JPH05508866A - N-alkylquinuclidinium salts as antagonists of substance P - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Concave F and 11 The present invention provides novel N-alkylquinuclidinium salts, pharmaceutical products containing such compounds, in pharmaceutical compositions and in the treatment and prevention of inflammatory diseases, gastrointestinal diseases and several other diseases. 1 Regarding the use of such compounds, the pharmaceutically active compounds of the invention are antagonists of substance P. be.

Substance P is a natural undecapeptide belonging to the tachykinin family of peptides, and is a natural undecapeptide belonging to the tachykinin family of peptides. It is so called because of its rapid stimulatory effect on tissues. In particular, substance P is A pharmacologically active neuropeptide produced in mammals (originally isolated from the intestine). disclosed by F. Veber in U.S. Pat. No. 4,680,283. It has a characteristic amino acid sequence. Pathophysiology of numerous diseases and substance P and other substances A wide range of relationships with chikinin have been demonstrated in detail in the prior art. For example, when substance P , Propagation of pain or layer headache (B, E, B, Sandberg Kasa, Journal Central nervous system disease (e.g. anxiety and schizophrenia), respiratory and inflammatory diseases (e.g. asthma and rheumatism) toid arthritis), rheumatic diseases (e.g. tissue inflammation), as well as gastrointestinal diseases and stomach Intestinal diseases (e.g. ulcerative colitis and Crohn's disease), etc. (F, 5 ieuteri “Trends in C1uster” edited by e” (Elsevier 5eientifice Publishers, ^m sterdam, pp, 85-95 (1987)) Nori, see Regoli) It was recently discovered that he was involved in

Quinuclidine derivatives and related compounds that exhibit activity as receptor antagonists of substance P are: PCT, filed November 20, 1989, both of which are assigned to the applicant. e-permission 1 [PcT/lls 89105338 and U.S. Patent filed July 23, 1990] 9 Similar compounds described in Application No. 557.442 were published on April 2, 1991. PCT patent entitled “3-amino-2-arylquinuclidine” filed on the 5th and PCT patent application entitled “Quinuclidine Derivatives” filed May 15, 1991. explained in the request. These applications are also assigned to the applicant.

U.S. Patent Application No. 6N9 filed November 28, 1990, assigned to the present applicant. , No. 361 and U.S. Patent Application No. 590,423 filed September 28, 1990. teeth,? Piperidine derivatives and related nitrogen-containing complexes effective as antagonists of l1jirp It describes ring compounds.

1st grade phantom The present invention is based on the formula: (In the formula, R' is (CI　C4)alkyl, allyl, phenyl-<CI-Ca)a Alkyl, HOOC-(CrCto)alkyl or (C,C4)alkoxy-0 0C-(C+-C+o)alkyl, and R2 is phenyl, chenyl, or selected from the group consisting of lyl and pyridyl, each of these groups R2 being cyano , nitro, amino, N-mono-(C+-C3) alkylamino, fluorine, chlorine , bromine, trifluoromethyl, (C+ -Cs)alkyl, (C+ -Cx) Alkoxy, alioxy, (C+ -C)) alkoxy-carbonyl, strength/ren From boxamide and N,N-di(CI-Ca)alkyl-carboxamide 1 to 3 substituents independently selected from the group consisting of any! and X- is a pharmaceutical Compatible counterions (e.g. chloride, bromide, fluoride, iodine) gate, mesylate, tosylate or trifluoromethanesulfonate) ).

Examples of pharmaceutically acceptable counterions are halides (e.g. fluoride, chloride). , bromide or iodite), (CI-Cs) alkyl mono- or dicarboxylic sylate, mesylate, tosylate, aryl carboxylate, alkyl moiety is one or more fluorine atoms, arylsulfonate, citrate, maleate, fluorine atom, malate, lactate, malate, sulfate, phosphate, nitrate, Can be optionally substituted with tartrate, saccharate and bamoate (CI Cx ) is an alkyl sulfonate.

Unless otherwise stated, the term "alkyl" as used herein refers to linear, segmented, Slightly saturated hydrocarbons with curved or cyclic moieties or a combination thereof It includes groups.

A preferred compound of formula (1) is a compound in which R2 is 2-methoxyphenyl.

The present invention further has the following features! Inflammatory diseases of mammals (e.g. humans) (e.g. arthritis, (e.g., asthma and inflammatory bowel disease), colitis, pain, allergies (e.g. eczema and rhinitis). ), chronic obstructive airway disease, hypersensitivity disorders (e.g. urushi), blood vessels 1! ! ! Disease (example) angina, migraines and Raynaud's disease), fibrotic and collagen diseases (e.g. scleroderma) syndrome and eosinophilic liver disease), reflex sympathetic dystrophy (e.g. shoulder-hand syndrome), peripheral nerve disorders, diseases related to immune enhancement or immunosuppression (e.g. systemic erythematosus 1!') and and rheumatic diseases R (e.g. connective tissue inflammation). a therapeutically or prophylactically effective amount of a compound of formula (■) or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier for the treatment or prophylaxis of the above-mentioned conditions. Between the preparations.

The present invention further relates to inflammatory diseases of mammals (e.g. humans) such as arthritis, psoriasis, asthma and inflammatory bowel disease), colitis, pain, allergies (e.g. eczema and rhinitis), Chronic obstructive airway diseases, hypersensitivity disorders (e.g. urticaria), vasospasm diseases (e.g. angina) fibrotic and collagenous diseases (e.g. scleroderma and acid liver fluke disease), reflex sympathetic dystrophy (e.g. shoulder-hand syndrome), peripheral neuropathy, Diseases related to infection enhancement or immunosuppression (G4, systemic lupus erythematosus) and rheumatoid arthritis treatment or prevention of conditions selected from the group consisting of: administering to a mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to A method of treating or preventing the above-mentioned conditions, comprising administering.

The present invention further provides an antagonistic amount of a compound of formula I to substance P or a pharmaceutically acceptable compound thereof. A mammalian (e.g. human) substance P comprising a salt and a pharmaceutically acceptable carrier It relates to a pharmaceutical composition for antagonizing the action of.

The present invention further provides an antagonistic amount of a compound of formula I to substance P or a pharmaceutically acceptable compound thereof. Action of substance P on a mammal (e.g. human), consisting of administering a salt to the mammal Concerning methods of antagonism.

The present invention further provides an antagonistic amount of a compound of formula I to substance P or a pharmaceutically acceptable compound thereof. salt and a pharmaceutically acceptable carrier. Lactation caused by excess of substance P The present invention relates to pharmaceutical compositions for treating or preventing disorders in animals (eg, humans).

The invention further provides an antagonistic amount of a compound of formula 1 to substance P or a pharmaceutically acceptable compound thereof. A mammal resulting from an excess of substance P, consisting of administering salt to the mammal ( For example, for methods of treating or preventing disorders in humans.

The present invention further provides for an amount of the formula ■ effective to antagonize the action of substance P at the receptor site comprising a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. , mammalian (e.g. human) inflammatory diseases (e.g. arthritis, psoriasis, asthma and inflammation) intestinal diseases), colitis, pain, allergies (e.g. eczema and rhinitis), chronic airway obstruction diseases, hypersensitivity disorders (e.g. urushi), vasospastic disorders (e.g. angina, migraine and fibrotic and collagenous diseases (e.g. scleroderma and eosinophilic fluke disease) , reflex sympathetic dystrophy (e.g. shoulder-hand syndrome), peripheral neuropathy, immune enhancement or Diseases related to epidemic control (e.g. systemic erythematosus 11) and rheumatic diseases (e.g. Pharmaceutical composition for the treatment or prevention of conditions selected from the group consisting of, for example, connective tissue inflammation) Regarding.

The present invention further provides for an amount of a compound of formula I effective to antagonize the action of substance P at a receptor site. a mammal, comprising administering a compound or a pharmaceutically acceptable salt thereof to the mammal; Inflammatory diseases (e.g. arthritis, psoriasis, asthma and inflammatory bowel disease) in animals (e.g. humans) disease), colitis, pain, allergies (e.g. eczema and rhinitis), chronic obstructive airway disease, hypersensitivity disorders (e.g. urticaria), vasospastic disorders (e.g. angina, migraine and lei) disease), fibrotic and collagenous diseases (e.g. scleroderma and eosinophilic fluke disease), reflex Sympathetic dystrophy (e.g. shoulder-hand syndrome), peripheral neuropathy, immunoenhancement or immunosuppression diseases related to (e.g. systemic erythematous lupus) as well as rheumatic diseases (e.g. The present invention relates to a method of treating or preventing a condition selected from the group consisting of (histolitis).

The present invention further provides for an amount of a compound of formula I effective to antagonize the action of substance P at a receptor site. comprising a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. carried out or facilitated by reducing substance P-mediated neurotransmission, The present invention relates to pharmaceutical compositions for the treatment or prevention of disorders in mammals (e.g., humans).

The present invention further provides for an amount of a compound of formula I effective to antagonize the action of substance P at a receptor site. A substance consisting of administering a compound or a pharmaceutically acceptable salt thereof to a mammal. Mammalian activity carried out or facilitated by reducing P-mediated neurotransmission The present invention relates to a method of treating or preventing a disorder in a human being.

The present invention further provides an effective amount of comprising a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. , carried out or facilitated by reducing substance P-mediated neurotransmission The present invention relates to pharmaceutical compositions for the treatment or prevention of disorders in mammals (eg, humans).

The present invention further provides an effective amount of a compound of formula I to treat or prevent a disorder as described above. A substance consisting of administering a compound or a pharmaceutically acceptable salt thereof to a mammal. Mammalian activity carried out or facilitated by reducing P-mediated neurotransmission The present invention relates to methods for treating or preventing disorders in objects (e.g., humans).

The compounds of formula I have chiral centers and therefore exist in different enantiomeric forms 1 The present invention covers all optical isomers and all stereoisomers of the compound of formula (2) and mixtures thereof. Regarding compounds.

The optically active compounds of formula 1 can also be used in combination with the corresponding racemic mixture as well as the opposite mirror isomer. Useful as a synthetic intermediate.

One or more hydrogen or carbon atoms are radioactive isotopes (e.g. tritium, carbon-1 4 isotope or nitrogen-15 isotope). Formula I above includes compounds identical to those mentioned above. Such radioactive compounds is useful as an investigational/diagnostic tool in metabolic pharmacokinetic studies and binding assays. . *Possible applications include radioligand binding assay and autoradiography. In particular, there are researches on the field of inflammation and research on the two connections between The group m that caused the t1! For example, immune-type cells or inflammatory bowel disease, etc. intervening cells) An example of this is the research into human substance P receptors by Sankyukai.

11 Liyu Feng I5” formula: A compound represented by the formula R'X In formula C, R+ is as defined above, and X is chloro, fluoro, bromo, iodine. tosyloxy, mesyloxy or trifluoromethanesulfonyloxy A compound of formula (2) can be produced by reacting with a compound represented by (1). Generally polar solutions medium (e.g. ethanol, acetone, dimethylformamide or 150°C, preferably at about the reflux temperature of the solvent. .

Pressures of about 0.5 to about 5 atmospheres are generally acceptable, and conveniently atmospheric pressure, i.e. about 1 atmosphere. is preferred.

The novel compound represented by formula ■ and its pharmaceutically acceptable salts can be used as antagonists of substance P. It is valid. that is, they antagonize the action of substance P at receptor sites in mammals. as a therapeutic agent for the above-mentioned diseases and disorders suffered by mammals. It can function as such.

Because the compounds of formula I are basic, they form a wide variety of salts with various inorganic and organic acids. It can be accomplished. Such salts must be pharmaceutically acceptable for administration to animals. , in practice, once the compound of formula I is isolated from the reaction mixture as a pharmaceutically unacceptable salt. such salts are then simply removed by standard ion exchange methods known to those skilled in the art. It is often desirable to convert the salts into alternative pharmaceutically acceptable salts. Furthermore in an aqueous or suitable organic solvent (e.g. methanol or ethanol) Treatment of a suitable compound with a selected substantially equivalent amount of a mineral or organic acid produces the Acid addition salts of the compounds of the present invention are easily prepared. If the solvent is carefully evaporated, The desired solid salt is easily obtained.

The compounds of formula I and their pharmaceutically acceptable salts exhibit binding activity of substance P to the receptor. Is it carried out by indicating the sexual activity and thus reducing substance P-mediated neurotransmission? or are useful in the treatment and prevention of a wide variety of clinical conditions. This kind of situation Conditions include inflammatory diseases (e.g. arthritis, psoriasis, asthma and inflammatory bowel disease), Enteritis, pain, allergies (e.g. eczema and rhinitis), chronic obstructive airway diseases, hypersensitivity disorders vasospastic diseases (e.g. angina, migraine and Raynaud's disease) , fibrotic and collagen diseases (e.g. scleroderma and eosinophilic fluke disease), reflex sympathetic nerves related to dystrophy (e.g. Buyer's syndrome), peripheral neuropathy, immune enhancement or immunosuppression. diseases (e.g. systemic lupus erythematosus) and rheumatic diseases (e.g. connective tissue inflammation) is included. Therefore, these compounds may be used in mammals (e.g. humans) as described above. therapeutic use as an antagonist of substance P for the examination and/or treatment of clinical conditions such as easily adaptable to

Compounds of formula 1 and their pharmaceutically acceptable salts can be administered orally, parenterally or topically. can be administered. Generally, these compounds are present in amounts of about 5.0 g/day to about 150 g/day. Most preferably administered at a dose of 0-g 7 days, depending on the weight and weight of the patient being treated. Variations will necessarily occur depending on the condition and the particular method of administration chosen. but However, using a dose of about 0.07 mg per 11 g of body weight to about 21 g/day. is the most preferred, but depends on the type of animal being treated, individual drug response, and the chosen physician. Variations in dosage will occur depending on the type of drug formulation and the time and interval of such administration. . It may be appropriate to use a lower dose than the lower end of the aforementioned range; If you divide it into several smaller doses and administer it throughout the day, the prescribed range will be exceeded. The doses used may not produce any harmful side effects.

The compounds of the invention, alone or in combination with pharmaceutically acceptable carriers or diluents, can be Administration may be by any of the three routes previously described. This kind of administration can be done only once. In particular, the novel therapeutic agent of the present invention can be administered in a wide variety of ways. It can be administered in various forms. That is, the therapeutic agent can be prepared in tablets, capsules, or sweetened tablets. agents, troches, hard candy-1 powder, sprays, creams, wax ointments, suppositories , jellies, gels, pastes, lotions, ointments, aqueous suspensions, solutions for injection, In combination with various pharmaceutically acceptable inert carriers in the form of xyl agents, syrups, etc. Such carriers may include solid diluents or fillers, sterile aqueous media and seeds. This includes various non-toxic organic solvents. Furthermore, suitable sweetness and/or Or flavor can be added.

Generally, the therapeutically effective compounds of the invention will be present at a concentration of about 5.0 to about 70% by weight. It exists in the form described above.

For oral administration, various excipients (e.g. microcrystalline cellulose, sodium citrate) tablets containing calcium carbonate, calcium phosphate, and glycine) in various Disintegrants such as starch (preferably corn, potato or tapioca) starch), alginic acid and several silicic acid double salts), and granule binders (e.g. (Livinylpyrrolidone, sucrose, gelatin and acacia) good.

Additionally, lubricants (e.g. magnesium stearate, lauryl) may be used to form tablets. (sodium sulfate and talc) are often very effective. Solid set of homogeneous molds Because of such binding, the composition may be used as a filler in gelatin capsules. Further preferred materials include lactose or milk sugar and high molecular weight polyethylene Includes recalls. Aqueous suspensions and/or elixirs are preferred for oral administration. When desired, the active ingredient may be combined with various sweetening agents or aromatics, colorants or dyes, and Emulsifying and/or suspending agents, diluents (e.g. water, ethanol, propylene (Lane glycol, glycerin and various combinations thereof) good.

For parenteral administration, therapeutic compounds of the invention may be administered in sesame oil, peanut oil or aqueous propylene. A solution in glycol may also be used. If necessary, mix the aqueous solution with M street solution. It should be treated appropriately (preferably to a pH of 8 or above) to make the liquid diluent more isotonic. do. These aqueous solutions are suitable for intravenous injection.

Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. This is sterile Preparation of all solutions is by standard pharmaceutical techniques well known to those skilled in the art. easily done.

Furthermore, when treating inflammatory conditions of the skin, the compounds of the invention may be administered topically. It is also possible to It can be used as a cream, jelly, or gel according to standard pharmaceutical origins. It is preferable to use a paste, wax, etc.

radioactive molecules to visualize tachykinin receptors by autoradiography. The ability of substance P to inhibit the binding of substance P at the receptor site in bovine tail tissue using a probe The activity of the compounds of the present invention as antagonists of phenotypic P is determined. Journal o f-Toyu Punishment 1st IJ” Shika RL (110f, 258. p, 5158 ( The standard by H^, Ca5cieri et al., as published in 1983)) The antagonistic activity of the compounds described herein against Substance P can be determined using standard assay methods. This method essentially involves radiation exposure at receptor sites in isolated bovine tissue. Individual compounds required to reduce the amount of ligand of sex-labeled substance P by 50% consists of measuring the concentration of IC, which is unique to each test compound, value is obtained.

In this method, bovine tail tissue is removed from a freezer at -70°C (~- 50 volume ratio (w/v) of 50 mM ice-cold Tris (i.e. trimethamine (2 -Amino-2-hydroxymethyl-1,3-propanediol)) Hydrochloride M solution (pH 7.7).

Centrifuge the homogenate for 20 minutes at 30,000 Resuspend the pellet in Tris buffer and homogenize again, then add 30,000 Centrifuge for another 20 minutes at 0, M magnesium chloride and 40g/ml bacitracin and 4μg/-1 leupepti Contains 2μg of chymostatin and 200g/ml bovine serum albumin. Re-incubate the pellet in 50mM ice-cold TrislI buffer (pt17.7) at a volume ratio of 40. Suspend thoroughly. This step completes tissue preparation production.

The radioligand attachment process is then carried out as follows. That is, the concentration is 1μ Add 100 μl of test compound, labeled H, then irradiate to a final concentration of 0.5 mM. A tissue preparation prepared by adding 100 μl of a sexual ligand to IkfIk as described above. Add 800 µl of the solution to start the reaction. Therefore, the final capacity is 1.01.

The reaction mixture is then stirred and incubated for 20 min at room temperature (approximately 20 °C). The tubes are then filtered using a cell harvester and a glass fiber filter (Whatman Wash F/B) four times with 505M) Lys buffer (PH 7,7). fill The filter was pre-soaked for 2 hours before the filtration process. Radioactivity was measured with a beta counter and IC, by standard statistical methods. calculate do.

The invention is illustrated by the following examples. However, the present invention does not apply to the following embodiments. is not limited to the specific details of the description.

Tue JLI ZS 3S - Sisu Aime Roux 2 - Diphenyl Meth Roux N-2-Method Phenyl methyl -1-bishiguchi 2.2.2 ri sea 3-monyoi : 500 mg in a 50 L round bottom flask equipped with a condenser and N2 inlet (L, 21 mmol) (7) (2S, 3S)-cis-2-(Schifznilmer) methyl)-N-((Z-methoxyphenyl)methyl)-1-azabicyclo(2,2 , 2) Octane-3-amine and 6 mL of ethanol were added. Bring the solution almost to a boil 207 mg (1,46 theory so I) of methyl iodide was added. . Heating was continued for 10 minutes and then the solution was cooled to yield a precipitate. the sediment After a while, it dried. 328 mg (yield 49%) of solid was obtained: melting point 2 39-244°C.

'H-NMR (δ, CDCI-): 1.8-2.0 (s, 2B), 2.1-2 ．． 3 (-, ZH), 2.47 (s, 3B), 2.59 (s, IH), 3.04 ( dd, J: 13.84, 2Hλ3.50 (m, 1B), 3.63 (s, 31), 3.67 (s, IF[), 3.95 (s+, 1tl), 4.12 (s, Ift) , 4.46 (d, 115, III), 5.42 (dd, J=6.5, 11. 5. III), 6.33, 6.68 and 7.07-7.2 (multiplet, 14H) , 7.7-7.9 (wide area floor, 2[1).

IC-NMR (δ, CDCl, ): 20.0, 22.4, 23.8, 46.1, 49.4, 53.9° 54.8.55.3, 55.6, 61.2.71.5.1 10.2.120.4, 126.9, 127.2.

127.9, 128.5, 129.6, 141.7, 143.5, 157.1° Mass spectrum (%): 4Z6 (1, parent), 259 (31), 245 (46) , 142(45), 121(100), 9H62).

The title compounds of Examples 2-8 were prepared in a manner similar to Example 1.

! 2S 3S -cis-1-4-le 1,ethyl-2-diphenyl methyl -N-2-) Diphenyl mel-1-Abishiro 2.2.2 Riso 3-Amine on par with L: The product yield was 13% and the melting point was 85°C.

Mass spectrum: 541 (1, parent), 373 (89), 359 (5B), 121 (100).

91(45).

Shaku 1 Toyu 2S　3S　-cis-1-4-rufly Cyphenylmer　-2-Diphenylmer　 Le -N-2-Meshienyl Mel-1-Bishiro Z, 2.2 Sea 3 −≧Nyo ′： The product yield was 13% and the melting point was 140-145°C.

Calculated value as C3aH4JzOil・1/311.0: C64,40,F1 a, 21°N3.95. Actual measurement value: C64.05, H6.16, N3.88°K 1■A 2S 3S -cis-1-5-l 1, methyl -2- diphenyl methyl -N-2-Mail -1-A Bicyclo 2.2.2 Rino -3-Amine triflate: (using acetonitrile as solvent instead of ethanol). oily The yield of the product obtained was 5%.

Calculated value as Cs5H4sNzOssFs・HCI・1/2820: C57 , 32°F1a, 55,83. F1. Actual value: C57, 29, 116, 48, 83,68゜K5■2 2S 3S -cis-1-5-lupocypenyl-2-diphenylmel- N-2-Methodiphenyl Meru-1-a Bicyclo 2.2.2 Ktacy 3-Amint 1 Freight: The compound was prepared by hydrolysis with potassium hydroxide in ethanol.

High-resolution mass spectrum: Calculated value as Cs4H+JzOa = 527.32 78, Actual value: 527.3288° 253S -cis-1-A1-2-diphenylmeth-N-2-methodif 2.2.2 No 3-amine bromide: The product yield was 58% and the melting point was 150-160°C.

C,, Calculated value as H=tN20Br'1.25HzO: C66,96,F 17,16°H5,04, Actual value: C66,95,117,06,84,97 ゜叉JLfi-ヱ 2S 3S -cis-1-benzyl-2-diphenylmethy-N-2-methodi Phenyl methyl-1-A bischiguchi 2.2.2 No-3-amine bromide :The yield of the product was 53%, and the melting point was 206-208°C.

Calculated value as C3sF13sNJBr-HzO: C69,87, [16,8 7, H4, 66° Actual value: C69, 48, F1a, 84. H4, 52゜゜ 2S 3S -cis-1-le 1, cis-le-2-schiffnirmel-N -2-Meshif Nil Lou 1-Abishiro 2.2.2 Sea 3-Minbu Romani: Product yield was 17%, melting point 125-135°C.

CsJ, 5NzOJr・[Calculated value as 1,0: C64,32,116,9 2, H4, 69° actual measurement, C50, 14, H6, 88, H4, 62°! Power The present invention provides novel N-alkylquinuclidinium salts, pharmaceutical products containing such compounds, Pharmaceutical compositions and in the treatment and prevention of inflammatory diseases, gastrointestinal diseases and several other diseases. During the use of such compounds, the N-alkylquinuclidinium salts of the present invention are , formula (I) (wherein the meanings of R', R2 and X- are as defined above) expressed.

international search report --------Bentouha JS 9110 birds%1, -knee bar-11 & PCTA IS 911081136 International Search Report Light to Is 91/Qa836 SA　S4G6X

Claims (13)

[Claims] 1. formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R1 is (C1-C4) alkyl Allyl, phenyl-(C1-C6)alkyl, HOOC-(C1-C10) Alkyl or (C1-C4)alkoxy-OOC-(C1-C10)alkyl , R2 is selected from the group consisting of phenyl, thienyl, furyl and pyridyl and each of these groups R2 is cyano, nitro, amino, N-mono-(C1-C 3) Alkylamino, fluorine, chlorine, bromine, trifluoromethyl, (C1-C3 ) alkyl, (C1-C3) alkoxy, alioxy, (C1-C3) alkoxy C-carbonyl, carboxamide and N,N-di-(C1-C3)alkyl- optionally with 1 to 3 substituents independently selected from the group consisting of carboxamides; substituted, X- is a pharmaceutically acceptable counterion or a pharmaceutically acceptable salt thereof A compound represented by 2. 2. A compound according to claim 1, wherein R2 is 2-methoxyphenyl. 3. 3. A compound according to claim 2, wherein R1 is methyl. 4. 4. A compound according to claim 3, wherein X- is iodide. 5. Mammalian inflammatory diseases, arthritis, colitis, pain, allergies, chronic obstructed airways diseases, hypersensitivity disorders, vasospasm disorders, fibrotic and collagen disorders, reflex sympathetic dysfunction Nutritional diseases, peripheral neuropathies, diseases related to immune enhancement or immunosuppression, and rheumatism claim for an amount effective to treat or prevent a condition selected from a group consisting of diseases; Treatment of the aforementioned conditions comprising a compound according to item 1 and a pharmaceutically acceptable carrier. Pharmaceutical composition for treatment or prevention. 6. an effective amount of a compound according to claim 1 to antagonize substance P and a pharmaceutically acceptable amount of the compound according to claim 1; A pharmaceutical composition for antagonizing the action of substance P in mammals, comprising: 7. of claim 1 in an amount effective to antagonize the action of substance P at the receptor site. Comprising a compound and a pharmaceutically acceptable carrier to reduce Substance P-mediated neurotransmission Treatment or prevention of a condition in a mammal carried out or facilitated by causing Pharmaceutical composition for. 8. of claim 1 in an amount effective to treat or prevent conditions such as those described above. comprising a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. , carried out or facilitated by reducing substance P-mediated neurotransmission A pharmaceutical composition for the treatment or prevention of a condition in a mammal. 9. formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R1 is (C1-C4) alkyl Allyl, phenyl-(C1-C6)alkyl, HOOC-(C1-C10) Alkyl or (C1-C4)alkoxy-OOC-(C1-C10)alkyl , R2 is selected from the group consisting of phenyl, thienyl, furyl and pyridyl and each of these groups R2 is cyano, nitro, amino, N-mono-(C1-C 3) Alkylamino, fluorine, chlorine, bromine, trifluoromethyl, (C1-C3 ) alkyl, (C1-C3) alkoxy, alioxy, (C1-C3) alkoxy C-carbonyl, carboxamide and N,N-di-(C1-C3)alkyl- optionally with 1 to 3 substituents independently selected from the group consisting of carboxamides; and X- is a pharmaceutically acceptable counterion) It is a method, and the formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R2 The meaning is as defined above) is a compound represented by the formula R1X (wherein R1 is As defined above, X is chloro, fluoro, bromo, iodo, tosyloxy compound represented by A method consisting of reacting with 10. The compound of formula I prepared by the above method is a compound in which R2 is 2-methoxyphenyl. 10. The method according to claim 9, wherein the method is a product. 11. 2. A compound of formula I prepared by said method, wherein R1 is methyl. 9. 12. The compound of formula I prepared by the above method may be a compound in which X- is iodide. The method described in claim 9. 13. The compound of formula I prepared by the above method has R1 as carboethoxybutyl, carboethoxybutyl, Boethoxyphenylmethyl, carbomethoxybenyl, carboxypentyl, ben Claim 9 is a compound selected from dyl, allyl and carboethoxymethyl. The method described in.