Description AMINOINDANE DERIVATIVE OR SALT THEREOF
TECHNICAL FIELD 5 [0001]
The present invention relates to an aminoindane derivative or a salt thereof which is useful as a medicine, especially as an NMDA receptor antagonist, and to an NMDA receptor antagonist comprising the same as an active
10 ingredient. The aminoindane derivative or a salt thereof and the NMDA receptor antagonist comprising the same as an active ingredient, of the present invention, are useful for treating or preventing Alzheimer's disease, cerebrovascular dementia, Parkinson's disease, ischemic apoplexy, pain, and
15 the like.
BACKGROUND ART [0002] Glutamic acid acts as a neurotransmitter in the
20 central nervous system of mammals, and controls the
activity of neurocytes or the release of neurotransmitters via a glutamate receptor existing in synapses. At present, a glutamate receptor is classified into an "ionotropic glutamate receptor" and a "metabotropic glutamate receptor"
25 from many pharmacological and biological studies (Hollmann M. and Heinemann S., Annu. Rev. Neurosci., 17 (1994) 31-

108) . An NMDA (N-methyl-D-aspartate) receptor is an ion-channel glutamate receptor specifically sensitive to the agonist NMDA (Moriyoshi K. et al., Nature, 354 (1991) 31-37; Meguro H. et al., Nature, 357 (1992) 70-74); and this 5 has high Ca 2+ permeability (lino M. et al., J. Physiol.,
424 (1990) 151-165). The NMDA receptor is expressed with a specific pattern in a central nervous system (Ozawa S. et al., Prog. Neurobiol., 54 (1998) 581-618). [0003]
10 From many pharmacological and biological studies, it is believed that an NMDA receptor may participate in high-order neurologic functions such as memory and learning (Morris RG., et al., Nature, 319 (1986) 774-776; Tsien JZ. et al., Cell, 87 (1996) 1327-1338). On the other hand, it
15 is suggested that the acute or chronic NMDA receptor
hyperactivity or hypoactivity may participate in various nervous system diseases, for example, ischemic apoplexy, hemorrhagic brain injury, traumatic brain injury, neurodegenerative disorders (e.g., Alzheimer's disease,
20 cerebrovascular dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis), glaucoma, AIDS encephalopathy, dependence, schizophrenia, depression, mania, stress-related diseases, epilepsy, and pain (Beal MF., FASEB J., 6 (1992) 3338-3344; Heresco-Levy U. and
25 Javitt DC, Euro. Neuropsychopharmacol., 8 (1998) 141-152; Hewitt DJ., Clin. J. Pain, 16 (2000) S73-79). Accordingly,

drugs capable of controlling the activity of an NMDA receptor would be extremely useful in clinical application. [0004]
As drugs capable of controlling the activity of an 5 NMDA receptor, a large number of non-competitive NMDA receptor antagonists are reported, but many of them have not been used in clinical application because of their side effects based on the NMDA receptor-antagonizing effect thereof, for example, mental aberration such as
10 hallucination or confusion, and giddiness. Some of
already-existing NMDA receptor antagonists, for example, ketamine and dextromethorphan have been tried against pain in clinical application (Fisher K. et al., J. Pain Symptom Manage., 20 (2000) 358-373), but the safety margin in the
15 treatment with them is narrow, and their clinical use is limitative (Eide PK., et al., Pain, 58 (1994) 347-354). Memantine is known as a non-competitive NMDA receptor antagonist that has comparatively few side effects (Parsons CG., et al., Neuropharmacol., 38 (1999) 735-767); and
20 recently, it has been reported that this may be effective for Alzheimer's disease (Reisberg B., et al., N. Engl. J. Med., 348 (2003) 1333-1341). However, the safety margin of memantine as a medicine is still not satisfactory, and an NMDA receptor antagonist having a broader safety margin is
25 desired (Ditzler K., Arzneimittelforschung, 41 (1991) 773-780; Maier C., et al., Pain, 103 (2003) 277-283; Riederer

P., et al., Lancet, 338 (1991) 1022-1023). It is expected that creation of such an NMDA receptor antagonist having a broader safety margin may bring about new clinical usefulness of the NMDA receptor antagonist. 5 [0005]
Patent Document 1 describes a pharmaceutical composition for preventing and treating cerebral ischemia, which comprises an adamantane derivative represented by the following general formula or its pharmaceutically 10 acceptable acid-addition salt:

(wherein Ri and R2 are the same or different, and each 15 represent hydrogen, a linear or branched alkyl group having 1 to 6 carbon atoms, or the like; R3 and R4 are the same or different, and each represent hydrogen, an alkyl group having 1 to 6 carbon atoms, or the like; and R 5 represents hydrogen or a linear or branched alkyl group having 1 to 6 20 carbon atoms. See the official gazette for other symbols in the formula).
In Patent Document 1, the above-mentioned memantine is described as Test Compound No. 1 (memantine is a

compound of the formula wherein Rlf R2 and R3 are hydrogen atoms, and R4 and R5 are methyl) . [0006]
Furthermore, Patent Document 2 describes 1-amino-5 alkylcyclohexane represented by the following general formula as an NMDA receptor antagonist.. [Chem. 2]

10 (wherein R* is - (CH2) n~ (CR6R7) m-NR8R9; n + m = 0, 1 or 2; R1 to R9 are each independently selected from a group consisting of a hydrogen atom and Ci_6 lower alkyl; and at least R1, R4 and R5 are lower alkyl. See the official gazette for other symbols in the formula).
15 [0007]
Furthermore, the present Applicant reports a cyclic amine derivative represented by the following general formula, as an NMDA receptor antagonist in Patent Document 3.


(wherein A represents a 5- to 8-membered cyclic amine 5 optionally having a double bond, optionally having a bridge structure and optionally having substituents of R7 to R11 in the ring, -NH2, -NH(lower alkyl), or -N(lower alkyl)2; ring B represents benzene, thiophene, furan, pyrrole, a 5- to 7-membered cycloalkane, or 5- to 7-membered cycloalkene; X1 10 represents a bond, a lower alkylene, or -L3-D-L4-; and Y1 represents -OH, -O-lower alkyl, -NH2, or -N3. See the official gazette for other symbols in the formula).
In addition, Patent Document 4 describes 1-aminoindane represented by the following general formula as 15 a therapeutic agent for Parkinson's disease, and the like.


(wherein R1 and R2 independently represent hydrogen, hydroxy, alkyl, alkoxy, or the like; R3 represents hydrogen, alkyl, hydroxy, alkoxy, and the like, R4 and R5 independently represent hydrogen, alkyl, aryl, or the like; 5 and n represents 0, 1, or 2).
[0009]
Patent Document 1: JP-A-2821233
Patent Document 2: Pamphlet of International Patent Publication WO 99/01416 10 Patent Document 3: Pamphlet of International Patent Publication WO 2006/033318
Patent Document 4: Pamphlet of International Patent Publication WO 95/18617
15 DISCLOSURE OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION [0010]
With the increase in the aging population, occurrence of Alzheimer's disease, cerebrovascular dementia, ischemic
20 apoplexy and the like increases these days, and thus it is earnestly desired in the medical field to create an NMDA receptor antagonist having a broader safety margin, which is effective for treating or preventing such diseases as well as Parkinson's disease, pain, and the like. It is an
25 object of the present invention to provide a novel aminoindane derivative or a salt thereof having an

excellent NMDA receptor antagonistic activity and having a broader safety margin, and it is another object to provide a medicine comprising the same.
5 MEANS FOR SOLVING THE PROBLEMS [0011]
The present inventors have found that a novel aminoindane derivative represented by the following general formula (I) or (la), or a salt thereof, which is
10 characterized in that it has an amino group and R1 (lower
alkyl, cycloalkyl, -lower alkylene-aryl, aryl which may be substituted, and the like) on carbon atoms of indane, cyclopenta[b]thiophene, cyclopenta[b]furan, cyclopenta[b]pyridine, or cyclopenta[c]pyridine ring, or
15 2,3-dihydrdo-l-benzofuran, 2,3-dihydrdo-l-benzothiophene, indoline ring, or the like, and has R2 and R3 (the same or different, each lower alkyl or aryl) on carbon atoms beside them has an excellent NMDA receptor antagonistic activity and a broad safety margin, and thus have completed the
20 present invention. Specifically, the present invention relates to an aminoindane derivative represented by the following general formula (I) or (la), or a salt thereof (hereinafter this may be referred to as "the compound (I) of the present invention" or "the compound (la) of the
25 present invention"). Further, the present invention also relates to an NMDA receptor antagonist, especially a

therapeutic agent or a preventing agent for Alzheimer's disease, cerebrovascular dementia, ischemic apoplexy, pain, etc., that comprises the compound (I) or (la), or a salt thereof of the present invention as an active component. 5 Furthermore, the term "aminoindane derivative" as used in the present invention encompasses a wide range of "aminoindane analogs" having rings other than an indane ring, such as cyclopenta[b]thiophene, cyclopenta[b]furan, cyclopenta[b]pyridine, and cyclopenta[c]pyridine rings as
10 described above, and it shall not be limited. [0012]
The compound (I) or (la) of the present invention is distinguished from the compounds as described in Patent Documents 3 and 4 in that it has an amino group, as well as
15 R1 (lower alkyl, cycloalkyl, -lower alkylene-aryl, aryl which may be substituted, and the like) other than a hydrogen atom on an indane ring, and the like, and has R2 and R3 (which may be the same or different, and each represent lower alkyl or aryl) other than hydrogen atoms on
20 a positions thereof.
[1] A compound represented by the following general formula (I) or a salt thereof:


(wherein the symbols in the formula (I) have the 5 following meanings, respectively:
ring A: a 5- or 6-membered hetero ring, or a benzene ring,
X: C(R4)(R5), 0, S, or N(R12),
R1: lower alkyl, cycloalkyl, -lower alkylene-aryl, 10 aryl which may be substituted, heteroaryl which may be
substituted, or lower alkyl substituted with one or more halogens,
R2 and R3: the same or different, each lower alkyl, or aryl, 15 R4 and R5: the same or different, each a hydrogen
atom, lower alkyl, -O-lower alkyl, -OH, -lower alkylene-OH, or -lower alkylene-O-lower alkyl,
R6 to R9: the same or different, each a hydrogen atom, lower alkyl, -O-lower alkyl, a halogen atom, lower 20 alkyl substituted with one or more halogens, OH, CN, lower alkenyl, or a nitrogen-containing heterocyclic group,
R10, and R11: the same or different, each a hydrogen atom, or lower alkyl, and

R12: a hydrogen atom or lower alkyl,
provided that R2 and R3 may be taken together with
the adjacent carbon atom to form cycloalkyl). [0013] 5 [2] A compound represented by the following general
formula (la) or a salt thereof:

10 (wherein the symbols in the formula (la) above have the following meanings, respectively:
R1: lower alkyl, cycloalkyl, -lower alkylene-aryl, aryl which may be substituted, heteroaryl which may be substituted, or lower alkyl substituted with one or more 15 halogens,
R2 and R3: the same or different, each lower alkyl, or aryl,
R4 and R5: the same or different, each a hydrogen atom, lower alkyl, -O-lower alkyl, -OH, -lower alkylene-OH, 20 or -lower alkylene-O-lower alkyl,
R6 to R9: the same or different, each a hydrogen atom, lower alkyl, -O-lower alkyl, a halogen atom, lower

alkyl substituted with one or more halogens, OH, CN, lower alkenyl, or a nitrogen-containing heterocyclic group,
R10 and R11: the same or different, each a hydrogen atom, or lower alkyl, 5 provided that R2 and R3 may be taken together with the adjacent carbon atom to form cycloalkyl). [0014]
[3] A compound or a salt thereof as described in [2], wherein R4, R5, R10, and R11 in the formula (la) above are 10 each a hydrogen atom.
[4] A compound or a salt thereof as described in [3], wherein R2 and R3 in the formula (la) above are the same as or different from each other, and each are lower alkyl, or cycloalkyl formed in combination with the adjacent carbon 15 atom.
[5] A compound or a salt thereof as described in [1], which is selected from 2,2-dimethyl-l-phenylindan-l-amine, 1-(4-fluorophenyl)-2,2-dimethylindan-l-amine, 1-(2-methoxyphenyl)-2,2-dimethylindan-l-amine, 1-(3-20 methoxyphenyl)-2,2-dimethylindan-l-amine, 1,2,2-
trimethylindan-1-amine, 1,2,2,5-tetramethylindan-l-amine, 1,2,2,6-tetramethylindan-l-amine, 4-fluoro-1,2,2-trimethylindan-1-amine, 5-fluoro-1,2,2-trimethylindan-l-amine, 7-fluoro-1,2,2-trimethylindan-l-amine, 5-methoxy-25 1, 2, 2-trimethylindan-l-amine, 6-methoxy-l,2,2-
trimethylindan-1-amine, 6-isopropoxy-l,2,2-trimethylindan-

1-amine, l-ethyl-2,2-dimethylindan-l-amine, 1-isopropyl-2,2-dimethylindan-l-amine, 1'-methyl-1', 3 ' -dihydrdospiro[cyclopropan-1,2'-indine]-1'-amine, 2,4,5,5-tetramethyl-5,5-dihydrdo-4H-cyclopenta[b]thiophene-4-amine. 5 [0015]
[6] A pharmaceutical composition comprising a compound or a salt thereof as described in [1] or [2].
[7] A pharmaceutical composition as described in [6], which is an NMDA receptor antagonist. 10 [8] A pharmaceutical composition as described in [6], which is a therapeutic agent for dementia.
[9] A use of a compound or a salt thereof as described in [1] or [2] for preparation of an NMDA receptor antagonist or a therapeutic agent for dementia. 15 [10] A method for treating dementia, comprising administering a therapeutically effective amount of a compound or a salt thereof as described in [1] or [2] to a patient.
20 EFFECTS OF THE INVENTION [0016]
The compound of the present invention have an NMDA receptor antagonistic activity, and is thus useful for treating or preventing Alzheimer's disease, cerebrovascular 25 dementia, Parkinson's disease, ischemic apoplexy, pain, and the like.

BEST MODE FOR CARRYING OUT THE INVENTION
Hereinbelow, the present invention is described in detail. Unless otherwise specifically indicated, the term "lower" as used in the definition of the general formulae in the present specification means a linear or branched carbon chain having 1 to 6 carbon atoms. Accordingly, "lower alkyl" is preferably linear or branched C1-6 alkyl, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl. Among these, preferred are alkyls having 1 to 4 carbon atoms; and particularly preferred are methyl and ethyl.
Example of the "lower alkylene" include methylene, ethylene, propylene, butylene, and also other branched lower alkylene. Preferred are lower alkylene having 1 to 3 carbon atoms; more preferred are methylene and ethylene; and particularly preferred is methylene.
Example of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, preferred are a fluorine atom, a chlorine atom, and a bromine atom.
The "lower alkyl substituted with one or more halogens" means
any of the hydrogen atoms of the "lower

alkyl" as described above that is substituted with one or more "halogen atoms". Particularly preferred is CF3.
The "cycloalkyl" means cycloalkyl having 3 to 8 carbon atoms. 5 The "R2 and R3 are taken together with the adjacent carbon atom to form cycloalkyl" specifically means that cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl are formed as such. Preferred is cyclopropyl.
Examples of the "lower alkenyl" include vinyl, 1- or 10 2-propenyl, isopropenyl, 2-methyl-l-propenyl, 2-methyl-2-propenyl, 1-methyl-l-propenyl, and l-methyl-2-propenyl. Preferred is vinyl.
Examples of the "lower alkynyl" preferably include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-15 butynyl, and l-methyl-2-propynyl.
[0018]
The "aryl" means a mono- to tri-cyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms. Preferably, examples thereof include phenyl, naphthyl, 20 anthryl, and phenanthryl, and particularly preferred is phenyl.
The "heteroaryl" means a 5- or 6-membered aromatic hetero ring group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. 25 Preferably, examples thereof include thienyl, furyl,

pyrrolyl, thiazolyl, pyridyl, and pyrimidyl, and particularly preferred is thienyl.
As the "-lower alkylene-aryl", particularly preferred are benzyl and phenethyl. 5 Examples of the "substituent" of the "aryl which may be substituted" or the "heteroaryl which may be substituted" include lower alkyl, -O-lower alkyl, a halogen atom, OH, CN, CF3, -NH2, -NH (lower alkyl), and -N (lower alkyl)2, but not limited thereto.
10 The "nitrogen-containing hetero ring group" means a 3 to 7-membered monocyclic nitrogen-containing hetero ring group comprising 1 to 3 nitrogen atoms. Preferred is a 4 to 6-membered monocyclic saturated hetero ring group, and more preferred are azetidyl, pyrrolidyl, and piperidyl.
15 The "5- or 6-membered hetero ring" means thiophene, furan, pyridine rings, and the like. Thus, in the present invention, it is taken together with an adjacent cyclopentane ring to form 5,6-dihydro-5H-cyclopenta[b]thiophene,5,6-dihydro-5H-cyclopenta[b]furan,
20 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[c]pyridine rings, and the like.
Furthermore, "X" means hetero atoms such as 0 and S, or NR12, as well as C(R4)(R5). Here, C(R4)(R5) means that carbon atoms have substituents of R4 and R5.

[0019]
Further, the compounds of the present invention include mixtures of various isomers such as tautomers and optical isomers, as well as individual isomers isolated 5 from them.
The compounds of the present invention may form acid-addition salts. Depending on the type of the substituent therein, the compounds may form salts with bases. Specifically, the salts include acid-addition salts with
10 mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,
15 tartaric acid, citric acid, methanesulfonic acid, and
ethanesulfonic acid; or acidic amino acids such as aspartic acid and glutamic acid; as well as salts with an inorganic base such as sodium, potassium, magnesium, calcium, and aluminum; an organic base such as methylamine, ethylamine,
20 and ethanolamine; or a basic amino acid such as lysine, ornithine; and ammonium salts.
Further, the compounds of the present invention include hydrates, pharmaceutically acceptable various solvates, and crystalline polymorphic substances.
25 In addition,' naturally, the compounds of the present invention are not limited to those described in the

Examples as described below, and include all the compounds of the above general formula (I) or (la), and their pharmaceutically acceptable salts. [0020] 5 In addition, the compounds of the present invention include prodrugs that are metabolized in living bodies to give the compounds of the above formula (I) or (la), or compounds to be converted to their salts. Examples of the groups to form prodrugs of the compounds of the present
10 invention include the groups as described in Prog. Med., 5:2157-2161 (1985), and the groups as described in Pharmaceutical Research, Drug Design, Hirokawa Publishing Company (1990), Vol. 7, Molecular Planning, p. 163-198. [0021]
15 [Production Processes]
Taking advantage of the characteristics based on the basic structure or the kind of the substituent therein, the compounds of the present invention may be prepared according to various known production processes. Depending
20 on the kind of the functional group, the functional group in the starting compounds or intermediates may be modified into a suitable protected group, or a group that may be readily converted into a functional group, which may be technically effective in preparing the compounds. After
25 the process, the protective group may be optionally
removed, and an intended compound may thus be obtained, if

necessary. Examples of the functional group include a hydroxyl group and a carboxyl group. Examples of their protective groups include the protective groups described in Greene & Wuts' "Protective Groups in Organic Synthesis", 5 2nd Ed. Depending on the reaction condition, these may be used suitably.
Typical production processes for the compounds (I) of the present invention are described below, but it goes without saying that the compounds (la) of the present
10 invention can also be prepared by the methods. [0022] (Production Processes)
The compound (lb) of the present invention can be prepared by the method represented by the scheme 1. That
15 is, indanone (1), and a Grignard reagent or an organic
lithium reagent (2) can be reacted in an inert solvent such as tetrahydrofuran (hereinafter referred to as "THF"), diethyl ether and dichloromethane, from under cooling to at room temperature, and if desired, under heat, to give an
20 alcohol (3) . Then, (3) can be further reacted with an azidizing agent such as sodium azide and trimethylsilyl azide, in a solvent such as chloroform, 1,2-dichloroethane, and toluene, in the presence of an acid such as trifluoroacetic acid, sulfuric acid, and methane sulfonic
25 acid, from under cooling to at room temperature, and if desired, under heat, to give an azide (4). Further, (4)

can be subjected to catalytic hydrogen reduction, under a hydrogen atmosphere from at normal pressure to under a pressurized condition, in an inert solvent such as ethanol, ethyl acetate, THF, and acetic acid, using a catalyst such 5 as palladium-carbon, a Raney nickel, and platinum oxide,
from at room temperature to under the heating condition, or subjected to hydride reduction in a solvent such as THF and diethyl ether, from under cooling to under heat, using a reducing agent such as lithium aluminum hydride, and (4)
10 can be further reacted with a phosphine reagent such as triphenylphosphine, and tributyl phosphine, in a solvent such as THF, methanol, toluene, water, or a mixed solvent thereof, from at room temperature to under heat, to prepare a compound (lb) wherein in the compound (I) of the present
15 invention, both of R10 and R11 are all hydrogen atoms. Furthermore, (lb) can be reacted with aldehyde in the presence of palladium-carbon, a rhodium carbon catalyst, or the like, in a solvent such as ethanol and THF, under a hydrogen atmosphere, from at room temperature to under heat
20 to prepare a compound (Ic) wherein in the compound (I) of the present invention, at least one of R10 and R11 is a lower alkyl group. In addition, the compound (I) of the present invention is represented by either the following general formula (lb) or (Ic).


5 (wherein A, X, R1 to R3, and R6 to R9 each have the same meanings as described above. Further, R12 represents hydrogen or a lower alkyl group, R13 represents — CH2-R12 or a hydrogen atom, and M represents alkali metals such as lithium and magnesium halides)
10 [0024]
The compounds (I) of the present invention may be subjected to reaction for group modification known to anyone skilled in the art to give a compound having a desired substituent. Typical reactions for it are
15 described below.
Among the compounds (I) of the present invention, a compound wherein any one of R6 to R9 is a cyano group may be prepared by processing the corresponding compound where R6 to R9 are bromo groups with Zn(CN)2 in the presence of a

catalyst such as Pd(PPh3)4 in a solvent such as DMF and N-methylpiperidone under heat.
Among the compounds (1) of the present invention, in case where X is C(R4) (R5) , a compound wherein any one of R3 5 to R6 is an aryl group which may be substituted, lower
alkenyl group, or a lower alkynyl group can be prepared by reacting the corresponding compound where any one of R3 to R6 is a bromo group or an iodo group, with an arylboronic acid, an alkenylboronic acid, an alkynylboronic acid, or a
10 boronate ester thereof in the presence of a catalyst such as Pd(PPh3)4, PdCl2(dppf), or Pd2 (dba) 3 along with a base such as K2CO2, Na2C02, KOH, CsF, and NaOEt, in a solvent such as DMF, N-methylpiperidone, DME, and toluene, or a mixed solvent thereof with water, under heat (Suzuki reaction).
15 [0025]
Furthermore, the deprotection may be attained in a suitable solvent in the presence of a suitable base. Specific examples of the base include NaOH, KOH, NaOMe, and NaOEt. Specific examples of the solvent include ethers
20 such as THF, dioxane, and diglyme; alcohols such as MeOH, EtOH, and i-PrOH; MeCN, water; or a mixed solvent. Depending on the type of the reaction substrate and the reaction condition, the solvent may be suitably selected. The reaction temperature may vary depending on the type of
25 the starting compound and the reaction condition, generally

covering from cooling to under reflux, preferably from about 0°C to about 100°C.
In addition, the deprotection may also be attained in the presence of a metal catalyst such as Pd-C, Pd(OH)2, and 5 Pt02 in a suitable solvent under a hydrogen atmosphere, but may be attained in the presence of a suitable Lewis acid in a suitable solvent. Examples of the Lewis acid are BCI3, BBr3, and AICI3, and examples of the solvent are ethers such as THF, dioxane; esters such as ethyl acetate; alcohols
10 such as MeOH, EtOH; MeCN; and a mixture thereof. Depending on the type of the reaction substrate and the reaction condition, the solvent may be suitably selected. The reaction temperature may vary depending on the type of the starting compound and the reaction condition, generally
15 covering from cooling to under reflux, preferably from about -80°C to about 30°C.
Thus prepared, the compounds (I) of the present invention may be isolated as free compounds or as their pharmaceutically acceptable salts. A salt of the compounds
20 (I) of the present invention may be prepared by processing the compounds (I) of the present invention that are in the form of free bases for ordinary reactions for salt formation.
[0026]
25 The compound (I) of the present invention or a
pharmaceutically acceptable salt thereof may be isolated

and purified as their hydrates, solvates, or crystalline polymorphic substances. The isolation and purification may be attained through ordinary chemical treatment of extraction, concentration, evaporation, crystallization, 5 filtration, recrystallization, and various types of chromatography.
Various isomers may be isolated by selecting suitable starting compounds, or by separating them based on the difference between the isomers in the physical or chemical
10 properties thereof. For example, optical isomers may be led into stereochemically pure isomers by selecting suitable starting compounds or by racemic resolution of racemic compounds (for example, leading them into diastereomer salts with ordinary optically active acid for
15 optical resolution).
2,2-Dimethyl-l-phenylindan-l-amine, 1-(4-fluorophenyl)-2,2-dimethylindan-l-amine, 1-(2-methoxy phenyl)-2,2-dimethylindan-l-amine, 1-(3-methoxy phenyl)-2,2-dimethylindan-l-amine, 1,2,2-trimethylindan-l-amine,
20 1,2, 2, 5-tetramethylindan-l-amine, 1,2,2,6-tetramethylindan-1-amine, 4-fluoro-l,2,2-trimethylindan-l-amine, 5-fluoro-1,2,2-trimethylindan-l-amine, 7-fluoro-1,2,2-trimethylindan-1-amine, 5-methoxy-l,2,2-trimethylindan-l-amine, 6-methoxy-l,2,2-trimethylindan-l-amine, 6-
25 isopropoxy-1,2,2-trimethylindan-l-amine, l-ethyl-2,2-
dimethylindan-1-amine, 1-iso propyl-2,2-dimethylindan-l-

amine, 1'-methyl-1',3'-dihydrospiro[cyclopropan-1,2'-inden]-1'-amine, 2,4,5,5-tetramethyl-5,5-dihydro-4H-cyclopenta[b]thiophene-4-amine of the compound of the present invention or a salt thereof can be subjected to 5 optical resolution to its (R)-isomers and (S)-isomers by the above-described method. [0027]
The NMDA receptor antagonistic activity of the compounds of the present invention was confirmed by the
10 following test methods. 1. MK-801 binding test: 1) Preparation of Specimens of Rat Meninges:
The whole brain was taken out from 30 10-week SD rats (Nippon SLC), and the cerebellum was removed from them. A
15 0.32 M sucrose solution was added to the part containing the cerebrum, cut in a mixer, and homogenized with a Teflon™ (trademark) homogenizer. This was centrifuged at 2800 rpm and 4°C for 15 minutes, and the resulting supernatant was again centrifuged at 15000 g and 4°C for 20
20 minutes. The pellets were suspended in 50 mM Tris-HCL (pH 7.5) containing 0.08% Triton X-100, and kept statically on ice for 30 minutes, then centrifuged at 15000 g and 4°C for 20 minutes. The pellets were suspended in 50 mM Tris-HCl (pH 7.5) added thereto, and centrifuged at 15000 g and 4°C
25 for 20 minutes. 50 mM Tris-HCl (pH 7.5) was again added to the pellets, and centrifuged in the same manner as before.

The pellets were suspended in 20 ml of 50 mM Tris-HCl (pH 7.5) added thereto, and homogenized with the Teflon™ (trademark) homogenizer. The membrane specimen was divided into small tubes and stored in a deep freezer (-80°C). 5 Before use, this was washed twice with 5 mM Tris-HCl (pH 7.5) of five times that of the membrane specimen. Its concentration was controlled at 1 mg protein/ml with 5 mM Tris-HCl (pH 7.5) added to it, and this was used for assay. [0028]
10 2) [3H] MK-801 binding Assay:
50 pi of the rat membrane specimen (1 mg protein/ ml) was added to a solution of a test compound dissolved in 1 pi of DMSO. Then, 50 pi of a ligand solution (600 nM glutamate, 600 nM glycine, 8 nM [3 H] MK-801 (Perkin-Elmer)
15 was added to it and well stirred, and reacted at room
temperature for 45 minutes. Using Uni Filter Plate GF/B 96 (Perkin-Elmer) previously coated with 0.2%
polyethyleneimine, the membrane specimen was collected, and the filter was well washed with 5 mM Tris-HCl (pH 7.5). 30
20 pi of Microscinti 20 (Perkin-Elmer) was added to the
filter, and the radioactivity trapped by the filter was determined by a microplate scintillation counter (TopCount™' by Beckman). Based on the MK-801 (final 1 pM) inhibition, 100%, of a control case of DMSO alone, the
25 concentration of the compound for 50% inhibition, IC50 was computed. The [3 H]MK-801 binding affinity for the rat

membrane specimen was obtained to be Kd = 1.6 nM through Scatchard analysis. The Ki value of the compound was computed according to the calculation equation: Ki = IC50/(1 + radioligand concentration (4 nM) in assay)/Kd 5 value (1.6 nM)).
As a result, the compounds of the present invention exhibited good NMDA receptor affinity. The Ki values of the NMDA receptor affinity of some typical compounds of the present invention are shown in Table 1 below. 10

[0029] 15 2. Intracellular Calcium Concentration Determination Test by FLIPR (Fluorometric Imaging Plate Reader): 1) Preparation of Rat First-Generation Neurocytes:
Anesthetized with ether, Wistar rats (Nippon SLC) of pregnancy 19 days were let die from loss of blood by breast 20 incision. The abdomen was cut open, and the womb was taken

out, and the fetus was taken out of it. The whole brain was taken out, then the hemicerebrum was isolated in Neurobasal medium (Glu, Asp-free) (Gibco), and the meninx was removed. The hemicerebrum was recovered by 5 centrifugation, and suspended in a cell-dispersing solution (0.36 mg/ml papain, 150 U/ml DNase 1, 0.02% L-cysteine monohydrochloride monohydrate, 0.02% bovine serum albumin, 0.5% glucose, Ca2+, Mg2+-free PBS), and processed at 37°C for 15 minutes. This was centrifuged at 400 g for 5
10 minutes, and the supernatant was removed by suction. This was suspended in a neurocyte culture medium (Sumitomo Bakelite), and the cell masses were removed by filtration. The number of the living cells was counted, and 100,000 cells/well were incubated on a 96-well plate (Biocoat
15 PDL96W black/clear, by Nippon Becton Dickinson) (at 37°C in 5% C02) .
[0030] 2) Intracellular Calcium Concentration Determination by FLIPR (Fluorometric Imaging Plate Reader):
20 The culture of rat first-generation neurocytes (DIV7-9) was removed by suction, and the cells were washed once with a 100 ul assay buffer (Hank's Balanced Salt Solution (Ca2+, Mg 2+-free) , 20 mM Hepes-NaOH (pH 7.4), 1 mM CaCl2) . 100 ul of the assay buffer containing Fluo3 (Dojin
25 Chemical) was added thereto, and incubated for 1 hour
(37°C, 5% CO 2). The cells were washed three times with 100

ul of the assay buffer, and then a compound solution dissolved in 1 ul of DMSO, and 100 ul of the assay buffer containing 2.5 uM (final concentration) tetrodotoxin were added to it and incubated for 30 minutes (37°C, 5% CO 2). The fluorescent intensity was measured at intervals of 2 seconds. Ten seconds after the measurement start, 50 ul of a ligand solution (Hank's Balanced Salt Solution (Ca 2+, Mg 2+ - free), 20 mM Hepes-NaOH (pH 7.4), 1 mM CaCl2, 9 uM NMDA, 30 uM glycine) containing the test compound solution dissolved in 0.5 ul of DMSO was added to it, and the fluorescent intensity of the system was measured for 120 seconds from the start of the measurement. The data measured for 120 seconds (60 times in total) were averaged. Based on the 10 uM MK-801 inhibition with a control case of DMSO alone of 100%, the concentration of the compound for 50% inhibition, IC5o, was computed.
As a result, the compounds of the present invention exhibited a good NMDA receptor antagonizing effect.
The Pharmaceutical composition that contains, as an active component thereof, one or mote of the compounds of the present invention and their pharmaceutically acceptable salts may be formulated, in conjunction with carriers and vehicles for ordinary pharmaceutical application and other additives, as tablets, powders, infinitesimal grains, granules, capsules, pills, liquids, injections,

suppositories, ointments, and fomentations, and is administered orally or parenterally.
The clinical dose to human of the compound of the present invention may be suitably determined, depending on 5 the symptom, the body weight, the age and the sex of a
patient to whom the compound is applied. It may be usually from 0.1 to 500 mg/adult/day for oral administration, and from 0.01 to 100 mg/adult/day for non-oral administration, and this may be administered all at once or in several
10 times. The dose may vary under various conditions, and as the case may be, it may be smaller than the above-mentioned dose range.
The solid composition for oral administration of the compound of the present invention may be tablets, powders,
15 granules, or the like. In the solid composition, one or
more active substances may be mixed with at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and magnesium metasilicate aluminate.
20 According to an ordinary manner, the composition may
contain any other additive than such an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrator such as calcium cellulose glycolate, a stabilizer such as lactose, a solubilizer, and a
25 solubilizing adjuvant such as glutamic acid and aspartic

acid. The tablets and pills may be coated with a sugar or with a gastric-coating or enteric-coating film. [0032]
The liquid composition for oral administration 5 includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, and contains ordinary inert diluents such as purified water and ethyl alcohol. The composition may contain any other additives than such an inert diluent, for example, auxiliary agents such as a
10 solubilizer, a dissolution promoter, a wetting agent, a suspending agent, as well as a sweetener, a flavoring, a fragrance, and a preservative. The injection for non-oral administration includes sterilized aqueous or non-aqueous solutions, suspensions, and emulsions. The diluent for the
15 aqueous solution and suspension include, for example,
distilled water for injection and physiological saline. The diluent for the non-aqueous solution and suspension includes, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as
20 ethyl alcohols, Polysorbate 80 (trade name).
The composition may further contain any other additive such as an isotonizer, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, a solubilizer, and a dissolution promoter. These may be
25 sterilized by filtration through a bacteria-trapping filter, or by addition of a germicide, or through

irradiation with light. As the case may be, a germ-free solid composition may be prepared, and it may be dissolved in germ-free water or germ-free solvent for injection to give the intended liquid composition before use. 5
EXAMPLES
[0033]
Hereinbelow, the compounds of the present invention are described with reference to the following Examples.
10 The starting compounds for the compounds of the present invention include novel compounds, and thus their production examples are illustrated as Reference Examples. Reference Example 1
To a solution of 3-hydroxymethylindan-l-one (1.23 g)
15 and methyl iodide (4.31 g) in THF (20 ml) was added 55%
oily sodium hydride (1.33 g) under ice-cooling, followed by stirring at the same temperature for 1 hour. To the reaction liquid was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl
20 acetate, washed with saturated brine, and then dried over
anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=10:1) to obtain a compound of Reference Example 1
25 as an oily substance.

Reference Example 2
To a solution of t-BuOK (3.0 g) in THF (7 ml) was added a solution of methyl 3-oxoindane-l-carboxylate (1.0 g) in THF (2 ml) at -20°C, followed by stirring at the same 5 temperature for 30 minutes. To this was added methyl
iodide (4.5 g), followed by stirring for 30 minutes while warming to room temperature. The reaction liquid was ice-cooled, and partitioned between 1 N hydrochloric acid and ethyl acetate. The organic layer was washed with saturated
10 brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a compound of Reference Example 2 (1.2 g) as an oily substance. Reference Example 3
15 To a solution of the compound of Reference Example 2 (3.2 g) in DMSO (20 ml) was added LiCl (1.2 g), followed by stirring at 200°C for 2 hours. After cooling the reaction, it was partitioned between 1 N hydrochloric acid and ethyl acetate, and the organic layer was washed with water and
20 saturated brine. It was dried over anhydrous magnesium
sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:l) to obtain a compound of Reference Example 3 (1.9 g) as an oily
25 substance.

Reference Example 4
To a solution of the compound of Reference Example 2 (2.6 g) in methanol (30 ml) was added sodium borohydride (2.1 g) under ice-cooling, followed by heating under reflux for 30 minutes. The reaction liquid was cooled, followed by addition of a saturated aqueous ammonium chloride solution and extraction with ethyl acetate. Further, it was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a compound of Reference Example 4 (2.0 g) as an oily substance. Reference Example 5
A compound of Reference Example 5 was prepared from the compound of Reference Example 4 in the same manner as in Reference Example 1. Reference Example 6
To a solution of the compound of Reference Example 5 (0.99 g) in methanol (8 ml) was added a 10 M aqueous sodium hydroxide solution (8 ml), followed by stirring at 60°C for 12 hours. Methanol was evaporated under reduced pressure, and then ice-cooled, followed by addition of concentrated hydrochloric acid for neutralization and further stirring at room temperature for 1 hour. The precipitate was collected by filtration, and dried under reduced pressure to obtain a

compound of Reference Example 6 (0.94 g) as a colorless
amorphous substance.
Reference Example 7
To a solution of the compound of Reference Example 6 5 (0.94 g) and ammonium chloride (0.64 g), 1-
hydroxybenzotriazole (0.54 g) in DMF (10 ml) was added N-
[3-(dimethylamino)propyl]-N'-ethylcarbodiimide
hydrochloride (1.2 g), followed by stirring at room
temperature for 3 days. To this was added saturated 10 aqueous ammonia solution, followed by stirring for one more
day, and then the precipitate was collected by filtration,
and dried under reduced pressure to obtain a compound of
Reference Example 7 (0.62 g) as a colorless crystal,
Reference Example 8 15 The present compound was prepared from 4-methylindan-
1-one in the same manner as in Reference Example 2.
Reference Example 9
The present compound was prepared from 4-
trifluoromethylindan-1-one in the same manner as in 20 Reference Example 2. [0035]
Reference Example 10
The present compound was prepared from 5-
trifluoromethylindan-1-one in the same manner as in 25 Reference Example 2.

Reference Example 11
To 3-(3-trifluoromethylphenyl)propionic acid was added trifluoromethanesulfonic acid at room temperature, followed by stirring at 60°C for 3 hours. The reaction 5 liquid was put into cold water, followed by extraction with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was
10 purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:l to 5:1) to obtain 5-trifluoromethylindane (2.2 g) and a compound of Reference Example 11 (0.70 g) as colorless solids, respectively. Reference Example 12
15 The present compound was prepared from the compound of Reference Example 11 in the same manner as in Reference Example 2. Reference Example 13
To a solution of 7-bromo-4-fluoro-2,2-dimethylindan-
20 1-one (3.7 g) in toluene (30 ml) were added tributyl(vinyl) tin (7.0 g), tris(dibenzylideneacetone)dipalladium (0.40 g) , and a 0.49 M solution (2.7 ml) of tri(t-butyl)phosphine in n-hexane, at followed by stirring at 70°C for 12 hours. The reaction liquid was cooled, and a saturated aqueous
25 potassium fluoride solution was added thereto, followed by stirring at room temperature for 30 minutes. Then, the

insoluble materials were removed by filtration through Celite. The filtrate was extracted with ethyl acetate, washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under 5 reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=10:1) to obtain a compound of Reference Example 13 (1.7 g) as an oily substance. Reference Example 14
10 A solution of 2-bromo-5-fluorobenzaldehyde (1.5 g) , malonic acid (1.5 g), and piperidine (0.07 ml) in pyridine (10 ml) was heated for 1 day under reflux. The reaction liquid was concentrated under reduced pressure, 1 N hydrochloric acid was then added thereto for
15 neutralization, and crystallized precipitates were
collected by filtration. This was dissolved in methanol (10 ml), and a 5% rhodium carbon catalyst (150 mg) was added thereto, followed by stirring at room temperature for 12 hours under a hydrogen atmosphere (1 atm). The
20 insoluble materials was removed by filtration through
Celite, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:1) to obtain a compound of Reference Example 14 (0.50 g) as a colorless
25 solid.

[0036] Reference Example 15
The present compound was prepared from the compound of Reference Example 14 in the same manner as in Reference 5 Example 11.
Reference Example 16
The present compound was prepared from the compound of Reference Example 15 in the same manner as in Reference Example 1. 10 Reference Example 17
The present compound was prepared from 3-(3-bromo-5-methoxy phenyl)propionic acid in the same manner as in Reference Example 11. Reference Example 18 15 The present compound was prepared from the compound of Reference Example 17 in the same manner as in Reference Example 2. Reference Examples 19 to 25
The present compound was prepared from each of the 20 corresponding indanone and a Grignard reagent in the same manner as in Reference Example 28. Reference Example 2 6
The present compound was prepared from l-bromo-2-fluorobenzene and the corresponding indanone in the same 25 manner as in Reference Example 29.

Reference Example 27
The present compound was prepared from each of the corresponding indanone and a Grignard reagent in the same manner as in Reference Example 28. 5 Reference Example 28
To a solution of 2,2-dimethylindan-l-one (0.63 g) in THF was added a 1 M solution of (4-fluorophenyl)magnesium bromide in THF (7.8 ml) at room temperature, followed by stirring at the same temperature for 2 hours. To the
10 reaction liquid was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine. It was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the
15 residue was purified by silica gel column chromatography
(eluent; n-hexane:ethyl acetate=30:1) to obtain a compound of Reference Example 28 (0.99 g) as an oily substance. Reference Example 29
To a solution of 2-bromoanisole (1.4 g) in diethyl
20 ether (10 ml) was added a 1.6 M solution (4.6 ml) of n-
butyl lithium in n-hexane at -78°C, followed by stirring at the same temperature for 1 hour. To this was added 2,2-dimethylindan-1-one (0.60 g), followed by further stirring at the same temperature for 1 hour. A saturated aqueous
25 ammonium chloride solution was added thereto, followed by extraction with ethyl acetate, and the organic layer was

washed with saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=30:1) 5 to obtain a compound of Reference Example 29 (0.62 g) as an oily substance.
[0037] Reference Example 30
The present compound was prepared from each of the 10 corresponding indanone and a Grignard reagent in the same manner as in Reference Example 28. Reference Examples 31 and 32
The present compound was prepared from each corresponding indanone in the same manner as in Reference 15 Example 29.
Reference Examples 33 to 41
The present compound was prepared from each corresponding indanone in the same manner as in Reference Example 42. 20 Reference Example 42
To a solution of 2,2,6-trimethylindan-l-one (1.8 g) in THF (35 ml) was added a 1.4 M solution (15 ml) of methyl magnesium bromide in THF/toluene (25:75), and warmed to room temperature, followed by stirring for 2 hours. After 25 completion of the reaction, a saturated aqueous ammonium chloride solution was added thereto under ice-cooling,

followed by stirring, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was 5 purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=10:1) to obtain a compound of Reference Example 42 (1.9 g) as an oily substance. Reference Example 43
To a solution of 6-methoxy-2,2-dimethylindan-l-one
10 (2.2 g) in THF (40 ml) was added a 1.4 M solution (17 ml) of methyl magnesium bromide in THF/toluene (25:75) under ice-cooling, and warmed to room temperature, followed by stirring for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added
15 thereto under ice-cooling, followed by stirring and extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel
20 column chromatography (eluent; n-hexane:ethyl acetate=10:1) to obtain a compound of Reference Example 43 (2.3 g) as an oily substance. Reference Example 4 4
To a solution of 6-fluoro-2,2-dimethylindan-l-one
25 (0.47 g) in THF (9 ml) was added a 0.96 M solution (5.5 ml) of methyl magnesium bromide in THF under ice-cooling,

followed by warming to room temperature and stirring for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added thereto under ice-cooling, followed by stirring and extraction with 5 ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=10:1) to obtain a compound
10 of Reference Example 44 (0.45 g) as an oily substance. [0038] Reference Example 4 5
To a solution of 6-bromo-2,2-dimethylindan-l-one (3.8 g) in THF (60 ml) was added a 1.4 M solution (17 ml) of
15 methyl magnesium bromide in THF/toluene (25:75) under ice-cooling, followed by warming to room temperature and stirring for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added thereto under ice-cooling, followed by stirring and
20 extraction with ethyl acetate. The organic layer was
washed with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:l)
25 to obtain a compound of Reference Example 45 (3.8 g) as an oily substance.

Reference Example 4 6
To a solution of 2,2-dimethyl-6-trifluoromethylindan-1-one (1.7 g) in THF (15 ml) was added a 1.4 M solution (10 ml) of methyl magnesium bromide in THF/toluene (25:75)
5 under ice-cooling, followed by warming to room temperature and stirring for 1 hour. After completion of the reaction, a saturated aqueous ammonium chloride solution was added thereto under ice-cooling, followed by stirring and extraction with ethyl acetate. The organic layer was
0 washed with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=6:l) to obtain a compound of Reference Example 4 6 (1.7 g) as an
5 oily substance.
Reference Examples 47 to 54
The present compound was prepared from the corresponding indanone in the same manner as in Reference Example 42.
0 [0039]
Reference Example 55
To a solution of 2,2-dimethylindan-l-one (2.0 g) and trimethyl(trifluoromethyl)silane (2.7 g) in THF (20 ml) was added a 1 M solution (12 ml) of tributyl ammonium fluoride
5 in THF under ice-cooling, followed by slowly warming to room temperature and stirring for 5 hours. 1 N
43

hydrochloric acid was added thereto, followed by extraction with diethyl ether, washing with a saturated aqueous sodium chloride solution, and then drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced 5 pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=10:1) to obtain a compound of Reference Example 55 (2.9 g) as an oily substance. Reference Example 56
10 To a solution of 2,2-dimethylindan-l-one (2.0 g) in THF (20 ml) was added a 0.5 M solution of ethyllithium in benzene/cyclohexane (9:1) (37 ml) at -78°C, followed by stirring at the same temperature for 2 hours. To the reaction liquid was added a saturated aqueous ammonium
15 chloride solution, followed by extraction with ethyl
acetate, and drying over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=3:l) to obtain a compound
20 of Reference Example 56 (2.1 g) as an oily substance. Reference Example 57
The present compound was prepared from the corresponding indanone in the same manner as in Reference Example 56.

Reference Example 58 to 61
The present compound was prepared from the corresponding indanone and Grignard reagent in the same manner as in Reference Example 42. 5 [0040] Example 1
2,2-Dimethyl-l-phenylindan-l-amine monofumarate To a solution of 2,2-dimethyl-l-phenylindan-l-ol (736 mg) in chloroform (10 ml) were added sodium azide (412 mg)
10 and trifluoroacetic acid (1.4 ml) under ice-cooling,
followed by stirring at the same temperature for 2 hours. It was alkalified by addition of 10% aqueous ammonia, and then extracted with ethyl acetate, and the organic layer was washed with saturated brine. The solvent was
15 evaporated under reduced pressure to obtain an azide (798 mg) . Thereafter, this was dissolved in methanol (10 ml), and 10% palladium/carbon (85 mg) was added thereto, followed by stirring at room temperature for 3 days under a hydrogen atmosphere (normal pressure). The reaction
20 mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent; n-hexane:ethyl acetate=30:l to 5:1) to obtain an amine (437 mg) . A portion thereof (119 mg) and fumaric acid (59 mg)
25 were dissolved in methanol, and the solvent was then evaporated under reduced pressure. The residue was

recrystallized from acetone to obtain a compound of Example 1 (168 mg) as a colorless crystal. Example 2
The present compound was prepared in the same manner 5 as in Example 1. Example 3
cis-3-(Methoxymethyl)-2,2-dimethyl-l-phenylindan-l-amine hydrochloride Example 4
10 trans-3-Hydroxy methyl-2,2-dimethyl-l-phenylindan-l-amine hydrochloride
To a solution of the compound of Reference Example 20 (1.8 g) in methylene chloride (30 ml) were added sodium azide (1.3 g) and trifluoroacetic acid (2.5 ml), followed
15 by stirring at the same temperature for 30 minutes. It was alkalified by addition of 10% aqueous ammonia, and extracted with ethyl acetate, and the organic layer was washed with saturated brine. The solvent was evaporated under reduced pressure to obtain an azide. Thereafter,
20 this was dissolved in methanol (30 ml), and 10%
palladium/carbon (0.5 g) was added thereto, followed by stirring at room temperature for 4 hours under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered through Celite, and the filtrate was concentrated
25 under reduced pressure. The residue was purified by silica gel column chromatography (eluent;

chloroform:methanol=20:1) to obtain an amine (1.2 g). Further, a portion thereof (1.1 g) was dissolved in methylene chloride (10 ml), and a 1 M solution (4.5 ml) of boron tribromide in methylene chloride was added thereto 5 under ice-cooling, followed by stirring for 2 hours. To the reaction liquid were added alumina and methanol, followed by stirring at room temperature for 1 hour, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column
10 chromatography (eluent; chloroform:methanol=4:1) to obtain free forms of the compounds of Examples 3 and 4, respectively. To each of the solutions in ethyl acetate was added a 4 N solutions of HCl in ethyl acetate, and the solvent was then evaporated under reduced pressure. The
15 residue was crystallized from n-hexane to obtain a compound of Example 3 (350 mg), and a compound of Example 4 (97 mg) as colorless crystals, respectively.
[0041] Example 5
20 trans-2-Methyl-l,2-diphenylindan-l-amine hydrochloride Example 6
cis-2-Methyl-l,2-diphenylindan-l-amine hydrochloride A hydrochloride of a diastereomer mixture obtained in
25 the same manner as in Example 17 from 1,2-diphenylindan-l-ol was recrystallized from ethanol to obtain a compound of

Example 5, and further, the filtrate was concentrated under reduced pressure, and then was purified by alumina/silica gel column chromatography (eluent; chloroform). Thus obtained residue was crystallized from n-hexane to make its 5 hydrochloride by an ordinary method, thereby obtaining a compound of Example 6 as a colorless crystal, respectively. Examples 7 and 8
The present compounds were prepared in the same manner as in Example 1.
10 Example 9
The present compound was prepared in the same manner as in Example 21. Example 10
N,2,2-trimethyl-l-phenylindan-l-amine hydrochloride
15 To a solution of a desalted compound of Example 1 (125 mg) in ethanol (5 ml) were added an aqueous 37% formaldehyde solution (0.2 ml) and 10% palladium/carbon, followed by stirring at room temperature for 1 day under a hydrogen atmosphere (normal pressure). The reaction
20 mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure, and then partitioned between a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium
25 sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel

column chromatography (eluent; n-hexane:ethyl acetate=20:l to 5:1). Then, the residue was dissolved in a 4 N solution of HC1 in ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was washed with a 5 mixed solvent of diisopropyl ether and 1,4-dioxane to obtain a compound of Example 10 (115 mg) as a colorless crystal. Example 11
The present compound was prepared by reacting for a 10 longer time in the same manner as in Example 10. Examples 12 to 16
The present compounds were prepared in the same manner as in Example 17. [0042] 15 Example 17
1-(4-Fluorophenyl)-2,2-dimethylindan-l-amine monofumarate
To a solution of the compound of Reference Example 28 (984 mg) in chloroform (12 ml) were added sodium azide (500 20 mg) and trifluoroacetic acid (1.7 ml) under ice-cooling, followed by stirring at room temperature for 3 hours. It was alkalified by addition of 10% aqueous ammonia, and extracted with chloroform, and then the organic layer was washed with saturated brine. It was dried over anhydrous 25 magnesium sulfate, and the solvent was then evaporated
under reduced pressure. The residue was purified by silica

gel column chromatography (eluent; n-hexane:ethyl acetate=40:1) to obtain an azide (1.08 g) . Thereafter, this was dissolved in methanol (13 ml), and 10% palladium/carbon (102 mg) was added thereto, followed by 5 stirring at room temperature for 3 hours under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent; n-hexane:ethyl
10 acetate=30:l to 5:1) to obtain an amine (562 mg). A
portion thereof (100 mg) and fumaric acid (51 mg) were dissolved in methanol, and the solvent was then evaporated under reduced pressure. The residue was washed with a mixed solvent of diisopropyl ether and 1,4-dioxane to
15 obtain a compound of Example 17 (127 mg) as a colorless crystal.
[0043] Example 18
1-(2-Methoxy phenyl)-2,2-dimethylindan-l-amine
20 hydrochloride
To a solution of the compound of Reference Example 2 9 (620 mg) in chloroform (9 ml) were added sodium azide (304 mg) and trifluoroacetic acid (1 ml) under ice-cooling, followed by stirring at room temperature for 3 hours. It
25 was alkalified by addition of 10% aqueous ammonia, and then extracted with chloroform, and the organic layer was washed

with saturated brine. It was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=30:1) to 5 obtain an azide (635 mg). Thereafter, this was dissolved in methanol (8 ml), and 10% palladium/carbon (62 mg) was added thereto, followed by stirring at room temperature for 3 hours under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered through Celite, and the
10 filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (eluent; chloroform:methanol=30:1) to obtain an amine (357 mg) . Further, this was dissolved in ethyl acetate, a 4 N solution of HC1 in ethyl acetate was added thereto, and the
15 solvent was evaporated under reduced pressure. The residue was washed with n-hexane to obtain a compound of Example 18 (231 mg) as a colorless crystal. Examples 19 and 20
The present compounds were prepared in the same
20 manner as in Example 18. [0044] Example 21
1-(3-Hydroxyphenyl)-2,2-dimethylindan-l-amine
To a solution of the compound of Example 19 (150 mg)
25 in methylene chloride (2 ml) was added a 1 M solution of
boron tribromide in methylene chloride (0.67 ml) under ice-

cooling, followed by stirring for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform, and drying over anhydrous magnesium sulfate, and the solvent was then 5 evaporated under reduced pressure. The residue was
purified by basic silica gel column chromatography (eluent; n-hexane:ethyl acetate=l:l to 0:1) to obtain a compound of Example 21 (51 mg) as a colorless amorphous substance. Example 22
10 The present compound was prepared in the same manner as in Example 18. Example 23
1,2,2-Trimethylindan-l-amine hydrochloride
To a solution of 1,2,2-trimethylindan-l-ol (406 mg)
15 in chloroform (6 ml) were added sodium azide (300 mg) and trifluoroacetic acid (1 ml) under ice-cooling, followed by stirring at room temperature for 1 hour. It was alkalified by addition of 10% aqueous ammonia, and then extracted with chloroform, and the organic layer was washed with saturated
20 brine. It was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain an azide. Then, this was dissolved in methanol (6 ml), and 10% palladium-carbon (40 mg) was added thereto, followed by stirring at room temperature for 3 hours under
25 a hydrogen atmosphere (normal pressure). The reaction
mixture was filtered through Celite, and the filtrate was

concentrated under reduced pressure. The residue was
purified by basic silica gel column chromatography (eluent;
n-hexane:ethyl acetate=30:l to 5:1) to obtain an amine (140
mg) as an oily substance. Further, this was dissolved in 5 ethyl acetate, a 4 N solution of HCl in ethyl acetate was
added thereto, and the solvent was evaporated under reduced
pressure. The residue was crystallized from diisopropyl
ether to obtain a compound of Example 23 (153 mg) as a
colorless crystal. 10 Example 24
cis-1,2,2,3-Tetramethylindan-l-amine hydrochloride
Example 25
trans-1,2,2,3-Tetramethylindan-l-amine hydrochloride The same procedure as in Example 23 using the 15 compound of Reference Example 33 was carried out, and the
resulting diastereomer was separated, and purified by
silica gel column chromatography (eluent;
chloroform:methanol: saturated aqueous ammonia=50:1:0.1 to
20:1:0.1), and each was made into its hydrochloride by an 20 ordinary method, thereby obtaining a compound of Example
24, and a compound of Example 25 as colorless crystals,
respectively.
Example 2 6
The present compound was prepared in the same manner 25 as in Example 23.

[0045] Example 27
cis-3-Methoxy-l,2,2-trimethylindan-l-amine hydrochloride 5 To a 3 N aqueous solution (10 ml) of sodium hydroxide were added bromine (0.18 ml) and the compound of Reference Example 7 (0.62 g) under ice-cooling, followed by stirring at room temperature for 3 days. An aqueous Na2S03 solution was added thereto, followed by stirring, extraction with
10 methylene chloride, and washing with saturated brine. It
was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1), and thereafter, by
15 neutral silica gel column chromatography (eluent;
chloroform:methanol:saturated brine=50:1:0.1) to obtain an amine (179 ml) as an oily substance. This was made into its hydrochloride, and then crystallized from n-hexane to obtain a compound of Example 27 (89 mg) as a colorless
20 crystal.
[0046] Example 2 8
1,2,2,4-Tetramethylindan-l-amine hydrochloride Example 2 9
25 4-Fluoro-l,2,2-trimethylindan-l-amine hydrochloride

Example 30
4-Trifluoromethyl-1,2,2-trimethylindan-l-amine hydrochloride Example 31 5 1,2,2,5-Tetramethylindan-l-amine hydrochloride Example 32
5-Methoxy-l,2,2-trimethylindan-l-amine hydrochloride Example 33
5-Fluoro-l,2,2-trimethylindan-l-amine•hydrochloride 10 Example 34V
5-Chloro-l,2, 2-trimethylindan-l-amine hydrochloride Example 35
5-Trifluoromethyl-1,2,2-trimethylindan-l-amine hydrochloride 15 The compounds of Examples 28 to 35 as described above were prepared from the corresponding alcohols in the same manner as in Example 23. Example 36
1,2,2,6-Tetramethylindan-l-amine-hydrochloride 20 To a solution of the compound of Reference Example 42 (1.9 g) in chloroform (38 ml) were added sodium azide (1.3 g) and trifluoroacetic acid (4.6 mg) under ice-cooling, followed by stirring at the same temperature for 1 hour. It was alkalified by addition of 10% aqueous ammonia, and 25 then extracted with chloroform, and the organic layer was washed with saturated brine. It was dried over anhydrous

magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain an azide. Then, this was dissolved in methanol (38 ml), and 10% palladium-carbon (200 mg) was added thereto, followed by stirring at room 5 temperature for 12 hours under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol=10:1)
10 to obtain an amine (720 mg) as an oily substance. Further, this was dissolved in ethyl acetate, a 4 N HC1 solution in ethyl acetate was added thereto, and the solvent was evaporated under reduced pressure. The residue was crystallized from n-hexane/diethylether to obtain a
15 compound of Example 36 (227 mg) as a colorless crystal. [0047] Example 37
6-Hydroxy-l,2,2-trimethylindan-l-amine hydrochloride To a solution of a free form (96 mg) of the compound
20 of Example 38 in 1,2-dichloroethane (2 ml) was added a 1 M boron tribromide solution in methylene chloride (0.5 ml) under ice-cooling, followed by stirring at room temperature for 3 hours. To the reaction liquid was slowly added water under ice-cooling and stirred, followed by extraction with
25 ethyl acetate, and then washing with saturated brine. It
was dried over anhydrous magnesium sulfate, and the solvent

was then evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether to obtain an amine (48 mg) as a colorless crystal. Further, this was made into its hydrochloride by an ordinary method, and then 5 crystallized from a mixed solvent of diethylether and n-hexane to obtain a compound of Example 37 (47 mg) as a colorless crystal. Example 38
6-Methoxy-l,2,2-trimethylindan-l-amine hydrochloride
10 To a solution of the compound of Reference Example 43 (2.3 g) in chloroform (40 ml) were added sodium azide (1.4 g) and trifluoroacetic acid (4.8 ml) under ice-cooling, followed by stirring at the same temperature for 1 hour. It was alkalified by addition of 10% aqueous ammonia, and
15 then extracted with chloroform, and the organic layer was washed with saturated brine. It was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain an.azide. Then, this was dissolved in methanol (25 ml), and 10% palladium-carbon
20 (330 mg) was added thereto, followed by stirring at room temperature for 12 hours under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel
25 column chromatography (eluent; chloroform: methanol=10:1) to obtain an amine (1.1 g) as an oily substance. Further,

a portion thereof (270 mg) was made into its hydrochloride by an ordinary method, and recrystallized from a mixed solvent of diethylether and ethyl acetate to obtain a compound of Example 38 (107 mg) as a colorless crystal. 5 Example 39
The present compound was prepared in the same manner as in Example 40.
[0048] Example 40
10 6-Isopropoxy-l,2,2-trimethylindan-l-amine hydrochloride
To a solution of a free form (179 mg) of the compound of Example 37 in THF (3 ml) were added 2-propanol (5 ml), diethylazodicarboxylate (0.55 ml), and triphenylphosphine
15 (300 mg), followed by stirring at room temperature for 1 day. The reaction liquid was concentrated under reduced pressure, and then partitioned between ethyl acetate and 1 N hydrochloric acid. The aqueous layer was neutralized with a 1 N aqueous sodium hydroxide solution, followed by
20 extraction with ethyl acetate, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent; n-hexane:ethyl acetate=10:1) to obtain an
25 isopropoxy derivative (171 mg) as an oily substance. This was made into its hydrochloride by an ordinary method, and

then crystallized from diethylether to obtain a compound of Example 40 (128 mg) as a colorless crystal. Example 41
6-Fluoro-l,2,2-trimethylindan-l-amine hydrochloride 5 To a solution of a compound of Reference Example 44 (444 mg) in chloroform (8 ml) were added sodium azide (300 mg) and trifluoroacetic acid (1 ml) under ice-cooling, followed by stirring at room temperature for 1 hour. It was alkalified by addition of 10% aqueous ammonia, and then
10 extracted with chloroform, and the organic layer was washed with saturated brine. It was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain an azide. Then, this was dissolved in methanol (6 ml), and 10% palladium-carbon (80
15 mg) was added thereto, followed by stirring at room
temperature for 3 hours under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel
20 column chromatography (eluent; n-hexane:ethyl acetate=l:l) to obtain an amine (327 mg) as an oily substance. Further, this was dissolved in ethyl acetate, a 4 N HC1 solution in ethyl acetate was added thereto, and the solvent was evaporated under reduced pressure. The residue was
25 crystallized from diethylether to obtain a compound of Example 41 (310 mg) as a colorless crystal.

Example 42
6-Bromo-l,2,2,-trimethylindan-1-amine hydrochloride To a solution of a compound of Example 45 (3.8 g) in chloroform (60 ml) were added sodium azide (1.9 g) and 5 trifluoroacetic acid (3.4 ml) under ice-cooling, followed by stirring at the same temperature for 1 hour. It was alkalified by addition of 10% aqueous ammonia, and then extracted with chloroform, and the organic layer was washed with saturated brine. It was dried over anhydrous
10 magnesium sulfate, and the solvent was then evaporated
under reduced pressure to obtain an azide. Then, this was dissolved in methanol (50 ml), and triphenylphosphine (7.8 g) was added thereto, followed by heating under reflux for 1 day.
15 Since the reaction was not completed,
tributylphosphine (3.0 g) was further added thereto, followed by stirring at room temperature for 3 hours, and then the reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column
20 chromatography (eluent; chloroform: methanol=10:1) to
obtain an amine (1.2 g) as an oily substance. Further, a portion thereof (204 mg) was made into its hydrochloride by an ordinary method, and recrystallized from ethyl acetate to obtain a compound of Example 42 (222 mg) as a colorless
25 crystal.

[0049] Example 43
6-Trifluoromethyl-1,2,2-trimethylindan-l-amine hydrochloride 5 To a solution of a compound of Example 4 6 (1.6 mg) in methylene chloride (20 ml) were added sodium azide (0.85 g) and trifluoroacetic acid (2.5 ml) under ice-cooling, followed by stirring at the same temperature for 1 hour. It was alkalified by addition of 10% aqueous ammonia, and
10 then extracted with chloroform, and the organic layer was washed with saturated brine. It was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain an azide. Then, this was dissolved in methanol (100 ml), and 10% palladium-carbon
15 (0.5 g) was added thereto, followed by stirring at room temperature for 15 hours under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned between 1 N
20 hydrochloric acid and ethyl acetate, and the aqueous layer was alkalified with sodium hydrogen carbonate, extracted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain an
25 amine (1.1 g) as an oily substance. Further, this was made into its hydrochloride by an ordinary method, and then

crystallized from a mixed solvent of n-hexane and diethylether to obtain a compound of Example 43 (1.1 g) as a colorless crystal. Example 44 5 6-Cyano-l,2,2-trimethylindan-l-amine hydrochloride To a solution of a free form of the compound of Example 42 (112 mg) in N-methylpyrrolidone were added zinc cyanide (63 mg), calcium hydroxide (40 mg) and tetrakis(triphenylphosphine)palladium (150 mg), followed by
10 stirring under heat at 110°C for 1 day. The reaction
liquid was cooled, and then ethyl acetate and water were added thereto, followed by stirring. The insoluble materials were removed by filtration through Celite. The filtrate was separated out, and the organic layer was
15 washed with saturated brine, and dried over anhydrous
sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent; chloroform:methanol=10:1) to obtain a cyano derivative form (78 mg) as an oily substance.
20 Further, this was made into its hydrochloride by an
ordinary method, and crystallized from ethyl acetate to obtain a compound of Example 44 (79 mg) as a colorless crystal.
[0050]
25 Example 4 5
1,2,2-Trimethyl-6-vinylindan-l-amine hydrochloride

To a solution of a free form of the compound of Example 42 (0.67 g) in toluene (7 ml) were added tributyl(vinyl)tin (1.3 g) ,
tris(dibenzylideneacetone)dipalladium (0.15 g) and tri(t-5 butyl)phosphine (0.32 g), followed by stirring under heat at 70°C for 2 hours. An aqueous potassium fluoride solution was added thereto, followed by stirring for 1 hour, and the insoluble materials were removed by filtration through Celite. The filtrate was extracted with
10 ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexanerethyl acetate=8:l) to obtain an amine (349 mg) as an
15 oily substance. Further, a portion thereof (157 mg) was made into its hydrochloride by an ordinary method, and crystallized from n-hexane to obtain a compound of Example 45 (38 mg) as a colorless crystal. Example 4 6
20 1,2,2-Trimethyl-6-(piperidine-1-yl)indan-1-amine hydrochloride
To a solution of a free form of the compound of Example 42 (144 mg) in toluene (3 ml) were added piperidine (0.07 ml), palladium diacetate (7 mg), sodium t-butoxide
25 (81 mg), and tri(2-methylphenyl)phosphine (18 mg), followed by stirring under heat at 80°C for 1 day. The reaction

liquid was cooled, and then partitioned between ethyl acetate and water, and the organic layer was washed saturated brine. Is was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent; chloroform:methanol=10:l) to obtain an amine (75mg) as an oily substance. Further, this was made into its dihydrochloride by an ordinary method, and crystallized from ethyl acetate to obtain a compound of Example 46 (61 mg) as a colorless crystal. Example 47
The present compound was prepared from compound of Example 47 in the same manner as in Example 41. Example 48
7-Fluoro-l, 2, 2-trimethylindan-l -amine hydrochloride
To a solution of the compound of Reference Example 51 (774 mg) in chloroform (15 ml) were added sodium azide (370 mg) and trifluoroacetic acid (1.3 ml) under ice-cooling, followed by stirring at the same temperature for 1 hour. It was alkalified by addition of 10% aqueous ammonia, and then extracted with chloroform, and the organic layer was washed with saturated brine. It was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain an azide (700 g). Then, a portion thereof (480 mg) was dissolved in methanol (10 ml), and 10% palladium-carbon (50 mg) was added thereto,

followed by stirring at room temperature for 1 day under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain an oily 5 substance. This was made into its hydrochloride by an ordinary method, and crystallized from ethyl acetate to obtain a compound of Example 48 (55 mg) as a colorless crystal.
[0051] 10 Example 4 9
The present compound was prepared in the same manner as in Example 41. Example 50
The present compound was prepared in the same manner 15 as in Example 42. Example 51
7-Ethyl-4-fluoro-1,2,2-trimethylindan-l-amine hydrochloride
To a solution of a free form of the compound of 20 Example 52 (79 mg) in methanol (20 ml) was added 10%
palladium-carbon (50 mg), followed by stirring at room temperature for 12 hours under a hydrogen atmosphere (normal pressure). The insoluble materials were removed by filtration through Celite, and the solvent was then 25 evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (eluent;

chloroform : methanol=10:l) and then made into its hydrochloride by an ordinary method to obtain a compound of Example 51 (53 mg) as a pale yellow amorphous substance. Examples 52 and 53
The present compounds were prepared in the same manner as in Example 43. Example 54
The present compound was prepared in the same manner as in Example 41. Example 55
The present compound was prepared in the same manner as in Example 42. Example 56
The present compound was prepared in the same manner as in Example 41. Example 57
2,2-Dimethyl-1 -trifluoromethylindan-1 -amine hydrochloride
To a solution of the compound of Example 55 (2.3 g) in chloroform (30 ml) were added sodium azide (1.3 g) and concentrated sulfuric acid (1.6 ml) under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction solution was further ice-cooled, and 10% aqueous ammonia was added thereto, followed by stirring and extraction with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate, and

the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (20 ml), and 10% palladium-carbon (200 mg) was added thereto, followed by stirring at room temperature for 12 hours under a hydrogen atmosphere (normal pressure). The insoluble materials were removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, followed by extraction with 1 M hydrochloric acid. The aqueous layer was alkalified with 1 M sodium hydroxide, and extracted with ethyl acetate. It was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain an amine (1.17 g). This was made into its hydrochloride by an ordinary method, and then crystallized from a mixed solvent of diethylether and ethyl acetate to obtain a compound of Example 57 (234 mg) as a colorless crystal.
Example 58
1 -Ethyl-2,2-dimethylindan-1 -amine hydrochloride
To a solution of a compound of Reference Example 56 (606 mg) in chloroform (9 ml) were added sodium azide (414 mg) and trifluoroacetic acid (1.4 ml) under ice-cooling, followed by stirring at room temperature for 1 hour. It was alkalified by addition of 10% aqueous ammonia, and then extracted with chloroform, and the organic layer was washed

with saturated brine. It was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain an azide. Then, this was dissolved in methanol (9 ml), and 10% palladium-carbon (700 5 mg) was added thereto, followed by stirring at room
temperature for 3 hours under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel
10 column chromatography (eluent; n-hexane:ethyl acetate=5:l) to obtain an amine (339 mg) as an oily substance. Further, this was made into its hydrochloride by an ordinary method, and then crystallized from diisopropyl ether to obtain a compound of Example 58 (190 mg) as a colorless crystal.
15 Example 59
The present compound was prepared in the same manner as in Example 58. Example 60
l-Isopropyl-2,2-dimethylindan-l-amine hydrochloride
20 To a solution of l-isopropyl-2,2-dimethylindan-l-ol (175 mg) in chloroform (3 ml) were added sodium azide (114 mg) and trifluoroacetic acid (0.4 ml) under ice-cooling, followed by stirring at room temperature for 3 days. It was alkalified by addition of 10% aqueous ammonia, and then
25 extracted with chloroform, and the organic layer was washed with saturated brine. It was dried over anhydrous

magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=30:l) to obtain an azide (106 mg) as an oily substance. Then, this was dissolved in methanol (3 ml), and 10% palladium-carbon (15 mg) was added thereto, followed by stirring at room temperature for 1 day under a hydrogen atmosphere (normal pressure). The reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure to obtain an amine (71 mg) as an oily substance. Further, a portion thereof (20 mg) was made into its hydrochloride by an ordinary method, and crystallized from diisopropyl ether to obtain a compound of Example 60 (16 mg) as a colorless crystal. Examples 61 to 63
The present compound was prepared in the same manner as in Example 60.
Example 64
trans-2-Ethyl-1,2-dimethylindan-1 -amine hydrochloride Example 65
cis-2-Ethyl-1,2-dimethylindan-1 -amine hydrochloride
The same procedure as in Example using the compound of Reference Example 60 was carried out, and the resulting diastereomer was separated and purified by basic silica gel column chromatography (eluent; n-hexane : ethyl acetate =20: 1

to 10:1), and the resulting amine was made into its hydrochloride by an ordinary method, thereby obtaining a compound of Example 64 and a compound of Example 65, as colorless amorphous substances, respectively. 5 Example 66
1'-Methyl-1',3'-dihydrdospiro[cyclopropan-1,2' -indene]-1'-amine hydrochloride Example 67
1'-Methyl-1',3'-dihydrdospiro[cyclopentan-1,2'-10 indene]-1'-amine hydrochloride
The present compound was prepared in the same manner as in Example 58. Examples 68 and 69
The present compounds were prepared in the same 15 manner as in Example 58. [0054]
The structural formulae and the physicochemical data of the compounds of the above Reference Examples and the compounds of the above Examples are shown in the following 20 Tables 2 to 14. The compounds shown in Table 15 may be readily produced similarly to the above Examples or Production Processes or according to the modifications apparent to one skilled in the art. The symbols in the Tables have the following meanings. 25 Rf.: Reference Example, Ex.: Example, STRUCTURE:
structural formula, DATA: data, SALT: salt, Ph: phenyl, Me:

methyl, Et: ethyl, OMe: methoxy, thienyl: thienyl, iPr: isopropyl, vinyl: vinyl, 1-Pip: 1-piperidinyl, n-Bu: normal butyl, c-Hex: cyclohexyl, c-Pr: cyclopropyl, c-Pn: cyclopentyl, Bn: benzyl, NMR: nuclear magnetic resonance 5 spectrum (TMS internal standard), MS: mass spectrometry,
fumarate: fumaric acid, HC1 salt: hydrochloride, 2HC1 salt: 2hydrochloride, free base: a free form

WE CLAIM
1. A compound or a salt, which is selected from 2, 2-dimethyl-l-phenylindan-l-amine, l-(4-fluorophenyl)-2, 2-dimethylindan-l-amine, l-(2-methoxyphenyl)-2, 2-dimethylindan-l-amine, l-(3-methoxyphenyl)-2, 2-dimethylindan-l-amine, 1, 2, 2-trimethylindan-l-amine, 1, 2, 2, 5-tetramethylindan-l-amine, 1, 2, 2, 6-tetramethylindan-l-amine, 4-fluoro-l, 2, 2-trimethylindan-l-amine, 5-fluoro-l, 2, 2-trimethylindan-l-amine, 7-fluoro-l, 2, 2-trimethylindan-l-amine, 5-methoxy-l, 2, 2-trimethylindan-l-amine, 6-methoxy-l, 2, 2-trimethylindan-1-amine, 6-isopropoxy-l, 2, 2-trimethylindan-l-amine, 1-ethyl-2, 2-dimethylindan-l-amine, l-isopropyl-2, 2-dimethylindan-l-amine, 1' -methyl-1', 3' -dihydrospiro [cyclopropan-1, 2' -inden] -1' -amine, 2, 4, 5, 5-tetramethyl-5, 5-dihydro-4H-cyclopenta [b] thiophen-4-amine.
2. A pharmaceutical composition comprising a compound or a salt thereof as claimed in claim 1.
3. A pharmaceutical composition as claimed in claim 2, which is an NMDA receptor antagonist.
86

4. A pharmaceutical composition as claimed in claim 2, which is a therapeutic agent for dementia.

ABSTRACT

Provided is a compound that is an NMDA receptor antagonist having a broader safety margin, and is useful as 5 an agent for treating or preventing Alzheimer's disease, cerebrovascular dementia, Parkinson's disease, ischemic apoplexy, or pain.
A novel compound or a salt thereof, which is characterized in that it has an amino group and R1 (lower
10 alkyl, cycloalkyl, -lower alkylene-aryl, aryl which may be substituted, and the like) on carbon atoms of indane, cyclopenta[b]thiophene, cyclopenta[b]furan, cyclopenta[b]pyridine, or cyclopenta[c]pyridine ring, or 2,3-dihydrdo-l-benzofuran, 2,3-dihydrdo-l-benzothiophene,
15 indoline ring, or the like, and has R2 and R3 (the same or
different, each lower alkyl or aryl) on carbon atoms beside them, and an NMDA receptor antagonist comprising the same as an active component.