Oxoazetidine derivatives, process for the preparation thereof and use thereof in human medicine and in cosmetics

Abstract

The present invention relates to novel compounds derived from oxoazetidine corresponding to general formula (I) to the compositions containing same, to the process for preparation thereof and to the use thereof in pharmaceutical or cosmetic compositions. ##STR00001##

Claims

1. A method for treating a disorder, disease, or dysfunction selected from the group consisting of: an inflammatory disease of the digestive tract selected from the group consisting of irritable bowel syndrome, ulcerative colitis, Crohn's disease, pancreatitis, hepatitis, an inflammatory pathological condition of the bladder and gastritis; an inflammatory disease of the locomotor system selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, traumatic arthritis, post-infectious arthritis, muscle degeneration and dermatomyositis; glomerulonephritis; an inflammatory disease of the cardiac system selected from the group consisting of pericarditis, myocarditis, atherosclerosis, transplant atherosclerosis, peripheral vascular disease, inflammatory vasculardisease, intermittent claudication, restenosis, stroke, transient ischaemic attack, myocardial ischaemia, myocardial infarction, hypertension, hyperlipidaemia, coronary artery disease, unstable angina, thrombosis, platelet aggregation induced by thrombin and atheroma plaque formation; an inflammatory disease of the respiratory and ENT system selected from the group consisting of asthma, acute respiratory distress syndrome, hayfever, allergic rhinitis, chronic obstructive pulmonary disease and allergies; an inflammatory disease of the central nervous system selected from the group consisting of Alzheimer's disease, other form of dementia, Parkinson's disease, Creutzfeldt Jacob disease, multiple sclerosis and meningitis; an inflammatory skin disease selected from the group consisting of urticaria, scleroderma, contact dermatitis, atopic dermatitis, psoriasis, ichthyosis, acne and other forms of folliculitis, rosacea and alopecia; an autoimmune disease selected from the group consisting of lupus erythematosus, a thyroid condition, an autoimmune disease of the adrenal gland, autoimmune gastritis, vitiligo and alopecia areata; an inflammation accompanying bacterial, viral or fungal infections selected from the group consisting of tuberculosis, septicaemia, fever, HIV, herpes, cytomegalovirus, hepatitis A, hepatitis B and hepatitis C; a transplant or graft rejection selected from the group consisting of kidney, liver, heart, lung, pancreas, bone marrow, cornea, intestine and skin; pain selected from the group consisting of post-operative pain, neuromuscular pain, headache, cancer-related pain, dental pain and osteoarticular pain; a disease with a pigmentation disorder selected from the group consisting of a benign dermatosis selected from the group consisting of vitiligo, albinism, melasma, lentigines, freckles, melanocytic naevi and post inflammatory pigmentation; and a pigmented tumor selected from the group consisting of melanoma and local metastases, regional metastases and systemic metastases thereof; or a method for inhibiting: actinic erythema, skin ageing, a skincancer, and a disease in which sunlight accelerates onset selected from the group consisting of xeroderma pigmentosum, basal cell naevus syndrome and familial melanoma; a photodermatosis due to an exogenous photosensitizing agent selected from the group consisting of furocoumarins, halogenated salicylanilides, local sulphamides, psoralens, tetracyclines, systemic sulphamides, phenothiazines, nalidixic acid, and tricyclic antidepressants; or for inhibiting a dermatosis attack with photosensitivity which is: a photoaggravated dermatosis selected from the group consisting of lupus erythematosus, recurrent herpes, congenital poikilodermal and telangiectasic conditions with photosensitivity selected from the group consisting of Bloom syndrome, Cockayne syndrome and Rothmund-Thomson syndrome, actinic lichen planus, actinic granuloma, disseminated superficial actinic porokeratosis, acne rosacea, juvenile acne, bullous dermatosis, Darier's disease, cutaneous lymphoma, psoriasis, atopic dermatitis, contact eczema, follicular mucinosis, erythema multiforme, fixed drug erythema, lymphocytoma cutis, reticular erythema with mucinosis and melasma, a dermatosis with photosensitivity caused by deficiency of the protection system with melanin formation or distribution anomalies selected from the group consisting of oculocutaneous albinism, phenylketonuria, anterior hypophyseal insufficiency, vitiligo, and piebaldism and with DNA repair system deficiency selected from the group consisting of xeroderma pigmentosum and Cockayne syndrome, a dermatosis with photosensitivity caused by metabolic anomalies which is a cutaneous porphyria selected from the group consisting of late cutaneous porphyria, mixed porphyria, erythropoietic protoporphyria, congenital erythropoietic porphyria Gnther's disease and erythropoietic coproporphyria, or which is pellagra or a pellagroid erythema or a tryptophan metabolism disorder; an idiopathic photodermatosis attack selected from the group consisting of polymorphous light eruption, benign summer light eruption, actinic prurigo, persistent photosensitization selected from the group consisting of actino-reticulosis, chronic actinic dermatosis, and photosensitive eczema, solar urticaria, hydroa vacciniforme, juvenile spring eruption and solar pruritus, or for modulating the color of the skin or of the hair and of body hairs by causing the skin to tan by increasing melanin synthesis or causing it to bleach by interfering with melanin synthesis, by preventing hair and body hair from turning white or grey; or for modifying the color of the hair and body hairs in cosmetic indications; or for modulating sebaceous function in treating: a condition with hyperseborrhoea selected from the group consisting of acne, seborrhoeic dermatitis, greasy skin and greasy hair, hyperseborrhoea in Parkinson's and epilepsy, and hyperandrogenism; a condition with decreasing sebaceous secretion selected from the group consisting of xerosis and dry skin; benign and malignant sebocyte and sebaceous gland proliferation; an inflammatory condition of the pilosebaceous follicle selected from the group consisting of acne, boils, carbuncles and folliculitis; a neurodegenerative disorder selected from the group consisting of depression, anxiety, an obsessive-compulsive disorder, a neurosis, a psychosis, insomnia, sleep apnea, and drug abuse; a male sexual dysfunction selected from the group consisting of impotence, loss of libido, and erectile dysfunction; a female sexual dysfunction selected from the group consisting of sexual stimulation disorders, or disorders related to desire, sexual receptivity, orgasm, and disturbances of the major points of sexual function; pain, preterm labor, dysmenorrhoea, excessive menstruation, and endometriosis; a disorder related to weight selected from the group consisting of obesity, anorexia, modification and impairment of appetite, spleen metabolism, innocent intake of fats and carbohydrates; diabetes mellitus; cancer selected from the group consisting of lung cancer, prostate cancer, colon cancer, breast cancer, ovarian cancer and bone cancer, an angiogenesis disorder, and the formation or growth of a solid tumor, said method comprising administering to a subject in need of such treatment a compound selected from the group consisting of: N[(S)-1-[(S)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide; N[(S)-1-[(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide; N[(S)-1-[(S)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide; N[(S)-1-[(S)-2-[3-butoxy-3-(3-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(2,4-dichlorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclopropyl methoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butyl-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(3-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-benzyl-2-(3-butoxy-3-phenylazetidin-1-yl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-[1,2,4]triazol-3-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide; N{(R)-1-(4-methoxybenzyl)-2-[3-(2-methoxyphenyl)-3-pentylazetidin-1-yl]-2-oxoethyl}-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2-chlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-benzyl-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,4-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(3-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(2,4-dichlorobenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,5-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,6-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)hexyramide; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)pentyramide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide; N[(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoroacetate; (S)N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-2-hydroxy-3-(1H-imidazol-4-yl)propionamide; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclohexylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; 3-(1H-imidazol-4-yl)-N{(R)-1-(4-methoxybenzyl)-2-oxo-2-[3-o-tolyl-3-(4,4,4-trifluorobutoxy)azetidin-1-yl]ethylpropionamide; N[(R)-2-(3-cyclobutylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide; and N{(R)-1-(4-methoxybenzyl)-2-[3-(3-methylbut-2-enyloxy)-3-o-tolylazetidin-1-yl]-2-oxoethyl}-3-(5-methyl-1H-imidazol-4-ylpropionamide; and the salts and enantiomers thereof.

2. A method for treating a disorder, disease, or dysfunction selected from the group consisting of: an inflammatory disease of the digestive tract selected from the group consisting of irritable bowel syndrome, ulcerative colitis, Crohn's disease, pancreatitis, hepatitis, an inflammatory pathological condition of the bladder and gastritis; an inflammatory disease of the locomotor system selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, traumatic arthritis, post-infectious arthritis, muscle degeneration and dermatomyositis; glomerulonephritis; an inflammatory disease of the cardiac system selected from the group consisting of pericarditis, myocarditis, atherosclerosis, transplant atherosclerosis, peripheral vascular disease, inflammatory vasculardisease, intermittent claudication restenosis, stroke, transient ischaemic attack, myocardial ischaemia, myocardial infarction, hypertension, hyperlipidaemia, coronary artery disease, unstable angina, thrombosis, platelet aggregation induced by thrombin and atheroma plaque formation; an inflammatory disease of the respiratory and ENT system selected from the group consisting of asthma, acute respiratory distress syndrome, hayfever, allergic rhinitis, chronic obstructive pulmonary disease and allergies; an inflammatory disease of the central nervous system selected from the group consisting of Alzheimer's disease, other form of dementia, Parkinson's disease, Creutzfeldt Jacob disease, multiple sclerosis and meningitis; an inflammatory skin disease selected from the group consisting of urticaria, scleroderma, contact dermatitis, atopic dermatitis, psoriasis, ichthyosis, acne and other forms of folliculitis, rosacea and alopecia; an autoimmune disease selected from the group consisting of lupus erythematosus, a thyroid condition, an autoimmune disease of the adrenal gland, autoimmune gastritis, vitiligo and alopecia areata; an inflammation accompanying bacterial, viral or fungal infections selected from the group consisting of tuberculosis, septicaemia, fever, HIV, herpes, cytomegalovirus, hepatitis A, hepatitis B and hepatitis C; a transplant or graft rejection selected from the group consisting of kidney, liver, heart, lung, pancreas, bone marrow, cornea, intestine and skin; pain selected from the group consisting of post-operative pain, neuromuscular pain, headache, cancer-related pain, dental pain and osteoarticular pain; a disease with a pigmentation disorder selected from the group consisting of a benign dermatosis selected from the group consisting of vitiligo, albinism, melasma, lentigines, freckles, melanocytic naevi and post inflammatory pigmentation; and a pigmented tumor selected from the group consisting of melanoma and local metastases, regional metastases and systemic metastases thereof; or a method for inhibiting: actinic erythema, skin ageing, a skincancer, and a disease in which sunlight accelerates onset selected from the group consisting of xeroderma pigmentosum, basal cell naevus syndrome and familial melanoma; a photodermatosis due to an exogenous photosensitizing agent selected from the group consisting of furocoumarins, halogenated salicylanilides, local sulphamides, psoralens, tetracyclines, systemic sulphamides, phenothiazines, nalidixic acid, and tricyclic antidepressants; or for inhibiting a dermatosis attack with photosensitivity which is: a photoaggravated dermatosis selected from the group consisting of lupus erythematosus, recurrent herpes, congenital poikilodermal and telangiectasic conditions with photosensitivity selected from the group consisting of Bloom syndrome, Cockayne syndrome and Rothmund-Thomson syndrome, actinic lichen planus, actinic granuloma, disseminated superficial actinic porokeratosis, acne rosacea, juvenile acne, bullous dermatosis, Darier's disease, cutaneous lymphoma, psoriasis, atopic dermatitis, contact eczema, follicular mucinosis, erythema multiforme, fixed drug erythema, lymphocytoma cutis, reticular erythema with mucinosis and melasma, a dermatosis with photosensitivity caused by deficiency of the protection system with melanin formation or distribution anomalies selected from the group consisting of oculocutaneous albinism, phenylketonuria, anterior hypophyseal insufficiency, vitiligo, and piebaldism and with DNA repair system deficiency selected from the group consisting of xeroderma pigmentosum and Cockayne syndrome, a dermatosis with photosensitivity caused by metabolic anomalies which is a cutaneous porphyria selected from the group consisting of late cutaneous porphyria, mixed porphyria, erythropoietic protoporphyria, congenital erythropoietic porphyria Gnther's disease and erythropoietic coproporphyria, or which is pellagra or a pellagroid erythema or a tryptophan metabolism disorder; an idiopathic photodermatosis attack selected from the group consisting of polymorphous light eruption, benign summer light eruption, actinic prurigo, persistent photosensitization selected from the group consisting of actino-reticulosis, chronic actinic dermatosis, and photosensitive eczema, solar urticaria, hydroa vacciniforme, juvenile spring eruption and solar pruritus, or for modulating the color of the skin or of the hair and of body hairs by causing the skin to tan by increasing melanin synthesis or causing it to bleach by interfering with melanin synthesis, by preventing hair and body hair from turning white or grey (canities or piebaldism); or for modifying the color of the hair and body hairs in cosmetic indications; or for modulating sebaceous function in treating: a condition with hyperseborrhoea selected from the group consisting of acne, seborrhoeic dermatitis, greasy skin and greasy hair, hyperseborrhoea in Parkinson's and epilepsy, and hyperandrogenism; a condition with decreasing sebaceous secretion selected from the group consisting of xerosis and dry skin; benign and malignant sebocyte and sebaceous gland proliferation; an inflammatory condition of the pilosebaceous follicle selected from the group consisting of acne, boils, carbuncles and folliculitis; a neurodegenerative disorder selected from the group consisting of depression, anxiety, an obsessive-compulsive disorder, a neurosis, a psychosis, insomnia, sleep apnea, and drug abuse; a male sexual dysfunction selected from the group consisting of impotence, loss of libido, and erectile dysfunction; a female sexual dysfunction selected from the group consisting of sexual stimulation disorders, or disorders related to desire, sexual receptivity, orgasm, and disturbances of the major points of sexual function; pain, preterm labor, dysmenorrhoea, excessive menstruation, and endometriosis; a disorder related to weight selected from the group consisting of obesity, anorexia, modification and impairment of appetite, spleen metabolism, innocent intake of fats and carbohydrates; diabetes mellitus; cancer selected from the group consisting of lung cancer, prostate cancer, colon cancer, breast cancer, ovarian cancer and bone cancer, an angiogenesis disorder, and the formation or growth of a solid tumor, said method comprising administering to a subject in need of such treatment a compound selected from the group consisting of: N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butyl-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide; N{(R)-1-(4-methoxybenzyl)-2-[3-(2-methoxyphenyl)-3-pentylazetidin-1-yl]-2-oxoethyl}-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2-chlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,4-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(3-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,5-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,6-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoroacetate; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide; N-[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclohexylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; 3-(1H-imidazol-4-yl)-N{(R)-1-(4-methoxybenzyl)-2-oxo-2-[3-o-tolyl-3-(4,4,4-trifluorobutoxy)-azetidin-1-yl]ethylpropionamide; N[(R)-2-(3-cyclobutyl m ethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide; and N{(R)-1-(4-methoxybenzyl)-2-[3-(3-methylbut-2-enyloxy)-3-o-tolylazetidin-1-yl]-2-oxoethyl}-3-(5-methyl-1H-imidazol-4-yl)propionamide; and the salts and enantiomers thereof.

3. A method for treating a disorder, disease, of dysfunction selected from the group consisting of: an inflammatory disease of the digestive tract selected from the group consisting of irritable bowel syndrome, ulcerative colitis, Crohn's disease, pancreatitis, hepatitis, an inflammatory pathological condition of the bladder and gastritis; an inflammatory disease of the locomotor system selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteoporosis, traumatic arthritis, post-infectious arthritis, muscle degeneration and dermatomyositis; glomerulonephritis; an inflammatory disease of the cardiac system selected from the group consisting of pericarditis, myocarditis, atherosclerosis, transplant atherosclerosis, peripheral vascular disease, inflammatory vasculardisease, intermittent claudication restenosis, stroke, transient ischaemic attack, myocardial ischaemia, myocardial infarction, hypertension, hyperlipidaemia, coronary artery disease, unstable angina, thrombosis, platelet aggregation induced by thrombin and atheroma plaque formation; an inflammatory disease of the respiratory and ENT system selected from the group consisting of asthma, acute respiratory distress syndrome, hayfever, allergic rhinitis, chronic obstructive pulmonary disease and allergies; an inflammatory disease of the central nervous system selected from the group consisting of Alzheimer's disease, other form of dementia, Parkinson's disease, Creutzfeldt Jacob disease, multiple sclerosis and meningitis; an inflammatory skin disease selected from the group consisting of urticaria, scleroderma, contact dermatitis, atopic dermatitis, psoriasis, ichthyosis, acne and other forms of folliculitis, rosacea and alopecia; an autoimmune disease selected from the group consisting of lupus erythematosus, a thyroid condition, an autoimmune disease of the adrenal gland, autoimmune gastritis, vitiligo and alopecia areata; an inflammation accompanying bacterial, viral or fungal infections selected from the group consisting of tuberculosis, septicaemia, fever, HIV, herpes, cytomegalovirus, hepatitis A, hepatitis B and hepatitis C; a transplant or graft rejection selected from the group consisting of kidney, liver, heart, lung, pancreas, bone marrow, cornea, intestine and skin; pain selected from the group consisting of post-operative pain, neuromuscular pain, headache, cancer-related pain, dental pain and osteoarticular pain; a disease with a pigmentation disorder selected from the group consisting of a benign dermatosis selected from the group consisting of vitiligo, albinism, melasma, lentigines, freckles, melanocytic naevi and post inflammatory pigmentation; and a pigmented tumor selected from the group consisting of melanoma and local metastases, regional metastases and systemic metastases thereof; or a method for inhibiting: actinic erythema, skin ageing, a skincancer, and a disease in which sunlight accelerates onset selected from the group consisting of xeroderma pigmentosum, basal cell naevus syndrome and familial melanoma; a photodermatosis due to an exogenous photosensitizing agent selected from the group consisting of furocoumarins, halogenated salicylanilides, local sulphamides, psoralens, tetracyclines, systemic sulphamides, phenothiazines, nalidixic acid, and tricyclic antidepressants; or for inhibiting a dermatosis attack with photosensitivity which is: a photoaggravated dermatosis selected from the group consisting of lupus erythematosus, recurrent herpes, congenital poikilodermal and telangiectasic conditions with photosensitivity selected from the group consisting of Bloom syndrome, Cockayne syndrome and Rothmund-Thomson syndrome, actinic lichen planus, actinic granuloma, disseminated superficial actinic porokeratosis, acne rosacea, juvenile acne, bullous dermatosis, Darier's disease, cutaneous lymphoma, psoriasis, atopic dermatitis, contact eczema, follicular mucinosis, erythema multiforme, fixed drug erythema, lymphocytoma cutis, reticular erythema with mucinosis and melasma, a dermatosis with photosensitivity caused by deficiency of the protection system with melanin formation or distribution anomalies selected from the group consisting of oculocutaneous albinism, phenylketonuria, anterior hypophyseal insufficiency, vitiligo, and piebaldism and with DNA repair system deficiency selected from the group consisting of xeroderma pigmentosum and Cockayne syndrome, a dermatosis with photosensitivity caused by metabolic anomalies which is a cutaneous porphyria selected from the group consisting of late cutaneous porphyria, mixed porphyria, erythropoietic protoporphyria, congenital erythropoietic porphyria Gnther's disease and erythropoietic coproporphyria, or which is pellagra or a pellagroid erythema or a tryptophan metabolism disorder; an idiopathic photodermatosis attack selected from the group consisting of PMLE (polymorphous light eruption), benign summer light eruption, actinic prurigo, persistent photosensitization selected from the group consisting of actino-reticulosis, chronic actinic dermatosis, and photosensitive eczema, solar urticaria, hydroa vacciniforme, juvenile spring eruption and solar pruritus, or for modulating the color of the skin or of the hair and of body hairs by causing the skin to tan by increasing melanin synthesis or causing it to bleach by interfering with melanin synthesis, by preventing hair and body hair from turning white or grey; or for modifying the color of the hair and body hairs in cosmetic indications; or for modulating sebaceous function in treating: a condition with hyperseborrhoea selected from the group consisting of acne, seborrhoeic dermatitis, greasy skin and greasy hair, hyperseborrhoea in Parkinson's and epilepsy, and hyperandrogenism; a condition with decreasing sebaceous secretion selected from the group consisting of xerosis and dry skin; benign and malignant sebocyte and sebaceous gland proliferation; an inflammatory condition of the pilosebaceous follicle selected from the group consisting of acne, boils, carbuncles and folliculitis; a neurodegenerative disorder selected from the group consisting of depression, anxiety, an obsessive-compulsive disorder, a neurosis, a psychosis, insomnia, sleep apnea, and drug abuse; a male sexual dysfunction selected from the group consisting of impotence, loss of libido, and erectile dysfunction; a female sexual dysfunction selected from the group consisting of sexual stimulation disorders, or disorders related to desire, sexual receptivity, orgasm, and disturbances of the major points of sexual function; pain, preterm labor, dysmenorrhoea, excessive menstruation, and endometriosis; a disorder related to weight selected from the group consisting of obesity, anorexia, modification and impairment of appetite, spleen metabolism, innocent intake of fats and carbohydrates; diabetes mellitus; cancer selected from the group consisting of lung cancer, prostate cancer, colon cancer, breast cancer, ovarian cancer and bone cancer, an angiogenesis disorder, and the formation or growth of a solid tumor, said method comprising administering to a subject in need of such treatment the compound N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoroacetate.

4. The method according to claim 1, wherein the disorder, disease, or dysfunction is selected from the group consisting of: a skin disease selected from the group consisting of urticaria, scleroderma, contact dermatitis, atopic dermatitis, psoriasis, ichthyosis, acne and other forms of folliculitis, rosacea and alopecia; an autoimmune disease selected from the group consisting of lupus erythematosus, a thyroid condition, an autoimmune disease of the adrenal gland, autoimmune gastritis, vitiligo and alopecia areata; a disease with a pigmentation disorder selected from the group consisting of a benign dermatosis selected from the group consisting of vitiligo, albinism, melasma, lentigines, freckles, melanocytic naevi and a post-inflammatory pigmentation disorder; and a pigmented tumor selected from the group consisting of melanoma and local metastases, regional metastases and systemic metastases thereof; actinic erythema, skin ageing, a skin cancer, and a disease in which sunlight accelerates onset selected from the group consisting of xeroderma pigmentosum, basal cell naevus syndrome and familial melanoma; a photodermatosis due to an exogenous photosensitizing agent selected from the group consisting of furocoumarins, halogenated salicylanilides, local sulphamides, psoralens, tetracyclines, systemic sulphamides, phenothiazines, nalidixic acid, and tricyclic antidepressants; a dermatosis attack with photosensitivity which is: a photoaggravated dermatosis selected from the group consisting of lupus erythematosus, recurrent herpes, congenital poikilodermal and a telangiectasic condition with photosensitivity selected from the group consisting of Bloom syndrome, Cockayne syndrome and Rothmund-Thomson syndrome, actinic lichen planus, actinic granuloma, disseminated superficial actinic porokeratosis, acne rosacea, juvenile acne, bullous dermatosis, Darier's disease, cutaneous lymphoma, psoriasis, atopic dermatitis, contact eczema, follicular mucinosis, erythema multiforme, fixed drug erythema, lymphocytoma cutis, reticular erythema with mucinosis and melasma, a dermatosis with photosensitivity caused by deficiency of the protection system with melanin formation or distribution anomalies selected from the group consisting of oculocutaneous albinism, phenylketonuria, anterior hypophyseal insufficiency, vitiligo and piebaldism) and with DNA repair system deficiency selected from the group consisting of xeroderma pigmentosum and Cockayne syndrome, a dermatosis with photosensitivity caused by metabolic anomalies which is a cutaneous porphyria selected from the group consisting of late cutaneous porphyria, mixed porphyrias, erythropoietic protoporphyria, congenital erythropoietic porphyria, Gnther's disease and erythropoietic coproporphyria, or which is pellagra or a pellagroid erythema or a tryptophan metabolism disorder; an idiopathic photodermatosis attack selected from the group consisting of polymorphous light eruption, benign summer light eruption, actinic prurigo, persistent photosensitization selected from the group consisting of actino-reticulosis, chronic actinic dermatosis, and photosensitive eczema, solar urticaria, hydroa vacciniforme, juvenile spring eruption and solar pruritus; or wherein the method is for modulating the color of the skin or of the hair and of body hairs by causing the skin to tan by increasing melanin synthesis or causing it to bleach by interfering with melanin synthesis, by inhibiting hair and body hair turning white or grey; or for modifying the color of the hair and body hairs in cosmetic indications.

5. The method according to claim 2, wherein the disorder, disease, of dysfunction is selected from the group consisting of: a skin disease selected from the group consisting of urticaria, scleroderma, contact dermatitis, atopic dermatitis, psoriasis, ichthyosis, acne and other forms of folliculitis, rosacea and alopecia; an autoimmune disease selected from the group consisting of lupus erythematosus, a thyroid condition, an autoimmune disease of the adrenal gland, autoimmune gastritis, vitiligo and alopecia areata; a disease with a pigmentation disorder selected from the group consisting of a benign dermatosis selected from the group consisting of vitiligo, albinism, melasma, lentigines, freckles, melanocytic naevi and a post-inflammatory pigmentation disorder; and a pigmented tumor selected from the group consisting of melanoma and local metastases, regional metastases and systemic metastases thereof; actinic erythema, skin ageing, a skin cancer, and a disease in which sunlight accelerates onset selected from the group consisting of xeroderma pigmentosum, basal cell naevus syndrome and familial melanoma; a photodermatosis due to an exogenous photosensitizing agent selected from the group consisting of furocoumarins, halogenated salicylanilides, local sulphamides, psoralens, tetracyclines, systemic sulphamides, phenothiazines, nalidixic acid, and tricyclic antidepressants; a dermatosis attack with photosensitivity which is: a photoaggravated dermatosis selected from the group consisting of lupus erythematosus, recurrent herpes, congenital poikilodermal and a telangiectasic condition with photosensitivity selected from the group consisting of Bloom syndrome, Cockayne syndrome and Rothmund-Thomson syndrome, actinic lichen planus, actinic granuloma, disseminated superficial actinic porokeratosis, acne rosacea, juvenile acne, bullous dermatosis, Darier's disease, cutaneous lymphoma, psoriasis, atopic dermatitis, contact eczema, follicular mucinosis, erythema multiforme, fixed drug erythema, lymphocytoma cutis, reticular erythema with mucinosis and melasma, a dermatosis with photosensitivity caused by deficiency of the protection system with melanin formation or distribution anomalies selected from the group consisting of oculocutaneous albinism, phenylketonuria, anterior hypophyseal insufficiency, vitiligo and piebaldism) and with DNA repair system deficiency selected from the group consisting of xeroderma pigmentosum and Cockayne syndrome, a dermatosis with photosensitivity caused by metabolic anomalies which is a cutaneous porphyria selected from the group consisting of late cutaneous porphyria, mixed porphyrias, erythropoietic protoporphyria, congenital erythropoietic porphyria, Gnther's disease and erythropoietic coproporphyria, or which is pellagra or a pellagroid erythema or a tryptophan metabolism disorder; an idiopathic photodermatosis attack selected from the group consisting of polymorphous light eruption, benign summer light eruption, actinic prurigo, persistent photosensitization selected from the group consisting of actino-reticulosis, chronic actinic dermatosis, and photosensitive eczema, solar urticaria, hydroa vacciniforme, juvenile spring eruption and solar pruritus; or wherein the method is for modulating the color of the skin or of the hair and of body hairs by causing the skin to tan by increasing melanin synthesis or causing it to bleach by interfering with melanin synthesis, by inhibiting hair and body hair turning white or grey; or for modifying the color of the hair and body hairs in cosmetic indications.

6. The method according to claim 3, wherein the disorder, disease, or dysfunction is selected from the group consisting of: a skin disease selected from the group consisting of urticaria, scleroderma, contact dermatitis, atopic dermatitis, psoriasis, ichthyosis, acne and other forms of folliculitis, rosacea and alopecia; an autoimmune disease selected from the group consisting of lupus erythematosus, a thyroid condition, an autoimmune disease of the adrenal gland, autoimmune gastritis, vitiligo and alopecia areata; a disease with a pigmentation disorder selected from the group consisting of a benign dermatosis selected from the group consisting of vitiligo, albinism, melasma, lentigines, freckles, melanocytic naevi and a post-inflammatory pigmentation disorder; and a pigmented tumor selected from the group consisting of melanoma and local metastases, regional metastases and systemic metastases thereof; actinic erythema, skin ageing, a skin cancer, and a disease in which sunlight accelerates onset selected from the group consisting of xeroderma pigmentosum, basal cell naevus syndrome and familial melanoma; a photodermatosis due to an exogenous photosensitizing agent selected from the group consisting of furocoumarins, halogenated salicylanilides, local sulphamides, psoralens, tetracyclines, systemic sulphamides, phenothiazines, nalidixic acid, and tricyclic antidepressants; a dermatosis attack with photosensitivity which is: a photoaggravated dermatosis selected from the group consisting of lupus erythematosus, recurrent herpes, congenital poikilodermal and a telangiectasic condition with photosensitivity selected from the group consisting of Bloom syndrome, Cockayne syndrome and Rothmund-Thomson syndrome, actinic lichen planus, actinic granuloma, disseminated superficial actinic porokeratosis, acne rosacea, juvenile acne, bullous dermatosis, Darier's disease, cutaneous lymphoma, psoriasis, atopic dermatitis, contact eczema, follicular mucinosis, erythema multiforme, fixed drug erythema, lymphocytoma cutis, reticular erythema with mucinosis and melasma, a dermatosis with photosensitivity caused by deficiency of the protection system with melanin formation or distribution anomalies selected from the group consisting of oculocutaneous albinism, phenylketonuria, anterior hypophyseal insufficiency, vitiligo and piebaldism and with DNA repair system deficiency selected from the group consisting of xeroderma pigmentosum and Cockayne syndrome, a dermatosis with photosensitivity caused by metabolic anomalies which is a cutaneous porphyria selected from the group consisting of late cutaneous porphyria, mixed porphyrias, erythropoietic protoporphyria, congenital erythropoietic porphyria, Gnther's disease and erythropoietic coproporphyria, or which is pellagra or a pellagroid erythema or a tryptophan metabolism disorder; an idiopathic photodermatosis attack selected from the group consisting of polymorphous light eruption, benign summer light eruption, actinic prurigo, persistent photosensitization selected from the group consisting of actino-reticulosis, chronic actinic dermatosis, and photosensitive eczema, solar urticaria, hydroa vacciniforme, juvenile spring eruption and solar pruritus; or wherein the method is for modulating the color of the skin or of the hair and of body hairs by causing the skin to tan by increasing melanin synthesis or causing it to bleach by interfering with melanin synthesis, by inhibiting hair and body hair turning white or grey; or for modifying the color of the hair and body hairs in cosmetic indications.

7. The method according to claim 1, wherein the disease, disorder, or dysfunction is selected from the group consisting of: a condition with hyperseborrhoea selected from the group consisting of acne, seborrhoeic dermatitis, greasy skin and greasy hair, hyperseborrhoea in Parkinson's and epilepsy, and hyperandrogenism; a condition with decreased sebaceous secretion selected from the group consisting of xerosis and dry skin; benign and malignant sebocyte and sebaceous gland proliferation; an inflammatory condition of the pilosebaceous follicle selected from the group consisting of acne, boils, carbuncles and folliculitis.

8. The method according to claim 2, wherein the disease, disorder, or dysfunction is selected from the group consisting of: a condition with hyperseborrhoea selected from the group consisting of acne, seborrhoeic dermatitis, greasy skin and greasy hair, hyperseborrhoea in Parkinson's and epilepsy, and hyperandrogenism; a condition with decreased sebaceous secretion selected from the group consisting of xerosis and dry skin; benign and malignant sebocyte and sebaceous gland proliferation; an inflammatory condition of the pilosebaceous follicle selected from the group consisting of acne, boils, carbuncles and folliculitis.

9. The method according to claim 3, wherein the disease, disorder, or dysfunction is selected from the group consisting of: a condition with hyperseborrhoea selected from the group consisting of acne, seborrhoeic dermatitis, greasy skin and greasy hair, hyperseborrhoea in Parkinson's and epilepsy, and hyperandrogenism; a condition with decreased sebaceous secretion selected from the group consisting of xerosis and dry skin; benign and malignant sebocyte and sebaceous gland proliferation; an inflammatory condition of the pilosebaceous follicle selected from the group consisting of acne, boils, carbuncles and folliculitis.

10. The method according to claim 4, wherein the disorder, disease, or dysfunction is selected from the group consisting of: a skin disease selected from the group consisting of urticaria, scleroderma, contact dermatitis, atopic dermatitis, psoriasis, ichthyosis, acne and other forms of folliculitis, rosacea and alopecia; and a disease with a pigmentation disorder selected from the group consisting of a benign dermatosis selected from the group consisting of vitiligo, albinism, melasma, lentigines, freckles, melanocytic naevi and a post-inflammatory pigmentation disorder and a pigmented tumor selected from the group consisting of melanoma and local metastases, regional metastases and systemic metastases thereof.

11. The method according to claim 5, wherein the disorder, disease, or dysfunction is selected from the group consisting of: a skin disease selected from the group consisting of urticaria, scleroderma, contact dermatitis, atopic dermatitis, psoriasis, ichthyosis, acne and other forms of folliculitis, rosacea and alopecia; and a disease with a pigmentation disorder selected from the group consisting of a benign dermatosis selected from the group consisting of vitiligo, albinism, melasma, lentigines, freckles, melanocytic naevi and a post-inflammatory pigmentation disorder and a pigmented tumor selected from the group consisting of melanoma and local metastases, regional metastases and systemic metastases thereof.

12. The method according to claim 6, wherein the disorder, disease, or dysfunction is selected from the group consisting of: a skin disease selected from the group consisting of urticaria, scleroderma, contact dermatitis, atopic dermatitis, psoriasis, ichthyosis, acne and other forms of folliculitis, rosacea and alopecia; and a disease with a pigmentation disorder selected from the group consisting of a benign dermatosis selected from the group consisting of vitiligo, albinism, melasma, lentigines, freckles, melanocytic naevi and a post-inflammatory pigmentation disorder and a pigmented tumor selected from the group consisting of melanoma and local metastases, regional metastases and systemic metastases thereof.

13. The method as defined in claim 1, wherein the method is for treating signs of ageing skin, said method comprising applying the composition as defined in claim 1 to the skin of a subject in need of such treatment.

14. The method as defined by claim 1 wherein the method is for treating signs of ageing skin, said method comprising applying the composition as defined in claim 1 to the skin of a subject in need of such treatment and the compound is N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoroacetate.

15. The method as defined by claim 1 wherein the method is for body or hair hygiene, said method comprising applying to the body or the hair of a subject in need of such treatment for body or hair hygiene, a composition as defined in claim 1.

16. The method as defined by claim 1, for body or hair hygiene, said method comprising applying to the body or the hair of a subject in need of such treatment for body or hair hygiene and the compound is N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoroacetate; a composition as defined in claim 1.

17. A method for modulating a melanocortin receptor MC1R or MC4R in a cell, said method comprising contacting the cell with a melanocortin receptor MC1R or MC4R modulating amount of a compound selected from the group consisting of: N[(S)-1-[(S)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide; N[(S)-1-[(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide; N[(S)-1-[(S)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide; N[(S)-1-[(S)-2-[3-butoxy-3-(3-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(2,4-dichlorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclopropyl methoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butyl-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(3-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-benzyl-2-(3-butoxy-3-phenylazetidin-1-yl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-[1,2,4]triazol-3-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide; N{(R)-1-(4-methoxybenzyl)-2-[3-(2-methoxyphenyl)-3-pentylazetidin-1-yl]-2-oxoethyl}-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2-chlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-benzyl-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,4-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(3-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(2,4-dichlorobenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,5-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,6-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)hexyramide; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)pentyramide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide; N[(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoroacetate; (S)N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-2-hydroxy-3-(1H-imidazol-4-yl)propionamide; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclohexylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; 3-(1H-imidazol-4-yl)-N{(R)-1-(4-methoxybenzyl)-2-oxo-2-[3-o-tolyl-3-(4,4,4-trifluorobutoxy)azetidin-1-yl]ethylpropionamide; N[(R)-2-(3-cyclobutylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide; and N{(R)-1-(4-methoxybenzyl)-2-[3-(3-methylbut-2-enyloxy)-3-o-tolylazetidin-1-yl]-2-oxoethyl}-3-(5-methyl-1H-imidazol-4-ylpropionamide; and the salts and enantiomers thereof.

18. A method for modulating a melanocortin receptor MC1R or MC4R in a cell, said method comprising contacting the cell with a melanocortin receptor MC1R or MC4R modulating amount of a compound selected from the group consisting of: N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclopropyl methoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butyl-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide; N{(R)-1-(4-methoxybenzyl)-2-[3-(2-methoxyphenyl)-3-pentylazetidin-1-yl]-2-oxoethyl}-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2-chlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,4-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(3-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,5-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-(2,6-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoroacetate; N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide; N-[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; N[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide; N[(R)-2-(3-cyclohexylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide; 3-(1H-imidazol-4-yl)-N{(R)-1-(4-methoxybenzyl)-2-oxo-2-[3-o-tolyl-3-(4,4,4-trifluorobutoxy)-azetidin-1-yl]ethylpropionamide; N[(R)-2-(3-cyclobutylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide; and N{(R)-1-(4-methoxybenzyl)-2-[3-(3-methylbut-2-enyloxy)-3-o-tolylazetidin-1-yl]-2-oxoethyl}-3-(5-methyl-1H-imidazol-4-yl)propionamide; and the salts and enantiomers thereof.

19. A method for modulating a melanocortin receptor MC1R or MC4R in a cell, said method comprising contacting the cell with a melanocortin receptor MC1R or MC4R modulating amount of the compound N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoroacetate.

Description

EXAMPLE 1

N[(S)-1-[(S)-2-(3-Butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide (compound No. 3; Table I)

1-1 (S)-2-[(S)-2-Benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propanoic acid

(1) 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-(1H-imidazol-4-yl)propanoic acid in 30 ml of DMF. The reaction medium is left to stir for 15 minutes at ambient 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 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 organic phase is dried in the presence of magnesium sulphate. After filtration, the solvents are evaporated off. 6.56 g of a pale yellow solid are obtained and dissolved in 100 ml of THF. 29 ml of a 1N solution of LiOH are added. The reaction medium is stirred at ambient temperature for 16 hours. 20 ml of a saturated solution of ammonium chloride are added, followed by extraction with diethyl ether. The aqueous phase is acidified to pH 5 with a 1N solution of HCl. The white precipitate obtained is filtered off and oven-dried under vacuum at 40 C. 5.6 g (12.8 mmol) of (S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propanoic acid are obtained with a yield of 88%.

1-2 N[(S)-1-[(S)-2-(3-Butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide

1-2-1 3-Hydroxy-3-phenyl-1-(tert-butoxycarbonyl)-azetidine

(2) 3.9 ml (11.7 mmol) of a 3M solution of phenylmagnesium 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 10 ml of THF. The medium is stirred for 1 hour at 50 C. and hydrolysed by adding a saturated solution of ammonium chloride. After a return to ambient temperature, a 1N solution of hydrochloric acid is added, followed by extraction with ethyl acetate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified on silica in a 7/3 heptane/ethyl acetate mixture. 253 mg in the form of a white powder are obtained with a yield of 35%.

1-2-2 3-Butoxy-3-phenyl-1-(tert-butoxycarbonyl)-azetidine

(3) A solution of 1 g (4.0 mmol) of 3-hydroxy-3-phenyl-1-(tert-butoxycarbonyl)azetidine dissolved in 5 ml of DMF is added dropwise to a suspension of 300 mg of 60% NaH in 3 ml of DMF, immersed in a bath at 0 C. 2.5 ml of n-iodobutane are added dropwise. The reaction medium is left to stir at 0 C. for 15 minutes and 72 hours at ambient temperature. The medium is hydrolysed by addition of a saturated solution of ammonium chloride, followed by extraction with ethyl acetate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified on silica in a 7/3 heptane/ethyl acetate mixture. 500 mg in the form of a light yellow oil are obtained with a yield of 41%.

1-2-3 3-Butoxy-3-phenylazetidine trifluoroacetate

(4) 1 ml of trifluoroacetic acid is added to a solution containing 500 mg (1.64 mmol) of 3-butoxy-3-phenyl-1-(tert-butoxycarbonyl)azetidine dissolved in 5 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 3 hours and then concentrated. The crude product obtained is purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 400 mg in the form of a pale yellow powder are obtained with a yield of 76%.

1-3 N[(S)-1-[(S)-2-(3-Butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide

(5) 1 ml of a 3/2 dichloromethane/trifluoroacetic acid solution is added to 200 mg (0.343 mmol) of (S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propanoic acid. After stirring at ambient temperature for 1 hour, the solvents are evaporated off. The residue obtained is dissolved in 5 ml of DMF, and 110 mg (0.343 mmol) of TBTU and 2.37 ml of DIEA are added. The reaction medium is left to stir for 15 minutes at ambient temperature. 47 mg (0.147 mmol) of 3-butoxy-3-phenylazetidine trifluoroacetate dissolved in 5 ml of a 1/4 DCM/DMF solution are added dropwise and stirred at ambient temperature for 16 hours. A 5% citric acid solution is added, followed by extraction with dichloromethane. The organic phase is washed with a saturated solution of potassium hydrogen carbonate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 9/1 dichloromethane/methanol). 55 mg of N[(S)-1-[(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide are obtained in the form of a white powder with a yield of 60%.

(6) HPLC: (method A); 2 peaks (mixtures of conformers): retention time: 16.44 min and 16.60 min, (34+57)%, M+H: 624.

EXAMPLE 2

[1-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3-(4-fluorophenyl)azetidin-3-yl] ester of butyric acid (compound No. 6; Table I)

2-1 3-(4-Fluorophenyl)-3-hydroxy-1-(tert-butoxycarbonyl)azetidine

(7) 6 ml (11.7 mmol) of a 2M solution of 4-fluorophenylmagnesium 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 10 ml of THF. The medium is stirred for 1 hour at 50 C. and hydrolysed by addition of a saturated solution of ammonium chloride. After a return to ambient temperature, a 1N solution of hydrochloric acid is added, followed by extraction with ethyl acetate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 7/3 heptane/ethyl acetate). 333 mg in the form of a white powder are obtained with a yield of 43%.

2-2 3-Butyryloxy-3-(4-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine

(8) 23 mg (0.188 mmol) of DMAP and 0.03 ml of pyridine are added to a solution containing 50 mg (0.187 mmol) of 3-butyryloxy-3-(4-fluorophenyl)-1-(tert-butoxy-carbonyl)azetidine in 1 ml of dichloromethane. After stirring at ambient temperature for 10 minutes, 0.06 ml of butyric anhydride are introduced. After 3 hours, a saturated solution of ammonium chloride is added, followed by extraction with dichloromethane. The organic phase is dried and evaporated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 7/3 heptane/ethyl acetate). 61 mg in the form of a colourless oil are obtained with a yield of 97%.

2-3 3-(4-Fluorophenyl)azetidin-3-yl butyrate trifluoroacetate

(9) 2 ml of trifluoroacetic acid are added to a solution containing 61 mg (0.181 mmol) of 3-hydroxy-3-(4-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine dissolved in 8 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 3 hours and then concentrated. The crude product obtained is purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 40 mg in the form of a pale yellow oil are obtained with a yield of 63%.

2-4 1-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3-(4-fluorophenyl)azetidin-3-yl ester of butyric acid

(10) 1 ml of a 3/2 dichloromethane/trifluoroacetic acid solution is added to 109 mg (0.252 mmol) of (S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propanoic acid (cf. procedure 1-1). After stirring at ambient temperature for 1 hour, the solvents are evaporated off. The residue obtained is dissolved in 5 ml of DMF and 81 mg (0.252 mmol) of TBTU and 1.74 ml of DIEA are added. The reaction medium is left to stir for 15 minutes at ambient temperature. 40 mg (0.114 mmol) of 3-(4-fluorophenyl)azetidin-3-yl butyrate trifluoroacetate dissolved in 5 ml of a 1/4 dichloromethane/dimethylformamide solution are added dropwise and stirred at ambient temperature for 16 hours. A 5% citric acid solution is added, followed by extraction with dichloromethane. The organic phase is washed with a saturated solution of potassium hydrogen carbonate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 9/1 dichloromethane/methanol). 19 mg of 1-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3-(4-fluorophenyl)azetidin-3-yl ester of butyric acid are obtained in the form of a white powder with a yield of 25%.

(11) HPLC: (method B): 2 peaks (mixtures of conformers): retention time: 13.51 min and 13.72 min, (28+55)%, M+H: 656.

EXAMPLE 3

N[(S)-1-[(S)-2-(3-cyclohexyl-3-hydroxyazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide (compound No. 7; Table I)

3-1 3-Cyclohexyl-3-hydroxy-1-(tert-butoxy-carbonyl)azetidine

(12) 0.5 ml of acetic acid and 40 mg of rhodium on alumina 5% are added to a solution containing 117 mg (0.470 mmol) of 3-hydroxy-3-phenyl-1-(tert-butoxy-carbonyl)azetidine (cf. procedure 1-2-1) dissolved in 4 ml of methanol. The reaction medium is placed at 4 bar of hydrogen and heated at 85 C. for 4 hours. The catalyst is filtered off and washed with methanol and the solvents are evaporated off. 120 mg in the form of a beige powder are obtained with a yield of 100%.

3-2 3-Cyclohexylazetidin-3-ol trifluoroacetate

(13) 1 ml of trifluoroacetic acid is added to a solution containing 120 mg (0.47 mmol) of 3-cyclohexyl-3-hydroxy-1-(tert-butoxycarbonyl)azetidine dissolved in 3 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 1 hour and then concentrated to dryness and used without further purification.

3-3 N[(S)-1-[(S)-2-(3-Cyclohexyl-3-hydroxyazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide

(14) 1 ml of a 3/2 dichloromethane/trifluoroacetic acid solution is added to 84 mg (0.193 mmol) of (S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propanoic acid (cf. procedure 1-1). After stirring at ambient temperature for 1 hour, the solvents are evaporated off. The residue obtained is dissolved in 1 ml of DMF, and 79 mg (0.246 mmol) of TBTU and 15 drops of DIEA are added. 0.235 mmol of 3-cyclohexylazetidin-3-ol trifluoroacetate dissolved in 1 ml of a DCM solution is added dropwise and stirred at ambient temperature for 2 hours. A saturated solution of potassium hydrogen carbonate is added, followed by extraction with dichloromethane. The organic phase is washed with a saturated solution of potassium hydrogen carbonate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 85/15 dichloro-methane/methanol mixture). 35 mg of N[(S)-1-[(S)-2-(3-cyclohexyl-3-hydroxyazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide are obtained in the form of a yellow powder with a yield of 32%.

(15) HPLC: (method B): 2 peaks (mixture of conformers): retention time: 10.68 min and 10.94 min, (36+62)%, M+H: 574.

EXAMPLE 4

N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide (compound No. 24; Table I)

4-1 3-Pentyloxy-3-o-tolyl-1-(tert-butoxy-carbonyl)azetidine

(16) A solution of 3.53 g (13.4 mmol) of 3-hydroxy-3-phenyl-1-(tert-butoxycarbonyl)azetidine (cf. procedure 1-2-1) is added dropwise to a suspension of 1.07 g (26.8 mmol) of 60% NaH in 17 ml of DMF, immersed in a bath at 0 C. 9.0 ml of n-iodopentane are added dropwise. The reaction medium is left to stir at 0 C. for 15 minutes and 24 hours at ambient temperature. The medium is hydrolysed by addition of a saturated solution of ammonium chloride, followed by extraction with ethyl acetate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 7/3 heptane/ethyl acetate). 3.41 g in the form of a light yellow oil are obtained with a yield of 76%.

4-2 3-pentoxy-3-phenylazetidine trifluoroacetate

(17) 5.5 ml of trifluoroacetic acid are added to a solution containing 3.34 g (10 mmol) of 3-pentoxy-3-phenyl-1-(tert-butoxycarbonyl)azetidine dissolved in 10 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 2 hours 30 min and then concentrated. The crude product obtained is purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 3.5 g in the form of a pale yellow oil are obtained with a yield of 100%.

4-3 tert-butyl [(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]carbamate

(18) 2.93 g (9.93 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid are dissolved in 10 ml 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-3-phenylazetidine trifluoroacetate in 15 ml of DMF are then added. 7 ml (40.2 mmol) of DIEA are added. The reaction medium is stirred at ambient temperature for 2 h 30 and then extracted with ethyl acetate. The organic phase is washed with 1N sodium hydroxide and then dried over magnesium sulphate, filtered and evaporated. The crude product obtained is purified by silica gel chromatography (eluent 6/4 heptane/ethyl acetate). 2.83 g in the form of a white powder are obtained with a yield of 56%.

4-4 (R)-2-Amino-3-(4-methoxyphenyl)-1-(3-pentyloxy-3-o-tolylazetidin-1-yl)propan-1-one trifluoroacetate

(19) 2.81 g (5.5 mmol) of tert-butyl [(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]carbamate are solubilized in 10 ml of dichloromethane. The reaction medium is cooled to 0 C. 6.5 ml of trifluoroacetic acid are then introduced. After a return to ambient temperature, the reaction medium is stirred for 5 hours and then concentrated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 9/1 dichloromethane/methanol). 2.81 g in the form of a white powder are obtained with a yield of 97%.

4-5 N[(R)-1-(4-Methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide

(20) 670 mg (2.08 mmol) of TBTU, 0.8 ml of triethylamine and then 1.0 g (1.91 mmol) of (R)-2-amino-3-(4-methoxyphenyl)-1-(3-pentyloxy-3-o-tolylazetidin-1-yl)propan-1-one trifluoroacetate are added to a solution containing 370 mg (2.10 mmol) of desamino-histidine hydrochloride in 15 ml of dimethylformamide. The reaction medium is stirred at ambient temperature for 21 hours. The reaction is stopped by adding a 1N solution of sodium hydroxide and then extraction with dichloromethane is carried out. The organic phases are combined and dried over sodium sulphate. After filtration, the solvents are evaporated off and the residue is then purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 598 mg of N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 59%.

(21) HPLC: (method M); retention time: 18.20 min, 99%, M+H: 533.

EXAMPLE 5

N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide (compound No. 26; Table I)

5-1 Methyl (R)-2-amino-3-(4-methoxyphenyl)propanoate

(22) 20 ml of sulphuric acid are added, dropwise, over a period of 30 minutes, to a solution containing 13 g (66.6 mmol) of (R)-2-amino-3-(4-methoxyphenyl)propionic acid in 150 ml of methanol. After stirring for 24 hours at ambient temperature, the reaction medium is basified to pH 8-9 by introducing 10N sodium hydroxide and a saturated solution of sodium hydrogen carbonate, followed by extraction with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated. 12.8 g in the form of a pale yellow oil are obtained with a yield of 92%.

5-2 Methyl (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoate

(23) 35.5 ml of DIEA are added to a solution containing 13.2 g (74.7 mmol) of desamino-histidine hydrochloride and 24 g (74.7 mmol) of TBTU in 100 ml of DMF. After stirring for 15 minutes at ambient temperature, 14.2 g (67.9 mmol) of methyl (R)-2-amino-3-(4-methoxyphenyl)-propanoate in 150 ml of DMF are added. The reaction medium is left to stir for 16 hours and then basified to pH=8-9 by introducing 1N sodium hydroxide and a saturated solution of sodium hydrogen carbonate, followed by extraction with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated. The crude product obtained is purified by silica gel chromatography (eluent 85/15 dichloromethane/methanol). 11.0 g in the form of an orange oil are obtained with a yield of 49%.

5-3 (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoic acid

(24) 40 ml of a 1N aqueous solution of lithium hydroxide are added to a solution containing 11.0 g (33.3 mmol) of methyl (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoate in 100 ml of THF. After stirring for 16 hours, the reaction medium is concentrated. The residue is purified by silica gel chromatography (eluent 70/30/1 dichloromethane/methanol/triethylamine). 8.4 g in the form of a white powder are obtained with a yield of 79%.

5-4-1 2-Phenylheptanenitrile

(25) 5 g (42.7 mmol) of phenylacetonitrile are added dropwise to a suspension of 2 g of 60% NaH in 50 ml of DMF cooled to 0 C. After stirring for 30 minutes at 0 C., 5.32 ml (42.7 mmol) of bromopentane are added dropwise. The reaction medium is stirred for 16 hours at ambient temperature and then treated with ice and extracted with ethyl ether. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulphate, filtered and evaporated under pressure. An orangey-yellow oil is obtained and purified by fractionated distillation under reduced pressure (70-75 C. under 110.sup.1 mbar). 5.14 g in the form of an orangey oil are obtained with a yield of 64%.

5-4-2 2-Hydroxymethyl-2-phenylheptanenitrile

(26) 5.14 g (27.4 mmol) of 2-phenylheptanenitrile are added to a suspension of 1.34 g of 60% NaH in 50 ml of DMF cooled to 0 C. After stirring for 30 minutes, 7.6 g (220 mmol) of paraformaldehyde are added portionwise. The reaction medium is left to stir at ambient temperature for 6 hours and then hydrolysed with ice and extracted with diethyl ether. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulphate, filtered and evaporated under pressure. The crude product obtained is purified by silica gel chromatography (eluent 8/2 heptane/ethyl acetate). 4.24 g in the form of a pale yellow oil are obtained with a yield of 71%.

5-4-3 2-cyano-2-phenylheptyl ester of toluene-4-sulphonic acid

(27) 4.1 g (21.5 mmol) of p-toluenesulphonyl chloride and 6 ml of triethylamine are added to a solution containing 4.24 g (19.5 mmol) of 2-hydroxymethyl-2-phenylheptanenitrile in 25 ml of dichloromethane. The reaction medium is left to stir for 15 hours at ambient temperature and then treated with a 1N solution of hydrochloric acid and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. A yellow oil is obtained and precipitated from a 9/1 heptane/diisopropyl ether mixture. The precipitate formed is filtered off and rinsed with diisopropyl ether. 5.26 g in the form of a beige powder are obtained with a yield of 72%.

5-4-4 3-Pentyl-3-phenylazetidine

(28) 600 mg (15.52 mmol) of powdered LiAlH.sub.4 are added carefully to a solution containing 5.26 g (14.15 mmol) of 2-cyano-2-phenylheptyl ester of toluene-4-sulphonic acid in 25 ml of THF under nitrogen. The reaction medium is left to stir for 1 hour at ambient temperature and then treated with an aqueous solution of sodium sulphate. After stirring for 30 minute at ambient temperature, the salts formed are filtered off and the filtrate is evaporated under reduced pressure. The residue is taken up in dichloromethane and washed with a 1N aqueous solution of sodium hydroxide. The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure. 2.90 g in the form of a colourless oil are obtained and used in the next stage without further purification.

5-4-5 N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide

(29) 70 mg (0.345 mmol) of 3-pentyl-3-phenylazetidine and 100 mg (0.315 mmol) of (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoic acid are solubilized in 1 ml of DMF. 67 mg (0.345 mmol) of EDC and 47 mg (0.345 mmol) of HOBT are added to this solution. The whole is left to stir for 4 hours and is then treated with 1N sodium hydroxide and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. The crude product obtained is purified by silica gel chromatography (eluent 9/1 dichloromethane/methanol). 85 mg of N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 49%.

(30) HPLC: (method L); retention time: 22.96 min, 97%, M+H: 503.

EXAMPLE 6

N[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-[1,2,3]triazol-4-yl)propionamide (compound No. 39; Table I)

6-1 3-(1H-[1,2,3]triazol-4-yl)propanoic acid

(31) 39 mg of palladium-on-charcoal at 10% are added to a solution containing 390 mg (1.7 mmol) of 3-(1-benzyl-1H[1,2,3]triazol-4-yl)propanoic acid in 3 ml of methanol. The reaction mixture is placed under 10 bar of hydrogen pressure and stirred at 60 C. for 16 hours. After filtration through celite, the solvents are evaporated off and the residue is purified by silica gel chromatography (eluent 95/5 dichloro-methane/methanol). 159.8 mg of 3-(1H[1,2,3]triazol-4-yl)propanoic acid are obtained in the form of a white powder with a yield of 67%.

6-2 (R)-2-amino-3-(4-methoxyphenyl)-1-(3-butyloxy-3-o-tolylazetidin-1-yl)propan-1-one hydrochloride

(32) 6 ml of a 4N solution of hydrochloric acid in ethyl acetate are added to 615 mg (1.24 mmol) of tert-butyl [(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate (procedure identical to 4-3). The reaction mixture is stirred at ambient temperature for 2 hours. The precipitate obtained is filtered off, washed with diethyl ether and then dissolved in methanol, followed by evaporation of the solvents. 441 mg of (R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one hydrochloride are obtained in the form of a white powder with a yield of 82%.

6-3 N[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H[1,2,3]triazol-4-yl)propionamide

(33) 146 mg (0.34 mmol) of (R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one hydrochloride in 2 ml of dimethylformamide are added to a solution of 47 mg (0.34 mmol) of 3-(1H[1,2,3]triazol-4-yl)propanoic acid, 119 mg (0.37 mmol) of TBTU and 0.15 ml (1.1 mmol) of triethylamine in 2 ml of dimethylformamide. The reaction mixture is stirred for 2 hours at ambient temperature. The reaction is stopped by adding 10 ml of water and then extracted with ethyl acetate. The organic phases are combined, washed with a 1N solution of sodium hydroxide and then a saturated solution of sodium chloride, and dried over sodium sulphate. After filtration, the solvents are evaporated off and the residue is then purified by silica gel chromatography (eluent 90/10 ethyl acetate/heptane). 78.6 mg of N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H[1,2,3]triazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 45%.

(34) HPLC: (method M); retention time: 19.03 min, 93%, M+H: 520.

EXAMPLE 7

N[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide (compound No. 41; Table I)

7-1 3-(5-Methyl-3H-imidazol-4-yl)propanoic acid

(35) 50 mg of palladium-on-charcoal at 10% are added to 500 mg (2.65 mmol) of 3-(5-methyl-3H-imidazol-4-yl)acrylic acid chloride in 10 ml of a 0.5N solution of sodium hydroxide. The reaction mixture is placed under 6 bar of hydrogen pressure and stirred at 80 C. for 72 hours. After having filtered off the catalyst through celite, the residue is acidified to pH 2 with hydrochloric acid, concentrated to dryness and taken up in ethanol. The insoluble material is filtered off and the filtrate is concentrated to dryness. 102 mg of 3-(5-methyl-3H-imidazol-4-yl)propanoic acid chloride are obtained in the form of a white powder with a yield of 16%.

7-2 N[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide

(36) 146 mg (0.34 mmol) of (R)-2-amino-3-(4-methoxyphenyl)-1-(3-butyloxy-3-o-tolylazetidin-1-yl)propan-1-one hydrochloride in solution in 2 ml of dimethylformamide are 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 mmol) of TBTU and 0.15 ml (1.1 mmol) of triethylamine in 2 ml of dimethylformamide. The reaction mixture is stirred for 2 hours at ambient temperature. The reaction is stopped by adding 10 ml of water and then extracted with ethyl acetate. The organic phases are combined, washed with a 1N solution of sodium hydroxide and then a saturated solution of sodium chloride, and dried over sodium sulphate. After filtration, the solvents are evaporated off and the residue is then purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 154 mg of N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 86%.

(37) HPLC: (method M); retention time: 17.65 min, 96%, M+H: 533.

EXAMPLE 8

N[(S)-2-(3-Hydroxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide (compound No. 11; Table I)

8-1 3-Hydroxy-3-phenylazetidine trifluoroacetate

(38) 1 ml of trifluoroacetic acid is added to a solution containing 50 mg (0.19 mmol) of tert-butyl 3-hydroxy-3-phenylazetidine-1-carboxylate dissolved in 4 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 3 hours and then concentrated. The crude product obtained is purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 36 mg in the form of a white powder are obtained with a yield of 68%.

8-2 N[(S)-2-(3-Hydroxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide trifluoroacetate

(39) 2 ml of DMF, 106 mg (0.33 mmol) of TBTU and 1 ml of DIEA are added to 105 mg (0.33 mmol) of (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoic acid. The reaction medium is left to stir for 15 minutes at ambient temperature. 36 mg (0.13 mmol) of 3-hydroxy-3-phenylazetidine trifluoroacetate dissolved in 5 ml of a 1/4 DCM/DMF solution are added dropwise and stirred at ambient temperature for 16 hours. A 5% citric acid solution is added, followed by extraction with dichloromethane. The organic phase is washed with a saturated solution of potassium hydrogen carbonate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 9/1 dichloromethane/methanol). 6 mg of N[(S)-2-(3-hydroxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide trifluoroacetate are obtained in the form of a white powder with a yield of 10%.

(40) HPLC: (method D); retention time: 9.25 min, 89%, M+H: 463.

EXAMPLE 9

N[(R)-2-[3-(4-Fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide (compound No. 38; Table I)

9-1-1 (4-Fluorophenyl)heptanenitrile

(41) 5 g (37.0 mmol) of (4-fluorophenyl)acetonitrile are added dropwise to a suspension of 1.62 g of 60% NaH in 50 ml of DMF cooled to 0 C. After stirring for 30 minutes at 0 C., 4.62 mmol (37.0 mmol) of bromopentane are added dropwise. The reaction medium is stirred for 16 hours at ambient temperature and then treated with ice and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. An orangey-yellow oil is obtained and used as it is in the next stage.

9-1-2 2-Hydroxymethyl-2-(4-fluorophenyl)-heptanenitrile

(42) The crude (4-fluorophenyl)heptanenitrile obtained in stage 9-1-1 is added to a suspension of 1.62 g of 60% NaH in 50 ml of DMF cooled to 0 C. After stirring for 30 minutes, 8.9 g (296 mmol) of paraformaldehyde are added portionwise. The reaction medium is left to stir at ambient temperature for 3 hours and then hydrolysed with ice and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. The crude product obtained is purified by silica gel chromatography (eluent 8/2 heptane/ethyl acetate). 3.85 g in the form of a pale yellow oil are obtained with a yield of 44%.

9-1-3 2-cyano-2-(4-fluorophenyl)heptyl ester of toluene-4-sulphonic acid

(43) 3.43 g (18.0 mmol) of p-toluenesulphonyl chloride and 5 ml of triethylamine are added to a solution containing 3.85 g (16.4 mmol) of 2-hydroxymethyl-2-(4-fluorophenyl)heptanenitrile in 40 ml of dichloromethane. The reaction medium is left to stir for 15 hours at ambient temperature and then treated with a 1N solution of hydrochloric acid and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. A yellow oil is obtained and precipitated from an 8/2 dichloromethane/diisopropyl ether mixture. The precipitate formed is filtered off. 4.4 g in the form of a beige powder are obtained with a yield of 65%.

9-1-4 3-Pentyl-3-(4-fluorophenyl)azetidine

(44) 471 mg (12.4 mmol) of powdered LiAlH.sub.4 are added carefully to a solution containing 4.4 g (11.3 mmol) of 2-cyano-2-(4-fluorophenyl)heptyl ester of toluene-4-sulphonic acid in 40 ml of THF under nitrogen. The reaction medium is left to stir for 1 hour at ambient temperature and then treated with an aqueous solution of sodium sulphate. After stirring for 30 minutes at ambient temperature, the salts formed are filtered off and the filtrate is evaporated under reduced pressure. The residue is taken up in dichloromethane and washed with a 1N aqueous solution of sodium hydroxide. The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure. 2.02 g in the form of a yellow oil are obtained and used in the next stage without further purification.

9-2 Tert-butyl [(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-(4-fluorophenyl)azetidin-1-yl)ethyl]carbamate

(45) 606 mg (2.05 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid and 500 mg (2.26 mmol) of 3-pentyl-3-(4-fluoro-phenyl)azetidine are dissolved in 10 ml of DMF. 473 mg (2.46 mmol) of EDC, 333 mg (2.46 mmol) of HOBt and 0.6 ml (4.5 mmol) of triethylamine are added to this solution. The reaction medium is stirred at ambient temperature for 5 h and then extracted with dichloromethane. The organic phase is washed with 1N sodium hydroxide and then dried over magnesium sulphate, filtered and evaporated. The crude product obtained is purified by silica gel chromatography (eluent 6/4 heptane/ethyl acetate). 780 mg in the form of a white powder are obtained with a yield of 76%.

9-3 (R)-2-Amino-3-(4-methoxyphenyl)-1-(3-pentyl-3-(4-fluorophenyl)azetidin-1-yl)-propan-1-one

(46) 780 mg (1.56 mmol) of tert-butyl [(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-(4-fluoro-phenyl)azetidin-1-yl)ethyl]carbamate are solubilized in 10 ml of dichloromethane. 4 ml of trifluoroacetic acid are introduced. The reaction medium is stirred for 1 hour and then concentrated to dryness. The residue is taken up in a 1N aqueous solution of sodium hydroxide and extracted with dichloromethane and then the resulting product is dried over magnesium sulphate, filtered and evaporated.

(47) 590 mg in the form of a colourless resin are obtained with a yield of 95%.

9-4 N[(R)-2-[3-(4-Fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

(48) 600 mg (1.86 mmol) of TBTU and 0.45 ml of triethylamine are added to a solution containing 330 mg (1.86 mmol) of desamino-histidine hydrochloride in 5 ml of dimethylformamide. After stirring for 15 minutes, 590 mg (1.55 mmol) of (R)-2-amino-3-(4-methoxyphenyl)-1-(3-pentyl-3-(4-fluorophenyl)azetidin-1-yl)-propan-1-one dissolved in 5 ml of dimethylformamide are added. The reaction medium is stirred at ambient temperature for 3 days. The reaction is stopped by adding a 1N solution of sodium hydroxide and then extracted with a 1/1 heptane/ethyl acetate mixture. The organic phases are combined and dried over sodium sulphate. After filtration, the solvents are evaporated off and the residue is then purified by silica gel chromatography (eluent 85/15 dichloromethane/methanol). 490 mg of N[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)-propionamide are obtained in the form of a white powder with a yield of 61%.

(49) HPLC: (method 0); retention time: 15.85 min, 99%, M+H: 521.

EXAMPLE 10

N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)hexyramide (compound No. 62; Table I)

10-1-1 6-(1-Trityl-1H-imidazol-4-yl)hex-5-enoic acid

(50) 13.5 ml (14.3 mmol) of a solution of lithium hexamethyldisilazane at 1.06 M in THF are added to 3.27 g (7.38 mmol) of (4-carboxybutyl)triphenyl-phosphonium bromide in suspension in 45 ml of THF cooled to 75 C. The reaction medium is stirred at 75 C. for 20 minutes and then at 0 C. for 15 minutes. After a return to 75 C., 1.50 g (4.43 mmol) of 1-trityl-1H-imidazole-4-carbaldehyde in suspension in 15 ml of THF are introduced. After a return to ambient temperature, the reaction medium is stirred for 20 hours and then at 90 C. with microwave-heating for 5 minutes. The reaction medium is filtered and concentrated in a rotary evaporator and then taken up in 1/1 heptane/EtOAc. The organic phase is washed with a saturated aqueous solution of NaHCO.sub.3. The aqueous phase obtained is acidified to pH=5 with an aqueous solution of citric acid at 5% and then extracted with a 1/1 heptane/EtOAc mixture. The organic phase is dried over MgSO.sub.4, filtered and concentrated in a rotary evaporator. 0.58 g of 6-(1-trityl-1H-imidazol-4-yl)hex-5-enoic acid in the form of a beige powder are obtained with a yield of 31%.

10-1-2 6-(1H-imidazol-4-yl)hex-5-enoic acid trifluoroacetate

(51) 2 ml of trifluoroacetic acid are added to 0.58 g (1.37 mmol) of 6-(1-trityl-1H-imidazol-4-yl)hex-5-enoic acid in suspension in 8 ml of dichloromethane. After the solvents have been evaporated off, the oil obtained is purified on a silica column (eluent 8/2 DCM/MeOH). 240 mg of 6-(1H-imidazol-4-yl)hex-5-enoic acid trifluoroacetate in the form of a yellow oil are isolated with a yield of 60%.

10-1-3 6-(1H-imidazol-4-yl)hexanoic acid trifluoroacetate

(52) 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-4-yl)hex-5-enoic acid trifluoroacetate. The reaction medium is placed under a hydrogen atmosphere at atmospheric pressure. After 13 hours, the reaction medium is filtered through celite. After the solvents have been evaporated off, 175 mg of 6-(1H-imidazol-4-yl)hexanoic acid trifluoroacetate in the form of a yellow oil are obtained with a yield of 80%.

10-2 N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)hexyramide

(53) 60 mg (0.186 mmol) of TBTU, 0.1 ml (0.715 mmol) of triethylamine and a solution of 79 mg (0.155 mmol) of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one trifluoroacetate (cf. procedure 4-4) in 1 ml of DMF are added to 55 mg (0.186 mmol) of 6-(1H-imidazol-4-yl)hexanoic acid trifluoroacetate dissolved in 1 ml of DMF. The reaction medium is stirred for 66 hours and is extracted with a 1/2 heptane/EtOAc mixture and then washed with 1N sodium hydroxide. The organic phase is dried over MgSO.sub.4, filtered and concentrated. The crude product obtained is purified on a silica column (eluent 8/2 DCM/MeOH). 40.8 mg of N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)hexyramide are obtained in the form of a white powder with a yield of 47%.

(54) HPLC: (method V); retention time: 18.05 min, 99%, M+H: 561.

EXAMPLE 11

N[(R)-1-(4-Methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide (compound No. 64; Table I)

11-1-1 5-(2-methoxycarbonylethyl)-1-methyl-3-trityl-3H-imidazol-1-ium iodide

(55) 720 mg (5.2 mmol) of potassium carbonate and 0.34 ml (5.72 mmol) of iodomethane are added to a solution of 1 g (2.6 mmol) of N-1-trityl-desamino-histidine in 10 ml of DMF. The reaction medium is heated at 60 C. for 3 hours. After a return to ambient temperature, the reaction medium is treated with water and acetic acid (to pH 4-5) and extracted with dichloromethane. The organic phase is dried over MgSO.sub.4, filtered and evaporated. The residue obtained is purified by silica chromatography (eluent 8/2 DCM/MeOH). 970 mg of 5-(2-methoxycarbonylethyl)-1-methyl-3-trityl-3H-imidazol-1-ium iodide are obtained with a yield of 69%.

11-1-2 Methyl 3-(3-methyl-3H-imidazol-4-yl)propionate trifluoroacetate

(56) 0.5 ml of trifluoroacetic acid is added to a solution of 200 mg (0.37 mmol) of 5-(2-methoxycarbonylethyl)-1-methyl-3-trityl-3H-imidazol-1-ium iodide in 2 ml of dichloromethane. The reaction medium is left to stir overnight at ambient temperature and the solvents are evaporated off. The residue is purified by silica chromatography (eluent 9/1 DCM/MeOH. 80 mg of methyl 3-(3-methyl-3H-imidazol-4-yl)propionate trifluoroacetate are obtained with a yield of 76%.

11-1-3 3-(3-Methyl-1H-imidazol-4-yl)propionic acid hydrochloride

(57) 2 ml of an aqueous solution of sodium hydroxide at 30% are added to a solution of 320 mg (1.13 mmol) of methyl 3-(3-methyl-3H-imidazol-4-yl)propionate trifluoroacetate in 10 ml of THF. The reaction medium is stirred at ambient temperature for 16 hours and then cooled to 0 C., and concentrated hydrochloric acid is added dropwise until pH 1 is obtained. After filtration, the filtrate is evaporated. 87 mg of 3-(3-methyl-1H-imidazol-4-yl)propionic acid hydrochloride are obtained with a yield of 39%.

11-2 N[(R)-1-(4-Methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide

(58) 0.17 ml (1.23 mmol) of triethylamine is carefully added to a solution containing 87 mg (0.45 mmol) of 3-(3-methyl-1H-imidazol-4-yl)propionic acid hydrochloride and 160 mg (0.49 mmol) of TBTU in 1 ml of DMF. After stirring for 60 minutes at ambient temperature, 200 mg (0.32 mmol) of (R)-2-amino-3-(4-methoxyphenyl)-1-(3-pentyl-3-phenylazetidin-1-yl)propan-1-one trifluoroacetate (cf. procedure 9-3) are added and the reaction medium is left to stir for three days. The reaction medium is treated with a 2 heptane/8 EtOAc mixture and a 1N aqueous solution of sodium hydroxide. The organic phase is dried over MgSO.sub.4, filtered and evaporated. The residue obtained is purified by silica chromatography (eluent 9 DCM/1 MeOH). 21 mg of N[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide are obtained with a yield of 9%.

(59) HPLC: (method W); retention time: 18.04 min, 96%, M+H: 517.

EXAMPLE NO. 12

N[(R)-2-(3-Cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide (compound No. 66; Table I)

12-1 3-Cyclohexyl-3-pentylazetidine oxalate

(60) 254 mg of rhodium-on-alumina at 5% are added to 652 mg (2.62 mmol) of 3-pentyl-3-phenylazetidine oxalate (cf.) in 13 ml of water and 6.5 ml of THF. The medium is placed under a hydrogen atmosphere at 6 bar of pressure and heated at 80 C. After 23 hours, the reaction medium is filtered through celite and the solvents are evaporated off. 0.43 g of 3-cyclohexyl-3-pentylazetidine oxalate is obtained with a yield of 64%.

12-2 tert-Butyl [(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate

(61) 0.36 g (1.98 mmol) of EDC, 0.25 g (1.85 mmol) of HOBt and 0.51 g (1.73 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid are added to 0.43 g (1.69 mmol) of 3-cyclohexyl-3-pentylazetidine oxalate dissolved in 8 ml of DMF. After 5 minutes, 0.9 ml (6.5 mmol) of triethylamine is added. After 1 hour 30 minutes, the reaction medium is extracted with a 1/1 EtOAc/heptane mixture and washed with a solution of 1N hydrochloric acid, of 1N sodium hydroxide and of water. The organic phase is dried over MgSO.sub.4, filtered and concentrated. The residue is purified on a silica column (eluent 6/4 heptane/EtOAc). 0.48 g of tert-butyl [(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate in the form of a colourless oil is obtained with a yield of 59%.

12-3 (R)-2-Amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one

(62) 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-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate dissolved in 10 ml of dichloromethane. After 2 hours, the solvents are evaporated off. The residue is taken up in dichloromethane and washed with 1N sodium hydroxide. The organic phases are combined, dried over MgSO.sub.4, filtered and concentrated. 327 mg of (R)-2-amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4-methoxyphen-yl)propan-1-one are obtained with a yield of 86%.

12-4 N[(R)-2-(3-Cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

(63) 100 mg (0.311 mmol) of TBTU and 0.1 ml (0.715 mmol) of triethylamine are added to 55 mg (0.311 mmol) of 3-(1H-imidazol-4-yl)propionic acid hydrochloride in 1 ml of DMF. After 10 minutes, 99 mg (0.256 mmol) of (R)-2-amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one dissolved in 1 ml of DMF are added. After stirring for 118 hours at ambient temperature, the reaction medium is extracted with a 1/2 heptane/EtOAc mixture and washed with 1N sodium hydroxide and a saturated sodium chloride solution. The organic phase is dried over MgSO.sub.4, filtered and concentrated. The residue is purified on a silica column (eluent 9/1 DCM/MeOH). 72 mg of N[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white powder, with a yield of 55%.

(64) HPLC: (method Y); retention time: 18.34 min, 98%, M+H: 509.

EXAMPLE 13

N[(R)-2-[3-butoxy-3-(2-fluorophenyl)-azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

13.1: 3-(2-Fluorophenyl)-3-hydroxy-1-(tert-butoxy-carbonyl)azetidine

(65) 3.1 ml (6.1 mmol) of a 2M solution of isopropylmagnesium chloride in tetrahydrofuran are added to a solution of 1.1 g (6.2 mmol) of 1-bromo-2-fluorobenzene in 4 ml of tetrahydrofuran, cooled beforehand to 25 C. After stirring for 30 minutes at 25 C., a solution of 0.65 g (3.7 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 7.5 ml of tetrahydrofuran is added. The reaction medium is stirred for 30 min and then a saturated aqueous solution of ammonium chloride is added. The organic compounds are extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate and then filtered and evaporated. The crude product is purified by silica gel chromatography, elution being carried out with a 5/5 heptane/ethyl acetate mixture. 135 mg of 3-(2-fluorophenyl)-3-hydroxy-1-(tert-butoxycarbonyl)-azetidine are obtained in the form of a white solid with a yield of 14%.

13.2: 3-Butoxy-3-(2-fluorophenyl)-1-(tert-butoxy-carbonyl)azetidine

(66) 135 mg (0.4 mmol) of 3-(2-fluorophenyl)-3-hydroxy-1-(tert-butoxycarbonyl)azetidine at 80% in 2 ml of dimethylformamide are added to a suspension of 65 mg (1.6 mmol) of sodium hydride at 60% in 1.5 ml of dimethylformamide, under nitrogen, at 0 C. After stirring for 20 minutes at 0 C., 0.2 ml (1.5 mmol) of iodobutane are added. The reaction medium is stirred at ambient temperature for 1 h 30 and is then hydrolysed with water and with a saturated aqueous solution of ammonium chloride and extracted with a 1/2 heptane/ethyl acetate mixture. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and evaporated. The crude product is purified by silica gel chromatography, elution being carried out with an 8/2 heptane/ethyl acetate mixture. 104 mg of 3-butoxy-3-(2-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine are obtained in the form of a yellow oil with a yield of 79%.

13.3: 3-Butoxy-3-(2-fluorophenyl)azetidine trifluoroacetate

(67) 1 ml of trifluoroacetic acid is added to a solution containing 104 mg (0.3 mmol) of 3-butoxy-3-(2-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine in 3 ml of dichloromethane at 0 C. After stirring for 30 minutes, the reaction medium is evaporated off under a stream of nitrogen. 126 mg of 3-butoxy-3-(2-fluorophenyl)azetidine trifluoroacetate are obtained in the form of a pale yellow oil with a yield of 100%.

13.4: tert-Butyl [(R)-2-[3-butoxy-3-(2-fluorophenyl)-azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]carbamate

(68) 68 mg of EDC (0.3 mmol), 45 mg (0.3 mmol) of HOBt and 100 mg (0.33 mmol) of Boc-D-methoxyphenylalanine are added successively to 126 mg (0.3 mmol) of 3-butoxy-3-(2-fluorophenyl)azetidine trifluoroacetate in 1.5 ml of dimethylformamide under nitrogen. After stirring for 5 minutes, 0.2 ml (1.3 mmol) of triethylamine is added. The reaction medium is then stirred for 23 hours at ambient temperature and extracted with a 1/1 ethyl acetate/heptane mixture in the presence of a 1N aqueous solution of sodium hydroxide. The organic phase is washed with a 1N aqueous solution of hydrochloric acid and then with water, dried over magnesium sulphate, filtered and evaporated. 94 mg of tert-butyl [(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]carbamate are obtained in the form of a yellow oil with a yield of 58%.

13.5: (R)-2-Amino-1-[3-butoxy-3-(2-fluorophenyl)-azetidin-1-yl]-3-(4-methoxyphenyl)propan-1-one trifluoroacetate

(69) 1 ml of trifluoroacetic acid is added to a solution of 94 mg (0.2 mmol) of tert-butyl [(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]carbamate in 10 ml of dichloromethane, cooled beforehand to 0 C. After stirring for 1 h 30 at ambient temperature, the reaction medium is evaporated off under a stream of nitrogen. 119 mg of (R)-2-amino-1-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-3-(4-methoxyphenyl)propan-1-one trifluoroacetate are obtained in the form of a yellow oil with a yield of 100%.

13.6: N[(R)-2-[3-Butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

(70) 81 mg (0.3 mmol) of TBTU and 0.1 ml (0.6 mmol) of triethylamine are added to a solution of 42 mg (0.25 mmol) of desamino-histidine hydrochloride in 1 ml of dimethylformamide. After stirring for 10 minutes, 119 mg (0.2 mmol) of (R)-2-amino-1-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-3-(4-methoxyphenyl)propan-1-one trifluoroacetate are added and the reaction medium is stirred for 64 h at ambient temperature. After extraction with a 1/2 heptane/ethyl acetate mixture, the organic phase is washed with 1N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The crude product is purified by silica gel chromatography, elution being carried out with a 90/10 dichloromethane/methanol mixture. 59 mg of N[(R)-2-[3-butoxy-3-(2-fluoro-phenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white solid with a yield of 57%.

(71) .sup.1H NMR/DMSO d.sup.6 100 C.: =0.78 (t, J=7.2-7.6 Hz, 3H); 1.23 (sext, J=6.8-7.2 Hz, 2H); 1.37 (quint, J=6.4-7.6 Hz, 2H); 2.38-2.42 (m, 2H); 2.68-2.94 (m, 7H); 3.10 (bt, J=5.6-6.4, 2H); 4.00-4.40 (m, 4H); 4.50 (q, J=7.2-7.6 Hz, 1H); 6.67-6.80 (m, 3H); 7.09-7.24 (m, 4H); 7.30-7.43 (m, 4H); 7.70-7.90 (m, 1H).

EXAMPLE 14

N[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide

14.1 Methyl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate

(72) 1 ml (5.5 mmol) of methyl diethylphosphonoacetate are added to a suspension of 220 mg (5.5 mmol) of sodium hydride at 60% in 5 ml of tetrahydrofuran cooled to 0 C. After stirring for 1 h, 500 mg (4.5 mmol) of 1-methyl-1H-imidazole-4-carbaldehyde are added and the mixture is stirred for 4 hours at ambient temperature and then hydrolysed with water and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulphate, filtered and evaporated. The product obtained is precipitated from heptane and filtered. 430 mg of methyl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate are obtained in the form of a yellow powder with a yield of 57%.

14.2 3-(1-Methyl-1H-imidazol-4-yl)propanoic acid hydrochloride

(73) 50 mg of palladium-on-charcoal at 10% are added to a solution of 100 mg (0.6 mmol) of methyl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate in 5 ml of a 1N aqueous solution of sodium hydroxide. The reaction medium is flushed with nitrogen and then stirred under a hydrogen atmosphere for 24 h. After filtration through celite, the filtrate is brought back to pH 2 with a concentrated aqueous solution of hydrochloric acid, toluene is added, and the medium is concentrated to dryness. The residue obtained is taken up in acetone and the precipitated salts are filtered off. The filtrate is concentrated. 160 mg of 3-(1-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride are obtained in the form of a solid with a yield of 32%.

14.3 N[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide

(74) 84 mg (0.3 mmol) of TBTU and 0.1 ml (0.5 mmol) of triethylamine are added to a solution of 50 mg (0.3 mmol) of 3-(1-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride in 2 ml of dimethylformamide. After stirring for 1 h at ambient temperature, 90 mg (0.2 mmol) of (R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one hydrochloride (prepared as described in Example 6.2) are added. The reaction medium is stirred at ambient temperature for 72 h, extracted with a 2/8 heptane/ethyl acetate mixture and then washed with a 1N aqueous solution of sodium hydroxide. The organic phase is dried over magnesium sulphate, filtered and evaporated.

(75) The crude product is purified by silica gel chromatography, elution being carried out with a 97/3 dichloromethane/methanol mixture. 22 mg of N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide are obtained in the form of a beige powder with a yield of 23%.

(76) HPLC: (Method U); retention time: 15.28 min, 96.5%, M+H: 533

EXAMPLE 15

N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoroacetate

15.1: 2-Benzyloxy-4-methoxybenzaldehyde

(77) 160 ml (1.3 mmol) of benzyl bromide and (1.3 mmol) of potassium carbonate are added to a solution of 2 g (1.3 mmol) of 2-hydroxy-4-methoxybenzaldehyde in 20 ml of acetone. The mixture is stirred at reflux for 6 hours and then evaporated. 50 ml of 1N aqueous solution of sodium hydroxide are added and the medium is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated. The residue obtained is precipitated from 1 heptane/ethyl acetate mixture (95/5). 2.75 g of 2-benzyloxy-4-methoxybenzaldehyde are obtained in the form of a white powder with a yield of 86%.

15.2: Methyl (E)-3-(2-benzyloxy-4-methoxyphenyl)-2-(tert-butoxycarbonyl)aminoacrylate

(78) 1.8 g (5.4 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene are added to a solution of 1.8 g (6.2 mmol) of ()-Boc--phosphonoglycine trimethyl ester in 10 ml of dichloromethane, 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 2-benzyloxy-4-methoxybenzaldehyde in 5 ml of dichloromethane is added and the reaction medium is then stirred for 18 h at ambient temperature. After the dichloromethane has been evaporated off, the residue is taken up in 50 ml of ethyl acetate. The organic phase is washed with a saturated aqueous solution of ammonium chloride, and water, dried over magnesium sulphate, filtered and evaporated. The residue obtained is purified by silica gel chromatography (eluent: 70/30 heptane/ethyl acetate). 1.5 g of methyl (E)-3-(2-benzyloxy-4-methoxyphenyl)-2-(tert-butoxycarbonylamino)acrylate are obtained in the form of a beige powder with a yield of 85%.

15.3: Methyl 2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)propanoate

(79) 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-benzyloxy-4-methoxyphenyl)-2-(tert-butoxycarbonylamino)acrylate in 15 ml of methanol. After stirring for hours under a hydrogen atmosphere, the reaction medium is filtered through celite and the filtrate is evaporated off. 850 mg of methyl 2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)-propanoate are obtained in the form of a grey powder with a yield of 74%.

15.4: 2-tert-Butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)propanoic acid

(80) 5 ml of a 1N aqueous solution of sodium hydroxide are added to a solution of 850 mg (2.6 mmol) of methyl 2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)-propanoate in 10 ml of tetrahydrofuran. The reaction medium is stirred for 4 hours at ambient temperature and then a 1N aqueous solution of hydrochloric acid is added until the pH is 1, and the medium is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated. 820 mg of 2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)propanoic acid are obtained in the form of a beige powder with a quantitative yield.

15.5: 3-butoxy-3-o-tolylazetidine trifluoroacetate

(81) 1 ml of trifluoroacetic acid is added to a solution containing 500 mg (1.65 mmol) of 3-butoxy-3-o-tolylazetidine-1-(tert-butoxycarbonyl)azetidine dissolved in 5 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 3 hours and then concentrated. The crude product obtained is purified by silica gel chromatography (eluent: 90/10 dichloromethane/methanol). 400 mg in the form of a pale yellow powder are obtained with a yield of 76%.

15.6: tert-Butyl [2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]carbamate

(82) 74 mg (0.4 mmol) of EDC and 52 mg (0.4 mmol) of HOBt are added to a solution of 100 mg (0.3 mmol) of 2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)-propanoic acid in 5 ml of dimethylformamide. The mixture is stirred for 15 min and 107 mg (0.3 mmol) of 3-butoxy-3-o-tolylazetidine trifluoroacetate are added. After stirring for a further 15 minutes at ambient temperature, 0.3 ml (1.3 mmol) of diisopropylethylamine is added. The reaction medium is stirred for 2 h, and then 10 ml of a 1N aqueous solution of hydrochloric acid are added and the medium is extracted with ethyl acetate. The organic phase is washed with water and then dried over magnesium sulphate, filtered and evaporated. The residue is filtered through silica gel (eluent: 70/30 heptane/ethyl acetate). 220 mg of tert-butyl [2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]carbamate are obtained in the form of a yellow oil and are used crude in the next stage.

15.7: 2-Amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(2-hydroxy-4-methoxyphenyl)propan-1-one trifluoroacetate

(83) 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-hydroxy-4-methoxybenzyl)-2-oxoethyl]carbamate in 2 ml of dichloromethane. After stirring for 1 hour at ambient temperature, the reaction medium is concentrated under vacuum. 250 mg of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(2-hydroxy-4-methoxyphenyl)propan-1-one trifluoroacetate are obtained in the form of a yellow oil with a quantitative yield.

15.8: N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoroacetate

(84) 0.25 ml (0.6 mmol) of triethylamine is added to a solution of 90 mg (0.6 mmol) of desamino-histidine and 207 mg (0.6 mmol) of TBTU in 2 ml of dimethylformamide. After stirring for 1 h at ambient temperature, 250 mg (0.4 mmol) of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(3-hydroxy-4-methoxyphenyl)propan-1-one trifluoroacetate are added and the mixture is stirred for 72 h at ambient temperature. 10 ml of a saturated aqueous solution of sodium hydrogen carbonate are then poured into the reaction medium, which is extracted with a 20/80 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. The product is purified by preparative thin layer chromatography (eluent: 90/10 dichloro-methane/methanol). 30 mg of N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide trifluoroacetate are obtained in the form of a beige powder with a yield of 11%.

(85) HPLC: (Method A1): retention time: 14.39 min, 94.2%, M+H: 535.

EXAMPLE 16

(S)N[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-2-hydroxy-3-(1H-imidazol-4-yl)propionamide

(86) 0.1 ml (0.8 mmol) of triethylamine is added to a solution containing 50 mg (0.3 mmol) of (S)-2-hydroxy-3-(1H-imidazol-4-yl)propanoic acid and 100 mg (0.3 mmol) of TBTU in 2 ml of dimethylformamide. After stirring for 1 hour at ambient temperature, 128 mg (0.3 mmol) of (R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one hydrochloride (described in Example 6.2) are added and the mixture is stirred for 72 h at ambient temperature. A 1N aqueous solution of sodium hydroxide is added and the medium is extracted with a 20/80 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. The crude product is purified by preparative thin layer chromatography (eluent: 90/10 dichloro-methane/methanol). 17 mg of (S)N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-2-hydroxy-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 13%.

(87) .sup.1H NMR/DMSO d.sup.6 100 C.: =0.78 (t, J=7.2 Hz, 3H); 1.23 (sext, J=7.3 Hz, 2H); 1.36 (quint, J=6.7 Hz, 2H); 2.12 (s, 3H); 2.55-2.75 (m, 1H); 2.86-2.98 (m, 7H); 3.68 (bs, 3H); 3.90-4.30 (m, 4H); 4.54 (bq, J=6.4 Hz, 1H); 5.25-5.45 (m, 1H); 6.55-6.95 (m, 3H); 7.09-7.27 (m, 6H); 7.43 (bs, 1H); 7.50-7.65 (m, 1H).

EXAMPLE 17

N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)-propionamide

17.1: tert-Butyl [2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]carbamate

(88) 205 mg (1.1 mmol) of EDC and then 145 mg (1.1 mmol) of HOBt are added to a solution of 250 mg (0.9 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-hydroxyphenyl)-propanoic acid in 5 ml of dimethylformamide. After stirring for 15 minutes at ambient temperature, 300 mg (1.1 mmol) of 3-butoxy-3-o-tolylazetidine trifluoroacetate (described in Example 15.5) and 0.5 ml (3.6 mmol) of triethylamine are added. The reaction medium is stirred for 2 h at ambient temperature and then a 1N aqueous solution of hydrochloric acid is added and the mixture is extracted with ethyl acetate. The organic phase is washed with water, and then dried over magnesium sulphate, filtered and evaporated. The residue is purified by silica gel chromatography, elution being carried out with a 60/40 heptane/ethyl acetate mixture. 410 mg of [2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide are obtained with a yield of 90%.

17.2: 2-Amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-hydroxyphenyl)propan-1-one trifluoroacetate

(89) 2 ml of trifluoroacetic acid are added to a solution of 410 mg (0.8 mmol) of tert-butyl [2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]carbamate in 5 ml of dichloromethane. After stirring for 1 hour at ambient temperature, the solvent is evaporated off. 440 mg of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-hydroxyphenyl)propan-1-one trifluoroacetate are obtained with a quantitative yield.

17.3: N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide

(90) 0.35 ml (2.6 mmol) of triethylamine are added to a solution containing 225 mg (1.3 mmol) of desamino-histidine hydrochloride and 410 mg (1.3 mmol) of TBTU in 5 ml of DMF. After stirring for 1 hour at ambient temperature, 440 mg (0.9 mmol) of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-hydroxyphenyl)propan-1-one trifluoroacetate are added. After stirring for 72 h at ambient temperature, the reaction medium is treated with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with a 20/80 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. The product is purified by preparative thin layer chromatography (eluent: 90/10 dichloro-methane/methanol). 205 mg of N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide are obtained in the form of a white powder with a yield of 47%.

(91) .sup.1H NMR/DMSO d.sup.6 100 C.: =0.80 (t, J=7.6 Hz, 3H,); 1.22 (m, 2H); 1.36 (quint, J=6.4 Hz, 2H,); 2.23 (s, 3H); 2.40 (t, J=8.8 Hz, 2H); 2.82-2.70 (m, 4H); 2.97 (t, J=6.4 Hz, 2H); 4.09 (d, J=10 Hz, 2H); 4.23 (d, J=7.6 Hz, 2H); 4.50 (q, J=7.6 Hz, 1H); 6.63 (m, 2H); 6.70 (s, 1H); 6.99 (m, 2H); 7.26-7.20 (m, 4H); 7.49 (s, 1H); 7.75 (s, 1H).

EXAMPLE 18

N-[1-(3-Butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-(1H-imidazol-4-yl)propionamide

18.1: Ethyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate hydrochloride

(92) 5 g (18.6 mmol) of ethyl N-(diphenylmethylene)glycinate in solution in 20 ml of tetrahydrofuran are added to a solution of 18.7 ml (18.6 mmol) of 1N potassium tert-butoxide in 20 ml of tetrahydrofuran cooled to 70 C. After stirring for 30 minutes, this mixture is added to a solution containing 3.2 g (18.6 mmol) of 4-methoxybenzoyl chloride in 20 ml of tetrahydrofuran at 70 C. One hour after the addition, the reaction medium is hydrolysed with a 1N aqueous solution of hydrochloric acid and concentrated. The residue is taken up in water and extracted with diethyl ether. The organic phase is dried over magnesium sulphate and the solvent is then evaporated off. 5.5 g of ethyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate hydrochloride are obtained with a quantitative yield.

18.2: Ethyl 2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-3-oxopropanoate

(93) 4 g (18.3 mmol) of di-tert-butyl dicarbonate and 2.6 ml (18.3 mmol) of triethylamine are added to 5 g (18.3 mmol) of ethyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate hydrochloride dissolved in 60 ml of tetrahydrofuran at 0 C. After stirring for 3 hours at ambient temperature, the mixture is treated with water and extracted with ethyl acetate. The organic phase is washed with a 1N aqueous solution of sodium hydrogen sulphate, and water and then dried over magnesium sulphate, filtered and concentrated. 4.1 g of ethyl 2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-3-oxopropanoate are obtained in the form of a yellow oil with a yield of 66%.

18.3: Ethyl 2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)propanoate

(94) 461 mg (0.7 mmol) of sodium borohydride are carefully added to a solution of 4.1 mg (12.2 mmol) of ethyl 2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-3-oxopropanoate in 40 ml of ethanol cooled to 78 C. After stirring for 15 minutes, the reaction medium is hydrolysed with a saturated aqueous solution of ammonium chloride. The ethanol is evaporated off and the aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is purified by silica gel chromatography, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 3 g of ethyl 2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)propanoate are obtained in the form of a yellow oil with a yield of 72%.

18.4: 2-tert-Butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)propanoic acid

(95) 15 ml of a 1N aqueous solution of sodium hydroxide are added to a solution containing 3 g (8.4 mmol) of 2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)-propanoic acid in 40 ml of tetrahydrofuran. The mixture is stirred for 4 hours at ambient temperature, treated with a 1N aqueous solution of hydrochloric acid until the pH is 1, and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is precipitated from a 1/1 diethyl ether/heptane mixture. 2.2 g of 2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)-propanoic acid are obtained in the form of a white powder with a yield of 84%.

18.5: tert-Butyl [1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]carbamate

(96) 740 mg (3.5 mmol) of EDC and 1.2 g (9.6 mmol) of 4-dimethylaminopyridine are added to a solution of 1 g (3.2 mmol) of 2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)propanoic acid, 1.1 g (3.5 mmol) of 3-butoxy-3-o-tolylazetidine trifluoroacetate and 480 mg (3.5 mmol) of HOAT in 10 ml of dichloromethane cooled to 0 C. After stirring for 24 hours at ambient temperature, the reaction medium is treated with a 1N aqueous solution of sodium hydroxide and then extracted with ethyl acetate. The organic phase is washed successively with a 1N aqueous solution of hydrochloric acid and water, and then dried over magnesium sulphate, filtered and concentrated. The residue obtained is purified by silica gel chromatography (eluent: 60/40 heptane/ethyl acetate). 1.4 g of tert-butyl [1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]carbamate are obtained in the form of a colourless oil with a yield of 87%.

18.6: 2-Amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-hydroxy-3-(4-methoxyphenyl)propan-1-one trifluoroacetate

(97) 10 ml of trifluoroacetic acid are added to a solution containing 1.4 g (2.8 mmol) of tert-butyl [1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]carbamate in 20 ml of dichloromethane. After stirring for 1 hour at ambient temperature, the reaction medium is concentrated. 1.5 g of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-hydroxy-3-(4-methoxyphenyl)propan-1-one trifluoroacetate are obtained in the form of a beige powder with a quantitative yield.

18.7: N-[1-(3-Butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-(1H-imidazol-4-yl)propionamide

(98) 0.2 ml (1.5 mmol) of triethylamine is added to a solution containing 100 mg (0.6 mmol) of desamino-histidine hydrochloride and 180 mg (0.6 mmol) of TBTU in 5 ml of dimethylformamide. After stirring for 1 h at ambient temperature, 200 mg (0.4 mmol) of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-hydroxy-3-(4-methoxyphenyl)propan-1-one trifluoroacetate are added. The reaction medium is stirred for 48 h at ambient temperature and then treated with a 1N aqueous solution of sodium hydroxide and extracted with a 20/80 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is purified by preparative thin layer chromatography (eluent: 90/10 dichloromethane/methanol). 80 mg of N-[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a beige powder with a yield of 39%.

(99) .sup.1H NMR/DMSO d.sup.6 100 C.: =0.78 (t, J=7.6 Hz, 3H); 1.23 (sext, J=7.3 Hz, 2H); 1.37 (quint, J=6.7 Hz, 2H); 2.25 (s, 3H); 2.40-2.50 (m, 2H); 2.75 (m, 2H); 3.01 (t,

(100) J=12 Hz, 2H); 3.70-3.80 (bs, 3H); 4.10-4.50 (m, 6H); 4.55 (m, 1H); 4.73 (m, 1H); 6.82 (m, 2H); 7.10-7.40 (m, 8H); 7.86 (m, 1H).

EXAMPLE 19

N[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide

19.1: tert-Butyl 3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate

(101) 2.15 ml (14.5 mmol) of tert-butyl bromoacetate are added dropwise to a solution of 1 g (15.3 mmol) of zinc 20 mesh in 20 ml of tetrahydrofuran, stirred for 15 min with a few drops of trimethylsilane chloride. After stirring for 15 minutes at ambient temperature, the temperature of the mixture is kept at 50 C. for 1 hour. After a return to ambient temperature, a solution containing 1.2 g (3.6 mmol) of 1-trityl-1H-imidazole-4-carbaldehyde in 10 ml of THF is added. The reaction medium is stirred for 6 h at ambient temperature, and then treated with a 1N aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic phase is washed successively with a saturated aqueous solution of sodium hydrogen carbonate and then with water. After drying over magnesium sulphate and filtration, the solvent is evaporated off. The residue obtained is precipitated from diisopropyl ether and filtered off. 1.4 g of tert-butyl 3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate are obtained in the form of a white powder with a yield of 84%.

19.2: 3-Hydroxy-3-(1H-imidazol-4-yl)propanoic acid

(102) 3 ml of trifluoroacetic acid are added to a solution of 1.4 g (3 mmol) of tert-butyl 3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate in 7 ml of dichloromethane. After stirring for 4 hours at ambient temperature, the reaction medium is concentrated. 0.5 g of crude product is used directly in the next stage.

19.3: N[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide

(103) 0.5 ml (3 mmol) of triethylamine are added to a solution containing 0.5 g (3 mmol) of 3-hydroxy-3-(1H-imidazol-4-yl)propanoic acid and 1.0 g (3 mmol) of TBTU in 2 ml of dimethylformamide. After stirring for 1 h at ambient temperature, 1.5 g (3 mmol) of (R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)-propan-1-one hydrochloride (prepared as described in Example 6.2) are added. The reaction medium is stirred for 24 h at ambient temperature, treated with a 1N aqueous solution of sodium hydroxide and extracted with a 20/80 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. The product is purified by silica gel chromatography, elution being carried out with a 97/3 dichloromethane/methanol mixture. 72 mg of N[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a beige powder with a yield of 5%.

(104) .sup.1H NMR/DMSO d.sup.6 100 C.: =0.78 (t, J=7.2 Hz, 3H); 1.23 (sext, J=7.3 Hz, 2H); 1.36 (quint, J=6.7 Hz, 2H); 2.21 (s, 3H); 2.55-2.65 (m, 2H); 2.70-2.90 (m, 3H); 2.90-3.00 (m, 2H); 3.68 (bs, 3H); 3.90-4.40 (m, 5H); 4.54 (bq, J=7.2 Hz, 1H); 4.92 (bs, 1H); 6.60-6.80 (m, 3H); 7.00-7.30 (m, 6H); 7.46 (bs, 1H); 7.81 (bs, 1H).

EXAMPLE 20

N[(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

20.1: tert-Butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate

(105) 60 ml (60 mmol) of 1M ortho-tolylmagnesium chloride in THF are added dropwise to a solution of 7.4 g (43 mmol) of tert-butyl 3-oxoazetidine-1-carboxylate in 60 ml of tetrahydrofuran cooled to 78 C. After stirring for 1 h at ambient temperature, the mixture is hydrolysed with a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated. The beige solid obtained is purified by silica gel chromatography, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 8.9 g of tert-butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate are obtained in the form of a white solid with a yield of 79%.

20.2: tert-Butyl 3-but-2-ynyloxy-3-o-tolylazetidine-1-carboxylate

(106) 1 ml (11.4 mmol) of 1-bromo-2-butyne is added to a suspension of 1.4 g (34.2 mmol) of sodium hydride at 60% in 14 ml of dimethylformamide cooled beforehand to 0 C. After stirring for 1 h, 3 g (11.4 mmol) of tert-butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate in 20 ml of dimethylformamide are added dropwise and the reaction mixture is then stirred for 1 h 30. After hydrolysis with water and with a saturated aqueous solution of ammonium chloride, the reaction medium is extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is dried over sodium sulphate, filtered and concentrated. The residue obtained is purified by silica gel chromatography, elution being carried out with a 80/20 heptane/ethyl acetate mixture. 2.9 g of 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%.

20.3: 3-But-2-ynyloxy-3-o-tolylazetidine hydrochloride

(107) 2.8 g (9 mmol) of tert-butyl 3-but-2-ynyloxy-3-o-tolylazetidine-1-carboxylate are solubilised in 40 ml (120 mmol) of a 3M solution of hydrochloric acid in ethyl acetate. After stirring for 1 hour 30 minutes at ambient temperature, the reaction medium is concentrated under vacuum. 2.2 g of 3-but-2-ynyloxy-3-o-tolylazetidine hydrochloride are obtained in the form of a beige solid with a yield of 96%.

20.4: tert-Butyl [(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate

(108) 1.9 g (10.2 mmol) of EDC, 1.4 g (10.2 mmol) of HOBt and 3.8 ml (27.2 mmol) of triethylamine are added to a solution containing 2.7 g (9.2 mmol) of Boc-D-methoxyphenylalanine in 55 ml of dimethylformamide. After stirring for 1 h, a solution of 2.2 g (8.7 mmol) of 3-but-2-ynyloxy-3-o-tolylazetidine hydrochloride in 35 ml of dimethylformamide is added to the mixture. The reaction medium is then stirred for 38 hours at ambient temperature. It is subsequently extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is washed successively with a 1N aqueous solution of sodium hydroxide and then with a 1N aqueous solution of hydrochloric acid, dried over sodium sulphate, filtered and concentrated. The residue obtained is purified by silica gel chromatography, elution being carried 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)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate are obtained in the form of a white solid with a yield of 41%.

20.5: (R)-2-Amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one

(109) 1.7 g (3.5 mmol) of tert-butyl [(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate are solubilised in 45 ml (135 mmol) of a 3M solution of hydrochloric acid in ethyl acetate. After stirring for 3 h at ambient temperature, the mixture is concentrated. 1.6 g of (R)-2-amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)-propan-1-one are obtained in the form of a beige solid with a quantitative yield.

20.6: N[(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

(110) 732 mg (2.3 mmol) of TBTU and 1 ml (7 mmol) of triethylamine are added to a solution of 408 mg (2.3 mmol) of desamino-histidine hydrochloride in 6 ml of dimethylformamide. After stirring for 10 min, 751 mg (1.8 mmol) of (R)-2-amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one in 6 ml of dimethylformamide are added. The reaction medium is stirred for 115 hours at ambient temperature and then a 1N aqueous solution of sodium hydroxide is added and the medium is extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is dried over sodium sulphate, filtered and concentrated. The residue obtained is purified by silica gel chromatography, elution being carried out with a 90/10 dichloro-methane/methanol mixture. 362 mg of N[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white solid with a yield of 40%.

(111) .sup.1H NMR/DMSO d.sup.6 100 C.: =1.74 (bs, 3H); 2.21 (s, 3H); 2.39-2.43 (m, 2H); 2.69-3.10 (m, 4H); 3.68 (m, 5H); 4.10-4.40 (m, 4H); 4.52 (q, J=7.2-8.0 Hz, 1H); 6.67-6.85 (m, 3H); 7.05-7.15 (m, 2H); 7.18-7.29 (m, 4H); 7.41 (s, 1H); 7.75-7.85 (m, 1H).

EXAMPLE 21

N[(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide

21.1: 3-(5-Methyl-1H-imidazol-4-yl)propanoic acid hydrochloride

(112) 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-imidazol-4-yl)acrylic acid hydrochloride in a 1/1 tetrahydrofuran/water mixture. The reaction medium is placed under a hydrogen atmosphere and stirred for 19 h, and then filtered through celite. The filtrate is concentrated under vacuum. The residue obtained is taken up in a heptane/diisopropyl ether mixture with stirring for 2 h. The white precipitate formed is filtered off and then dried. 326 mg of 3-(5-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride are obtained in the form of a white solid with a yield of 83%.

21.2: N[(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide

(113) 389 mg (1.2 mmol) of TBTU and 0.5 ml (3.7 mmol) of triethylamine are added to a solution containing 229 mg (1.2 mmol) of 3-(5-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride in 4 ml of dimethylformamide. After 5 min, 402 mg (0.9 mmol) of (R)-2-amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)-propan-1-one dissolved in 4 ml of dimethylformamide are added. The reaction medium is then stirred for 90 h at ambient temperature, and then a 1N aqueous solution of sodium hydroxide is added and the medium is extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is washed with a saturated aqueous solution of sodium chloride and then dried over sodium sulphate, filtered and concentrated. The residue obtained is purified by silica gel chromatography, elution being carried out with an 88/12 dichloromethane/methanol mixture. 45 mg of N[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide are obtained in the form of a white solid with a yield of 9%.

(114) .sup.1H NMR/DMSO d.sup.6 100 C.: =1.74 (s, 3H); 2.06 (s, 3H); 2.21 (s, 3H); 2.30-2.45 (m, 2H); 2.55-2.70 (m, 2H); 2.74-3.10 (m, 2H); 3.55-3.80 (m, 5H); 4.00-4.45 (m, 4H); 4.50 (bq, J=8.0 Hz, 1H); 6.65-6.85 (m, 2H); 7.00-7.15 (m, 2H); 7.15-7.35 (m, 5H); 7.75-7.90 (m, 1H).

(115) Table I illustrates the examples of compounds according to the invention.

(116) In this table: in the salt column, TFA represents a compound in trifluoroacetate form, purity (%) represents the purity of the product, obtained by HPLC, mass (M+H) represents the mass+1 (hydrogen) derived from the mass spectrum, associated with the HPLC peak of the expected product.

(117) TABLE-US-00027 TABLE I HPLC Synthesis pathway Purity HPLC retention Mass method used: refer to No. Name Salt (%) time (min) (M + H) used example No. 1 1-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4- TFA 38 + 51 (20.02 + 20.26)* 638 C 2 yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3- phenylazetidin-3-yl ester of butyric acid 2 N-[(S)-1-[(S)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- 34 + 60 (16.61 + 16.74)* 638 A 1 methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H- imidazol-4-yl)ethyl]benzamide 3 N-[(S)-1-[(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4- 34 + 57 (16.44 + 16.80)* 624 A 1 methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H- imidazol-4-yl)ethyl]benzamide 4 N-[(S)-1-[(S)-2-(3-hydroxy-3-o-tolylazetidin-1-yl)-1-(4- TFA 29 + 62 (11.36 + 11.61)* 582 B 1 + 8 methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H- imidazol-4-yl)ethyl]benzamide 5 1-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4- TFA 27 + 68 (12.33 + 12.53)* 624 B 2 yl)propionylamino]-3-(4- methoxyphenyl)propionyl]-3-o- tolylazetidin-3-yl acetate 6 1-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4- 28.55 (13.51 + 13.72)* 656 B 2 yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3- (4-fluorophenyl)azetidin-3-yl ester of butyric acid 7 N-[(S)-1-[(S)-2-(3-cyclohexyl-3-hydroxyazetidin-1-yl)- 36 + 62 (10.68 + 10.94)* 574 B 3 1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H- imidazol-4-yl)ethyl]benzamide 8 N-[(S)-1-[(S)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1- TFA 38 + 58 (12.93 + 13.15)* 642 B 1 yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H- imidazol-4-yl)ethyl]benzamide 9 N-[(S)-1-[(S)-2-[3-butoxy-3-(3-fluorophenyl)azetidin-1- TFA 39 + 55 (13.11 + 13.33)* 642 B 1 yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H- imidazol-4-yl)ethyl]benzamide Synthesis pathway HPLC HPLC used: Config- Purity retention time Mass method refer to No. Name uration Salt (%) (min) (M + H) used example No. 10 N-[(S)-2-(3-cyclohexyl-3-hydroxyazetidin-1-yl)-1-(4- L 96 9.68 455 D 3 + 8 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 11 N-[(S)-2-(3-hydroxy-3-o-tolylazetidin-1-yl)-1-(4- L TFA 89 9.25 463 D 8 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 12 N-[(R)-1-(3,4-dichlorobenzyl)-2-(3-hydroxy-3-phenylazetidin- D TFA 96 12.1 487 J 8 1-yl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide 13 N-[(S)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4- L 95 14.77 491 E 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 14 N-[(S)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4- L 97 15.65 517 E 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 15 N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- D 99.8 16.52 517 E 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 16 N-[(S)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- L 99.2 16.51 519 E 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 17 N-[(R)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4- D 98.7 14.8 491 E 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 18 N-[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1- D TFA 84 17.45 481 E 1 + 8 cyclohexylmethyl-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 19 N-[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(2,4- D TFA 99 17.68 543 E 1 + 8 dichlorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 20 N-[(R)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4- D 96 15.22 517 F 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 21 N-[(S)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o- L 99.4 13.59 504 G 4 tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide 22 N-[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o- D 99.4 13.57 505 G 4 tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide 23 N-[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4- D 96.2 10.36 523 A 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 24 N-[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o- D 99 18.2 533 M 4 tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide 25 N-[(R)-2-(3-hexyloxy-3-o-tolylazetidin-1-yl)-1-(4- D 97 17.1 547 H 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 26 N-[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3- D 97 22.9 503 L 5 phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide 27 N-[(R)-2-(3-butyl-3-phenylazetidin-1-yl)-1-(4- D 98 15.72 489 I 5 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 28 N-[(R)-2-(3-cyclopropylmethoxy-3-phenylazetidin-1-yl)-1-(4- D 94 14.47 503 I 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 29 N-[(R)-2-(3-hydroxy-3-o-tolylazetidin-1-yl)-1-(4- D TFA 100 13.46 463 K 4 + 8 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide HPLC Synthesis pathway Purity HPLC retention Mass method used: refer to No. Name Salt (%) time (min) (M + H) used example No. 31 N-[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1- 95 15.95 511 I 4 (3-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 32 N-[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1- 99 15.54 511 I 4 (4-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 33 N-[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4- 93 15.75 493 I 4 fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 34 N-{(R)-1-benzyl-2-[3-butoxy-3-(4-fluoro- 100 15.42 493 I 4 phenyl)azetidin-1-yl]-2-oxoethyl}-3-(4H-imidazol-2- yl)propionamide 35 N-[(R)-1-benzyl-2-(3-butoxy-3-phenylazetidin-1-yl)-2- 91 15.75 475 I 4 oxoethyl]-3-(1H-imidazol-4-yl)propionamide 36 N-[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4- TFA 90 16.93 505 M 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 37 N-[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-o- 97 16.13 517 N 5 tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 38 N-[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1- 99 15.85 521 O 9 (4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 39 N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- 93 19.03 520 M 6 methoxybenzyl)-2-oxoethyl]-3-(1H-[1,2,3]triazol-4- yl)propionamide 40 N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- 98 17.33 534 M 4 methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H- [1,2,4]triazol-3-yl)propionamide 41 N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- 96 17.65 533 M 7 methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol- 4-yl)propionamide 42 N-{(R)-1-(4-methoxybenzyl)-2-[3-(2-methoxyphenyl)- 99 16.37 553 P 9 3-pentylazetidin-1-yl]-2-oxoethyl}-3-(1H-imidazol-4- yl)propionamide 43 N-[(R)-2-[3-(2-fluorophenyl)-3-pentylazetidin-1-yl]-1- 99 15.65 521 Q 9 (4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 44 N-[(R)-2-[3-(2-chlorophenyl)-3-pentylazetidin-1-yl]-1- 98 16.04 537 Q 9 (4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 45 N-[(R)-1-(4-chlorobenzyl)-2-oxo-2-(3-pentyl-3- 97 14.85 M = 507 R 9 phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 46 N-[(R)-1-(4-fluorobenzyl)-2-oxo-2-(3-pentyl-3- 96 14.39 491 R 9 phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 47 N-[(R)-1-benzyl-2-oxo-2-(3-pentyl-3-phenylazetidin-1- 95 14.3 473 R 9 yl)ethyl]-3-(1H-imidazol-4-yl)propionamide 48 N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)- 98 10.87 517 S 4 2-oxoethyl]-3-(1H-imidazol-4- yl)acrylamide 49 N-[(R)-2-[3-(2,4-difluorophenyl)-3-pentylazetidin-1-yl]- 98 15.89 539 T 9 1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 50 N-[(R)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)-1-(3- 98 16.61 541 T 9 trifluoromethylbenzyl)ethyl]-3-(1H-imidazol-4- yl)propionamide 51 N-[(R)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)-1-(4- 98 16.5 541 T 9 trifluoromethylbenzyl)ethyl]-3-(1H-imidazol-4- yl)propionamide 52 N-[(R)-1-(3,4-dichlorobenzyl)-2-oxo-2-(3-pentyl-3- 96 16.78 M = 541 T 9 phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 53 N-[(R)-1-(3,4-difluorobenzyl)-2-oxo-2-(3-pentyl-3- 97 16.02 509 T 9 phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 54 N-[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1- 99 17.79 M = 571 P 9 yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 55 N-[(R)-2-[3-(3-fluorophenyl)-3-pentylazetidin-1-yl]-1- 96 15.77 521 U 9 (4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 56 N-[(R)-1-(3-fluorobenzyl)-2-oxo-2-(3-pentyl-3- TFA 98 15.82 491 U 9 phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 57 N-[(R)-1-(2-fluorobenzyl)-2-oxo-2-(3-pentyl-3- TFA 99 15.76 491 U 9 phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 58 N-[(R)-1-(2,4-dichlorobenzyl)-2-oxo-2-(3-pentyl-3- 98 17.3 M = 541 U 9 phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 59 N-[(R)-2-[3-(4-dichlorophenyl)-3-pentylazetidin-1-yl]- 97 16.67 537 U 9 1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 60 N-[(R)-2-[3-(2,5-difluorophenyl)-3-pentylazetidin-1-yl]- 97 18.66 539 V 9 1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 61 N-[(R)-2-[3-(2,6-difluorophenyl)-3-pentylazetidin-1-yl]- 98 18.67 539 V 9 1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 62 N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- 99 18.05 561 V 10 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)hexyramide 63 N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- TFA 97 17.56 547 V 10 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)pentyramide 64 N-[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3- 96 18.04 517 W 11 phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4- yl)propionamide 65 N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2,4- 95 17.49 599 X 10 dichlorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)hexyramide 66 N-[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4- 98 18.34 509 Y 12 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 67 N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- 95 15.24 533 Z 11 methoxybenzyl)-2-oxoethyl]-3-(3-methyl-3H-imidazol- 4-yl)propionamide HPLC retention HPLC Purity time Mass method No. Name (%) (min) (M + H) used 68 N-[(R)-2-[3-Butoxy-3-(2- fluorophenyl)azetidin-1-yl]-1-(4- methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol- 4-yl)propionamide 69 N-[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1- 96 15.28 533 U (4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl- 1H-imidazol-4-yl)propionamide 70 N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(2- 94 14.39 535 T hydroxy-4-methoxybenzyl)-2-oxoethyl]-3- (3H-imidazol-4-yl)propionamide trifluoroacetate 71 (S)-N-[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)- 1-(4-methoxybenzyl)-2-oxoethyl]-2-hydroxy- 3-(1H-imidazol-4-yl)propionamide 72 N-[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1- (4-hydroxybenzyl)-2-oxoethyl]-3-(3H- imidazol-4-yl)propionamide 73 N-[1-(3-Butoxy-3-o-tolylazetidine-1- carbonyl)-2-hydroxy-2-(4- methoxyphenyl)ethyl]-3-(1H-imidazol-4- yl)propionamide 74 N-[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1- (4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3- (1H-imidazol-4-yl)propionamide 75 N-[(R)-2-(3-But-2-ynyl-3-o-tolylazetidin-1-yl)- 1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H- imidazol-4-yl)propionamide 76 N-[(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1- yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5- methyl-1H-imidazol-4-yl)propionamide 77 N-[(R)-2-(3-Cyclohexylmethoxy-3-o- tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2- oxoethyl]-3-(1H-imidazol-4-yl)propionamide 78 3-(1H-Imidazol-4-yl)-N-[(R)-1-(4- methoxybenzyl)-2-oxo-2-[3-o-tolyl-3-(4,4,4- trifluorobutoxy)azetidin-1- yl]ethylpropionamide 79 N-[(R)-2-(3-Cyclobutylmethoxy-3-o- tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2- oxoethyl]-3-(5-methyl-1H-imidazol-4- yl)propionamide 80 N-[(R)-1-(4-Methoxybenzyl)-2-[3-(3- methylbut-2-enyloxy)-3-o-tolylazetidin-1-yl]- 2-oxoethyl)-3-(5-methyl-1H-imidazol-4- yl)propionamide Synthesis pathway used: refer to No. .sup.1H NMR/DMSO D.sub.6 100 C. Example No. 68 .sup.1H NMR/DMSO.sub.D6 100 C.: = 0.78 (t, J = 7.2-7.6 Hz, 3H); 13 1.23 (sext. J = 6.8-7.2 Hz, 2H); 1.37 (quint, J = 6.4-7.6 Hz, 2H); 2.38-2.42 (m, 2H); 2.68-2.94 (m, 7H); 3.10 (bt, J = 5.6-6.4, 2H); 4.00-4.40 (m, 4H); 4.50 (q, J = 7.2-7.6 Hz, 1H); 6.67-6.80 (m, 3H); 7.09-7.24 (m, 4H); 7.30-7.43 (m, 4H); 7.70-7.90 (m, 1H). 69 14 70 15 71 .sup.1H NMR/DMSO.sub.D6 100 C.: = 1.40 (m, 4H); 2.22 (s, 3H); 16 2.84-2.81 (m, 6H); 2.96 (m, 2H); 3.33 (t, J = 6.4 Hz, 2H); 3.68 (m, 3H); 4.08 (d, J = 10 Hz, 2H); 4.21 (m, 2H); 4.55 (q, J = 7.2 Hz, 1H); 6.76 (m, 2H); 7.11 (m, 2H); 7.27-7.18 (m, 5H); 7.91 (m, 1H); 8.63 (s, 1H). 72 .sup.1H NMR/DMSO.sub.D6 100 C.: = 0.78 (t, J = 7.2 Hz, 3H); 17 1.23 (sext, J = 7.3 Hz, 2H); 1.36 (quint, J = 6.7 Hz, 2H); 2.12 (s, 3H); 2.55-2.75 (m, 1H); 2.86-2.98 (m, 7H); 3.68 (bs, 3H); 3.90-4.30 (m, 4H); 4.54 (bq, J = 6.4 Hz, 1H); 5.25-5.45 (m, 1H); 6.55-6.95 (m, 3H); 7.09-7.27 (m, 6H); 7.43 (bs, 1H); 7.50-7.65 (m, 1H). 73 .sup.1H NMR/DMSO.sub.D6 100 C.: = 0.80 (t, J = 7.6 Hz, 3H); 18 1.22 (m, 2H); 1.36 (quint, J = 6.4 Hz, 2H); 2.23 (s, 3H); 2.40 (t, J = 8.8 Hz, 2H); 2.82-2.70 (m, 4H); 2.97 (t, J = 6.4 Hz, 2H); 4.09 (d, J = 10 Hz, 2H); 4.23 (d, J = 7.6 Hz, 2H); 4.50 (q, J = 7.6 Hz, 1H); 6.63 (m, 2H); 6.70 (s, 1H); 6.99 (m, 2H); 7.26-7.20 (m, 4H); 7.49 (s, 1H); 7.75 (s, 1H). 74 .sup.1H NMR/DMSO.sub.D6 100 C.: = 0.78 (t, J = 7.6 Hz, 3H); 19 1.23 (sext, J = 7.3 Hz, 2H); 1.37 (quint, J = 6.7 Hz, 2H); 2.25 (s, 3H); 2.40-2.50 (m, 2H); 2.75 (m, 2H); 3.01 (t, J = 12 Hz, 2H); 3.70-3.80 (bs, 3H); 4.10-4.50 (m, 6H); 4.55 (m, 1H); 4.73 (m, 1H); 6.82 (m, 2H); 7.10-7.40 (m, 8H); 7.86 (m, 1H). 75 .sup.1H NMR/DMSO.sub.D6 100 C.: = 0.78 (t, J = 7.2 Hz, 3H); 20 1.23 (sext, J = 7.3 Hz, 2H); 1.36 (quint, J = 6.7 Hz, 2H); 2.21 (s, 3H); 2.55-2.65 (m, 2H); 2.70-2.90 (m, 3H); 2.90-3.00 (m, 2H); 3.68 (bs, 3H); 3.90-4.40 (m, 5H); 4.54 (bq, J = 7.2 Hz, 1H); 4.92 (bs, 1H); 6.60-6.80 (m, 3H); 7.00-7.30 (m, 6H); 7.46 (bs, 1H); 7.81 (bs, 1H). 76 .sup.1H NMR/DMSO.sub.D6 100 C.: = 1.74 (bs, 3H); 2.21 (s, 3H); 21 2.39-2.43 (m, 2H); 2.69-3.10 (m, 4H); 3.68 (m, 5H); 4.10-4.40 (m, 4H); 4.52 (q, J = 7.2-8.0 Hz, 1H); 6.67-6.85 (m, 3H); 7.05-7.15 (m, 2H); 7.18-7.29 (m, 4H); 7.41 (s, 1H); 7.75-7.85 (m, 1H). 77 = 0.79-1.59 (m, 11H); 2.21 (s, 3H); 2.39-2.43 (m, 2H); 8 2.70-2.90 (m, 6H); 2.93 (s, 3H); 4.04-4.40 (m, 4H); 4.53 (q, J = 7.2-7.6 Hz, 1H); 6.67-6.80 (m, 3H); 7.09-7.26 (m, 7H); 7.40 (s, 1H); 7.77 (s, 1H). 78 = 1.60 (quintl, 2H); 2.08-2.19 (m, 2H); 2.22 (s, 3H); 8 2.39-2.43 (m, 2H); 2.68-2.93 (m, 7H); 3.02-3.06 (m, 2H); 4.07-4.40 (m, 4H); 4.52 (q, J = 7.2-7.6 Hz, 1H); 6.65-6.90 (m, 3H); 7.00-7.30 (m, 7H); 7.40 (s, 1H); 7.70-7.85 (m, 1H). 79 = 1.55 (quintl, J = 7.6-10.8 Hz, 2H); 1.70-1.83 (m, 2H); 9 1.88-1.96 (m, 2H); 2.06 (s, 3H); 2.22 (s, 3H); 2.31-2.38 (m, 3H); 2.60-2.70 (m, 2H); 2.74-2.80 (m, 1H); 2.80-3.05 (m, 3H); 3.69 (bs, 3H); 4.00-4.40 (m, 4H); 4.52 (bq, J = 7.2-7.6 Hz, 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 = 1.43 (s, 3H); 1.63 (s, 3H); 2.06 (s, 3H); 2.22 (s, 3H); 9 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); 4.00-4.45 (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

Transactivation Test: Melanocortin Receptors

(118) Cells:

(119) HEK293 lines are transfected with the pCRE-Luc and hMC1R, hMC3R, hMC4R or hMC5R vectors. The cells are cultured at 37 C., 5% CO.sub.2, in DMEM medium supplemented with 10% of foetal calf serum.

(120) Principle of the Test:

(121) In the presence of an activator (agonist), the melanocortin receptor will activate the cAMP pathway which, via the CRE-Luc vector, will result in the synthesis of luciferase. After the addition of a lysis buffer containing a luminescent substrate for luciferase, it will be possible to measure the luminescence proportional to the degree of activation or of inhibition of the receptor.

(122) Product Test:

(123) The products are solubilized at 10 mM in DMSO. They are tested in the form of dose-response at a final DMSO concentration of 0.1%. The range comprising 10 points and one zero begins at 10 M with 4-fold dilutions. For testing agonists, the products are tested alone. For determining the behaviour of antagonists, the products of interest are tested in the presence of 1 nM NDP-MSH (reference agonist). The cells are seeded at a rate of 5000 cells per well (384 well plate) in serum-free DMEM medium, and incubated overnight at 37 C., 5% CO.sub.2.

(124) The products and the reference ligand (NDP-MSH) are added the following day, and the plates are again incubated for 6 h at 37 C., 5% CO.sub.2. After the addition of lysis buffer containing luciferin, the plates are read on a Top-Count instrument. The results are standardized as % activity using the 100% (cells+NDP-MSH at 10 nM) and 0% (cells alone) controls. An EC50 is calculated for each product using the XLFit software. The results are given in nM.

(125) TABLE-US-00028 Example No. EC50 hMC1R (nM) EC50 hMC4R (nM) 1 500 NT 2 30 8000 3 60 4000 4 250 4000 5 4000 8000 6 2000 8000 7 500 4000 8 120 4000 9 120 1000 10 8000 IA 11 4000 8000 12 8000 IA 13 2000 15000 14 2000 15000 15 120 4000 16 2000 15000 17 250 8000 18 8000 8000 19 2000 120 20 120 4000 21 4000 IA 22 120 10000 23 60 1000 24 250 4000 25 1000 8000 26 500 4000 27 500 8000 28 1000 8000 29 1000 IA 31 500 4000 32 1000 4000 33 500 2000 34 1000 2000 35 500 2000 36 1000 3000 37 250 2000 38 250 NT 39 8000 2000 40 8000 500 41 120 1000 42 60 30 43 30 NT 44 30 NT 45 2000 2000 46 1000 4000 47 500 4000 48 4000 500 49 15 2000 50 1000 500 51 1000 IA 52 2000 250 53 1000 4000 54 250 NT 55 120 1000 56 4000 8000 57 1000 4000 58 2000 500 59 NT IA 60 120 100 61 120 100 62 4000 500 63 500 500 64 2000 500 65 IA 100 66 250 250 67 500 500 68 60 2000 69 1000 8000 70 4000 IA 71 60 4000 72 2000 IA 73 500 8000 74 250 8000 75 60 4000 76 30 4000 77 120 2000 78 120 2000 79 15 1000 80 15 4000 IA: inactive NT: not tested