Substituted alkyltetramine derivatives

Abstract: An object of the present invention to offer a novel substituted alkyltetraamine derivative which is useful as a tachykinin antagonist. This invention relates to a substituted alkyltetraamine derivative represented by the following formula (I) or a pharmaceutically acceptable salt, a complex compound or a solvate thereof. The compound of the present invention is entirely different from the tachykinin antagonists is useful as anti-inflammatory agent, anti-allergic agent, analgesic, antiemetic, agent for irritable colon syndrome, agent for dermal disease, agent for vasospastic disease, agent for cerebral ischemic disease, antidepressant, antianxiety agent, agent for autoimmune disease, muscle relaxant, antispasmodic, etc.

Description: The present invention relates to a novel substituted alkyltetraamine derivative which is useful as a tachykinin antagonist. Tachykinin is a general term for a group of peptides having similar structures and, in mammals, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) are representative ones. They are neuro-peptides widely distributed in living body and substance P has been most fully investigated for physiological functions among them. Substance P is a peptide consisting of 11 amino acids and has been known to exhibit hypotensive action, smooth muscle constricting action, sialagogue action, neuron exciting action, pain inducing action, etc. Substance P has been known to act in broad areas such as in diseases of digestive system, nervous system and respiratory system and is believed to be deeply associated especially with inflammation, allergy, carcinoid syndrome, chronic pain, headache, Crohn disease, depression and vomiting. Accordingly, a tachykinin antagonist is applicable to a lot of diseases and is useful as anti-inflammatory agent, anti-allergic agent, analgesic, antiemetic, agent for irritable colon syndrome, agent for dermal disease, agent for vasospastic disease, agent for cerebral ischemic disease, antidepressant, antianxiety agent, agent for autoimmune disease, muscle relaxant or antispasmodic. Various tachykinin antagonists have been developed and reported with an object of development of therapeutic agents for those diseases in which tachykinins participate. Up to now, several tachykinin receptor antagonists have been reported. Most of them reported in 1980's were developed by derivation of intrinsic tachykinin of mammals, namely, a part of amino acids constituting the intrinsic tachykinin was substituted with D-amino acid or the like. Since they are peptides, preferred pharmacokinetic properties are not achieved and so there is a limit for expression of activity in vivo . In order to overcome such a disadvantage, tachykinin receptor antagonists of non-peptide type are now being developed although none of them have been put into the market as a pharmaceutical agent. An object of the present invention is to offer a tachykinin antagonist having a novel chemical structure. The structure of the present compound is entirely different from the tachykinin receptor antagonists of non-peptide type which have already been developed. The present inventors have carried out an intensive investigation for substituted alkyltetraamine compounds extracted and purified from Matricaria chamomilla which is a plant belonging to family Compositae, and have prepared derivatives thereof. As a result, they have found that those compounds have a tachykinin antagonistic action and accomplished the present invention. Detailed Description of the Invention The present invention relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt, a complex compound or a solvate thereof and also relates to a tachykinin antagonist containing the compound as an effective ingredient. R 1 , R 2 , R 3 , and R 4 , independently represent phenyl groups, which may be substituted by: one or more hydroxyl groups; one or more linear or branched alkoxy groups having 1 to 6 carbon atoms; one or more linear or branched acyloxy groups having 1 to 4 carbon atoms; and/or one or more benzoyloxy groups. The linear or branched alkoxy groups having 1 to 6 carbon atoms may be selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, isohexyloxy and dimethylbutoxy; and the linear or branched acyloxy groups having 1 to 4 carbon atoms may be selected from formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, and t-butyryloxy. The compounds represented by the above formula (I) include the pharmaceutically acceptable salts. Also, the present invention includes cis-trans isomers. Further, the present invention includes a solvate of the compounds represented by the formula (I) with water, methanol, ethanol or acetonitrile, namely, a pharmaceutically acceptable solvate such as hydrate, methanolate, ethanolate or acetonitrate. Preferred embodiments of the present invention are given as follows. The substituted alkyltetraamine derivatives represented by the above formula (I) or a pharmaceutically acceptable salt, a complex compound or a solvate thereof. The substituted alkyltetraamine derivatives according to formula (I) wherein R 1 , R 2 , R 3 and R 4 are phenyl groups substituted with one or two hydroxyl group(s), one or two methoxy group(s) and/or one or two acetoxy group(s). Further preferred compounds are N1,N5,N10,N14-Tetrakis[3-(4-acetoxyphenyl)-2-propenoyl]tetraazatetradecane, N1,N5,N10,N14-Tetrakis[3-(4-hydroxyphenyl)-2-propenoyl]tetraazatetradecane, N1,N5,N10,N14-Tetrakis[3-(4-acetoxy-3-methoxyphenyl)-2-propenoyl]tetraazatetradecane, N1,N5,N10,N14-Tetrakis[3- (4-hydroxy-3-methoxyphenyl)-2-propenoyl]tetraazatetradecane, N1,N5,N10,N14-Tetrakis[3-(3,4-diacetoxyphenyl)-2-propenoyl]tetraazatetradecane, N1,N5,N10,N14-Tetrakis[3-(3,4-dihydroxyphenyl)-2-propenoyl]tetraazatetradecane, a pharmaceutically acceptable salt, a complex compound or a solvate thereof. A pharmaceutical composition containing any substituted alkyltetraamine derivative according to formula (I), where preferred derivatives are those mentioned above. Especially preferred is the pharmaceutical composition, wherein the composition is a tachykinin antagonist. The compound represented by the formula (I) may be manufactured as shown by the following reaction formulae. This method is an acid amide reaction of spermine represented by the formula (II): with a carboxylic acid or a reactive derivative thereof represented by the formula (III): whereas R in formula (III) corresponds to the above definitions of R 1 , R 2 , R 3 and R 4 . Furthermore several compounds according to formula (III) with different groups R may be used. When the carboxylic acid of the formula (III) is made to react in a free acid form, it is preferred to conduct the reaction using an appropriate organic solvent in the presence of a coupling reagent. Applicable examples of the coupling reagent are 1,1-carbonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline, N,N'-dicyclohexylcarbodiimide and diphenylphosphoryl azide. As a reactive derivative of the carboxylic acid, acid halide such as acid chloride or acid bromide; acid azide; active ester of 1-hydroxybenzotriazole or N-hydroxysuccinimide; acid anhydride of symmetric type; alkyl carbonate mixed acid anhydride; p-toluenesulfonic acid mixed acid anhydride and the like may be employed. In the reaction, compound (II) or a reactive derivative thereof and the compound (III) are used in about the same amount of moles or one of them is used in an excessive amount. Preferred is an excess of moles of compound (III), more preferred is a molar ratio of compound (III) to compound (II) of about 4.0-4.8, and the most preferred is a ratio of about 4.1-4.4. Both compounds are reacted in an inert organic solvent which does not affect the reaction such as tetrahydrofuran, dioxane, benzene, methylene chloride, dichloroethane, chloroform, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide or pyridine. According to the type of the reactive derivative, it may be advantageous for carrying out the reaction in a smooth manner that a base such as N-methylmorpholine, triethylamine, pyridine, lutidine, N,N-dimethylaniline, potassium carbonate or sodium hydroxide is added to the reaction mixture. Reaction temperature may vary depending upon the type of the reactive derivative and so can be appropriately set. When the substituents R 1 , R 2 , R 3 and R 4 are different in the compound of the formula (I), the synthesis is possible from an intermediate thereof where a protective group is introduced to any of the amino groups. Alternatively, it is possible to utilize a transferase such as spermine hydroxycinnamoyl transferase. For isolation and purification of the objective product from the reaction mixture, common means such as extraction with solvent, concentration, recrystallization and chromatography may be appropriately used. One of the compounds of the present invention (Compound 2 in Example 2) may be extracted and isolated from plants of family Compositae such as Matricaria chamomilla and Carthamus tinctorius . A common method for extraction from plant materials may be utilized, for example, an extraction method using an extracting solvent such as an organic solvent (e.g., methanol, ethanol or acetone) or an aqueous organic solvent is employed. For isolation of the aimed compound from the extract, a purification method frequently used in this field may be utilized, for example, chromatography such as silica gel chromatography or HPLC is used for isolation and purification of the compound of the present invention. The compound of the present invention can be made into pharmaceutical preparations by a combination with suitable pharmaceutical carriers or diluents. Any of the known methods may be used to produce the pharmaceutical preparation for oral or parenteral administrations such as solid, semi-solid or liquid preparation. In the preparations, the compound of the present invention may be used in the form of its pharmaceutically acceptable salt, and also can be used either solely or jointly together with other pharmaceutically active components. In the case of preparations for oral administration, the compound of the present invention as it is or together with commonly-used excipients such as a suitable additive (e.g. lactose, mannitol, corn starch or potato starch, etc.) is mixed with binders such as crystalline cellulose, cellulose, gum arabicum, corn starch and gelatin, disintegrating agents such as corn starch, potato starch and potassium carboxymethylcellulose, lubricating agents such as talc and magnesium stearate, and other bulking agents, moisturizing agents, buffers, preservatives, perfumes and the like, to give tablets, powders, granules or capsules. Alternatively, suppositories may be prepared by mixing with fatty/oily bases such as cacao butter, emulsified bases, water-soluble bases such as macrogol, hydrophilic bases, etc. In the case of injections, it is possible to prepare the solutions or the suspensions in an aqueous or nonaqueous solvents such as distilled water for injection, physiological saline solution, Ringer's solution, plant oil, synthetic fatty acid glycerides, higher fatty acid esters and propylene glycol. In case of inhalations or aerosol preparations, the compound of the present invention in the form of liquid or fine powder can be filled up in an aerosol container with gas or liquid spraying agent, and if desired, with conventional additives such as humidifying agent or dispersing agent. They can also be prepared as a non-pressurized preparation such as in a nebulizer or an atomizer. It is also possible, depending upon the type of the disease, to prepare other pharmaceutical preparations suitable for the therapy such as collyriums, ointments, cataplasms, etc. The preferred dose of the compound of the present invention may vary depending upon the object to be administered the patient, form of the preparation, method and term for the administration. In order to achieve a desired effect by oral route, 0.01 - 100 mg per day, preferably 0.05 - 25 mg per day may be usually given to common adults either once daily or several times a day. In the case of a parenteral administration such as by injection, it is preferred that a dose of from 1/3 to 1/10 of the above-given dose by oral route is administered. The present invention will be further illustrated by way of the following examples. Examples Example 1 1) 3-(4-Acetoxyphenyl)-2-propenoic acid In 40 ml of pyridine were dissolved 3.28 g (20 mmol) of 3-(4-hydroxyphenyl)-2-propenoic acid, then 6.5 ml of acetic anhydride were added thereto and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness in vacuo and 150 ml of ethyl acetate and 150 ml of 1M hydrochloric acid was added thereto followed by mixing. The organic phase was dried over sodium sulfate and the solvent was evaporated therefrom in vacuo. Ether was added to the residue to crystallize whereupon 3.79 g (yield: 92%) of the title compound were obtained. 2) 3-(4-Acetoxyphenyl)-2-propenoyl chloride In 100 ml of dichloromethane were dissolved 3.79 g (19.4 mmol) of 3-(4-acetoxyphenyl)-2-propenoic acid, then 4.8 ml (67 mmol) of thionyl chloride were added thereto and the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness in vacuo and ether-hexane (1/1) was added to the residue to crystallize whereupon 2.89 g (yield: 70%) of the title compound were obtained. 3) N1,N5,N10,N14-Tetrakis[3-(4-acetoxyphenyl)-2-propenoyl]tetraazatetradecane (Compound 1) To 80 ml of tetrahydrofuran in which 1.01 g (5 mmol) of spermine and 2.12 g (21 mmol) of triethylamine were dissolved were added 4.70 g (21 mmol) of 3-(4-acetoxyphenyl)-2-propenoyl chloride and the mixture was stirred overnight at room temperature. To the reaction solution were added 10-fold by volume of water were added, the solvent was filtered off and the residue was washed with water to give 3.96 g (yield: 83%) of the title compound as white powder. 1 H-NMR (δ, DMSO): 1.49-1.62 (m, 4H), 1.70-1.81 (m, 4H), 2.24 (s, 3H), 2.25 (s, 3H), 2.27 (Br, s, 6H), 3.14-3.54 (m, 12H), 6.57-6.63 (m, 2H), 7.00-7.06 (m, 4H), 7.09-7.18 (m, 6H), 7.40-7.53 (m, 4H), 7.57-7.62 (m, 4H), 7.64-7.79 (m, 4H), 8.09-8.14 (m, 1H), 8.21-8.26 (m, 1H). 4) N1,N5,N10,N14-Tetrakis[3-(4-hydroxyphenyl)-2-propenoyl]tetraazatetradecane (Compound 2) To 954 mg of N1,N5,N10,N14-tetrakis[3-(4-acetoxyphenyl)-2-propenoyl]tetraazatetradecane were added 4.8 equivalents of 1M sodium hydroxide and the mixture was allowed to stand at room temperature for 1 hour. After this was neutralized with 4.8 equivalents of 1M hydrochloric acid, an excessive amount of water was added thereto and the resulting precipitate was washed with water to give 676 mg (yield 86%) of the title compound as white powder. 1 H-NMR (δ, DMSO): 1.45-1.80 (m, 8H), 3.12-3.55 (m, 12H), 6.36-6.44 (m, 2H), 6.68-6.94 (m, 10H), 7.29-7.56 (m, 12H), 7.94-7.98 (m, 1H), 8.05-8.11 (m, 1H), 9.69-9.92 (m, 4H). Example 2 1) 3-(4-Acetoxy-3-methoxyphenyl)-2-propenoic acid In 80 ml of pyridine were dissolved 7.77 g (40 mmol) of 3-4-hydroxy-3-methoxyphenyl)-2-propenoic acid, then 12 ml of acetic anhydride were added thereto and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness in vacuo and 400 ml of ethyl acetate and 400 ml of 1M hydrochloric acid were added thereto followed by mixing. The organic phase was dried over sodium sulfate and the solvent was evaporated therefrom in vacuo. Ether was added to the residue to crystallize whereupon 8.71 g (yield: 92%) of the title compound were obtained. 2) 3- (4-Acetoxy-3-methoxyphenyl) -2-propenoyl chloride In 80 ml of dichloromethane were dissolved 4.72 g (20 mmol) of 3-(4-acetoxy-3-methoxyphenyl)-2-propenoic acid, then 5.2 ml of thionyl chloride were added thereto and the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated to dryness in vacuo and ether-hexane (1/1) was added to the residue to crystallize whereupon 4.27 g (yield: 84%) of the title compound were obtained. 3) N1,N5,N10,N14-Tetrakis[3-(4-acetoxy-3-methoxyphenyl)-2-propenoyl]tetraazatetradecane (Compound 3) To 50 ml of tetrahydrofuran in which 404 mg (2 mmol) of spermine and 850 mg (8.4 mmol) of triethylamine were dissolved were added 2.13 g (8.4 mmol) of 3-(4-acetoxy-3-methoxyphenyl)-2-propenoyl chloride and the mixture was stirred overnight at room temperature. The solvent was filtered, the filtrate was evaporated to dryness in vacuo and the residue was dissolved in 10 ml of chloroform. Purification was carried out by means of a chromatographic treatment on silica gel using a mixture of 4% methanol and 96% chloroform as an eluent whereupon 1.88 g (yield: 88%) of the title compound were obtained as white powder. 1 H-NMR (δ, DMSO): 1.52-1.64 (m, 4H), 1.69-1.80 (m, 4H), 2.23-2.27 (m, 12H), 3.16-3.59 (m, 12H), 3.78-3.82 (m, 12H), 6.58-6.65 (m, 2H), 6.93-7.52 (m, 18H), 8.08-8.13 (m, 1H), 8.17-8.22 (m, 1H). 4) N1,N5,N10,N14-Tetrakis[3-(4-hydroxy-3-methoxyphenyl)-2-propenoyl]tetraazatetradecane (Compound 4) In 20 ml of methanol were dissolved 1.07 g of N1,N5,N10,N14-tetrakis[3-(4-acetoxy-3-methoxyphenyl)-2-propenoyl]tetraazatetradecane, 4.8 equivalents of 1M sodium hydroxide were added thereto and the mixture was allowed to stand at room temperature for 1 hour. After this was neutralized with 4.8 equivalents of 1M hydrochloric acid, an excessive amount of water was added thereto and the resulting precipitate was washed with water to give 0.834 g (yield 92%) of the title compound as pale yellow powder. 1 H-NMR (δ, DMSO): 1.46-1.76 (m, 8H), 3.16-3.49 (m, 12H), 6.30-6.36 (m, 2H), 6.68-6.85 (m, 8H), 6.92-7.10 (m, 6H), 7.21-7.35 (m, 4H), 7.98-8.01 (m, 1H), 8.06-8.09 (m, 1H), 8.91-9.54 (Br, m, 8H). Example 3 1) 3-(3,4-Diacetoxyphenyl)-2-propenoic acid In 80 ml of pyridine were dissolved 7.21 g (40 mmol) of 3-(3,4-dihydroxyphenyl)-2-propenoic acid, then 24 ml of acetic anhydride were added thereto and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness in vacuo and 200 ml of ethyl acetate and 200 ml of 1M hydrochloric acid were added thereto followed by mixing. The organic phase was dried over sodium sulfate and the solvent was evaporated therefrom in vacuo. Ether was added to the residue to crystallize whereupon 8.89 g (yield: 84%) of the title compound were obtained. 2) 3-(3,4-Diacetoxyphenyl)-2-propenoyl chloride In 150 ml of dichloromethane were dissolved 8.89 g (33.67 mmol) of 3-(3,4-diacetoxyphenyl)-2-propenoic acid, then 8.8 ml of thionyl chloride were added thereto and the mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated to dryness in vacuo and ether-hexane (1/1) was added to the residue to crystallize whereupon 7.90 g (yield: 83%) of the title compound were obtained. 3) N1,N5,N10,N14-Tetrakis[3-(3,4-diacetoxyphenyl)-2-propenoyl]tetraazatetradecane (Compound 5) To 50 ml of tetrahydrofuran in which 404 mg (2 mmol) of spermine and 850 mg (8.4 mmol) of triethylamine were dissolved were added 2.37 g (8.4 mmol) of 3-(3,4-diacetoxyphenyl)-2-propenoyl chloride and the mixture was stirred overnight at room temperature. The solvent was filtered, the filtrate was evaporated to dryness in vacuo, the residue was dissolved in 10 ml of chloroform and purification was carried out by means of a chromatographic treatment on silica gel using a mixture of 4% methanol and 96% chloroform as an eluent whereupon 2.06 g (yield: 87%) of the title compound were obtained as white powder. 1 H-NMR (δ, DMSO): 1.48-1.60 (m, 4H), 1.66-1.79 (m, 4H), 2.26-2.31 (m, 24H), 3.16-3.54 (m, 12H), 6.56-6.63 (m, 2H), 7.07-7.66 (m, 18H), 8.08-8.13 (m, 1H), 8.16-8.22 (m, 1H). 4) N1,N5,N10,N14-Tetrakis[3-(3,4-dihydroxyphenyl)-2-propenoyl]tetraazatetradecane (Compound 6) In 40 ml of methanol were dissolved 2.06 g of N1,N5,N10,N14-tetrakis[3-(3,4-diacetoxyphenyl)-2-propenoyl]-tetraazatetradecane, 9.6 equivalents of 1M sodium hydroxide were added thereto and the mixture was allowed to stand at room temperature for 1 hour. After this was neutralized with 4.8 equivalents of 1M hydrochloric acid, an excessive amount of water was added thereto and the resulting precipitate was recovered and washed with water to give 0.926 g (yield 74%) of the title compound as pale brown powder. 1 H-NMR (δ, DMSO): 1.49-1.76 (m, 8H), 3.16-3.53 (m, 12H), 3.77-3.81 (m, 12H), 6.24-6.46 (m, 2H), 6.70-7.43 (m, 18H), 7.66-7.98 (m, 1H), 7.99-8.02 (m, 1H), 9.47 (s, 4H). Pharmacological Test: Tachykinin antagonistic action The compounds of the present invention were tested by an assay using ileum isolated from guinea pigs. Male guinea pigs of Hartley strain (400 g to 500 g) were fainted and bled out. Then, ileum was isolated and hung in an organ bath filled with a nutritive solution. After an equilibration for 60 minutes, isotonic contraction was recorded. Substance P, a tachykinin agonist, was administered in a dose of 10-8 M every 15 minutes. Administration of substance P was repeated for 3 to 4 times and it was confirmed that a contraction height for each run became constant. The constant contraction was used as a control. A treatment with the test drug was carried out for 10 minutes and then substance P was administered again and a concentration vs. action curve was prepared. A 50% suppression concentration (IC 50 ) was determined from the concentration vs. action curve of the test drug. The compound of the present invention was used as a test drug and an example of the result of its antagonistic action to substance P is shown in Table 1. Compound No. to be tested Antagonistic action to Substance P IC 50 (µM) 1 0.014 2 0.011 3 0.71 4 0.58 Merit of the Invention It is apparent from the result of the above-mentioned pharmacological test that the compounds of the present invention have an antagonistic action to tachykinins such as substance P and neurokinin A. Accordingly; they are useful for treatment or prevention of tachykinin-related diseases such as anxiety, depression, schizophrenia, asthma, senile pollakiuria, incontinence, Crohn disease, irritable colon syndrome, inflammatory intestinal disease, chronic articular rheumatism, vomiting, vomiting due to anticancer agents, migraine, pain, ulcer, diseases of respiratory system such as chronic bronchitis, ocular diseases such as conjunctivitis, dermal diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematous dermatitis, inflammatory disease and diabetic neuropathy. The compounds of the present invention are the novel compound (Compound 2) which was isolated and purified from an extract of Matricaria chamomilla which is a plant belonging to family Compositae, and synthetic analogous new compounds thereof. Among the tachykinin antagonists derived from plants, any substances having such a high activity have not been known yet at all. Since the compounds of the present invention have a very high tachykinin antagonistic activity and their source is an extract of Matricaria chamomilla which is a quite frequently used plant for galenicals in Europe, it is expected that they have excellent property in view of safety and side effect whereby their usefulness is very high. Tachykinins such substance P are neuro-peptides widely distributed in living body and have been known to act in broad areas such as in diseases of digestive system, nervous system and respiratory system. In particular, they deeply participate in inflammation, allergy, carcinoid syndrome, chronic pain, headache, Crohn disease, depression, vomiting, etc. Accordingly, a tachykinin antagonist is applicable to a lot of diseases as follows. As an anti-inflammatory agent, a tachykinin antagonist is useful for inflammation caused by asthma, influenza, adult respiratory distress syndrome (ARDS), chronic bronchitis, bronchospasm, chronic rheumatism, Crohn disease, ulcerative colitis, inflammatory intestinal disease, NSAID induced injury, blister, eczema, cystitis or incontinence, and inflammatory diseases in eye or teeth. A tachykinin antagonist also useful for an allergic disease such as asthma, skin allergic disease, urticaria, allergic respiratory disease, hypersensitivity to Rhus verniciflua , rhinitis, atopic dermatitis, contact-type dermatitis, etc. As an analgesic, it is useful for various pain diseases such as traumatic pain, postoperative pain, traumatic avulsion pain, brachial plexus pain, chronic pain, arthritic pain, herpetic neuralgia, arthrosteitis, chronic rheumatism, psoriatic arthritis, pain accompanied by nerve disease, post-herpetic neuralgia, burn-induced pain, intercostal neuralgia, opioid-resistant pain, causalgia, diabetic neuropathy, chemotherapy induced nerve disease, AIDS related nerve disease, occipital nerve disease, knee pain syndrome, glossopharyngeal nerve disease, sympathetic dystrophy, phantom limb pain, migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache, toothache, cancer pain, gastrointestinal pain, athletic disturbance pain, pain accompanied with parturition, menorrhalgia, pritonitis, arachnoiditis, musculoskeletal pain, low back pain, spinal stricture, urogenital pain such as cystitis, sciatica, anginal; pain, ankylosing spondylitis, gout, burn, scar pain, thalamic pin, etc. A tachykinin antagonist is useful as an antidepressant, antianxiety agent or antipsychotic for treatment of phychosis, schizophrenis, mania, dementia, cognitional disease, Alzheimer disease, anxiety, AIDS-related dementia, nerve degenerated disease such as Down syndrome, stroke, diabetic nerve disease, multiple sclerosis, depression, Parkinson disease, habitual disease such as alcoholism, drug-or substance-abuse and dependence, etc. It also useful for vomiting and therefore applicable to symptoms such as nausea, retching, sicchasia, acute vomiting, delayed or anaphase vomiting, or expectation vomiting. The pharmaceutical composition of the present invention is effective for vomiting induced by various causes, for example, vomiting as adverse reaction caused by drugs such as chemotherapeutic agent, alkylating agent, opioid analgesic, cytotoxic antibiotic and anti-metabolic agent, vomiting accompanied by radiation disease by exposure to radiation, chest or abdominal radio-irradiation treatment or radiotherapy in cancer treatment, or vomiting caused by metabolic disease, infective disease, motor disease, vertigo, Meniere disease, postoperative disease, gastrointestinal obstruction, decreased gastrointestinal motility, visceralgia, conjunctivitis, migraine, change of intracranial pressure, dyspepsia, overeating, gastric hyperacidity, etc. In addition, the present composition is effective for gastrointestinal disease such as irritable colon syndrome, dermal disease such as psoriasis, itching or sunburn, angiospastic disease such as angina, vascular headache or Raynaud disease, cerebral ischemic disease such as subarachnoid hemorrhage, graft rejection, and autoimmune disease such as fibrosis, collagen disease, systemic lupus erythematosus or rheumatic disease. A tachykinin antagonist is also useful as muscle relaxant or antispasmodic and is therefore effective for peripheral nervous disorder, stress related disease, sympathetic reflex dystrophy, shoulder-arm syndrome, dysthymic disorder and plasma transudation caused by cytokine chemotherapy. As mentioned above, a substituted alkyltetraamine derivative of the present invention has an excellent tachykinin antagonistic activity and is, therefore, highly useful as a remedy for said various diseases.

Claims: A compound of general formula (I) : wherein R 1 , R 2 , R 3 , and R 4 , which may be the same or different from each other, represent phenyl groups, which may be substituted by: one or more hydroxyl groups; one or more linear or branched alkoxy groups having 1 to 6 carbon atoms; one or more linear or branched acyloxy groups having 1 to 4 carbon atoms; and/or one or more benzoyloxy groups, or a pharmaceutically acceptable salt, a solvate, or a cis-trans-isomer thereof. A compound according to claim 1, wherein the linear or branched alkoxy groups having 1 to 6 carbon atoms are selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, isohexyloxy and dimethylbutoxy; and the linear or branched acyloxy groups having 1 to 4 carbon atoms are selected from formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, and t-butyryloxy. A compound according to claim 1 or 2, wherein R 1 , R 2 , R 3 , and R 4 are independently selected from phenyl substituted with one or two hydroxyl group(s), phenyl substituted with one or two methoxy group(s) and/or phenyl substituted with one or two acetoxy group(s). A compound according to any of claims 1 to 3, wherein R 1 , R 2 , R 3 , and R 4 are independently selected from 4-acetoxyphenyl, 4-hydroxyphenyl, 4-acetoxy-3-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 3,4-diacetoxyphenyl, and/or 3,4-dihydroxyphenyl. A compound according to any of claims 1 to 4, wherein R 1 , R 2 , R 3 , and R 4 are the same substituent. A compound according to any of claims 1 to 5, which is N1,N5,N10,N14-Tetrakis[3-(4-hydroxyphenyl)-2-propenoyl]-tetraazatetradecane. A compound according to any of claims 1 to 6, for use as a medicament. A pharmaceutical composition which comprises as an active ingredient at least one compound as defined in any of the preceding claims, and a pharmaceutically acceptable carrier and/or diluent therefor. A pharmaceutical composition according to claim 8 for use as a tachykinin antagonist. Use of a compound according to any of claims 1 to 7 for the preparation of a pharmaceutical composition for the treatment or prevention of tachykinin-related diseases comprising anxiety; depression; schizophrenia; asthma; senile pollakiuria; incontinence; Crohn disease; irritable colon syndrome, inflammatory intestinal disease; chronic articular rheumatism; vomiting, vomiting due to anticancer agents; migraine; pain; ulcer; diseases of respiratory system comprising chronic bronchitis; ocular diseases comprising conjunctivitis; dermal diseases comprising contact dermatitis, atopic dermatitis, urticaria, and eczematous dermatitis; inflammatory disease and diabetic neuropathy.

Inventors: NAKAMURA KO, OTSUKA MASANORI, YAMAMOTO ATSUSHI, NAKAMURA, KO, OTSUKA, MASANORI, YAMAMOTO, ATSUSHI, Nakamura, Ko, c/o Inst.of Bio-Active Sciences, Otsuka, Masanori, c/o Inst.of Bio-Active Sciences, Yamamoto, Atsushi, c/o Inst.of Bio-Active Sciences
Applicants: NIPPON ZOKI PHARMACEUTICAL CO, NIPPON ZOKI PHARMACEUTICAL CO., LTD.
Application year: 2000
Main classification: C07C233
IPC codes: A61P1, C07C233, C07C235, A61P25, A61K31, A61P27, A61P29, A61P11, A61P43