TWI303991B - Use of nk-1 receptor antagonists for the treatment of brain,spinal or nerve injury - Google Patents

Description

1303991

The present invention relates to the use of a sputum-l receptor antagonist, a heart sputum, and its use in the treatment and/or prevention of a spinal cord or nerve injury. The brain's spinal cord or nerve damage often occurs due to accidents, and often causes loss of exercise and cognition, causing significant rickets in accidental survivors. Because of the lifestyle, the younger members of the society are particularly vulnerable. The economic losses caused by the ten-sounding traumatic hall are significant. Therefore, it can increase accidents; any method of surviving the nerves of the shellfish and enhancing its reclamation will be of great benefit to the society. Neuromusma-1 (NK-1) or substance p is a naturally occurring eleventh skin, belonging to the tachykinin family, which is so named because it promotes contraction of extravascular smooth muscle tissue. The receptor for neurokinin-1 or substance p is a member of the G protein-coupled receptor superfamily and is referred to as the NK-1 receptor. This receptor is widely distributed throughout the mammalian nervous system (especially the brain and spinal ganglia) and is also present in the circulatory and peripheral tissues (especially the duodenum, jejunum and reproductive-urinary tract). Salty receptors are involved in the regulation of various biological processes, as described below. The central and peripheral effects of mammalian tachykinin substance P, associated with many inflammatory conditions, including: migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease, as well as the regulation of vomiting reflexes and central nervous system (CNS) Regulation of disorders such as Parkinson's disease (Neurosci·Res, 7, 187-214, (1996)), anxiety (Can. J. Phys, 75, 612-621, (1997)) and depression ( Science, 281, 1640-1645, (1998)) 〇 清 £ £11 receptor antagonist in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, morphine withdrawal, cardiovascular changes , water-5 This paper scale applies to China National Standard (CNS) Α4 specifications (210X 297 mm) 1303991 A7 B7 V. Description of invention (2) edema caused by heat damage, chronic inflammatory diseases such as rheumatoid joints Evidence of usefulness in inflammation, asthma/bronchial hyperactivity and other respiratory diseases, including allergic rhinitis, intestinal inflammatory diseases including colonic ulcers and Crohn's disease, eye injuries and ocular inflammatory diseases can be summarized in "Tachykinin Receptor and Tachykinin Receptor Antag Onists'', J. Auton. Pharmacol., 13, 23-93 (1993) 0 Furthermore, neurokinin-1 receptors have been developed to treat various types of tachykinin excess or imbalance. The physiological disorder, especially the substance P. Examples of conditions involving substance P include disorders of the central nervous system, such as anxiety, depression, and psychosis (International Patent Application, Publication Nos., WO 95/16679, WO 95/18124, and WO 95/23798). Further, the Xianxin neurokinin-1 receptor antagonist can be used to treat motion sickness and to treat induced vomiting. Reducing cisplatin-induced ρ-region vomiting with a selective neurokinin-1 receptor antagonist, described in The New England Journal of Medicine, Vol. 340, No. 3, 190-195, (1999). Furthermore, US Pat. No. 5,972,938 describes a method of treating psychogenic or psychosomatic disorders with a tachykinin receptor, such as an NK-1 receptor antagonist. The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in Neuropeptides, 32 (1), 1-49, (1998) and Eur J. Pharmacol, 383(3), 297 -303, (1999). European Patent No. EP-A-721 778 is a special compound made of medicine for the treatment of disorders of the lower extremity, selected from stroke, epileptic head trauma, spinal trauma, as a result of stroke or vascular obstruction. Meta-damage, stimulation _ -6- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303991 A7 B7 V. Description of invention (3) Toxic neuronal damage and amyotrophic sclerosis in mammals . It has also been reported that NK-1 receptor antagonists are also beneficial in the treatment of traumatic brain damage (International Patent Application No. PCT/AU 01/00046, Publication N.o WO 01/52844). The benefits of the NK-1 receptor antagonist N · acetyl-L-tryptophan in improving neurological outcomes following traumatic brain injury have been presented in the oral report of Porf. Nimmo at the International Tachykinin Conference 2000. La Grande Motte, France, October 17-20,2000 (author: Nimmo A. J ·, Bennett C. J ·, Hu X ·, Cernak I ·, Vink R ·). The use of NK-1 receptor antagonists for the treatment or prevention of chronic non-bacterial prostatitis and prostate pain is described in International Patent No. WO 99/59583. International Patent No. WO 01/01922 describes the use of substance P antagonists for the treatment of adenocarcinomas, particularly genital-urinary tract tumors, such as prostate cancer. It has been found that the selective, brain penetrating NK-1 receptor antagonist of the formula

Wherein R is hydrogen, lower alkyl, lower alkoxy, halo or trifluoromethyl; R1 is hydrogen or _; or R and R1 may together be -CH=CH-CH=CH-; China National Standard (CNS) A4 Specification (210 X 297 mm) 1303991 A7 B7 V. Description of Invention (4) R2 and R2· are independently hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy Or a cyano group; or R2 and R2' may together be -CH=CH-CH=CH-, optionally substituted with one or two substituents selected from the group consisting of lower alkyl, _ or lower alkane Alkyl; R3, if two, independently of each other, is hydrogen, lower alkyl or, if two, may form a cycloalkyl group with the attached carbon atom; R4 is hydrogen, -N(R5)2,- N(Rl)(CH2)n〇H,-N(R5)S(0)2-lower alkyl, -N(R5)S(0)2-phenyl,-NH=CH-N(R5) 2,-N(R5)C(0)R5-cyclic tertiary amine, formula r6-〇 or

/(CH2)nN(R5) - a cyclic tertiary amine or R4 is -(OC)mR7 or -(CR丨eCR丨丨)mR7 wherein R7 is a) halo, b) cyano, or the following groups: c) -(CR丨R")m-R8 d) -C(〇)NR,Rn, e) -C(0)0(CH2)nR8, fT-C(0)R8 g) -N(OHHCH2) nR8, -8- This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1303991 A7 B7 V. Invention description (5) h) -NR,C(0)-(CH2)nR8, i ) -N[C(0)-R']2 ^ j) -OR9, k) -(Cil2)n-SR9,-(CH2)nS(0)R9, or -(CH2)nS(0)2R9, l) an aryl group, optionally substituted with one or more substituents selected from the group consisting of: trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'Rn, ' 'tip, -(CH2)mOR·, -C(0)NR'R·', -C(0)0R' or -C(0)R', m) is a five or six member heteroaryl containing One to four heteroatoms are selected from N, hydrazine or S and may be substituted with one or more substituents selected from the group consisting of i, trifluoromethyl, lower alkyl, lower alkoxy, cyano, # Base, -NR'Rn, nitro, -(CH2)mOR,, -C(0)0R', -C(0)NR'R" or -C(0)R', η) is the following formula or Six-membered saturated cyclic tertiary amine

It may contain an additional hetero atom selected from N, hydrazine or S, R, /R 丨丨 independently of hydrogen, hydroxy, lower alkyl, cycloalkyl or aryl, wherein lower alkyl, naphthenic The aryl or aryl group may be substituted with one or more substituents selected from the group consisting of halo, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR"'R";,nitro,-RH2)mOR''',-C(0)NR,''R''',-C(0)0R''' or -C(0)Rn,,R"'/R "" Independent of each other is hydrogen, lower alkyl, cycloalkyl or aryl, -9 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1303991 A7 B7 V. Description of invention (6) R8 is hydrogen, cyano, hydroxy, halo, trifluoromethyl, -C(〇)〇R, , -〇C(0)R' or aryl, optionally having one or more substituents selected from the group consisting of Substitutions include ||, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'R'1, nitro, -(CH2)mOR, -C(0)NR, R,, '-C(0)0R' or -C(0)IV, or a five or six member heteroaryl containing one to four heteroatoms From N, hydrazine or S, and optionally required to be one or more substituents selected from the group consisting of: halo, trifluoromethyl, lower alkyl, lower carbon, cyano, phenyl, -N R1R, ', nitro, -(CH2)mOR,, -C(0)NR, Rf丨, -C(0)0R丨 or -C(0)R,, R9 is hydrogen, lower alkyl , a trifluoromethyl or aryl group, wherein the lower alkyl or aryl group may be substituted with more than one substituent as desired, and is selected from the group consisting of halo, trifluoromethyl, lower alkyl, lower decyloxy, Cyano, hydroxy, -NR, R", nitro, -C(0)NR, R,,, -(CH2)mOR,, -C(0)0R' or -C(0)R', or a five or six membered heteroaryl group containing from one to four heteroatoms selected from N, hydrazine or S and optionally substituted with one or more substituents selected from the group consisting of dentate, trifluoromethyl, lower alkyl , lower alkoxy, cyano, hydroxy, -NRfR", nitro, -(CH2)mOR·, -C(0)NR'Rn, -C(0)0Rf or -C(0)R·, R1Q is -C(〇HCH2)mOH or a ketone group; or R4 is an N-oxide of the formula

Wherein RH and R11· are each independently -(CH2)P0R12 or lower alkyl, the paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303991 A7 __JB7__ V. Invention description (7) where R12 Is hydrogen, lower alkyl or phenyl; or R11 and Rii plus the attached N-atom together form a cyclic tertiary amine of the formula

Wherein R 1 3 is hydrogen, hydroxy<, lower alkyl, lower alkoxy, -(CH2)pOH, -COOR3, -C0N(R3)2'-N(R3)c〇-lower alkyl Or -C(0)R3; R5 is independently of each other hydrogen, C3-6-cycloalkyl, fluorenyl, phenyl or lower alkyl; R6 hydrogen, hydroxy, lower alkyl, -(C Η 2) nc 0 〇-lower alkyl, -N ( R 5) C 0 -lower alkyl, hydroxy-lower alkyl, cyano, -(CH2)n〇(CH2)nOH, -CHO- or 5 - or 6-membered heterocyclic group, optionally bonded via an alkyl group; X is -C(〇)N(R5)-, -(CH2)m〇-,-0(CH2)m-,-(CH2)mN (R5)-'-N(R5)C(0)- or -N(R5)(CH2)m-; n is 〇, 1, 2 or 3 or 4; m is 1 or 2; and P is 1, 2 or 3; and its pharmaceutically acceptable acid addition salts, and prodrugs thereof, are particularly suitable for the treatment and/or prevention of brain 'spinal or nerve damage. The present invention relates to the use of an NK-1 receptor antagonist of the general formula (I) which can be formulated into a therapeutic substance for the treatment and/or prevention of brain, spinal cord or nerve damage. The invention also relates to the treatment and/or prevention of brain and spinal cord in mammals _________-11- The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1303991

Neuroprotective properties. The following general terms are used in this description, regardless of the language in which they are discussed or used in combination. In the treatment and / or prevention of brain, spinal cord or nerve injury ', in the middle, treatment," refers to the NK-1 receptor in the brain, spinal cord or nerve injury caused by the impact in a few minutes to several hours after the impact Antagonist for any application (living individuals such as mammals or humans). However, protection refers to the possibility of combining or expected shocks, which can cause damage to the brain, spinal cord or nerves of the individual, and any preventive treatment done to the patient. The preventive treatment can be administered immediately within a few minutes before the impact, within 1 to 24 hours, or within one to several days before the expected impact. Administration can occur once or repeatedly before the expected impact (preferably at regular intervals). In the selective 'brain penetrating NK-1 receptor antagonist', "selectivity," refers to the affinity of the NK-2 and/or NK-3 receptor, which is related to the Νκ_1 receptor. There is a 100 to 10,000 times higher affinity. "Brain penetrability in this phrase" means that the NK-丨 receptor antagonist used in the present invention has good brain penetration, and can cross the blood brain barrier (BBB). This and the N-acetyl group The opposite of the amine acid, which shows only minimal brain penetration. The preferred compounds used in accordance with the present invention exhibit excellent anxiety and antidepressant activity, and can also cross the BBB. Treatment of the animal with preferred compounds for treatment and / or prevention of brain, spinal cord or nerve damage also showed a significant reduction in post-traumatic depression. "Lower alkyl" as used in this context means a straight or branched alkyl group containing from 丨 to 7 carbon atoms. Such as methyl, ethyl, propyl, isopropyl, n-butyl 'isobutyl, 2-butyl, tert-butyl and others. Lower low-13 - This paper scale applies to Chinese national standards ( CNS) A4 size (210X297 mm) binding

Line 1303991

The carbon group is a group having from 丨 to 4 carbon atoms. "Low carbonyl oxy group" means a group wherein the alkyl group is as defined above, and which is attached via an oxygen atom. Halogen '' represents chlorine, ki, fluorine, and bromine. • 'cycloalkyl group' means 3 to A saturated carbocyclic group of 6 carbon atoms. "A cyclic tertiary amine, which means, for example, pyrrolidinyl-indoleyl, imidazolium-hydrazino-yl, piperidinyl-thio-porphyrin-4-yl, 1,1-dione-sulfofuron- 4, yl, 2,3•dihydro-[M]pyridazin-4-yl, or [1,2,4]triazole-i. group. The so-called "five or six-membered heteroaryl, which contains one to four The hetero atom is selected from n, 〇 or s '' represents the following group: pyrrole-丨-yl, imidazolium-yl or 2-yl, pyrazol-1-yl, pyridin-2, 3 or 4-yl, Pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, pyrenyl, fluorene, 2, hongtriazolyl, oxadiazolyl 'four gas p than decidyl' Base or thiol. ''Five or six-membered saturated tertiary amines'" are, for example, pyrrolidinyl, indolizine, pyrazolyl, piperidinyl, piperazinyl, morpholinyl, thiophyllinylthio福福琳-1,1-dione or thiofolfin-1 · g is the same group. π 5 or 6 membered heterocyclic group means pyridyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazole Base, triazolyl, thienyl, furyl, piperidyl, pyrrolyl, imidazolyl, pyrazolyl, iso-Pyrazolyl, pyridazinyl or acridinyl. "Aryl" means a monocyclic aromatic hydrocarbon group or a bicyclic or tricyclic ring system wherein at least one ring is aromatic, preferably phenyl, benzyl or naphthyl ring. , pharmaceutically acceptable acid addition salt "including salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, Yan-14-

1303991 A7 B7 V. INSTRUCTIONS (n) Hussoic acid, maleic acid, acetic acid, bit-toluenesulfonic acid and others. ''Pharmacological Dosage of Magnesium" means a magnesium agent provided by any suitable method: such as the addition of a non-toxic magnesium salt such as magnesium chloride 'magnesium sulfate, the grasshopper "beauty" by the magnesium may be separately or in combination The receptor antagonist is administered down to the patient. The dose is from 0 J to 30 mg/kg body weight. The preferred method of the patent application is that the compound is in the formula i -C(9)Ν(10) and wherein R5 is methyl, Ethyl or cyclopropyl, as follows = fluoromethyl-benzyl)-N-methyl-4 butadiene) τ丞4·ortho-tolyl·nicotinium methyl-pyrustyyl)-Ν-A Base.4_(2 phenyl)_ 验 铋 铋, tartaric acid, formazan acid, for the compound: Ν-(3,5-bisguanamine, Ν-(3,5-dual amine, NAS-double -trifluoromethyl 4 yl)·Ν·methyl, 2—trifluoromethylphenyl nicotinic acid decylamine, NAS-bis-trifluoromethyl-nodal group, good methyl _4 仏 _ phenyl ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ) good methyl _4_ stupyl _ amide, hydrazine-(3,5-bis-trifluoromethyl- benzyl) good ethyl _4, ortho-tolyl _ Amine, Ν-(ίΓ5: bis-trifluoromethyl-¥yl)-yicyclopropyl_4_ortho-tolyl_in the amine, -15- This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm)" ---- i order line 1303991 A7 B7 V. Description of invention (12) N-[l-(3,5-bis-difluoromethyl-phenyl)·B Keb N-methyl-4-o-tolyl-nicotinium amide, N-(3,5-bis-difluoroindolyl)-N-methyl-4-o-tolyl-tobacco Alkaline decylamine, N-(3,5-bis-di-chloroindenyl)-N-methyl-4-ortho-tolyl-nicotinium amide, 1^-(3,5-bis-difluoro Methyl-g-yl)-]^-methyl-6-(4-methyl-carbo-1-yl)-4-o-tolyl-nicotinium amide, 2'-methyl-5- (4-methyl-piperazine-i-yl)-biphenyl-2-carboxylic acid _(3,5-bis-trifluoromethyl-benzyl)-methyl-decylamine, N-(3, 5-bis-di-methyl-methyl-aryl)methyl-6-(4-methyl-peak 17-methyl-1-yl)-4-indol-1-yl-nicotinium amide, (4-{5 -[(3,5-bis-difluoromethyl-indenyl)-methyl-aminomethyl]-4-o-tolyl-pyridine-1-piperazine-l-yl)-acetic acid Ethyl vinegar, 5^[(3,5-bis-di-methyl-methyl-aryl)-methyl-amine-mercaptopurine 4,-ortho-toluene Base - 3,4,5,6·tetraoxy-2H-[1,2']-linked p-pyroyl-4-acid acetate, 1^-(3,5-bis-difluoromethyl-section Base)-]^-methyl-6-(4-propyl-peak-l-yl)*· 4-ortho-tolyl-in the amine, (RS)-6-[3-(B Mercapto-methyl-amino) pyrrolidine_1β-yl]-N-(3,5-bis-trifluoromethyl-indenyl)-N-methyl-4-ortho-1-tolyl. For the test cancer amine, >!-(3,5-bis-trifluoromethyl-yl)-;^-methyl-6-[methyl-(2-?? 17-lin*·4-yl· Ethyl)-amino]-4-ortho-tolyl-yield amine, N-(3,5-bis-trifluoromethyl-indenyl)-N-methyl-6-morpholine- 4-yl-4-ortho-tolyl-yield amine, Ν-(ίΤ5: bis-trifluoromethyl-indenyl)-N-methyl-6-thiofefofolin-4-yl-4 - ortho-tolyl-fentanamine,

___-16- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1303991 A7 B7 V. Description of invention (13) N-(3,5-bis-trifluoromethyl-benzyl) -N-methyl-6-(1-keto-1λ4-thiophene p-indol-4-yl)-4-ortho-amidyl-------(3,5-bis- Trifluoromethyl-indenyl-6-(1,1-dione-lλ6-thiomorpholin-4-yl)-indole-methyl-4-ortho-tolyl-nicotinium amide Ν-(3,5-bis-trifluoromethyl-indenyl)-indole-methyl-6-piperazine-1-yl-4-o-tolyl-nicotinium amide, Ν-(3, 5-_bis-trifluoromethyl-oxime 1)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-indole-methyl-4-o-position-methyl-based- Test. S-amine Ν-(3,5-bis-trifluoromethyl-indenyl)-6-(4-cyanomethyl-piperazin-1-yl)-indole-methyl-4-ortho -tolyl-nicotine decylamine, N-(3,5-bis-trifluoromethyl-indenyl)-6-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperidyl Pyrazin-1 · kib N-methyl-4-o-tolyl-nicotinium decylamine, 1(3,5-bis-trifluoromethyl-indenyl)-1methyl-6-(4- [1,2,4]oxadiazol-3-yl-methyl-Brigade-1·*yl)-4-ortho-tolyl-inhabited amine 'N-(3,5-bis-three Fluoromethyl-fluorenyl)-6-[ 4-(5-keto-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-piperazin-1-yl]-4-ortho-tolyl- Nicotinamide, N-(3,5-bis-trifluoromethyl-indenyl)-6-(4-methylindolyl-piperazin-1-yl)-N-methyl-4-ortho- Tolyl-pronolamine and N-methyl-N-(2-methyl-indol-1-yl-methyl)-6-morpholine-4-yl-4-o-tolyl- Nicotine amide. Further preferred compounds in the use of the scope of the patent application are wherein X is TN(R5)-CO- in the formula (I), and wherein R5 is hydrogen or methyl, such as the following compound: 2-(3,5-bis- Trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazine-l- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

1303991 A7 _ B7 V. INSTRUCTIONS (14 ) BASE)-4 -ortho-amwyl-p-predated-3-yl]-isobutylenamine, 2-(3,5-bis-trifluoromethyl -phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methyl-carbo-1-yl-pred--3-yl]-N-methyl-isobutyric acid amine , 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl- shouting σ- 1-based)-pyridin-3-yl]-N-methyl-isobutylamine, 2-(3,5-bis-trifluoromethyl-phenyl)-indole-[4-(2-chloro· Phenyl)-pyridin-3-yl]-indole-methyl-isobutylamine, 2-(3,5-bis-trifluoromethyl-phenyl-indole-methyl-indole-(4-o-) -tolyl-pyridin-3-yl)-isobutylamine, 2-(3,5-bis-trifluoromethyl-phenyl)-indole-(4-ortho-tolyl-pyridine-3- Ibuprofenamide, 2-(3,5-bis-trifluoromethyl-phenyl)-indole-methyl-indole-(4-ortho-tolyl-exopurin-3-yl)- Acetamine, 2-(3,5-bis-trifluoromethyl-phenyl)-indole-methyl-indole-(4-ortho-tolyl-p-precipitate-3-yl)-propanol , 2-(3,5-bis-trifluoromethyl-phenyl)-indole-methyl-indole-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl )·Isobutylamine, 2-(3,5-bis-trifluoromethyl-phenyl)- Ν-[4-(2-Chloro-phenyl)-6-morpholine-4-yl-pyridin-3-yl]-N-methyl-isobutylamine, 2-(3,5-bis Trifluoromethyl-phenyl)-N-methyl-N-{6-[methyl-(2-morpholine-4-ylethyl)-amino]-4-o-tolyl-pyridine -3 -yl} • Isobutylamine, bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-pyrimidin-2-yl------yl)-4 -ortho-tolyl-p-pred-3-yl]-isobutyric acid amine -18- This paper scale is suitable for @@家料(CNS) A4 specification (X 297 mm) 1303991 A7 ___Β7__ V. Invention Description (15) 2-(3,5-Bis-trifluoromethyl-phenyl)^-(6-morpholine-4-yl-4-ortho-methyl-p-predyl-3-yl )-Isobutylamine, 2-(3,5-bis-trifluoromethyl-phenyl)-1^-[4-(2-chloro-phenyl)-6-dimethylamino] -3 -yl]-isobutylamine, 2 gas 3,5-bis-trifluoromethyl-phenyl)-1 methyl-yi (6-piperazin-1-yl-4-o-tolyl) -ρ ratio bit-3-yl)-isobutylenamine, 2 gas 3,5-bis-trifluoromethyl-benzene "yl)-oxime-(4-hydroxy-4'-ortho-tolyl- 3,4,5,6-tetrahydro-2-indole-[1,2']bipyridin-5'-yl)-indole-methyl-isobutylamine, 2 gas 3,5-bis-trifluoromethyl -phenyl)-Ν-{6-[(2-hydroxyl -ethyl)-methylamino]-4-o-tolyl ratio-3-yl}*^-methyl-isobutylenamine '(R)-2-(3,5-bis-trifluoro Methyl-phenyl)-indole-[6-(3-hydroxypyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-indole-methyl-isobutylamine, 2 gas 3,5-bis-trifluoromethyl-phenyl)-N-methyl-indole-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)- Acetamide, and [2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propyl]-[4-(4-^-2-methyl-phenyl)- 6-(4-Methyl-piperazin-1 -yl)-pyridin-3-yl]-methylamine. The preparation of the above compounds is detailed in EP-A-1,035,1 15. The value of the affinity of the selected compound for the NK-1 receptor, also shown, is shown as pKi, of which the better compound? The phantom value is in the range of 8.00 to 9.80, and a further application for a suitable blend of NK-1 receptor antagonists is proposed, which is also suitable for use in the scope of the patent application. Other compounds within the scope of the general formula (I), which are also suitable for use in the present application, are described in Int Pat. Appl. No. PCT/EP 01/08432, published in July 2001. 7th 'Eur Pat· Appl· No· -19- t paper scale applicable to China National Standard (CNS) A4 specification (210X297 Gongdong) 1303991 A7 B7 V. Invention description (16) 001 15846.8, according to its announcement, in 2000 July 24th. Examples of such compounds are as follows: A) A compound of the formula (I) wherein X is -C(0)N(R5)- and R5 is methyl, ethyl or cyclopropyl' such as 1^-(3,5 - bis-difluoromethyl-yl)-]^-methyl-4-ortho-tolyl-6-[1,2,4]dis-1-yl--pro-amine, N-( 3,5-bis-trifluoromethyl-benzyl i > N-methyl-6 gas 2-hydroxy-ethylaminomethyl-4 - ortho-tolyl-nicotinium amide, 4-hydroxy-4 '-ortho-tolyl-3,4,5,6-tetrahydro-2H-[1,2,]bipyridyl-5f-carboxylic acid (3,5-bis-trifluoromethyl-fluorenyl) Methyl-nonylamine, 4-(2-trans)ethoxyphenyl-4'-ortho-tolyl-3,4,5,6-tetrahydro-2H-[1,2,]症基-5, a few acids (3,5-bis-trifluoromethyl-yl)-methylamine, (R)-N-(3,5-bis-dimethyl-methyl )-6-(3-trans-p-pyrrol-1 -yl)·N-methyl-4 -ortho-tolyl-smoke decylamine, 4f-(2- gas-phenyl)-4 -Spene ·3,4,5,6-tetrahydro-2-indole [1,2'] in combination with decyl- 5'-carboxylic acid (3,5-bis-trifluoromethyl-indenyl)- Methyl-nonylamine. A compound of formula (I) wherein X is -N(R5)-C(0)- and R5 is hydrogen or methyl such as 2-(3,5-bis-dimethylmethyl -winter-ethylamine -4-o-tolyl-pyridin-3-yl]-N-methyl-isobutylamine, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6- (2,3-Dihydro-[1,4]oxazin-4-yl)-4-o-tolyl-pyridin-3-yl]methyl-isobutylamine, N-(6-acetamidine) Amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutylamine, N-[ 6-(Ethyl-nonylamino)-4-o-tolyl-pyridin-3-yl]-2- -20- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1303991 A7 B7 V. INSTRUCTIONS (17 ) (3,5-Bis-Trifluoromethyl-phenyl)-N-toluene-isobutylamine, cyclopropanecarboxylic acid (5-{[2-(3,5) - bis-trifluoromethyl-phenyl)-2-methyl-propenyl]-methylamino}-4 -ortho-tolylpyrimidin-2-yl)-bristamine, cyclopropanecarboxylic acid ( 5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propenyl]-methylamino}-4 -ortho-tolyl-p-precipitate-2 -yl)-methyl-bristamine, 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-imidazol-1-yl-4-o-tolyl-pyridine-3 -yl)methyl-3⁄4 butylamine, or 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-( 2-Hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutylamine. The most preferred compound which can be used according to the invention is N-(3,5-bis-trifluoromethyl-indenyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4 - ortho-tolyl-nicotinamide, disclosed in ΕΡ-Α-1, 〇35,115β. Preferred are also compounds of formula (1) wherein R4 is -(CsC)mR7 or -(CR,=CR,,) mR7. Typical compounds in this group can be characterized as follows: Compounds of formula (I) wherein X is -C(O)N(CH3)-, and -(R2)n*3,5-di-CL represents the first group of compounds. Preferred compounds of this group are those wherein RW is hydrogen and R is methyl, such as the following compound: N-(3,5-bis-trifluoromethyl-indenyl)-6-(4-hydroxyethyl)- Piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinium amide, N-(3,5-bis-trifluoromethyl-indenyl)·6•chloro, N- Methyl-4-ortho-tolyl-in the case of decylamine, Ν-(3,5-bis-trifluoromethyl-benzyl) cyanomethyl hydrazine-methyl-4-ortho-tolyl- In the test of amine, Ν-(3,5-bis-trifluoromethyl-benzyl iodide-indole-methyl-4-ortho-toluene ____ -21 - This paper scale applies to Chinese National Standard (CNS) Α4 Specification (21〇X 297 mm) -- 1303991 A7B7 V. Description of the invention (18) Base--protonamine ' 4- ortho-tolyl-[2,4f]bipyridyl-5-carboxylic acid (3 , bis-trifluoromethyl-indenyl)-methyl decylamine, 5-[(3,5-bis-trifluoromethyl-indenyl)-methyl-amine-methylmethyl]-4-ortho- Mercapto-p-precipitate-2 - decanoic acid for the 'N-(3,5-bis-trifluoromethyl-indenyl)-6-hydroxymethylmethyl-4-o-tolyl- For the detection of decylamine ' 6-(5-acetoxy-sulfo-2-yl)-N-(3,5-bis-dimethyl-indenyl)-indole·methyl-4-ortho-toluene Base-nicotine guanamine, 4- -tolyl-lf, 2,3',6'-tetrahydro-[2,4']bipyridyl-5-carboxylic acid (3,5-bis-trifluoromethyl-indenyl)-methyl Indoleamine, N-(3,5-bis-trifluoromethyl-indenyl)-6-(4-hydroxymethyl-phenyl)-N-methyl-4-o-position-tolyl-inspection peak Amine 2'-Methyl-4-o-tolyl-[2,4']bipyridyl-5-carboxylic acid (3,5-bis-dimethylmethyl-fluorenyl)-methyl-bristamine 'N-(3,5-Bis-Trifluoromethyl-indenyl)-N-methyl-6-(3-methyl-[1,2,4]indole yttrium-5-yl)-4 - ortho-methyl-based - acid test amine, 6-(3-amine tomb-propan-1-yl)-fluorene-(3,5-bis-tris-methyl-aryl)-Ν-甲Base-4-ortho-tolyl-in acid-amine '(RS)-N-(3,5-bis-trifluoromethyl-indenyl)-6-(2-hydroxy-ethanesulfinyl) Methyl)-N-methyl-4 -ortho-tolyl-nicotinium decylamine, N-(3,5-bis-trifluoromethyl-indenyl)-N-methyl-6-(1- Methyl-indole-imidazole-2 - f-sulfanylmethyl)-4-o-tolyl-nicotinium decylamine, (RS)-N-(3,5-bis-mainly fluoromethyl-oxime Base)-N-methyl-6-(pyridine-2-sulfin-22- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1303991 A7 ____________ Β7 V. Description of invention (19) Brewing base)_'ortho-$phenyl-nicotine decylamine, Ν_(3,5-bis-trifluoromethyl-fluorenyl)_Ν-methyl-6 -(pyridin-2-yl-sulfonyl)_ 4-ortho-tolyl-nicotinium amide, or N-(3,5-bis-trifluoromethyl--yl) winter (3-hydroxy- Propoxy>Nm ortho-tolyl-nicotinium amide. Further preferred are compounds of formula (I) wherein R4 is -(CsC)mR7 or -(CR'=CR")mR7 and wherein X is /N(CH3)(c〇)KR2)n is 3 5•di-CF3. Preferred compounds exemplified in this group are those wherein R 3/R 3 are methyl and R is methyl, such as the following compound: 2 ( 3'5-bis-di-methyl-methyl-l-yl)-1^-{6-[radio-(2-)-yl-ethyl)-amino]> 4-ortho-tolyl-pyridine- }}·Ν•Methyl-isobutylamine, 2·(3,5-bis-trifluoromethyl-phenylmethyl-indole-{6-(3-keto-morpholine·4-yl) -4-o-tolyl-pyridine-1,3-yl]-isobutylamine, vinegar S-father (5·{[2-(3,5-bis-trifluoromethyl-phenyl)-2- Methyl-propenyl]-methyl-aminopyr 4-o-tolyl-n-pyridin-2-ylaminocarbamoyl)·methyl ester, 2-(3,5-bis-trifluoromethyl Base-phenyl)_n-[6-(2- Hydroxy-acetamido)-4-ortho-tolyl-p-predative 3-yl]-N-methyl-isobutylamine, 2_(3,5-bis-trifluoromethyl-benzene -N-[6-(2-Hydroxyethylidene-methyl-amino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutylamine, 2_( 3,5-bis-trifluoromethyl-phenyl)-N-[6-(2,5-dione-pyrrolidin-1 -yl)-4- ortho-tolyl-pyridin-3-yl ]-N-methyl-isobutylamine, cyclopropanecarboxylic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propenyl)methyl -amino} -4- ortho-tolyl-pyridine-2 ·yl)-cyclopropanecarbonyl-nitramine, ____-23- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1303991 A7 B7 V. INSTRUCTIONS (20) 2-(3,5-Bis-Trifluoromethyl-phenylchloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutylamine , 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-2,-methyl-[2,4*]bipyrrolidin-5 -yl]-N-methyl-isobutylamine, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-ethylidene-4-o-tolyl-leaf匕丁·3 -yl)-N-methyl-isobutylenamine, 2-(3,5-bis-trifluoromethyl-benzene cap)-N-[6-( 3-hydroxymethyl-isoxazol-5-yl)-4-o-p-phenyl-pyridin-3-yl]-N-methyl-isobutylamine, 2-(3,5-bis- Trifluoromethyl-phenyl)-N-[6-(3-hydroxy-propan-1-ynyl)-4-o-position-methylglycosyl-p-precipitate-3-yl]-N-methyl- Isobutylamine, or (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-methoxy-phenylsulfinyl)-4-o- Bit-tolyl-pyridin-3-yl]-N-methyl-isobutylamine. Further preferred are compounds of formula (I) wherein R4 is -(C=C)mR7 or -(CR/=CRn)mR7 wherein RVR3 is methyl and R is chloro, such as the following compound: 2-(3 ,5-bis-trifluoromethyl-phenyl)-N-{4-(2-chloro-phenyl)-6-[hydroxy-(2-)-ethyl)-amino]-p -3 -yl}--N-methyl-isobutylenamine, or 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-a-phenyl)- 6-(3-Ketyl-norfosolin-4-yl)-pyridin-3-yl]-N-methyl-isobutylamine. A process for the preparation of a compound of formula (1), wherein R4 is -(〇C)mR7 or -(CRbCR, %!^, as described in International Patent No. PCT/EP 01/08686, published on July 27, 2001, European Patent No. 001 17003.4, published on August 8th, 2000. As indicated above, the NK-1 receptor antagonist according to the usage of the present invention can be applied to the Chinese National Standard (CNS) on the scale of the prodrug-24-paper. A4 size (210 X 297 mm) 1303991 A7 B7 V. Description of the invention (21) Type presentation. The preferred prodrug of the compound of formula (I) is N-oxide, such as the following compound: bis-dimethylmethyl -mercapto)·methyl-amine methyl-based] ortho-tolyl-pyridine-2-yl}-4-yloxy-pyroazine-1 _acid acid tert-butyl ester, 5'-[( 3,5-bis-trifluoromethyl-indenyl)-methyl-amine-mercapto]-4,_ortho-tolyl-1-oxy-3,4,5,6-tetrahydro-2H -[1,2,]ethylpyridyl-4-carboxylate, (RS)-6-[3-(ethylindenylmethylaminoketylpyrrolidinyl)·N_ (3,5 - bis-difluoromethyl-indenyl)-N-methyl-4 - Zheng-tolyl-nicotinine | Amine, N-(3,5-bis-trifluoromethyl.indenyl)-N -methyl_6-(4-oxo-morpholine·4_yl)-4 -ortho-tolyl-in the test of amine, N-(3,5-bis-difluoromethyl-benzyl)-6-(1,1_di-g-iso-yl·ιχ6·4-oxyl Morpholine-4 -yl)-oxime-methyl-4-o-position-tolyl-nicotinium decylamine, Ν-(3,5-bis-trifluoromethyl-fluorenyl)-6-(4- Mercapto-1 oxy-piperazine] yl)-N-methyl-4 - ortho-tolyl-in the case of decylamine, N-methyl-N-(2-methyl-naphthalene-1- Methyl)·Bu (4-oxy-morphine y)-4-ortho-tolyl-final g stupid amine, N-methyl-6-(4-oxy-moffin -4-yl)_n-荇-1 -yl.a f., τ % '4- Jr?--tolyl-nicotinium amide, N-(2-methoxy-oxime-l-yl-- Methyloxy, morphine 4-yl)-4-ortho-tolyl-in the case of decylamine, ''N-(2dimethoxy-benzyl)-N-methyl-6-(4 , oxy-morpholine, 4, ortho-tolyl-toluene, 4 N-(5-chloro-2-methoxyindolyl)-N-methyloxy-? Dog mouth, 4 · ___-25·

This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1303991 A7 ____ ___B7 V. Description of invention (22) Base)-4-ortho-tolyl'nicotinium amide, N-(2 -Chloro-5-methyl-indenyl)methyl·6 _hofolinyl·4·ortho-methionyl--pro-amine, Ν-methyl-6-(4-oxy'? Folinolyl) pentafluorophenylmethyl·'ortho-tolyl-nicotinium decylamine, Ν-methyl-6-(4-oxo-moffin ice-based)·Νυ_yl·methyl winter neighbor Bit·tolyl-nicotinium amide, ♦ Ν-[2-methoxy _ (5-trifluoromethyl·tetrazolylbenzyl benzyl) 6-(4-oxy-morpholine _4·yl )-4-ortho-tolyl_nicotine decylamine, N-(l,4-dimethoxy-tea-methyl)·Ν_methyl-6 —(4•methoxy-? Porphyrin_4-yl)·'ortho-tolyl-nicotinium decylamine, 5^[(3,5·bis-trifluoromethyl-indenyl)-methyl-amine-methylhydrazine-based ortho-tolyl -Oxo-3,4,5,6-tetrahydro-2Η-[1,2'] linked ρ ratio decyl-4-carboxylic acid, 2-(3,5-bis-trifluoromethyl-phenyl Ν-Ν-[6-(4-oxy-morpholine-4-yl)-4-o-tolyl-pyridine-3-yl]•isobutylamine, 2-(3,5-double -trifluoromethyl-benzene >仏[4-(2-Gasylphenyl)oxy-moffa-4-yl)-p ratio acetyl-3-yl]-N-methyl-isobutylenamine, 2-(3, 5-bis-trifluoromethyl-phenyl)-indole_[6·(4-oxy-morpholine-4-yl)-4-ortho-tolyl-pyridin-3-yl]-isobutylene Amine, 2-(3,5-bis-trifluoromethyl-phenyl)-indole-[4,-(2-chloro-phenyl)-1-oxy-3,4,5,6-tetrahydro -211-[1,2"bipyridyl-5,-yl]-N-methyl-isobutylamine, 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6 -oxy-dimethylamino-4-o-toluene U-pyridin-3-yl)-N-methyl-isobutylamine, 2-(3,5-bis-trifluoromethyl-phenyl )-Ν·[4-(2-Chloro-phenyl)-6-oxy-二26- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)

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Line trm 1303991 A7 B7 V. Description of invention (23) Methylamino-pyridin-3-yl]-isobutylamine,

2-(3,5-bis-difluoromethyl-phenyl)-]^-1-(4-pyridyl-1-oxy-4,-ortho-3,4,5,6-tetra Hydrogen-2^1-[1,2'] linked to the group 5-'-yl)-1\[-methyl-isobutylamine, 2-(3,5-bis-trifluoromethyl-benzene -N-{6-[(2-hydroxy-ethyl)-i-oxy-methyl-amino]-4-ortho-tolyl-p ratio -3-yl}-N-methyl - Isobutamide, (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[(3-hydroxy-1-oxy-pyroxyl-1) ))-4/o-tolyl-p-precipitate-3-kib N-methyl-isobutylamine, 2-(3,5-bis-trifluoromethyl-phenyl)-indole-[ 6·(4.oxy-morpholin-4-yl)-4-o-tolyl-pyridine-3-yl]-acetamide, 2-(3,5-dimethoxy-phenyl ) 仏 仏 methyl-; ^-[6-(4-oxy-morphine-4-yl)-4-ortho-tolyl-ρ ratio benzyl-3-yl]-acetamide; or 2·(3-Fluoro-5-trifluoromethyl-phenyl)_Ν_methyl·Ν_[6_(4-oxy·N-Phen-4--4-yl)-4-o-tolyl-pyridine- 3_基]•Acetamine. Order

A method for preparing the above ruthenium-oxide prodrug is described in International Patent No. PCT/EP 〇1/〇785〇, published on July 9, 2002, in European Patent No. 001 15287.5, The announcement was made on July 14, 2000. The best formula for the use of the patent (ί) N• oxide prodrug is 孓(3,5• bis-trifluoromethyl phenyl)-N-methyl-N-[6-(4-oxo Base-morpholine _ 4 · yl) · 'ortho. tolyl _ p pyridine-3-yl>-isobutyl amide. A Ν·丨 receptor antagonist for use in a patent application can be administered alone or in combination with a therapeutic agent, and is preferably formulated to contain a pharmaceutically acceptable carrier or diluent. Things. The pharmaceutical preparations which can be used according to the invention may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners.

1303991 A7 B7 V. INSTRUCTIONS (24) 'Colorants, fragrances, salts of varying isotonic pressures, buffer solutions, opaque agents or antioxidants. An NK-1 receptor antagonist modulating and self-emulsifying drug delivery system (Emulsifyig rug 2_elivery Systems (SEDDS)) consisting of a mixture of oils and surfactants, ideally omnidirectional, wherein Potential solvents are also sometimes included. This mixture is emulsifiable under mild agitation, similar to what can be encountered in the gastrointestinal tract. When the modulating substance is released into the intestinal lumen, it can be dispersed to form a finely divided emulsion, so that the drug remaining in the emulsion can be left in the intestinal solution. 'To avoid dissociation, the absorption rate of the hydrophobic drug from the crystalline state is usually limited. . SEDDS can improve the bioavailability and/or a more consistent temporary profile of intestinal absorption. SEDDS has been Pouton C. W., described in Advanced Drug Delivery Reviews, 25, (1997), 47.58. The ΝΚ-1 receptor antagonist or the pharmaceutical composition containing the same is preferably administered intravenously. The solution for injection may have the following composition: Compound of formula I 1 mg 1 n HC1 2 0 μl of cesium acetate · 5 mg of NaCl δ gram of phenol 1 〇 1 NaOH NaOH Add to pH 5 H20 Add to 1 ml ΝΚ - Know The antagonist or the pharmaceutical composition containing the same may also be administered orally, such as in the form of a lozenge, an ingot, a pill, a hard and soft gelatin capsule, a solution, an emulsion or a suspension. However, administration can also be achieved via the rectum, such as in the form of a suppository, or -28- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm 1303011)

After %, such as Wang Ying solution. The Νκ]receptor antagonist or a pharmaceutical composition containing the same may also be administered by other suitable means known to the artisan. The dosage can vary over a wide range and, of course, in individual cases, with individual requirements. The dosage range at which a beneficial effect is achieved in a mammal will of course depend on the activity of the antagonist, which is used in the range of 5 to 1 mg/kg/day, and preferably 25 and 1 mg/kg/day. between. There are: L Ben's pharmaceutical combination can also contain pharmaceutically inert, inorganic or _: machine, suitable for the production of tablets, tablets, pills and hard gelatin capsules (4). It can be used as an excipient here, talc, stearic acid or its salt, etc., such as the shore. It is especially suitable for excipients, pills and hard gelatin. Suitable excipients for gelatin capsules such as vegetable oil, tannin, tiantianbei, semi-solid and liquid polyol. Use: to make the liquid (4), suitable excipients such as: water, multi-dimension, sugar, invert sugar, glucose, etc. Suitable excipients for injectable solvents are, for example, water, alcohols, polyols, glycerin, vegetable oils and the like. It is suitable for the suppository of the sputum. #Ησ: natural or hardened oil, 曰 ’ 半 semi-liquid or liquid polyol. * In addition, the pharmaceutical preparations may contain a salt-storing substance, a masking agent or an antioxidant 2: ; = a therapeutic price of Ίϊ. And s have other as shown in the following examples, the present invention has shown that the receptor-like antagonist, special -29 - 2" PCT) - this paper scale applies to the Chinese National Standard (CNS) Α 4 specifications (210 Χ 1303991 A7 __B7 V. INSTRUCTIONS (27) " A rat with an NMDA antagonist showed a similar tendency (Fig. 1), which was significantly impaired at various time points after injury' and was not significantly different from vehicle-treated animals. In contrast, administration of the NK-1 receptor antagonist N-(3,5-bis-trifluoromethyl-indenyl)-N-methyl-6-(4-methyl-piperazin-1-yl) -4-O-o-tolyl-nicotine guanamine animal has a significantly better motor outcome after brain injury, compared with saline or MK801 treated animals (Figure 1). About cognitive behavior after injury Similar results. Before the injury, the rat was trained to be in an escape hole (to escape the annoying sound and light) within 20 seconds. This time factor depends on the ability of the animal to learn and remember where to escape the hole. Later, in the saline-treated group, the incubation period for avoiding unpleasant stimuli increased to 36 seconds and was assessed 1 day after trauma. There has never been a significant improvement (Figure 2). The MK801 treated animal group also had a longer incubation period to avoid unpleasant stimuli at 24 hours. However, during the 9 days of the death, these MK801 animals did gradually improve to the pre-injury level. (Fig. 2). Conversely, the ΝΚ1 receptor antagonist N-(3, bis-trifluoromethyl-indenyl) oxime methyl winter (methyl-piperazine-1-yl) was administered. -4-O-tolyl-nicotinyl nicotinamide, the animal did not show an increase in latency during escape of annoying stimuli at any point after traumatic brain injury. Indeed, after the injury, the time to escape It was improved at each evaluation (Fig. 2), and it was inferred that the NK-1 receptor antagonist significantly protected the loss of antagonism function after traumatic brain injury. In addition to improvement after traumatic brain injury In addition to the post-traumatic neurological outcome, the NK-1 dimeric antagonist ν·(3,5-bis-trifluoromethyl-indenyl)-N-methyl-6-(4-methyl-indole per- 1 -yl)-4-ortho-tolyl-nicotinamide can also reduce mortality. The mortality rate of this severe injury pattern in rats is usually 2〇 and 3〇% - _ 31 - (Iv) the scale sheet material S s home (CNS) M Specification (2iqx 297 well Po) 1303991 A7

between. In the saline-treated animals, the mortality rate was indeed 30%. The post-traumatic MK801 mortality rate increased to 5%, and after a trauma, ^ Ά Δί) 0 / ^ one died in this one injury group. . The death rate of this business is consistent with serious injuries and can be confirmed by all head corpse analysis. In all other groups, the opposite of this high κ rate was observed, antagonized by NK-1...)-N-methyl-o-methyl-pyroazine small base)奉%〇 创伤 Post-traumatic mortality is associated with edema formation, especially in children, where severe edema causes 50% of deaths. The edema formed immediately after the trauma is thought to be derived from blood f, and the increase in the permeability of the blood-brain barrier causes the extra-protein spillage and water to accumulate in the brain interstitial. We used EvanBln_Emergence as a marker of blood-brain permeability after traumatic brain injury, and the N κ · i receptor antagonist n -(3,5-bis.trifluoromethyl-benzyl) The base-6_(4-methyl-piperazine-1_yl)4. ortho-tolyl- is treated with decylamine. 4.5 hours after the induction of brain injury, the animals were dosed to Evans Blue at Lv•, which was cycled for approximately 30 minutes. At this point in time, the animals were sacrificed and the brain was analyzed for the penetration of Evans Blue. The amount of Evans Blue accumulated in the brain of the saline-treated animal was standardized to 1%. Compared with saline-treated animals, the MK801 treatment group had 82% accumulation of Evans Blue, suggesting that there is still significant penetration of the blood-brain barrier in these animals (Fig. 3). Significantly opposite, with the NK-1 receptor antagonist N-(3,5-bis-trifluoromethyl-indenyl)-N•methylj(4-methyl-pyrazine-1-yl)- 4. The ortho-tolyl-nicotinamide treatment of animals, Evans lue penetration has a significant reduction (18%), showing that the compound can significantly reduce the penetration of blood-brain barrier after trauma, and related edema formation ( image 3 ). -32- 1303991

As expected

The accumulation of Blue. Uninjured (pseudo) animals in the brain tissue were not significantly Evans after taking 'Wu Temple noticed ΝΚ-1 拈面拈4上十丨x# 1 and Xiaodou L 杬N-(3,5-double-three Fluoromethyl-indenyl)-N-methyl·6-(4-methyl-form # , ^ , Tuchen i 1 ·yl)-4-ortho-tolyl-nicotine

There are many general effects on Sj f animals, which is beneficial to the results. After administration of the NK-1 receptor antagonist, the animal exhibited a respiratory pattern that was stable compared to the water and MK8G1 treated control group I. Indeed, animals treated with the "receptor. Bacterial compound" discard the snorkel faster than any other treatment group after a brain injury. The stability of this point in the action of beer is considered to be the respiration effect. The central role and the i receptor antagonist can be caused by the reduction of pulmonary edema formation in brain-scarred animals. This clearly shows that the NK_i receptor antagonist N-(3,5-bis-trifluoromethyl)_N•methyl-6-purine methyl·piperazine-1-yl)-4-ortho·toluene The base-nicotine guanamine stabilizes respiration and reduces the formation of pulmonary edema. All animals exhibit reduced investigative behavior after a brain injury and limit their own care. 'Inferred to be post-traumatic depression. Animals with Νκ-1 receptor antagonist N-(3,5-bis-trifluoromethyl-indenyl)w methyl-6-(4-methyl-piperazin-1-yl)· 4-ortho After treatment with toluyl-nicotine decylamine, the behavior of inquiry and self-care were not significantly different from those of uninjured animals. Although the mechanism is unknown, this effect is considered to be mediated via a mid-frame effect, as this improvement was not observed with NK-1 receptor antagonists with limited C N S penetration. From this point, it can be inferred that the NK-1 receptor antagonist N-(3,5-bis-trifluoromethyl-indenyl)-N-methyl-6-(4-methyl-piperidin-1 -yl) • 4_ortho-tolyl-nicotine decylamine is also useful in reducing post-traumatic sputum after a brain injury. -33 ~ This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1303991

A,.1S The above results show that the NK-1 receptor antagonist N-(3,5-bis-trifluoromethyl=indolyl)chunmethyl-6-(4-methyl L-methyl small group M-ortho- Tolyl-to-amine: minus (four) mortality after injury 'sports and lack of understanding. #然月月'J is no longer available (International Patent No. PCT/AU 01/00046) ΝΚ-1 suffers from bone _ The neuroprotective effect can be enhanced by adding a pharmacological dose to the i v. solution: melamine. Therefore, the receptor used in the present invention is N (3,5-bis-difluoromethyl); )·Ν_methyl_6_(4_methyl-slightly small base)·^ o-tolyl-nicotinium amide, preferably co-administered with a pharmacological dose of magnesium salt (10-100 pg/kg), To enhance the neuroprotective properties. -34- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

13〇3 potential (^(1) complete patent application Chinese patent replacement scope (July 1997) Patent application scope! • The use of a neurokinin-UNK-D receptor antagonist for the preparation of a medicament for the treatment and/or prevention of brain, spinal cord or nerve damage, wherein the nk-1 receptor antagonist is of the formula ( I) compounds, Wherein R is hydrogen, C"alkyl, Cl-7 alkoxy, _ or trifluoromethyl R1 is hydrogen or halogen; or R and R1 may together be -CH=CH-CH=CH-; R2 and R2· Independently hydrogen, _, trifluoromethyl, Cl·?, Ci-7 alkoxy or cyano; or R2 and R2· together may be -CH=CH-CH=CH_, as needed Or two substituents selected from C" alkyl, dentate or C"alkoxy; R3 is (if there are two, independent of each other) hydrogen, C]·? An alkyl group, or two if present, may form a C36 cycloalkyl group with the carbon atom to which it is attached; R4 is hydrogen, _N(R5)2, -N(R5)(cH2)nOH, 7 alkyl, -N (R5)S(0)2-本基,·ν=(^Η-Ν(Ι15)2, This paper scale applies to China National Standard (CNS) Α4 specification (210 297 297 DON) 1303991 A8 B8 C8 D8 Patent Application No. N(R5)C(〇)R5-, a cyclic tertiary amine rL of the following formula (3 or the following formula: wherein the cyclic tertiary amine is selected from pyrrole-1-yl, imidazolium-1 -yl , piperazine-1 -yl, oxazol-1 -yl, phlorin-4-yl, thiophene-4-yl, 1-steel-sulfofol-4-yl, 1,1 -*-mercapto-thiofofol-4-yl, pyrrole.-1-yl, piperidin-1-yl, 2,3-dihydro-[1,4]pyridazin-4-yl, or [1,2,4]triazol-1-yl; R5 is independently hydrogen, C3-6-cycloalkyl, fluorenyl or alkyl; R6 is hydrogen, hydroxy, Cu alkyl, -(CH2 nC〇〇-Ci-7 alkyl, NCROCO-Cu alkyl, hydroxy-Ci-7 alkyl, cyano, ·(CH2)n〇(CH2)nOH or -CHO ; X is -C(0)N (R5)·; η is 〇'1, 2, 3 or 4; and a pharmaceutically acceptable acid addition salt thereof. Uses wherein R5 is fluorenyl, ethyl or cyclopropyl. 3. Use according to item 2 of the scope of the patent application 'where the compound is selected from the following: - 2 - The paper scale applies to the Chinese National Standard (CNS) Α 4 Specifications (210X297 public) Order 1303991 - C8 D8 VI. Scope of Application Ν·(3,5-Bis-Trifluoromethyl--yl)-N-Methyl-4-o-tolyl-toluene-N-(3, 5-bis-dimethylmethyl-indenyl)-N-methyl-4-(2-chloro-phenyl)-in the base amide, N-(3,5-bis-trifluoromethyl-benzyl -N-methyl-4-(2-trifluorodecyl-phenyl)-nicotinium amide, N-(3,5-bis-trifluoromethyl-yl)-N-methyl-4 -(2-fluoro-phenyl)-in the base amide, N-(3,5-bis-trifluoromethyl-yl)-N-mercapto-4-(2-methoxy-phenyl) - Nicotinamide, N-(3,5-bis-di-indolyl-indenyl)-N-indenyl-4-phenyl-in the amine II 'N_(3,5-bis-two gas -N-ethyl-4-ortho-tolyl-in the case of decylamine, N-(3,5-bis-dimethyl-methyl-kethoxypropyl-4 -ortho-tolyl - Nicotinamide, N-[l-(3,5-bis-trisinyl-phenyl)-ethyl]-oxime-methyl-4-o-position-tolyl-nicotinium amide, Ν_ (3,5-bisdifluorobenzyl)-fluorenyl-indenyl-4·ortho-tolyl-nicotinium decylamine, fluorene-(3,5-bis-dichlorobenzyl)-indole-methyl- 4-ortho-tolyl·nicotine decylamine, N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazine-1-yl )-4- Ortho-p-phenyl-nicotinium amide, 2f-mercapto-5-(4.methyl-----1 -yl)-biphenyl-2-indole--(3,5 _bis-three Fluoromethyl-benzyl)-methyl-decylamine, N-(3,5-bis-dimethylmethyl-indenyl)-N-methyl-6 - (4-methyl-calling-1 _ -3- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) AB c D 1303991 VI. Patent application base) -4 -Ny-1-yl------- {5-[(3,5-Bis-Trifluoromethyl-benzyl)-methyl-amine-mercapto]-4-o-tolyl-p-pyridin-2-yl}-Brigade 17 Qin -1 -yl)-acetic acid ethyl vinegar '5f-[(3,5-bis-trifluoromethyl-yl)L-methyl-amineyl]W-ortho]tolyl-3,4,5 ,6·tetrahydro-2H-[l,2f]bipyridyl-4-carboxylic acid ethyl ester, N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-( 4-propyl-piperazin-1-yl)-4-ortho-indolyl-phenyl-Identified amine '(RS)-6-[3-(ethyl-methyl-amino)-p ratio洛-1-yl]-N-(3,5-bis-di-indolyl-indenyl)-N-methyl-4-o-tolyl-in-the-amine, N-(3,5- Bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-moff plin-4-yl-ethyl)-amino]-4-o -tolyl-------(3,5-bis-dihydromethyl-indenyl)-N-indolyl-6-moffa-4-yl-4-ortho-p-phenyl - in the test of amines] ^-(3,5-bis-dioxamethyl-fluorenyl)-]^-methyl-6-thiophene 17 _4-yl-4-ortho-tolyl - Nicotinamide, N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(1-keto-1λ4-thiofifelin-4-yl)-4 -ortho-tolyl-nicotinium decylamine, Ν-(3,5-bis-trifluoromethyl-benzyl)-6-(1,1-dione-lλ6-thiophene p-line-4 -yl)-oxime-mercapto-4-ortho-tolyl-in the amine, Ν-(3,5-bis-trifluoromethyl-benzyl)·Ν·methyl-6-piperazine- 1-yl-4-o-p-phenyl-nicotinium decylamine, Ν-(3,5-bis-difluoromethyl-yl)-6-[4-(2-trans-ethyl) - 嗦 嗦 _ 1-yl]- Ν-methyl-4-ortho-tolyl------------------------------------ The paper size applies to Chinese National Standard (CNS) Α4 size (210 X 297 mm) 1303991 ABCD N-(3,1-bis-trifluoromethyl-benzyl)-6-(4-cyanomethyl-piperazinyl)_small methyl-4_ortho-tolyl nicotinamide (3'1 bis-difluoromethyl benzyl)-6-{4-[2-(2-hydroxy"•ethoxy]ethyl)]- }}·Ν-mercapto-4 -ortho-tolyl-nicotinium amide, ('1 bis-difluoromethyl aryl)-N-methyl-6-(4-[1,2, 4] ρ No. 2 yl-methyl-piperazine small group) _ heart ortho-p-phenyl-nicotinium amide, N-(3,1-bis-trifluoromethyl-benzyl)- 6-[4·(5·keto_4,5-dihydro_1Η_,] _3_yl-methyl)- Chenzin-1-yl]-4-ortho-tolyl- , Γ 3 S >fefe mono-bis-tris-methyl-benzyl)-6-(4-carbamimido-piperazine q-ylbu N-methyl-4 _ ortho-tolyl-nicotine Indoleamine, and N-mercapto^-(2-methyl-indole-buyl-methyl)_ 6 _morpholine _ 4 _ group _ oxime-tolyl-nicotinium amide. 4. According to the application for patent section, the use of any of the 1st to 3rd, including the pharmacological dose of magnesium. A further pharmaceutical composition for treating cerebral venous/inflammation, or preventing brain, spinal cord or nerve damage, the sentence table aa, one work - 3 one or more as claimed in the scope of patents 1 to 3 A neurokinin-1 (NK-1) receptor antagonist as defined in any one of the items, and a pharmaceutically acceptable excipient. ', 6. The pharmaceutical composition according to item 5 of the patent application, the dosage of magnesium. article 1 This paper scale is suitable for the product(s) (CNS)纟(格(21()><297 public)-