mixture is stirred at 80(0)C for 5 minutesand for 18 hours at room temperature. The organic phase is washed with 1 N sodium hydroxide, extracted with dichloromethane and then dried over MgSO[4], filtered and concentrated.
The crude product obtained is purified by preparative HPLC. 3 mg of ethyl 4-cyclohexyl-1 - [(R)-2-{3-[5-(1 H-imidazol-4-yl)pentyl]ureido}-3-(4-methoxy- phenyl)propionyl]piperidine-4- carboxylate are obtained in a yield of 10%.
Preparative HPLC method: Modulo-cart strategy C18 100x21.2 mm, 5 . micro. m column
UV detector: 210-400 nm Flow rate: 17 ml/min
Solvent A: H[2]O+0.05 TFA
Solvent B: CH[3]CN+0.05 TFA
Gradient: Time composition 0.0 min A=90%, B=10% 10.0 min A=2%, B=98%
12.0 min A=2%, B=98%
12.1 min A=90%, B= 10% 15.0 min A=90%, B= 10% HPLC/SM:
Gemini C6 i Phenyl 150x3 mm, 3 . micro. m column UV detector: 190-900 nm
Flow rate: 0.5 ml/min
Solvent A: CH[3]CN+0. 02 TFA
Solvent B: H[2]0+0. 02 TFA
Gradient:
Time composition
0.0 min A=10%, B=90%
20.0 min A=90%, B= 10%
30.0 min A=90%, B= 10%
Retention time: 12.62 min, 91 %, M+H: 595

Claims

1. A method of treating patients suffering from xeroderma or from a symptom associated therewith, comprising the steps of :
Administering either topically or orally a MC1 R agonist allowing sufficient time to be absorbed by the skin of the subject
Exposing skin areas to visible light.
Wherein the sequence of these steps could simultaneous or in any order provided visible light is filtered out from UV rays.
2. A method according to claim 1 wherein the MC1 R absorption time is comprised between 0 to 48 hours.
3. A method according to claim 1 wherein the visible light wavelength is comprised between 380nm to 780nm
4. A method according to claim 1 wherein the exposure time to visible light is at least 5 min
5. A method according to claim 1 wherein the MC1 R agonist is of form
Figure imgf000031_0001
in which: R1 represents a hydrogen atom, an aryl, a substituted aryl, an alkyl, a cycloalkyl, a cycloalkylalkyl or a cycloalkylalkylalkyl,
R2 represents a hydrogen atom, a hydroxyl, a lower alkyl, a substituted lower alkyl, a higher alkyl, a substituted higher alkyl, a cycloalkyl, a cycloalkylalkyl, a lower alkoxy, a substituted lower alkoxy, a higher alkoxy, a substituted higher alkoxy, a cycloalkylalkoxy, an acyloxy, an acyl, an alkoxycarbonyl, a carboxamide, a carboxylic acid, a cyano, or an amino disubstituted with an acyl and an aryl or alkyl, R3 represents an aralkyl or a substituted aralkyl, R4 represents a heteroaralkyl or a substituted heteroaralkyl, R5 represents a hydrogen atom or an alkyl, X represents an oxygen atom or a sulfur atom, n, m may be equal to 1 or 2; and also the corresponding salts and enantiomers.
6. A method according to claim 1 wherein the MC1 R agonist are
1 -[(S)-2-(4-Butyryl-4-phenylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea
1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-[1 -(4-methoxybenzyl)-2-oxo-2-(4-oxo-1 -phenyl-1 ,3,8- triazaspiro[4.5]dec-8-yl)ethyl]urea 1 -[2-(4-Cyano-4-phenylpiperidin-1 -yl)-1 -(4- methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea
1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-[1 -(4-methoxybenzyl)-2-oxo-2-(4-phenylpiperidin-1 - yl)ethyl]urea
1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-[1 -(4-methoxybenzyl)-2-oxo-2-piperidin-1 -yl-ethyl]urea Ethyl 4-cyclohexyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate
N-{1 -[2-{3-[2-(1 H-lmidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]piperidin- 4-yl}- N-phenylpropionamide
1 -[2-{3-[2-(1 H-lmidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]-3-phenyl- azetidin- 3-yl butyrate
Ethyl 1-[2-{3-[2-(1 H-lmidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]piper- idine-4- carboxylate
1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-{1 -(4-methoxybenzyl)-2-[4-(2-methoxyphenyl)- piperidin-1 - yl]-2-oxoethyl}urea 1 -[2-(3-Butoxy-3-phenylazetidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]- 3-[2-(1 H- imidazol-4-yl)ethyl]urea
Methyl 4-cyclohexyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylamide
1 -A-(S-Cyclohexanecarbonylazetidin-l -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]ureaEthyl 4-cyclohexyl-1 -[2-{3-ethyl-3-[2-(1 H-imidazol-4-yl)ethyl]ureido}- 3-(4-methoxy- phenyl)propionyl]piperidine-4-carboxylate
N-Cyclopropyl-N-{1-[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-nnethoxyphenyl)- propionyl]piperidin-4-yl}propionamide Ethyl 4-cyclohexyl-1 -(2-{3-[2-(1 H-imidazol-4- yl)ethyl]ureido}-3-phenylpropionyl)- piperidine-4-carboxylate
1 -[2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2-(3H- imidazol-4-yl)ethyl]urea
1 -[2-(4-Butoxy-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea
Ethyl 4-cyclohexyl-1 -(2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-2-phenylacetyl)- piperidine-4- carboxylate Methyl 4-cyclohexyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate 1 -[2-(4-Cyclohexyl-4-ethoxypiperidin-1 -yl)-1 -(4- methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea
1 -[2-(4-Acetyl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea
Methyl 4-cyclohexyl-1 -(2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-2-phenylacetyl)- piperidine-4- carboxylate
Ethyl 4-ethyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate
1 -[2-(4-Cyclohexyl-4-propoxypiperidin-1 -yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-
(1 H-imidazol-4-yl)ethyl]urea 4-Cyclohexyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4- methoxyphenyl)- propionyl]piperidine-4-carboxylic acid
1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-{1 -(4-methoxybenzyl)-2-[3-(2-nnethylcyclohexyl)-3- propoxyazetidin-1 -yl]-2-oxoethyl}urea
Propyl 4-cyclohexyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate
1 -[2-(1 H-lmidazol-4-yl)ethyl]-3-[1 -(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenyl- azetidin-1 -yl)ethyl]urea
Ethyl 1 -((R)-3-(4-chlorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}propionyl)-4- cyclohexylpiperidine-4-carboxylate
Ethyl 1 -((S)-3-(4-chlorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}propionyl)-4- cyclohexylpiperidine-4-carboxylate
1 -[2-(4-Cyclohexyl-4-propionylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]urea
1 -[2-(4-Cyclohexyl-4-propionylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-(1 H- imidazol-4-ylmethyl)urea Ethyl 4-cyclohexyl-1 -[(R)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3- (4-methoxyphenyl)- propionyl]piperidine-4-carboxylate
Ethyl 4-cyclopropylmethyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxy- phenyl)propionyl]piperidine-4-carboxylate
Propyl 4-cyclohexyl-1 -(2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-phenylpropionyl)- p i pe ri d i n e-4-ca rboxy I ate
Ethyl 4-cyclopentyl-1 -(2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-phenylpropionyl)- piperidine- 4-carboxylate
Ethyl 4-cyclopentyl-1 -[2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate Ethyl 4-cyclohexyl-1 -[(S)-2-{3-[2-(1 H-imidazol-4- yl)ethyl]ureido}-3-(4-methoxyphenyl)- propionyl]piperidine-4-carboxylate 1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]urea
1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-fluorobenzyl)-2-oxoethyl]-3-[2-(1 H- imidazol-4-yl)ethyl]urea
1 -[(R)-1 -Benzyl-2-(4-butyryl-4-cyclohexylpiperidin-1 -yl)-2-oxoethyl]-3-[2-(1 H-imidazol- 4- yl)ethyl]urea
1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3- [2- (3- methyl-3H-imidazol-4-yl)ethyl]urea
1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-chlorobenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]urea
Ethyl 4-cyclohexyl-1 -((R)-3-(3,4-dichlorophenyl)-2-{3-[3-(1 H-imidazol-4-yl)propyl]- ureido}propionyl)piperidine-4-carboxylate
Ethyl 4-cyclohexyl-1 -((R)-3-(4-methoxyphenyl)-2-{3-[2-(3-methyl-3H-innidazol-4- yl)ethyl]ureido}propionyl)piperidine-4-carboxylate
Ethyl 4-cyclohexyl-1 -[(R)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]thioureido}-3-(4-methoxy- phenyl)propionyl]piperidine-4-carboxylate
1 -[(R)-2-(4-Butyryl-4-cyclohexylpiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]thiourea
1 -[(R)-2-(4-Cyclohexyl-4-propoxypiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]thiourea
1 -[(R)-1 -Benzyl-2-(4-cyclohexyl-4-propoxypiperidin-1 -yl)-2-oxoethyl]-3-[2-(1 H- imidazol-4- yl)ethyl]thiourea
1 -[(R)- 1 -Benzyl-2-(4-cyclohexyl-4-propoxypiperidin-1 -yl)-2-oxoethyl]-3-[2-(1 H- imidazol-4- yl)ethyl]urea
Ethyl 4-cyclohexyl-1 -((R)-3-(4-methoxyphenyl)-2-{3-[2-(3-methyl-3H-imidazol-4- yl)ethyl]thioureido}propionyl)piperidine-4-carboxylate
Ethyl 4-cyclohexyl-1 -((R)-2-{3-[2-(3-methyl-3H-imidazol-4-yl)ethyl]ureido}-3-phenyl- propionyl)piperidine-4-carboxylate
1 -[(R)-2-(4-Cyclohexyl-4-propoxypiperidin-1 -yl)-1 -(4-methoxybenzyl)-2-oxoethyl]-3-[2- (3- methyl-3H-imidazol-4-yl)ethyl]urea
Ethyl 1 -((R)-3-(4-chlorophenyl)-2-{3-[2-(3-methyl-3H-imidazol-4-yl)ethyl]ureido}- propionyl)- 4-cyclohexylpiperidine-4-carboxylate
Ethyl 4-cyclohexyl-1 -((R)-3-(4-fluorophenyl)-2-{3-[2-(3-methyl-3H-imidazol-4-yl)ethyl]- ureido}propionyl)piperidine-4-carboxylate
Ethyl 4-cyclohexyl-1-((R)-3-(4-fluorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]ureido}- propionyl)piperidine-4-carboxylate Ethyl 4-cyclohexyl-1 -((R)-3-(4-fluorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]thio- ureido}propionyl)piperidine-4-carboxylate
Ethyl 1 -((R)-3-(4-chlorophenyl)-2-{3-[2-(1 H-imidazol-4-yl)ethyl]thioureido}propionyl)-4- cyclohexylpiperidineA-carboxylate
Ethyl 1-((R)-3-(4-chlorophenyl)-2-{3-[2-(3-methyl-3H-imidazol-4-yl)ethyl]thioureido}- propionyl)-4-cyclohexylpiperidine-4-carboxylate
1 -[(R)-2-(4-Cyclohexyl-4-propoxypiperidin-1 -yl)-1 -(4-fluorobenzyl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]urea
1 -[(R)-1 -(4-Chlorobenzyl)-2-(4-cyclohexyl-4-propoxypiperidin-1 -yl)-2-oxoethyl]-3-[2- (1 H- imidazol-4-yl)ethyl]urea
a-Melanotropin , 4-L-norleucine-7-D-phenylalanine-
7. A method according to claim 1 wherein the concentration of MC1 R is comprised between 0.01 % to 20%
8. A method according to claiml wherein the light source is selected from the list artificial light or sunlight
9. A method according to claiml wherein the light source wavelength is in the range of 380nm to 780nm
10. A method according to claiml wherein the skin type is selected from the list skin type IV, skin type V or skin type VI.
1 1. A method according to claim 1 wherein further step comprise the topical administration of a sunscreen
PCT/EP2012/055955 2011-03-31 2012-04-02 Method for treatment of xeroderma pigmentosum WO2012131090A1 (en)

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