CA1109080A - Indanamine derivatives - Google Patents
Indanamine derivativesInfo
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- CA1109080A CA1109080A CA328,466A CA328466A CA1109080A CA 1109080 A CA1109080 A CA 1109080A CA 328466 A CA328466 A CA 328466A CA 1109080 A CA1109080 A CA 1109080A
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- Prior art keywords
- compound
- indanamine
- formula
- lower alkyl
- alkyl group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Indanamine derivatives having specific substituents are represented by the following formula:
wherein R1 represents a lower alkyl group R2 and R3 each, which may be the same or different, represents a hydrogen atom, a lower alky' group or an acyl group having 1 to 6 carbon atoms: R4 represents a hydrogen atom or a lower alkyl group and n represents 0, 1 or 2;
and pharmaceutically acceptable non-toxic salts thereof.
The indanamine derivatives represented by the formula (I) exhibit excellent analgesic activity with minimized toxicity and are useful for alleviating pains by oral or parenteral administration thereof.
Indanamine derivatives having specific substituents are represented by the following formula:
wherein R1 represents a lower alkyl group R2 and R3 each, which may be the same or different, represents a hydrogen atom, a lower alky' group or an acyl group having 1 to 6 carbon atoms: R4 represents a hydrogen atom or a lower alkyl group and n represents 0, 1 or 2;
and pharmaceutically acceptable non-toxic salts thereof.
The indanamine derivatives represented by the formula (I) exhibit excellent analgesic activity with minimized toxicity and are useful for alleviating pains by oral or parenteral administration thereof.
Description
i~()9~80 The present invention relates to indanamine compounds repre-sented by the formula:
6 ~ N\ (I) (R40n Rl wherein Rl represents a lower alkyl group; R2 and R3, which may be the same or different, represent a hydrogen atom, a lower alkyl group or an acyl group' R4 represents a hydrogen atom or a lower alkyl group; and n represents 0, 1 or 2; and non-toxic pharmaceu-tically acceptable salts thereof.
The present invention also relates to pharmaceutical composi-tions containing the indanamine compound (I) and further to a method of treating the patient with pains.
It is known that Indanamine or 2-aminoindane of the formula:
~ NH2 possesses analgesic activity in the test of mouse (L.B. Witkin et al., J. Pharm. Exp. Therapy, vol. 133, page 400 (1961)). The prior art compound is, however, unsatisfactory because of its serious toxicity and side effects, and has not yet been commer-cially available.
An object of the present invention is to provide a satisfac-tory therapeutic agent having high order of analgesic activity but minimized toxicity, which is the substituted indanamine compou~ds of the formula(I) above.
A further object of the present invention is to provide a therapeutic composition containing the compound of the formula(I) which exhibit analgesic activity, and a method of treating the patient with pains.
In more detail, the alkyl group for Rl to R4 represents a lower alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms; and the acyl group for R2 and R3 represents an acyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
The substituted indanamine compounds of the formula(I) can be prepared, depending upon the products desired, by alkylation, acylation, reduction, hydrolysis, a Curtius rearrangement, etc., which are illustratively shown below using the compound of the formula(I) wherein Rl to R4 are all a methyl group. _ ~9~80 ,~'``~
~ 11 ~ COOH (II-l) CH30 CH / \CH
socl2 ~ ~ -COCl (II-2 NaN3 II-3) X
O
CH30 CH3 CH3 (CH30)n CH3 CH3 1. Curtius Rearrangement ~ / ~ Reduction
6 ~ N\ (I) (R40n Rl wherein Rl represents a lower alkyl group; R2 and R3, which may be the same or different, represent a hydrogen atom, a lower alkyl group or an acyl group' R4 represents a hydrogen atom or a lower alkyl group; and n represents 0, 1 or 2; and non-toxic pharmaceu-tically acceptable salts thereof.
The present invention also relates to pharmaceutical composi-tions containing the indanamine compound (I) and further to a method of treating the patient with pains.
It is known that Indanamine or 2-aminoindane of the formula:
~ NH2 possesses analgesic activity in the test of mouse (L.B. Witkin et al., J. Pharm. Exp. Therapy, vol. 133, page 400 (1961)). The prior art compound is, however, unsatisfactory because of its serious toxicity and side effects, and has not yet been commer-cially available.
An object of the present invention is to provide a satisfac-tory therapeutic agent having high order of analgesic activity but minimized toxicity, which is the substituted indanamine compou~ds of the formula(I) above.
A further object of the present invention is to provide a therapeutic composition containing the compound of the formula(I) which exhibit analgesic activity, and a method of treating the patient with pains.
In more detail, the alkyl group for Rl to R4 represents a lower alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms; and the acyl group for R2 and R3 represents an acyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
The substituted indanamine compounds of the formula(I) can be prepared, depending upon the products desired, by alkylation, acylation, reduction, hydrolysis, a Curtius rearrangement, etc., which are illustratively shown below using the compound of the formula(I) wherein Rl to R4 are all a methyl group. _ ~9~80 ,~'``~
~ 11 ~ COOH (II-l) CH30 CH / \CH
socl2 ~ ~ -COCl (II-2 NaN3 II-3) X
O
CH30 CH3 CH3 (CH30)n CH3 CH3 1. Curtius Rearrangement ~ / ~ Reduction
2. Hydrolysis ~
~ ~ ~32 ~ 2 ~ COC~3 (OH)n 3 3(CH30)n CH3 CH3 (CH30)n CH3 3 (I-5) (I-l) Acylation (I-2) Hydrolysis /~
o Hydrolysis Alkylation ô~ (mono) ~eduction ~ N ~ 3 ~ ~ NHCH2CH3 ~Alkylation (3 n 2 3 ( 3 )n 3 3 (I-8) 1 (I-7) , `l l Hydrolysis lAlkylation (mono) CH
< CH3 ~ N-COCH
~ or-C~ ~ CH. ~
(OH)n 3 CH3 ( (CH 0) 3 3 3 n 3 3 Hydrolysis ~Reductlon (I-6) ~ (I-3) (I-4) X= H or 2 halogen atom, e.g.Cl, Br, I
n= O, 1 or 2. 3 ~O9¢~E30 The reactions shown above also proceed with compounds of formula (I) wherein Rl to R4 represent a group other than a methyl group.
The hydroxyimino compound represented by the formula(II) is subjected to catalytic hydrogenation in organic solvents in the presence of Raney-nickel, platinum oxide, palladium-carbon, etc.
preferably using palladium-carbon in acetic acid under pressure and heating to thereby obtain the compounds represented by the formula (I-l) and/or (I-2). Typical examples of organic solvents include acetic acid, ethanol, methanol, etc. The pressure is usually 20 to 50 atoms, preferably 20 to 30 atoms. The heating is performed generally at temperatures from 50 to 100C., preferably 70 to 80C.
The reaction time is not limitative but generally for 2 to 10 hrs., preferably 6 to 7 hrs.
The compound of the formula (I-2) can be converted into the -compound of the formula (I-l) by hydrolysis. The hydrolysis generally proceeds by heating to reflux for about to about 48 hours, preferably 15 to 24 hours in the presence of ~aO in organic solvents such as ethylene glycol.
The compounds of the formulae (I-2(, (I-3) and (I-4) can be prepared by monoalkylation, dialkylation and acylation of the Compound of the formula(I-l), respectively. The acylated compounds of the formulae (I-2) and (I-4) can be converted into the corres-ponding mono- or dialkylated compound of the formula(I-3) by reduction.
In more detail, the alkylation is usually performed by reac-ting the compound of the formula (I-l) or (I-2) with an equimolar amount to excess of alkyl halides (e.g., methyl halides, ethyl halides, propyl halides, butyl halides wherein the halides include chlorides, bromides, iodides, etc.) at a boiling point of the 1 solvent used (i.e., reflux temperature) for about 1 to about 20 hours, preferably 5 to 10 hours under normal pressure, in the presence of alkali carbonates (e.g., potassium carbonate, sodium carbonate, etc.). If necessary, reaction accelerators such as sodium hydride, sodium amide, etc. can be employed.
Alternatively, the alkylation can also be performed by reacting the compound of the formula (I-l) with an equimolar amount or somewhat excess of formic acid and carbonyl compounds (e.g.
formaldehyde, acetaldehyde, etc.) in combination, under reaction conditions similar to the above.
The acylation is ordinarily conducted by reacting the com-pound of the formula (I-l) with an equimolar amount to excess of organic carboxylic acids (e.g. formic acid, acetic acid, pro-pionic acid, butyric acid, etc.) at about 0 degrees C to reflux temperature for about 30 min. to about 6 hours, preferablyl to 1.5 hours in non-polar solvents (e.g. benzene, toluene, xylene, etc.) or withour using any solvent, under normal pressure.
~ he acylated compounds of the formulae (I-2) and (I-4) can be converted into the corresponding alkylated compound (I-3) by mild reduction using lithium aluminum hydride at reflux temperature for about 3 to 20 hours, preferably 4 to 6 hours.
This reduction should be performed in the absence of water, as is well known in the art.
The Curtius rearrangement which occurs in the preparation of the compound of the formula (I-l) from the compound of the formula (II-3) in the presence of solvents, e.g., water, acetone, benzene, etc. to form the corresponding isocyanate.
The isocyanate is successively hydrolyzed to give the compound of formula (I). The hydrolysis is generally carried out in the presence of organic or inorganic acids, e.g. hydrochloric acid, 1 sulfuric acid, acetic acid, etc., water, or mixture thereof, at reflux temperature for 1 to 10 hours, preferably 3 to 5 hours.
The compound of the formula (II-3) is prepared by reaeting indane carboxylie acid of the formula (II-l) with an exeess of thionyl ehloride at room temperature for 0.5 to 2 hours and then reaeting the resulting acid chloride of the formula (II-2) with an equimolar -to exeess of sodium azide.
The compound of the present invention represented by the formula (I) can be converted into pharmaceutically acceptable acid addition salts using inorganic acids (e.g. hydrochlorie aeid, hydrobromie aeid, sulfurie aeid, ete.) or organie aeids (e.g. maleie aeid, fumarie aeid, eitrie aeid, tartaric aeid, oxalie acid, succinic aeid, ete.) in a eonventional manner.
The novel indanamine eompounds of the formula (I) posses exeellent analgesie aetivity and are valuable as medieine as well as intermediates for preparing analgesies.
The eompound of the formula (II) is also novel and is preparea as follows:
1) isoamyl nitrate eone, HCl in EtOH
50C, 2 - 3 hours X O 2) in MeOH NaOMeX
O - 5, overnight ~
~ 1 ) or 2) ~ N
; (R40 ) R ~ (R4O)n Rl ; 90 100C ~\ \ O O in AcOH
30 min. or PPA* \ r 3 1 hour \ or 20, 10 hrs.
X \ * PPA: polyphos-~R4O~ 1 IR4'~ Rl phorie aeid o The hydrolysis for converting the R40-substituted compounds into the OH-substituted compounds can be performed by heating with diluted hydrohalogenic acids (preferably 4,3O/o hydrobromic acid) at 100-120C. for 2 to 10 hours. (preferably 3-4 hours.) The raw compound of formula (II-l) can be synthesized in accordance with the following reaction schemes:
l0~ l ~ B reduction, ~aBB4 OH
~ ~ reflux in benzene in the CH O ~ 3 3 presence of p-toluenesul-
~ ~ ~32 ~ 2 ~ COC~3 (OH)n 3 3(CH30)n CH3 CH3 (CH30)n CH3 3 (I-5) (I-l) Acylation (I-2) Hydrolysis /~
o Hydrolysis Alkylation ô~ (mono) ~eduction ~ N ~ 3 ~ ~ NHCH2CH3 ~Alkylation (3 n 2 3 ( 3 )n 3 3 (I-8) 1 (I-7) , `l l Hydrolysis lAlkylation (mono) CH
< CH3 ~ N-COCH
~ or-C~ ~ CH. ~
(OH)n 3 CH3 ( (CH 0) 3 3 3 n 3 3 Hydrolysis ~Reductlon (I-6) ~ (I-3) (I-4) X= H or 2 halogen atom, e.g.Cl, Br, I
n= O, 1 or 2. 3 ~O9¢~E30 The reactions shown above also proceed with compounds of formula (I) wherein Rl to R4 represent a group other than a methyl group.
The hydroxyimino compound represented by the formula(II) is subjected to catalytic hydrogenation in organic solvents in the presence of Raney-nickel, platinum oxide, palladium-carbon, etc.
preferably using palladium-carbon in acetic acid under pressure and heating to thereby obtain the compounds represented by the formula (I-l) and/or (I-2). Typical examples of organic solvents include acetic acid, ethanol, methanol, etc. The pressure is usually 20 to 50 atoms, preferably 20 to 30 atoms. The heating is performed generally at temperatures from 50 to 100C., preferably 70 to 80C.
The reaction time is not limitative but generally for 2 to 10 hrs., preferably 6 to 7 hrs.
The compound of the formula (I-2) can be converted into the -compound of the formula (I-l) by hydrolysis. The hydrolysis generally proceeds by heating to reflux for about to about 48 hours, preferably 15 to 24 hours in the presence of ~aO in organic solvents such as ethylene glycol.
The compounds of the formulae (I-2(, (I-3) and (I-4) can be prepared by monoalkylation, dialkylation and acylation of the Compound of the formula(I-l), respectively. The acylated compounds of the formulae (I-2) and (I-4) can be converted into the corres-ponding mono- or dialkylated compound of the formula(I-3) by reduction.
In more detail, the alkylation is usually performed by reac-ting the compound of the formula (I-l) or (I-2) with an equimolar amount to excess of alkyl halides (e.g., methyl halides, ethyl halides, propyl halides, butyl halides wherein the halides include chlorides, bromides, iodides, etc.) at a boiling point of the 1 solvent used (i.e., reflux temperature) for about 1 to about 20 hours, preferably 5 to 10 hours under normal pressure, in the presence of alkali carbonates (e.g., potassium carbonate, sodium carbonate, etc.). If necessary, reaction accelerators such as sodium hydride, sodium amide, etc. can be employed.
Alternatively, the alkylation can also be performed by reacting the compound of the formula (I-l) with an equimolar amount or somewhat excess of formic acid and carbonyl compounds (e.g.
formaldehyde, acetaldehyde, etc.) in combination, under reaction conditions similar to the above.
The acylation is ordinarily conducted by reacting the com-pound of the formula (I-l) with an equimolar amount to excess of organic carboxylic acids (e.g. formic acid, acetic acid, pro-pionic acid, butyric acid, etc.) at about 0 degrees C to reflux temperature for about 30 min. to about 6 hours, preferablyl to 1.5 hours in non-polar solvents (e.g. benzene, toluene, xylene, etc.) or withour using any solvent, under normal pressure.
~ he acylated compounds of the formulae (I-2) and (I-4) can be converted into the corresponding alkylated compound (I-3) by mild reduction using lithium aluminum hydride at reflux temperature for about 3 to 20 hours, preferably 4 to 6 hours.
This reduction should be performed in the absence of water, as is well known in the art.
The Curtius rearrangement which occurs in the preparation of the compound of the formula (I-l) from the compound of the formula (II-3) in the presence of solvents, e.g., water, acetone, benzene, etc. to form the corresponding isocyanate.
The isocyanate is successively hydrolyzed to give the compound of formula (I). The hydrolysis is generally carried out in the presence of organic or inorganic acids, e.g. hydrochloric acid, 1 sulfuric acid, acetic acid, etc., water, or mixture thereof, at reflux temperature for 1 to 10 hours, preferably 3 to 5 hours.
The compound of the formula (II-3) is prepared by reaeting indane carboxylie acid of the formula (II-l) with an exeess of thionyl ehloride at room temperature for 0.5 to 2 hours and then reaeting the resulting acid chloride of the formula (II-2) with an equimolar -to exeess of sodium azide.
The compound of the present invention represented by the formula (I) can be converted into pharmaceutically acceptable acid addition salts using inorganic acids (e.g. hydrochlorie aeid, hydrobromie aeid, sulfurie aeid, ete.) or organie aeids (e.g. maleie aeid, fumarie aeid, eitrie aeid, tartaric aeid, oxalie acid, succinic aeid, ete.) in a eonventional manner.
The novel indanamine eompounds of the formula (I) posses exeellent analgesie aetivity and are valuable as medieine as well as intermediates for preparing analgesies.
The eompound of the formula (II) is also novel and is preparea as follows:
1) isoamyl nitrate eone, HCl in EtOH
50C, 2 - 3 hours X O 2) in MeOH NaOMeX
O - 5, overnight ~
~ 1 ) or 2) ~ N
; (R40 ) R ~ (R4O)n Rl ; 90 100C ~\ \ O O in AcOH
30 min. or PPA* \ r 3 1 hour \ or 20, 10 hrs.
X \ * PPA: polyphos-~R4O~ 1 IR4'~ Rl phorie aeid o The hydrolysis for converting the R40-substituted compounds into the OH-substituted compounds can be performed by heating with diluted hydrohalogenic acids (preferably 4,3O/o hydrobromic acid) at 100-120C. for 2 to 10 hours. (preferably 3-4 hours.) The raw compound of formula (II-l) can be synthesized in accordance with the following reaction schemes:
l0~ l ~ B reduction, ~aBB4 OH
~ ~ reflux in benzene in the CH O ~ 3 3 presence of p-toluenesul-
3 ~ fonic acid 15~ ~ CH phosphorous chloride in CH30 CH3 3 dimethyl formamide CHO
~ ~ CH Photo-oxidation 20CH30 lCH3 3 ~ ~ Cll 2CH reduction, Pd/C or Pt CH3O l 3 3 (II-l) -The compound of the present invention represented by the formula(I) exhibits strong analgesic activity with minimized side effects and minimized toxicity. The high order of this activity of the active agent of the present invention, together with its reduced side effects, is evidenced by test in lower animals. The compound of the present invention represented by the formula(I) ~ 9~o can be administered per os, e.g., in the form of pills or tablets, in which it may be present together with the usual pharmaceutical carriers, conventionally by compounding the compound of the present invention together with a customary carrier or adjuvant, such as talc, magnesium stearate, starch, lactose, gelatin, any of numerous gums, and the like. Thus in its most advantageous form, the compo-sitions of the invention will contain a non-toxic pharmaceutical carrier in addition to the active ingredient of the present inven-tion. Exemplary solid carriers are lactose, magnesium stearate, calcium stearate, starch, terra alba, dicalcium acacia, or the like. Representative liquid carriers are peanut oil, sesame oil, olive oil, water, or the like. The active agent of the invention can be conveniently administered in such compositions containing active ingredient so as to eventually be within the dosage range illustrated hereafter. Thus, a wide variety of pharmaceutical forms suitable for many modes of administration and dosages may be employed. For oral administration, the active ingredient and pharmaceutical carrier may, for example, take the form of a granule, pill, tablet, lozenge, elixir, syrup, or other liquid suspension or emulsion, whereas, for parenteral administration such as intra-venous or intramuscular injection, the composition may be in the form of a sterile solution.
The method of using the compound of the present invention comprises internally or externally administering the compound of the invention, preferably orally or parenterally and preferably admixed with the pharmaceutical carrier, for example, in the form of any of the above compositions, or filled into a capsule, to alleviate conditions to be treated and symptoms thereof in a living animal body. Illustratively, it may be preferably 10 to 100 mg.
for an oral dose, while parenteral dosages are usually less and ordinarily about one-half of the oral dose. The unit dose is pre-ferably given a suitable number of times daily, typically three times. The daily dose may vary depending upon the number of times given. Naturally, a suitable clinical dose must be adjusted in accordance with the condition, age, and weight of the patient, and it goes without saying that the enhanced activity of the compound of the invention, together with its reduced side effects, also make it suitable for wide variations, and the invention therefore should not be limited by the exact ranges stated. The exact dosage, both unit dosage and daily dosage, will of course have to be determined according to established medical principles.
Analgesic activity of representative compounds of the present invention was examined by acetic acid stretching method using animal.
Using ddY-strain male mice, weighing about 20 g., six(6) as one grouping, the number of rising was measured after administering a pain-inducing agent(acetic acid) in aceordance with aeetie aeid stretehing method.
A test compound was orally administered at a dose of 100 mg.
20 (100 mg. of the eompound was dissolved in 0.2 ml. of water, whieh was administered per os). A 0.7% aeetie aeid aqueous solution was then intraperitoneously administered 30 minutes after the adminis-tration of the test compound. Then, the number of rising was measured during 4 to 15 minutes after the administration of aeetie aeid. As control, only water was administered instead of the test compound, in which the number of rising occurred was made 100. The results are shown below, wherein percentage indicates inhibition of rising as compared to the control. Therefore, the higher the inhibition percentage, the better the analgesic activity.
~9~t~80 Compound Inhibition %
2-Indanamine 77 l,l-Diethyl-6-methoxy-2-indanamine lO0 l,l-Dimethyl-6-methoxy-2-indanamine 79 5 N-Ethyl-6-methoxy-l,l-dimethyl-2-indanamine91 l,l-Dimethyl-2-indanamine 91 l,l-Dimethyl-7-methoxy-2-indanamine 85 N-Ethyl-7-methoxy-1,1-diethyl-2-indanamine 89 It is understood from the results above that the compounds of the invention possess superior in analgesics to known 2-indan-amine.
The present invention will be described in detail below with reference to the examples, in which pressure is normal pressure and atmosphere is in the air, unless otherwise indicated.
15 Example 1 1,1-Dimethyl-6-methoxy-2-indanamine hydrochloride:
To 0.8 g. of 2,3-dihydro-1,1-dimethyl-6-methoxy-lH-indene-2-carboxylic acid was added 2.0 ml. of thionyl chloride under ice-cooling. The mixture was stirred at room temperature. Then, anhydrous benzene was added to the mixture to thereby remove an excess of thionyl chloride by ageotropic distillation. The resul-ting acid chloride was dissolved in 7 ml. of anhydrous benzene and 0.24 g. of sodium azide was added to the solution. The mixture was heated under refluxing for 22 hrs. After cooling, the mixture was filtered. To the filtrate, 4 ml. of conc. hydrochloric acid was added and the mixture was heated under refluxing for 3 hrs.
After completion of the reaction, the aqueous layer was made alkaline with sodium hydroxide, followed by axtraction with ether.
The ethereal layer was washed with water and dried. The solvent was removed by distillation. To the residue was added ethereal hydrochloric acid to convert into the hydrochloride. By recrystal-lization from ethanol, 0.07 g. of colorless prisms were obtained;
m.p. 238 to 240C. (decomposed).
Elemental Analysis for C12H17NO. H2O . HC1 C _ N
Calcd. 58.65 8.20 5.70 Found 58.13 8.43 5.40 Example 2 1,1-Dimethyl-6-methoxy-2-indanamine hydrochloride:
In 100 ml. of acetic acid was dissolved 10 g. of 3,3-dimethyl-2-hydroxyimino-5-methoxy-1-indanone. To the solution was added 4 g. of 5% palladium-carbon. The mixture was subjected to catalytic reduction for 6.5 hrs. under pressure and heating ( 30 kg/cm , 80C.). The catalyst was removed by filtration and the filtrate was distilled to dryness under reduced pressure.
After adding a 10% aq. hydrochloric acid to the residue, the mixture was washed with ether. The aqueous layer was made alkaline with potassium carbonate, followed by extraction with ether. The ethereal layer was washed with water and dried.
The solvent was removed by distillation so that 3.94 g. of a slightly yellow oil was obtained. The oil was converted into the hydrochloride using ethanolic hydrochloride. By recrystal-lization from ethanol, colorless prisms having a melting point of 238 to 240C. (decomposed) were obtained. The hydrochloride so obtained possessed IR spectrum identical with that of the compound obtained in Example 1. No reduction in melting point occurred when mixed with the compound of Example 1.
Example 3 1,1-Dimethyl-6-ethoxy-2-indanamine hydrochloride:
To a solution of 30 g. of 3,3-dimethyl-2-hydroxyimino-5-ethoxy-1-indanone in 150 ml. of acetic acid was added 12 g.of 10% palladium-carbon. The mixture was treated as in Example 2 to obtain 12.3 g. of the hydrochloride. By recrystallization from ethanol-ether, colorless needles having a melting point of 270 ~, -- 1 1 --to 272C. (decomposed) were obtained.
Elemental Analysis for C13HlgN0. HCl. 1/4 H20 C H N
Calcd. 63.40 8.39 5.69 Found 63.44 8.48 5.58 Example 4 1,1-Diethyl-6~methoxy-2-indanamine hydrochloride:
To a solution of 7.42 g. of 3,3-diethyl-2-hydroxyimino-5-methoxy-l-indanone in 100 ml. of acetic acid was added 2.6 g of 10 % palladium-carbon. The mixture was treated as in Example 2 to obtain 2.46 g. of the hydrochloride. By recrystallization from ethanol-isopropyl ether, colorless needles having a melting point of 218 to 220C. were obtained.
Elemental analysis for C14H21NO. HCl. 1/4 H2O
C H
Calcd. 64.60 8.71 5.38 Found 64.54 8.84 5.46 Example 5 6-Methoxy-l,l,~,N-tetramethyl-2-indanamine hydrochloride A mixture of 6.0 g. of 6-methoxy-1,1-dimethyl-2-indanamine, 9.3 ml. of a 37% aq. formaldehyde solution and 6.58 ml. of formic acid was heated at 80 to 100C for 4 hrs. with stirring. After completion of the reaction, water was poured into the reaction mixture. After rendering the system alkaline with sodium hydrox-ide, the system was extracted with ether. The ethereal layer was washed with water and dried. After removing the solvent by dis-tillation, the residue was converted into the hydrochloride usingethanolic hydrochloric acid. Colorless crystals were obtained in an amount of 4.41 g. By recrystallization from ethanol-isopropyl ether, colorless needles having a melting point of 215 to 216C.
(decomposed) were obtained.
Elemental Analysis for C14 21 2 ~9~o C H N
Calcd. 64.60 8.62 5.38 Found 64.42 8.7L 5.23 Example 6 N-Acetyl-6-methoxy-1,1-dimethyl-2-indanamine:
To a solution of 10 g. of 3,3-dimethyl-2-hydroxyimino-5-methoxy-l-indanone in 100 ml. of acetic acid was added 4 g. of 5 %
palladium-carbon. The mixture was subjected to catalytic reduc-tion for 6.5 hrs. under pressure and heating (30 kg/cm , 80C).
After removing the catalyst by distillation, the filtrate was dis-tilled to dryness. To the residue was added a 10 % aq. hydro-chloric acid. The mixture was extracted with ether and the ethereal layer was washed with water and dried. After removing the solvent by distillation, 4.86 g. of colorless crystals were obtained. By recrystallization from isopropyl ether, colorless 15 crystals having a melting point of 99 to 100C were obtained.
Elemental Analysis for C14HlgNO2 C H N
Calcd. 72.07 8.21 6.00 Found 71.92 8.39 5.85 This compound can also be obtained by the reaction of 1,1-dimethyl-6-methoxy-2-indanamine with acetic anhydride. The thus obtained compound is well consistent with the compound obtained as above.
Example 7 N-Ethyl-6-methoxy-1.1-dimethyl-2-indanamine hydro-chloride:
To a suspension of 2.45 g. of lithium aluminum hydride in 10 ml. of anhydrous tetrahydrofuran was added a solution of 5 g. of N-acetyl-6-methoxy-1,1-dimethyl-2-indanamine in 10 ml. of anhydrous tetrahydrofuran. The mixture was stirred at room temperature for 20 mins. and then heated under refluxing for 1 hr. After completion 3C3 8(1 of the reaction, aqueous ether and water were added in succession to the reaction mixture under ice cooling. Thereafter, the mix-ture was filtered by suction and the filtrate was distilled to dryness under reduced pressure. After adding a 10 % aq. hydro-chloric acid solution to the residue, the mixture was washed withether. The aqueous layer was made alkaline with sodium hydroxide, followed by extraction with ether. The ethereal phase was washed with water and dried. After removing the solvent by distillation, the residue was converted into the hydrochloride with ethanolic hydrochloric acid. Thus 4.01 g. of colorless crystals were obtained. By recrystallization from ethanol-isopropyl ether, colorless needles having a melting point 217 to 218C. (decomposed) were obtained.
Elemental Analysis for C14H21NO. HCl C H N
Calcd. 65.48 8.64 5.45 Found 65.43 8.76 5.42 Example 8 N-Acetyl-6-methoxy-l,l,N-trimethyl-2-indanamine:
A suspension of 5 g. of N-acetyl-6-methoxy-1,1-dimethyl-2-20 indanamine and 2.1 g. of 50 % sodium hydride in 70 ml. of dimethyl formamide was heated at 30 to 50C. for 1 hr. with stirring. Then, 7.63 g. of methyl iodide was added to the suspension. The mixture was stirred for 15 mins. at 30 to 50C. and then for 1 hr. at room temperature. After completion of the reaction, water was poured into the reaction mixture, followed by extraction with ether. The ethereal layer was washed with water and dried. After removing the solvent by distillation, the residue was crystallized from n-hexane to obtain 5.2 g. of colorless crystals. By recrystallization from isopropyl ether, colorless crystals having a melting point of 97 to 98C. were obtained.
Elemental Analysis for C15H21N02 C H N
Calcd. 72.84 8.56 5.66 Found 72.68 8.66 5.61 5 ExamPle 9N-Ethyl-6-hvdroxy-1~1-dimethyl-2-indanamine hvdro-bromide:
To 1.92 g. of N-ethyl-6-methoxy-1,1-dimethyl-2~indanamine hydrochloride was added 30 ml. of 48 % hydrobromic acid. The mix-ture was heated at 100 to 120C. for 3.5 hrs. with stirring.
After completion of the reaction, ethanol was added to the reac-tion mixture. The mixture was filtered by suction to obtain 2.08 g of light brown powders. By recrystallization from water-containing ethanol, brown prisms having a melting point of 298 to 299C. were 7 obtained.
Elemental Analysis for C13HlgNO.HBr C H N
Calcd. 54.55 7.04 4.89 Found 54.33 7.19 4.77 ExamPle 10 6-HYdroxy-1 l,N N-tetramethYl-2-indanamine hydrobro-.
mide:
In a manner similar to Example 9 but using 2.5 g. of 6-methoxy-l,l,N,N-tetramethyl-2-indanamine hydrochloride, 2.61 g. of light green crystals were obtained. By recrystallization from ethanol, lightly green scales having a melting point of 229 to 230C. were obtained.
Elemental Analysis for C13HlgNO. HBr. H2O
C H N
Calcd. 51.32 7.29 4.60 Found 51.08 7.30 4.49 Example 11 N-AcetYl-6-ethoxy-1 1-dimethyl-2-indanamine:
~9~
To a solution of 30 g. of 3,3-dimethyl-2-hydroxyimino-5-ethoxy-l-indanone in 150 ml. of acetic acid was added 12 g. of 10 %
palladium-carbon. The mixture was treated in a manner similar to Example 6 to obtain 10.9 g. of colorless crystals. By recrystal-lization from ethyl acetate-isopropyl ether, colorless scales having a melting point of 137 to 138C were obtained.
Elemental Analysis for C15H21NO2 C H N
Calcd. 72.84 8.56 5.66 Found 72.79 8.83 5.60 Example 12 N-Ethyl-6-ethoxy-1,1-dimethvl-2-indanamine hydro-chloride:
To a suspension of 2.16 g. of lithium aluminum hydride in 20 ml. of anhydrous tetrahydrofuran was added a solution of 4.0 g.
of N-acetyl-6-ethoxy-1,1-dimethyl-2-indanamine in 25 ml. of anhy-drous tetrahydrofuran. The mixture was heated under refluxing for 6 hrs. Thereafter, the mixture was treated as in Example 7 to obtain 3.42 g. of the hydrochloride. By recrystallization from ethanol-isopropyl ether, colorless needles having a melting point of 207 to 208C. were obtained.
Elemental Analysis for C15H23N0. HCl C H N
Calcd. 66.77 8.97 5.19 Found 66.54 9.21 4.98 Example 13 6-EthoxY-l,l,N,N-tetramethyl-2-indanamine hydro-chloride:
In a similar manner to Example 5 but using 4.0 g. of 6-ethoxy-1,1-dimethyl-2-indanamine, 2.16 g. of the hydrochloride was obtained. From recrystallization from ethanol-isopropyl ether, colorless needles having a melting point of 219 to 220C were obtained.
Example 14 N-Acetyl-l,l-diethyl-6-methoxy-2-indanamine;
To a solution of 7.42 g. of 3,3-diethyl-2-hydroxyimino-5-methoxy-l-indanone in 100 ml. of acetic acid was added 2.6 g. of lOo/o palladium-carbon. Then, the system was treated in a manner similar to Example 6 to obtain 3.28 g. of colorless crystals.
By recrystallization from benzene, colorless needles having a melting point of 115 to 116C. were obtained.
Elemental Analysis for C16H23NO2 C H N
Calcd. 73.53 8.87 5.36 Found 73.65 9.08 5.33 Example 15 1 l,N-Triethyl-6-methoxv-2-indanamine hydrochloride:
In a manner similar to Example 7 but using 3.0 g. of N-acetyl-1,1-diethyl-6-methoxy-2-indanamine, the hydrochloride was obtained.
By recrystallization from ethanol-isopropyl ether, 1.18 g. of colorless needles having a melting point of 208 to 210C. were obtained.
Elemental Analysis for C16H25N0. HCl. 1/4H2O
C H N
Calcd. 66.65 9.26 4.86 Found 66.91 9.44 4.98 Example 16 1,1-Diethyl-N,N-dimethyl-6-methoxy-2-indanamine hydrochloride:
In a manner similar to Example 5 but using 1.0 g. of 6-methoxy-l,l-diethyl-2-indanamine, the hydrochloride was obtained.
By recrystallization from isopropanol, colorless needles having a melting point of 176 to 178C. were obtained.
Elemental Analysis for C16H25NO. HCl. 1/4H2O
. . .
~9~'~30 Example 17 N-Ethoxycarbonyl-l,l-dimethyl-6-methoxy-2-lndanamine:
To a solution of 4.3 g. of 6-methoxy-1,1-dimethyl-2-indan-amine hydrochloride in 50 ml. of wate:r were added 30 ml. of ether and 1.5 g. of sodium hydroxide. Then, 2.64 g. of ethyl chlorocar-bonate was dropwise added to the mixture. The mixture was stirredat room temperature overnight. After insoluble matters were removed by filtration, the ethereal layer was separated and washed with dil. hydrochloric acid and then with water and dried. The resulting residue was recrystallized from benzene to obtain 3.7 g.
of colorless needles having a melting point of 153 to 154C.
Elemental Analysis for C15H21N03.3/4H20 C H N
Calcd. 65.08 8.19 5.06 Found 64.92 7.89 5.15 ExamPle 18 1,l,N-Trimethyl-6-methoxy-2-indanamine hydrochloride:
To a suspension of 3.3 g. of lithium aluminum hydride in 40 ml. of anhydrous tetrahydrofuran was added a solution of 3.3 g. of ~ 18 ~$~ 0 N-ethoxycarbonyl-l,l-dimethyl-6-methoxy-2-indanamine in 40 ml. of anhydrous tetrahydrofuran. The mixture was heated under refluxing for 7 hrs. Thereafter, the system was treated as in Example 7 to obtain 2.46 g. of the hydrochloride. By recrystallization from ethanol, colorless needles having a melting point 288 to 289C.
were obtained.
Elemental Analysis for C13HlgN0. HCl C H N
Calcd. 64.59 8.34 5.79 10 Found 64.53 8.62 5.75 Example 19 1,1-Dimethyl-2-indanamine hydrochloride:
To a solution of 22.3 g. of 3,3-dimethyl-2-hydroxyimino-1-indanone in 100 ml. of acetic acid was added 8 g. of 10 % palladium-carbon. The mixture was subjected to catalytic hydrogenation for 15 8 hrs. under pressure and heating (30 kg/cm , 80C.). The cata-lyst was removed by filtration and the filtrate was distilled to dryness under reduced pressure. After adding 10 % hydrochloric acid to the residue, the mixture was washed with ether. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and extracted with ether. The ethereal layer was washed with water and dried. After the solvent was evaporated off, the residue was converted into the hydrochloride with ethanolic hydro-chloride. By recrystallization from ethanol-ether, 8.4 g. of colorless needles having a melting point of 251 to 252C. were obtained.
Elemental Analysis for CllH14N.HCl. 1/2H20 C H N
Calcd. 63.91 8.29 6.78 Found 64.10 8.10 6.63 0 Example 20 N-AcetYl-l,l-dimethyl-2-indanamine:
~39~0 The ether-washed liquid collected after rendering the system acidic with hydrochloric acid in Example 19 was washed with water and dried. After the solvent was evaporated off, the resulting residue was distilled under reduced pressure to obtain 4.32 g. of a colorless viscous oil having a boiling point of 157 to 161C.
(2 mmHg).
Mass Spectrum as C13H17~0 m/e: 203 (M ), 144 (base peak) Example 21 1,1-Dimethyl-5-methoxy-2-indanamine hydrochloride:
In a manner similar to Example 19 but using 30 g. of 3,3-dimethyl-2-hydroxy-6-methoxy-1-indanone, the hydrochloride was obtained. By recrystallization from ethanol, 5.0 g. of colorless prisms having a melting point of 279 to 281C. were obtained.
Elemental analysis for C H NO HCl C H
Calcd. 63.91 8.29 6.78 Found 64.10 8.10 6.63 Example 22 N-Acetyl-l,l-dimethyl-5-methoxy-2-indanamine:
The ether-washed liquid collected after rendering the system acidic with hydrochloric acid in Example 21 was washed with water and dried. After the solvent was evaporated off, 4.65 g. of a slight}y brownish oil was obtained.
Mass Spectrum as C14HlgN02 m/e: 233 (M ), 92 (base peak) -Example 23 1,1-Dimethyl-5,6-dimethoxy-2-indanamine hydrochloride:
In a manner similar to Example 19 but using 9.5 g. of 3,3-dimethyl-2-hydroxyimino-5,6-dimethoxy-1-indanone, the hydrochlor-ide was obtained. By recrystallization from ethanolisopropyl ether, 0.86 g. of colorless plates having a melting point of 228 to 230C were obtained.
~lr3C~o Elemental Analysis for C13HlgN02.HCl C EI N
Calcd. 60.58 7.82 5.43 Found 60.34 8.05 5.62 Example 24 N-Acetyl-l,l-dimethyl-5,6-dimethoxy-2-indanamine:
The ether-washed liquid obtained after rendering the system acidic with hydrochloric acid in Example 23 was washed with water and dried. After solvent was removed by distillation, the resul-ting residue was recrystallized from benzene-hexane to obtain
~ ~ CH Photo-oxidation 20CH30 lCH3 3 ~ ~ Cll 2CH reduction, Pd/C or Pt CH3O l 3 3 (II-l) -The compound of the present invention represented by the formula(I) exhibits strong analgesic activity with minimized side effects and minimized toxicity. The high order of this activity of the active agent of the present invention, together with its reduced side effects, is evidenced by test in lower animals. The compound of the present invention represented by the formula(I) ~ 9~o can be administered per os, e.g., in the form of pills or tablets, in which it may be present together with the usual pharmaceutical carriers, conventionally by compounding the compound of the present invention together with a customary carrier or adjuvant, such as talc, magnesium stearate, starch, lactose, gelatin, any of numerous gums, and the like. Thus in its most advantageous form, the compo-sitions of the invention will contain a non-toxic pharmaceutical carrier in addition to the active ingredient of the present inven-tion. Exemplary solid carriers are lactose, magnesium stearate, calcium stearate, starch, terra alba, dicalcium acacia, or the like. Representative liquid carriers are peanut oil, sesame oil, olive oil, water, or the like. The active agent of the invention can be conveniently administered in such compositions containing active ingredient so as to eventually be within the dosage range illustrated hereafter. Thus, a wide variety of pharmaceutical forms suitable for many modes of administration and dosages may be employed. For oral administration, the active ingredient and pharmaceutical carrier may, for example, take the form of a granule, pill, tablet, lozenge, elixir, syrup, or other liquid suspension or emulsion, whereas, for parenteral administration such as intra-venous or intramuscular injection, the composition may be in the form of a sterile solution.
The method of using the compound of the present invention comprises internally or externally administering the compound of the invention, preferably orally or parenterally and preferably admixed with the pharmaceutical carrier, for example, in the form of any of the above compositions, or filled into a capsule, to alleviate conditions to be treated and symptoms thereof in a living animal body. Illustratively, it may be preferably 10 to 100 mg.
for an oral dose, while parenteral dosages are usually less and ordinarily about one-half of the oral dose. The unit dose is pre-ferably given a suitable number of times daily, typically three times. The daily dose may vary depending upon the number of times given. Naturally, a suitable clinical dose must be adjusted in accordance with the condition, age, and weight of the patient, and it goes without saying that the enhanced activity of the compound of the invention, together with its reduced side effects, also make it suitable for wide variations, and the invention therefore should not be limited by the exact ranges stated. The exact dosage, both unit dosage and daily dosage, will of course have to be determined according to established medical principles.
Analgesic activity of representative compounds of the present invention was examined by acetic acid stretching method using animal.
Using ddY-strain male mice, weighing about 20 g., six(6) as one grouping, the number of rising was measured after administering a pain-inducing agent(acetic acid) in aceordance with aeetie aeid stretehing method.
A test compound was orally administered at a dose of 100 mg.
20 (100 mg. of the eompound was dissolved in 0.2 ml. of water, whieh was administered per os). A 0.7% aeetie aeid aqueous solution was then intraperitoneously administered 30 minutes after the adminis-tration of the test compound. Then, the number of rising was measured during 4 to 15 minutes after the administration of aeetie aeid. As control, only water was administered instead of the test compound, in which the number of rising occurred was made 100. The results are shown below, wherein percentage indicates inhibition of rising as compared to the control. Therefore, the higher the inhibition percentage, the better the analgesic activity.
~9~t~80 Compound Inhibition %
2-Indanamine 77 l,l-Diethyl-6-methoxy-2-indanamine lO0 l,l-Dimethyl-6-methoxy-2-indanamine 79 5 N-Ethyl-6-methoxy-l,l-dimethyl-2-indanamine91 l,l-Dimethyl-2-indanamine 91 l,l-Dimethyl-7-methoxy-2-indanamine 85 N-Ethyl-7-methoxy-1,1-diethyl-2-indanamine 89 It is understood from the results above that the compounds of the invention possess superior in analgesics to known 2-indan-amine.
The present invention will be described in detail below with reference to the examples, in which pressure is normal pressure and atmosphere is in the air, unless otherwise indicated.
15 Example 1 1,1-Dimethyl-6-methoxy-2-indanamine hydrochloride:
To 0.8 g. of 2,3-dihydro-1,1-dimethyl-6-methoxy-lH-indene-2-carboxylic acid was added 2.0 ml. of thionyl chloride under ice-cooling. The mixture was stirred at room temperature. Then, anhydrous benzene was added to the mixture to thereby remove an excess of thionyl chloride by ageotropic distillation. The resul-ting acid chloride was dissolved in 7 ml. of anhydrous benzene and 0.24 g. of sodium azide was added to the solution. The mixture was heated under refluxing for 22 hrs. After cooling, the mixture was filtered. To the filtrate, 4 ml. of conc. hydrochloric acid was added and the mixture was heated under refluxing for 3 hrs.
After completion of the reaction, the aqueous layer was made alkaline with sodium hydroxide, followed by axtraction with ether.
The ethereal layer was washed with water and dried. The solvent was removed by distillation. To the residue was added ethereal hydrochloric acid to convert into the hydrochloride. By recrystal-lization from ethanol, 0.07 g. of colorless prisms were obtained;
m.p. 238 to 240C. (decomposed).
Elemental Analysis for C12H17NO. H2O . HC1 C _ N
Calcd. 58.65 8.20 5.70 Found 58.13 8.43 5.40 Example 2 1,1-Dimethyl-6-methoxy-2-indanamine hydrochloride:
In 100 ml. of acetic acid was dissolved 10 g. of 3,3-dimethyl-2-hydroxyimino-5-methoxy-1-indanone. To the solution was added 4 g. of 5% palladium-carbon. The mixture was subjected to catalytic reduction for 6.5 hrs. under pressure and heating ( 30 kg/cm , 80C.). The catalyst was removed by filtration and the filtrate was distilled to dryness under reduced pressure.
After adding a 10% aq. hydrochloric acid to the residue, the mixture was washed with ether. The aqueous layer was made alkaline with potassium carbonate, followed by extraction with ether. The ethereal layer was washed with water and dried.
The solvent was removed by distillation so that 3.94 g. of a slightly yellow oil was obtained. The oil was converted into the hydrochloride using ethanolic hydrochloride. By recrystal-lization from ethanol, colorless prisms having a melting point of 238 to 240C. (decomposed) were obtained. The hydrochloride so obtained possessed IR spectrum identical with that of the compound obtained in Example 1. No reduction in melting point occurred when mixed with the compound of Example 1.
Example 3 1,1-Dimethyl-6-ethoxy-2-indanamine hydrochloride:
To a solution of 30 g. of 3,3-dimethyl-2-hydroxyimino-5-ethoxy-1-indanone in 150 ml. of acetic acid was added 12 g.of 10% palladium-carbon. The mixture was treated as in Example 2 to obtain 12.3 g. of the hydrochloride. By recrystallization from ethanol-ether, colorless needles having a melting point of 270 ~, -- 1 1 --to 272C. (decomposed) were obtained.
Elemental Analysis for C13HlgN0. HCl. 1/4 H20 C H N
Calcd. 63.40 8.39 5.69 Found 63.44 8.48 5.58 Example 4 1,1-Diethyl-6~methoxy-2-indanamine hydrochloride:
To a solution of 7.42 g. of 3,3-diethyl-2-hydroxyimino-5-methoxy-l-indanone in 100 ml. of acetic acid was added 2.6 g of 10 % palladium-carbon. The mixture was treated as in Example 2 to obtain 2.46 g. of the hydrochloride. By recrystallization from ethanol-isopropyl ether, colorless needles having a melting point of 218 to 220C. were obtained.
Elemental analysis for C14H21NO. HCl. 1/4 H2O
C H
Calcd. 64.60 8.71 5.38 Found 64.54 8.84 5.46 Example 5 6-Methoxy-l,l,~,N-tetramethyl-2-indanamine hydrochloride A mixture of 6.0 g. of 6-methoxy-1,1-dimethyl-2-indanamine, 9.3 ml. of a 37% aq. formaldehyde solution and 6.58 ml. of formic acid was heated at 80 to 100C for 4 hrs. with stirring. After completion of the reaction, water was poured into the reaction mixture. After rendering the system alkaline with sodium hydrox-ide, the system was extracted with ether. The ethereal layer was washed with water and dried. After removing the solvent by dis-tillation, the residue was converted into the hydrochloride usingethanolic hydrochloric acid. Colorless crystals were obtained in an amount of 4.41 g. By recrystallization from ethanol-isopropyl ether, colorless needles having a melting point of 215 to 216C.
(decomposed) were obtained.
Elemental Analysis for C14 21 2 ~9~o C H N
Calcd. 64.60 8.62 5.38 Found 64.42 8.7L 5.23 Example 6 N-Acetyl-6-methoxy-1,1-dimethyl-2-indanamine:
To a solution of 10 g. of 3,3-dimethyl-2-hydroxyimino-5-methoxy-l-indanone in 100 ml. of acetic acid was added 4 g. of 5 %
palladium-carbon. The mixture was subjected to catalytic reduc-tion for 6.5 hrs. under pressure and heating (30 kg/cm , 80C).
After removing the catalyst by distillation, the filtrate was dis-tilled to dryness. To the residue was added a 10 % aq. hydro-chloric acid. The mixture was extracted with ether and the ethereal layer was washed with water and dried. After removing the solvent by distillation, 4.86 g. of colorless crystals were obtained. By recrystallization from isopropyl ether, colorless 15 crystals having a melting point of 99 to 100C were obtained.
Elemental Analysis for C14HlgNO2 C H N
Calcd. 72.07 8.21 6.00 Found 71.92 8.39 5.85 This compound can also be obtained by the reaction of 1,1-dimethyl-6-methoxy-2-indanamine with acetic anhydride. The thus obtained compound is well consistent with the compound obtained as above.
Example 7 N-Ethyl-6-methoxy-1.1-dimethyl-2-indanamine hydro-chloride:
To a suspension of 2.45 g. of lithium aluminum hydride in 10 ml. of anhydrous tetrahydrofuran was added a solution of 5 g. of N-acetyl-6-methoxy-1,1-dimethyl-2-indanamine in 10 ml. of anhydrous tetrahydrofuran. The mixture was stirred at room temperature for 20 mins. and then heated under refluxing for 1 hr. After completion 3C3 8(1 of the reaction, aqueous ether and water were added in succession to the reaction mixture under ice cooling. Thereafter, the mix-ture was filtered by suction and the filtrate was distilled to dryness under reduced pressure. After adding a 10 % aq. hydro-chloric acid solution to the residue, the mixture was washed withether. The aqueous layer was made alkaline with sodium hydroxide, followed by extraction with ether. The ethereal phase was washed with water and dried. After removing the solvent by distillation, the residue was converted into the hydrochloride with ethanolic hydrochloric acid. Thus 4.01 g. of colorless crystals were obtained. By recrystallization from ethanol-isopropyl ether, colorless needles having a melting point 217 to 218C. (decomposed) were obtained.
Elemental Analysis for C14H21NO. HCl C H N
Calcd. 65.48 8.64 5.45 Found 65.43 8.76 5.42 Example 8 N-Acetyl-6-methoxy-l,l,N-trimethyl-2-indanamine:
A suspension of 5 g. of N-acetyl-6-methoxy-1,1-dimethyl-2-20 indanamine and 2.1 g. of 50 % sodium hydride in 70 ml. of dimethyl formamide was heated at 30 to 50C. for 1 hr. with stirring. Then, 7.63 g. of methyl iodide was added to the suspension. The mixture was stirred for 15 mins. at 30 to 50C. and then for 1 hr. at room temperature. After completion of the reaction, water was poured into the reaction mixture, followed by extraction with ether. The ethereal layer was washed with water and dried. After removing the solvent by distillation, the residue was crystallized from n-hexane to obtain 5.2 g. of colorless crystals. By recrystallization from isopropyl ether, colorless crystals having a melting point of 97 to 98C. were obtained.
Elemental Analysis for C15H21N02 C H N
Calcd. 72.84 8.56 5.66 Found 72.68 8.66 5.61 5 ExamPle 9N-Ethyl-6-hvdroxy-1~1-dimethyl-2-indanamine hvdro-bromide:
To 1.92 g. of N-ethyl-6-methoxy-1,1-dimethyl-2~indanamine hydrochloride was added 30 ml. of 48 % hydrobromic acid. The mix-ture was heated at 100 to 120C. for 3.5 hrs. with stirring.
After completion of the reaction, ethanol was added to the reac-tion mixture. The mixture was filtered by suction to obtain 2.08 g of light brown powders. By recrystallization from water-containing ethanol, brown prisms having a melting point of 298 to 299C. were 7 obtained.
Elemental Analysis for C13HlgNO.HBr C H N
Calcd. 54.55 7.04 4.89 Found 54.33 7.19 4.77 ExamPle 10 6-HYdroxy-1 l,N N-tetramethYl-2-indanamine hydrobro-.
mide:
In a manner similar to Example 9 but using 2.5 g. of 6-methoxy-l,l,N,N-tetramethyl-2-indanamine hydrochloride, 2.61 g. of light green crystals were obtained. By recrystallization from ethanol, lightly green scales having a melting point of 229 to 230C. were obtained.
Elemental Analysis for C13HlgNO. HBr. H2O
C H N
Calcd. 51.32 7.29 4.60 Found 51.08 7.30 4.49 Example 11 N-AcetYl-6-ethoxy-1 1-dimethyl-2-indanamine:
~9~
To a solution of 30 g. of 3,3-dimethyl-2-hydroxyimino-5-ethoxy-l-indanone in 150 ml. of acetic acid was added 12 g. of 10 %
palladium-carbon. The mixture was treated in a manner similar to Example 6 to obtain 10.9 g. of colorless crystals. By recrystal-lization from ethyl acetate-isopropyl ether, colorless scales having a melting point of 137 to 138C were obtained.
Elemental Analysis for C15H21NO2 C H N
Calcd. 72.84 8.56 5.66 Found 72.79 8.83 5.60 Example 12 N-Ethyl-6-ethoxy-1,1-dimethvl-2-indanamine hydro-chloride:
To a suspension of 2.16 g. of lithium aluminum hydride in 20 ml. of anhydrous tetrahydrofuran was added a solution of 4.0 g.
of N-acetyl-6-ethoxy-1,1-dimethyl-2-indanamine in 25 ml. of anhy-drous tetrahydrofuran. The mixture was heated under refluxing for 6 hrs. Thereafter, the mixture was treated as in Example 7 to obtain 3.42 g. of the hydrochloride. By recrystallization from ethanol-isopropyl ether, colorless needles having a melting point of 207 to 208C. were obtained.
Elemental Analysis for C15H23N0. HCl C H N
Calcd. 66.77 8.97 5.19 Found 66.54 9.21 4.98 Example 13 6-EthoxY-l,l,N,N-tetramethyl-2-indanamine hydro-chloride:
In a similar manner to Example 5 but using 4.0 g. of 6-ethoxy-1,1-dimethyl-2-indanamine, 2.16 g. of the hydrochloride was obtained. From recrystallization from ethanol-isopropyl ether, colorless needles having a melting point of 219 to 220C were obtained.
Example 14 N-Acetyl-l,l-diethyl-6-methoxy-2-indanamine;
To a solution of 7.42 g. of 3,3-diethyl-2-hydroxyimino-5-methoxy-l-indanone in 100 ml. of acetic acid was added 2.6 g. of lOo/o palladium-carbon. Then, the system was treated in a manner similar to Example 6 to obtain 3.28 g. of colorless crystals.
By recrystallization from benzene, colorless needles having a melting point of 115 to 116C. were obtained.
Elemental Analysis for C16H23NO2 C H N
Calcd. 73.53 8.87 5.36 Found 73.65 9.08 5.33 Example 15 1 l,N-Triethyl-6-methoxv-2-indanamine hydrochloride:
In a manner similar to Example 7 but using 3.0 g. of N-acetyl-1,1-diethyl-6-methoxy-2-indanamine, the hydrochloride was obtained.
By recrystallization from ethanol-isopropyl ether, 1.18 g. of colorless needles having a melting point of 208 to 210C. were obtained.
Elemental Analysis for C16H25N0. HCl. 1/4H2O
C H N
Calcd. 66.65 9.26 4.86 Found 66.91 9.44 4.98 Example 16 1,1-Diethyl-N,N-dimethyl-6-methoxy-2-indanamine hydrochloride:
In a manner similar to Example 5 but using 1.0 g. of 6-methoxy-l,l-diethyl-2-indanamine, the hydrochloride was obtained.
By recrystallization from isopropanol, colorless needles having a melting point of 176 to 178C. were obtained.
Elemental Analysis for C16H25NO. HCl. 1/4H2O
. . .
~9~'~30 Example 17 N-Ethoxycarbonyl-l,l-dimethyl-6-methoxy-2-lndanamine:
To a solution of 4.3 g. of 6-methoxy-1,1-dimethyl-2-indan-amine hydrochloride in 50 ml. of wate:r were added 30 ml. of ether and 1.5 g. of sodium hydroxide. Then, 2.64 g. of ethyl chlorocar-bonate was dropwise added to the mixture. The mixture was stirredat room temperature overnight. After insoluble matters were removed by filtration, the ethereal layer was separated and washed with dil. hydrochloric acid and then with water and dried. The resulting residue was recrystallized from benzene to obtain 3.7 g.
of colorless needles having a melting point of 153 to 154C.
Elemental Analysis for C15H21N03.3/4H20 C H N
Calcd. 65.08 8.19 5.06 Found 64.92 7.89 5.15 ExamPle 18 1,l,N-Trimethyl-6-methoxy-2-indanamine hydrochloride:
To a suspension of 3.3 g. of lithium aluminum hydride in 40 ml. of anhydrous tetrahydrofuran was added a solution of 3.3 g. of ~ 18 ~$~ 0 N-ethoxycarbonyl-l,l-dimethyl-6-methoxy-2-indanamine in 40 ml. of anhydrous tetrahydrofuran. The mixture was heated under refluxing for 7 hrs. Thereafter, the system was treated as in Example 7 to obtain 2.46 g. of the hydrochloride. By recrystallization from ethanol, colorless needles having a melting point 288 to 289C.
were obtained.
Elemental Analysis for C13HlgN0. HCl C H N
Calcd. 64.59 8.34 5.79 10 Found 64.53 8.62 5.75 Example 19 1,1-Dimethyl-2-indanamine hydrochloride:
To a solution of 22.3 g. of 3,3-dimethyl-2-hydroxyimino-1-indanone in 100 ml. of acetic acid was added 8 g. of 10 % palladium-carbon. The mixture was subjected to catalytic hydrogenation for 15 8 hrs. under pressure and heating (30 kg/cm , 80C.). The cata-lyst was removed by filtration and the filtrate was distilled to dryness under reduced pressure. After adding 10 % hydrochloric acid to the residue, the mixture was washed with ether. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and extracted with ether. The ethereal layer was washed with water and dried. After the solvent was evaporated off, the residue was converted into the hydrochloride with ethanolic hydro-chloride. By recrystallization from ethanol-ether, 8.4 g. of colorless needles having a melting point of 251 to 252C. were obtained.
Elemental Analysis for CllH14N.HCl. 1/2H20 C H N
Calcd. 63.91 8.29 6.78 Found 64.10 8.10 6.63 0 Example 20 N-AcetYl-l,l-dimethyl-2-indanamine:
~39~0 The ether-washed liquid collected after rendering the system acidic with hydrochloric acid in Example 19 was washed with water and dried. After the solvent was evaporated off, the resulting residue was distilled under reduced pressure to obtain 4.32 g. of a colorless viscous oil having a boiling point of 157 to 161C.
(2 mmHg).
Mass Spectrum as C13H17~0 m/e: 203 (M ), 144 (base peak) Example 21 1,1-Dimethyl-5-methoxy-2-indanamine hydrochloride:
In a manner similar to Example 19 but using 30 g. of 3,3-dimethyl-2-hydroxy-6-methoxy-1-indanone, the hydrochloride was obtained. By recrystallization from ethanol, 5.0 g. of colorless prisms having a melting point of 279 to 281C. were obtained.
Elemental analysis for C H NO HCl C H
Calcd. 63.91 8.29 6.78 Found 64.10 8.10 6.63 Example 22 N-Acetyl-l,l-dimethyl-5-methoxy-2-indanamine:
The ether-washed liquid collected after rendering the system acidic with hydrochloric acid in Example 21 was washed with water and dried. After the solvent was evaporated off, 4.65 g. of a slight}y brownish oil was obtained.
Mass Spectrum as C14HlgN02 m/e: 233 (M ), 92 (base peak) -Example 23 1,1-Dimethyl-5,6-dimethoxy-2-indanamine hydrochloride:
In a manner similar to Example 19 but using 9.5 g. of 3,3-dimethyl-2-hydroxyimino-5,6-dimethoxy-1-indanone, the hydrochlor-ide was obtained. By recrystallization from ethanolisopropyl ether, 0.86 g. of colorless plates having a melting point of 228 to 230C were obtained.
~lr3C~o Elemental Analysis for C13HlgN02.HCl C EI N
Calcd. 60.58 7.82 5.43 Found 60.34 8.05 5.62 Example 24 N-Acetyl-l,l-dimethyl-5,6-dimethoxy-2-indanamine:
The ether-washed liquid obtained after rendering the system acidic with hydrochloric acid in Example 23 was washed with water and dried. After solvent was removed by distillation, the resul-ting residue was recrystallized from benzene-hexane to obtain
4.27 g. of colorless needles having a melting point of 145 to 146C.
Elemental Analysis for C15H21N03 C H N
Calcd. 68.42 8.04 5.32 Found 68.29 8.28 5.21 ExamPle 25 1,1-Dimethyl-7-methoxy-2-indanamine hydrochloride: ~ -In a manner similar to Example 19 but using 6.0 g. of 7-chloro-3,3-dimethyl-2-hydroxyimino-4-methoxy-1-indanone, the hydrochloride was obtained. By recrystallization from isopropanol-isopropyl ether, 0.7 g. of colorless needles having a melting point of 248 to 249C. were obtained.
Elemental Analysis for C12H17NO. ~Cl C H N
Calcd. 63.29 7.97 6.15 Found 63.11 8.13 6.04 Example 26 N-Acetyl-l,l-dimethyl-4-methoxy-2-indanamine:
To a solution of 6.0 g. of 3,3-dimethyl-2-hydroxyimino-7-methoxy-l-indanone in 100 ml. of acetic acid was added 2.5 g. of 10 % palladium-carbon. The mixture was subjected to catalytic hydrogenation for 7 hrs. under pressure and heating (30 kg/cm , 70C). The catalyst was removed by filtration and the filtrate i21 o was distilled to dryness under reducecl pressure. After adding 10 % hydrochloric acid to the residue, the mixture was extracted with ether. The ethereal layer was washed with water and dried.
The solvent was removed by distillation. The resulting residue was crystallized from benzene to obtain 0.85 g. of colorless plates having a melting point of 140 to 141C.
Elemental Analysis for Cl4HlgNO2 C H N
Calcd. 72.07 8.21 6.00 Found 72.25 8.49 5.83 Example 27 ~-Ethyl-l~l-dimethyl-4-methoxy-2-indanamine hydro-chloride:
To a suspension of 0.91 g. of lithium aluminum hydride in 10 ml. of anhydrous tetrahydrofuran was dropwise added a solution of 1.4 g. of N-acetyl-l,l-dimethyl-4-methoxy-2-indanamine in 20 ml of anhydrous tetrahydrofuran. The mixture was heated under refluxing for 4 hrs. After completion of the reaction, water-containing ether and water were in succession added to the reac-tion mixture. Then, the mixture was filtered by suction and the filtrate was extracted with lO % hydrochloric acid. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and extracted with ether. The ethereal layer was washed with water and dried. The solvent was removed by distillation and the resulting residue was converted into the hydrochloride by adding thereto ethanolic hydrochloric acid. By recrystallization from ethanol-ether, 0.8 g. of colorless plates having a melting point of 300C. or higher were obtained.
Elemental Analysis for Cl4H2lNO.HCl C H N
Calcd. 65.74 8.67 5.48 Q
Found 65.39 8.92 5.40 Example 28 N-Ethyl-l,l-dimethyl-2-indanamine hydrochloride:
In a manner similar to Example 27 but using 2.82 g. of N-acetyl-l,l-dimethyl-2-indanamine, 1.8 g. of the hydrochloride was obtained, which was recrystallized from ethanol-isopropyl ether to give colorless needles having a melting point of 203 to 204C.
Elemental Analysis for C13HlgN.HCl C H N
Calcd. 69.16 8.93 6.20 Found 69.38 9.19 6.12 Example 29 N-Ethyl-l,l-dimethyl-5-methoxy-2-indanamine hydro-chloride:
In a manner similar to Example 27 but using 4.29 g. of N-acetyl-l,l-dimethyl-5-methoxy-2-indanamine, the hydrochloride was obtained, which was recrystallized from ethanol to give 1.28 g. of colorless prisms having a melting point of 239 to 242C.
Elemental Analysis for C14H21NO.HCl. 1/4H2O ~ -C H N
Calcd. 64.60 8.71 5.38 Found 64.37 8.79 5.42 Example 30 N-Ethyl-l,l-dimethyl-5,6-dimethoxy-2-indanamine hydro-chloride:
In a manner similar to Example 27 but using 2.63 g. of N-acetyl-l,l-dimethyl-5,6-dimethoxy-2-indanamine, 1.59 g. of the hydrochloride was obtained, which was recrystallized from ethanol to obtain colorless prisms having a melting point of 289 to 290C.
Elemental Analysis for C15H23NO2. HCl C H N
Calcd. 63.04 8.46 4.90 Found 62.88 8.57 4.99 ~9~o Example 31 1 l,N,N-Tetramethyl-2-indanamine hydrochloride:
A mixture of 3.26 g. of 1,1-dimethyl-2-indanamine, 6 ml. of 37 % an aq. formaldehyde solution and 4.3 ml. of 90 % formic acid was heated with stirring for 4 hrs. at 100C. After completion of the reaction, the system was made alkaline with an aqueous sodium hydroxide solution and extracted with ether. The ethereal layer was washed with water and dried. The solvent was removed by dis-tillation and the resulting residue was converted into the hydro-chloride with ethanolic hydrochloric acid. By recrystallization from ethanol-isopropyl ether, 3.4 g. of colorless needles having a melting point of 263 to 264C. were obtained.
Elemental Analysis for C13HlgN.Hcl. 1/2H2O
C H N
Calcd. 66.51 9.02 5.97 Found 66.61 8.92 5.91 While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
s~o SUPPLEMENTARY DISCLOSURE
The conversion of the compounds of the formula (I-l) into the compounds of the formula (I-5) can also be performed by dealkylation, i.e,, by heating the system in the presence of a Lewis acid (aluminum chloride, borotribromide) and inert organic solvents (halogenated hydrocarbons, benzene, toluene, zylene, etc.), or in the presence of a strong mineral acid ( e.g., hydrobromic acid, hydroiodic acid).
_EXAMPLE A
1,1-Dimethyl-6- hydroxy-2-indanamine hydrochloride;
To 5.0 g. of 1,1-dimethyl-6-methoxy-2-indanamine hydro-chloride was added 50 ml. of a 48% hydrobromic acid. The mixture was heated at 140C for 1.5 hours in,,a nitrogen flow.
After completion of the reaction, the system was rendered alkaline with an aqueous sodium hydroxide solution, followed by washing with ether. The ethereal layer was rendered acidic ' -with hydrochloric acid and then weakly alkaline with ammonia water. The mixture was extracted with ethyl acetate. The organic acid was washed with water and dried. After the solvent was removed by distillation, the residue was converted into the hydrochloride with ethanolic hydrochloric acid. By recrystallization from methanol-ethyl acetate, 1.9 g. of cûlor-less needles having a melting point of 150 to 153C. were obtained.
Elemental analysis for CllH15NO.HCl. 1/2 H2O
C _ N
Calcd. 59.32 7.69 6.29 Found 59.51 7.92 6.05 ~39~
EXAMPLE B
1,1-Diethyl-6-hydroxy-2-indanamine:
In a manner similar to Example A, 2.5 g. of colorless plate-like crystals having a melting point of 142 to 144C
were obtained.
Elemental analysis for C13H NO
C _ N
Calcd. 76.06 9.33 6.82 Found 75.97 9.54 6.77 ., '~.
Elemental Analysis for C15H21N03 C H N
Calcd. 68.42 8.04 5.32 Found 68.29 8.28 5.21 ExamPle 25 1,1-Dimethyl-7-methoxy-2-indanamine hydrochloride: ~ -In a manner similar to Example 19 but using 6.0 g. of 7-chloro-3,3-dimethyl-2-hydroxyimino-4-methoxy-1-indanone, the hydrochloride was obtained. By recrystallization from isopropanol-isopropyl ether, 0.7 g. of colorless needles having a melting point of 248 to 249C. were obtained.
Elemental Analysis for C12H17NO. ~Cl C H N
Calcd. 63.29 7.97 6.15 Found 63.11 8.13 6.04 Example 26 N-Acetyl-l,l-dimethyl-4-methoxy-2-indanamine:
To a solution of 6.0 g. of 3,3-dimethyl-2-hydroxyimino-7-methoxy-l-indanone in 100 ml. of acetic acid was added 2.5 g. of 10 % palladium-carbon. The mixture was subjected to catalytic hydrogenation for 7 hrs. under pressure and heating (30 kg/cm , 70C). The catalyst was removed by filtration and the filtrate i21 o was distilled to dryness under reducecl pressure. After adding 10 % hydrochloric acid to the residue, the mixture was extracted with ether. The ethereal layer was washed with water and dried.
The solvent was removed by distillation. The resulting residue was crystallized from benzene to obtain 0.85 g. of colorless plates having a melting point of 140 to 141C.
Elemental Analysis for Cl4HlgNO2 C H N
Calcd. 72.07 8.21 6.00 Found 72.25 8.49 5.83 Example 27 ~-Ethyl-l~l-dimethyl-4-methoxy-2-indanamine hydro-chloride:
To a suspension of 0.91 g. of lithium aluminum hydride in 10 ml. of anhydrous tetrahydrofuran was dropwise added a solution of 1.4 g. of N-acetyl-l,l-dimethyl-4-methoxy-2-indanamine in 20 ml of anhydrous tetrahydrofuran. The mixture was heated under refluxing for 4 hrs. After completion of the reaction, water-containing ether and water were in succession added to the reac-tion mixture. Then, the mixture was filtered by suction and the filtrate was extracted with lO % hydrochloric acid. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and extracted with ether. The ethereal layer was washed with water and dried. The solvent was removed by distillation and the resulting residue was converted into the hydrochloride by adding thereto ethanolic hydrochloric acid. By recrystallization from ethanol-ether, 0.8 g. of colorless plates having a melting point of 300C. or higher were obtained.
Elemental Analysis for Cl4H2lNO.HCl C H N
Calcd. 65.74 8.67 5.48 Q
Found 65.39 8.92 5.40 Example 28 N-Ethyl-l,l-dimethyl-2-indanamine hydrochloride:
In a manner similar to Example 27 but using 2.82 g. of N-acetyl-l,l-dimethyl-2-indanamine, 1.8 g. of the hydrochloride was obtained, which was recrystallized from ethanol-isopropyl ether to give colorless needles having a melting point of 203 to 204C.
Elemental Analysis for C13HlgN.HCl C H N
Calcd. 69.16 8.93 6.20 Found 69.38 9.19 6.12 Example 29 N-Ethyl-l,l-dimethyl-5-methoxy-2-indanamine hydro-chloride:
In a manner similar to Example 27 but using 4.29 g. of N-acetyl-l,l-dimethyl-5-methoxy-2-indanamine, the hydrochloride was obtained, which was recrystallized from ethanol to give 1.28 g. of colorless prisms having a melting point of 239 to 242C.
Elemental Analysis for C14H21NO.HCl. 1/4H2O ~ -C H N
Calcd. 64.60 8.71 5.38 Found 64.37 8.79 5.42 Example 30 N-Ethyl-l,l-dimethyl-5,6-dimethoxy-2-indanamine hydro-chloride:
In a manner similar to Example 27 but using 2.63 g. of N-acetyl-l,l-dimethyl-5,6-dimethoxy-2-indanamine, 1.59 g. of the hydrochloride was obtained, which was recrystallized from ethanol to obtain colorless prisms having a melting point of 289 to 290C.
Elemental Analysis for C15H23NO2. HCl C H N
Calcd. 63.04 8.46 4.90 Found 62.88 8.57 4.99 ~9~o Example 31 1 l,N,N-Tetramethyl-2-indanamine hydrochloride:
A mixture of 3.26 g. of 1,1-dimethyl-2-indanamine, 6 ml. of 37 % an aq. formaldehyde solution and 4.3 ml. of 90 % formic acid was heated with stirring for 4 hrs. at 100C. After completion of the reaction, the system was made alkaline with an aqueous sodium hydroxide solution and extracted with ether. The ethereal layer was washed with water and dried. The solvent was removed by dis-tillation and the resulting residue was converted into the hydro-chloride with ethanolic hydrochloric acid. By recrystallization from ethanol-isopropyl ether, 3.4 g. of colorless needles having a melting point of 263 to 264C. were obtained.
Elemental Analysis for C13HlgN.Hcl. 1/2H2O
C H N
Calcd. 66.51 9.02 5.97 Found 66.61 8.92 5.91 While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
s~o SUPPLEMENTARY DISCLOSURE
The conversion of the compounds of the formula (I-l) into the compounds of the formula (I-5) can also be performed by dealkylation, i.e,, by heating the system in the presence of a Lewis acid (aluminum chloride, borotribromide) and inert organic solvents (halogenated hydrocarbons, benzene, toluene, zylene, etc.), or in the presence of a strong mineral acid ( e.g., hydrobromic acid, hydroiodic acid).
_EXAMPLE A
1,1-Dimethyl-6- hydroxy-2-indanamine hydrochloride;
To 5.0 g. of 1,1-dimethyl-6-methoxy-2-indanamine hydro-chloride was added 50 ml. of a 48% hydrobromic acid. The mixture was heated at 140C for 1.5 hours in,,a nitrogen flow.
After completion of the reaction, the system was rendered alkaline with an aqueous sodium hydroxide solution, followed by washing with ether. The ethereal layer was rendered acidic ' -with hydrochloric acid and then weakly alkaline with ammonia water. The mixture was extracted with ethyl acetate. The organic acid was washed with water and dried. After the solvent was removed by distillation, the residue was converted into the hydrochloride with ethanolic hydrochloric acid. By recrystallization from methanol-ethyl acetate, 1.9 g. of cûlor-less needles having a melting point of 150 to 153C. were obtained.
Elemental analysis for CllH15NO.HCl. 1/2 H2O
C _ N
Calcd. 59.32 7.69 6.29 Found 59.51 7.92 6.05 ~39~
EXAMPLE B
1,1-Diethyl-6-hydroxy-2-indanamine:
In a manner similar to Example A, 2.5 g. of colorless plate-like crystals having a melting point of 142 to 144C
were obtained.
Elemental analysis for C13H NO
C _ N
Calcd. 76.06 9.33 6.82 Found 75.97 9.54 6.77 ., '~.
Claims (33)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a substituted indanamine compound of the formula:
(I) wherein R1 represents a lower alkyl group; R2 and R3 each, which may be the same or different, represents a hydrogen atom, a lower alkyl group or an acyl group having 1 to 6 carbon atoms;
R4 represents a hydrogen atom or a lower alkyl group; and n represents 0, 1 or 2; and pharmaceutically accpetable non-toxic salts thereof, which process being selected from the group consisting of:
(a) a process for producing said compound of formula (I) wherein R1 and n are defined as above, R2 is a hydrogen atom or an acetyl group, R3 is a hydrogen atom, and R4 is a hydrogen atom or a lower alkyl group, which comprises subjecting to catalytic reduction a compound of formula (II):
(II) wherein R1, R4 and n are defined as above; and X is halogen atom or a hydrogen atom in an organic solvent;
(b) a process for producing the compound of formula (I) wherein R1 is a lower alkyl group, R2 and R3 each, is a hydrogen atom, R4 is a hydrogen atom or a lower alkyl group, and n is 0, 1 or 2, which comprises subjecting a compound of formula (III):
(III) wherein R1, R4 and n are defined as above, to a Curtius reaction involving heating the compound of formula (III) and then hydrolyzing in the presence of an organic or inorganic acid;
(c) A process for producing the compound of formula (I) wherein R1 is a lower alkyl group, R2 is a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group, R4 is a hydrogen atom or a lower alkyl group, n is 0, 1 or 2, which comprises reacting a compound of formula (IV) (IV) wherein R1, R2, R4 and n are defined as above with an alkylating agent selected from the group consisting of an alkyl halide of formula:
(wherein R3 is defined as above and X is a halogen atom), formic acid and a carbonyl compound;
(d) a process for producing the compound of formula (I) wherein R1 is a lower alkyl group, R2 is a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group R4 is a hydrogen atom or a lower alkyl group, and n is 0, 1 or 2, which comprises reducing a compound of formula (v):
(V) wherein R1, R2, R4 and n are defined as above and R3' is a lower alkyl group or a lower alkoxy group, in the presence of a lithium aluminum hydride;
(e) a process for producing the compound of formula (I) wherein R1 and R3 each is a lower alkyl group, R2 is an acyl group having 1 to 6 carbon atoms; R4 is a hydrogen atom or a lower alkyl group, and n is 0, 1 or 2, which comprises reacting a compound of formula (VI):
(VI) wherein R1, R2, R4 and n are defined as above, with an alkyl halide of formula:
wherein R3 is defined as above and X is a halogen atom;
(f) a process for producing the compound of formula (I) wherein R1 is a lower alkyl group, R2 is an acyl group having 1 to 6 carbon atoms, R3 is a hydrogen atom, R4 is a hydrogen atom or a lower alkyl group, and n is 0, 1 or 2, which comprises reacting a compound of formula (VII):
(VII) wherein R1, R4 and n are defined as above, with an acid halide or acid anhydride, with an acid halide of formula:
R3'-COX
wherein R3' is a lower alkyl group and X is a halogen atom, or an acid anhydride of formula:
R3' - CO-O-CO-R3' wherein R3' is defined as above; and (g) a process for producing the compound of formula (I) wherein R1 is a lower alkyl group, R2 and R3 each, which may be the same or different, is a hydrogen atom or a lower alkyl group, R4 is a hydrogen atom and n is 1 or 2, which comprises dealkylating a compound of formula (VIII):
(VIII) wherein R1, R2, R3 and n are defined as above, and R4 is a lower alkyl group.
(I) wherein R1 represents a lower alkyl group; R2 and R3 each, which may be the same or different, represents a hydrogen atom, a lower alkyl group or an acyl group having 1 to 6 carbon atoms;
R4 represents a hydrogen atom or a lower alkyl group; and n represents 0, 1 or 2; and pharmaceutically accpetable non-toxic salts thereof, which process being selected from the group consisting of:
(a) a process for producing said compound of formula (I) wherein R1 and n are defined as above, R2 is a hydrogen atom or an acetyl group, R3 is a hydrogen atom, and R4 is a hydrogen atom or a lower alkyl group, which comprises subjecting to catalytic reduction a compound of formula (II):
(II) wherein R1, R4 and n are defined as above; and X is halogen atom or a hydrogen atom in an organic solvent;
(b) a process for producing the compound of formula (I) wherein R1 is a lower alkyl group, R2 and R3 each, is a hydrogen atom, R4 is a hydrogen atom or a lower alkyl group, and n is 0, 1 or 2, which comprises subjecting a compound of formula (III):
(III) wherein R1, R4 and n are defined as above, to a Curtius reaction involving heating the compound of formula (III) and then hydrolyzing in the presence of an organic or inorganic acid;
(c) A process for producing the compound of formula (I) wherein R1 is a lower alkyl group, R2 is a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group, R4 is a hydrogen atom or a lower alkyl group, n is 0, 1 or 2, which comprises reacting a compound of formula (IV) (IV) wherein R1, R2, R4 and n are defined as above with an alkylating agent selected from the group consisting of an alkyl halide of formula:
(wherein R3 is defined as above and X is a halogen atom), formic acid and a carbonyl compound;
(d) a process for producing the compound of formula (I) wherein R1 is a lower alkyl group, R2 is a hydrogen atom or a lower alkyl group, R3 is a lower alkyl group R4 is a hydrogen atom or a lower alkyl group, and n is 0, 1 or 2, which comprises reducing a compound of formula (v):
(V) wherein R1, R2, R4 and n are defined as above and R3' is a lower alkyl group or a lower alkoxy group, in the presence of a lithium aluminum hydride;
(e) a process for producing the compound of formula (I) wherein R1 and R3 each is a lower alkyl group, R2 is an acyl group having 1 to 6 carbon atoms; R4 is a hydrogen atom or a lower alkyl group, and n is 0, 1 or 2, which comprises reacting a compound of formula (VI):
(VI) wherein R1, R2, R4 and n are defined as above, with an alkyl halide of formula:
wherein R3 is defined as above and X is a halogen atom;
(f) a process for producing the compound of formula (I) wherein R1 is a lower alkyl group, R2 is an acyl group having 1 to 6 carbon atoms, R3 is a hydrogen atom, R4 is a hydrogen atom or a lower alkyl group, and n is 0, 1 or 2, which comprises reacting a compound of formula (VII):
(VII) wherein R1, R4 and n are defined as above, with an acid halide or acid anhydride, with an acid halide of formula:
R3'-COX
wherein R3' is a lower alkyl group and X is a halogen atom, or an acid anhydride of formula:
R3' - CO-O-CO-R3' wherein R3' is defined as above; and (g) a process for producing the compound of formula (I) wherein R1 is a lower alkyl group, R2 and R3 each, which may be the same or different, is a hydrogen atom or a lower alkyl group, R4 is a hydrogen atom and n is 1 or 2, which comprises dealkylating a compound of formula (VIII):
(VIII) wherein R1, R2, R3 and n are defined as above, and R4 is a lower alkyl group.
2. A process according to any one of the steps of claim 1, wherein said lower alkyl group has 1 to 4 carbon atoms.
3. A process according to any one of the steps of claim 1, wherein n is 1.
4. A process according to either steps (a) or (b) of claim 1 for preparing 1,1-dimethyl-6-methoxy-2-indanamine, wherein R1 is methyl, R2 and R3 are both hydrogen and R4 is methyl and n is 1.
5. A process according to any one of steps (a), (b), (c) or (d) of claim 1 for preparing N-ethyl-l,l-dimethyl-6-methoxy-2-indanamine, wherein R1 is methyl, one of R2, and R3 is ethyl and the other is hydrogen, R4 is methyl and n is 1.
6. A process according to either of steps (a) or (b) of claim 1 for preparing 1,1-dimethyl-2-indanamine, wherein R1 is methyl, R2 and R3 are both hydrogen and n is 0.
7. A process according to any one of steps (a), (b), (c) or (d) of claim 1 for preparing N-ethyl-l,l-dimethyl-2-indanamine, wherein R1 is methyl, one of R2 and R3 is ethyl and the other is hydrogen and n is 0.
8. A process according to either of steps (a) or (b) of claim 1 for preparing 1,1-dimethyl-5-methoxy-2-indanamine, wherein R1 is methyl, R2 and R3 are both hydrogen, R4 is methyl and n is 1.
9. A process according to either of steps (a) or (b) of claim 1 for preparing 1,1-dimethyl-7-methoxy-2-indanamine, wherein R1 is methyl, R2 and R3 are both hydrogen, R4 is methyl and n is 1.
10. A process according to either of steps (a) or (b) of claim 1 for preparing 1,1-dimethyl-5,6-dimethoxy-2-indanamine, wherein R1 is methyl, R2 and R3 are both hydrogen, R4 is methyl and n is 2.
11. A process according to either of steps (a) or (b) of claim 1 for preparing 1,1-diethyl-6-methoxy-2-indanamine, wherein R1 is ethyl, R2 and R3 are both hydrogen, R4 is methyl and n is 1.
12. A process according to any one of steps (a), (b), (c) or (d) of claim 1 for preparing N-ethyl-l,l-diethyl-6-methoxy-2-indanamine, wherein R1 is ethyl, one of R2 and R3 is ethyl and the other is hydrogen, R4 is methyl and n is 1.
13. A substituted indanamine compound of the formula:
wherein R1 represents a lower alkyl group; R2 and R3 each, which may be the same or different, represents a hydrogen atom, a lower alkyl group or an acyl group having 1 to 6 carbon atoms;
R4 represents a hydrogen atom or a lower alkyl group; and n represents 0, 1 or 2; and pharmaceutically acceptable non-toxic salts thereof, when prepared by the process of claim 1.
wherein R1 represents a lower alkyl group; R2 and R3 each, which may be the same or different, represents a hydrogen atom, a lower alkyl group or an acyl group having 1 to 6 carbon atoms;
R4 represents a hydrogen atom or a lower alkyl group; and n represents 0, 1 or 2; and pharmaceutically acceptable non-toxic salts thereof, when prepared by the process of claim 1.
14. The substituted indanamine compound of claim 13, wherein said lower alkyl has 1 to 4 carbon atoms, when prepared by the process of claim 2.
15. The substituted indanamine compound of claim 13, wherein said n has 1, when prepared by the process of claim 3.
16. The compound 1,1-dimethyl-6-methoxy-2-indanamine, when prepared by the process of claim 4.
17. The compound N-ethyl-l,l-dimethyl-6-methoxy-2-indanamine, when prepared by the process of claim 5.
18. The compound 1,1-dimethyl-2-indanamine, when prepared by the process of claim 6.
19. The compound N-ethyl-l,l-dimethyl-2-indanamine, when prepared by the process of claim 7.
20. The compound 1,1-dimethyl-5-methoxy-2-indanamine, when prepared by the process of claim 8.
21. The compound 1,1-dimethyl-7-methoxy-2-indanamine, when prepared by the process of claim 9.
22. The compound 1,1-dimethyl-5,6-dimethoxy-2-indanamine, when prepared by the process of claim 10.
23. The compound 1,1-diethyl-6-methoxy-2-indanamine, when prepared by the process of claim 11.
24. The compound N-ethyl-l,l-diethyl-6-methoxy-2-indanamine, when prepared by the process of claim 12.
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
25. A process for the preparation of compounds of the formula:
wherein R1 represents methyl or ethyl and the pharmaceutically acceptable non-toxic salts thereof, comprising dealkylating a compound of the formula:
by heating said compound either in the presence of a Lewis acid and an inert organic solvent, or in the presence of a strong mineral acid.
wherein R1 represents methyl or ethyl and the pharmaceutically acceptable non-toxic salts thereof, comprising dealkylating a compound of the formula:
by heating said compound either in the presence of a Lewis acid and an inert organic solvent, or in the presence of a strong mineral acid.
26. A process for the preparation of compounds of the formula:
wherein R1 represents methyl or ethyl and the pharmaceutically acceptable non-toxic salts thereof, comprising dealkylating a compound of the formula;
wherein R1 is as defined above and R4 is lower alkyl, by heating said compound in the presence of a Lewis acid and an inert organic solvent or in the presence of a strong mineral acid.
wherein R1 represents methyl or ethyl and the pharmaceutically acceptable non-toxic salts thereof, comprising dealkylating a compound of the formula;
wherein R1 is as defined above and R4 is lower alkyl, by heating said compound in the presence of a Lewis acid and an inert organic solvent or in the presence of a strong mineral acid.
27. A process according to claim 25, wherein the Lewis acid is selected from the group aluminum chloride or borotribromide and the inert organic solvent is selected from the group halogenated hydrocarbons, benzene, toluene or xylene.
28. A process according to claim 25, wherein the strong mineral acid is hydrobromic acid or hydroiodic acid.
29. A process according to claim 26 for the preparation of l,l-dimethyl-6-hydroxy-2-indanamine hydrochloride wherein R1 is methyl.
30. A process according to claim 26 for the preparation of l,l-diethyl-6-hydroxy-2-indanamine, wherein R1 is ethyl.
31. Compounds of the formula:
wherein R1 is methyl or ethyl or its pharmaceutically acceptable non-toxic salts, when prepared by the process of claim 26.
wherein R1 is methyl or ethyl or its pharmaceutically acceptable non-toxic salts, when prepared by the process of claim 26.
32. A compound according to claim 31, namely l,l-dimethyl-6-hydroxy-2-indanamine hydrochloride when prepared by the process of claim 29.
33. A compound according to claim 31, namely, l,l-diethyl-6-hydroxy-2-indanamine, when prepared by the process of claim 30.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63821/1978 | 1978-05-30 | ||
| JP6382278A JPS54157552A (en) | 1978-05-30 | 1978-05-30 | Indanamine derivative |
| JP6382178A JPS54157551A (en) | 1978-05-30 | 1978-05-30 | Indanamine derivative |
| JP63822/1978 | 1978-05-30 | ||
| JP54034349A JPS581102B2 (en) | 1979-03-26 | 1979-03-26 | indanamine derivatives |
| JP34349/1979 | 1979-03-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1109080A true CA1109080A (en) | 1981-09-15 |
Family
ID=27288395
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA328,466A Expired CA1109080A (en) | 1978-05-30 | 1979-05-28 | Indanamine derivatives |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0005821B1 (en) |
| CA (1) | CA1109080A (en) |
| DE (1) | DE2964198D1 (en) |
| DK (1) | DK225279A (en) |
| ES (1) | ES481102A0 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2603035B1 (en) * | 1986-08-21 | 1988-12-09 | Roussel Uclaf | NEW INDANE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2617480B1 (en) * | 1987-07-03 | 1990-12-07 | Roussel Uclaf | NEW INDANE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| CH664359A5 (en) * | 1983-03-04 | 1988-02-29 | Otsuka Pharma Co Ltd | INDANDERIVATES AND THEIR SALTS. |
| FR2640625B2 (en) * | 1986-08-21 | 1993-05-21 | Roussel Uclaf | NOVEL OPTICALLY ACTIVE COMPOUNDS DERIVED FROM INDANE, THEIR APPLICATION AS DRUGS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| DE3781627T2 (en) * | 1986-08-21 | 1993-05-06 | Roussel Uclaf | INDANDERIVATES, METHODS FOR THEIR PRODUCTION, THEIR USE AS MEDICINAL PRODUCTS, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THE INTERIM PRODUCTS OBTAINED. |
| US4876269A (en) * | 1986-09-10 | 1989-10-24 | E. I. Du Pont De Nemours And Company | Benoz-fused cycloalkane trans-1,2-diamine derivatives |
| JPH0542252Y2 (en) * | 1986-11-11 | 1993-10-25 | ||
| DK626889A (en) * | 1988-12-16 | 1990-06-17 | Roussel Uclaf | INDANDER DERIVATIVES, THEIR PREPARATION AND MEDICINES WITH CONTENTS |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3142619A (en) * | 1961-07-24 | 1964-07-28 | Ciba Geigy Corp | Amino compounds |
| US3196181A (en) * | 1963-03-01 | 1965-07-20 | Ciba Geigy Corp | Catalytic reduction of 2-oximinoindane to 2-amino-indane |
| DE1443664A1 (en) * | 1964-09-10 | 1968-11-07 | Albert Ag Chem Werke | Process for the preparation of pharmaceutically active derivatives of 2-aminoindane |
| US3770828A (en) * | 1967-10-20 | 1973-11-06 | Mead Johnson & Co | Substituted 3-phenylindan-1-one oximes |
| US3746495A (en) * | 1971-06-01 | 1973-07-17 | American Home Prod | Anti-ulcer therapy |
-
1979
- 1979-05-28 CA CA328,466A patent/CA1109080A/en not_active Expired
- 1979-05-29 EP EP19790101641 patent/EP0005821B1/en not_active Expired
- 1979-05-29 DE DE7979101641T patent/DE2964198D1/en not_active Expired
- 1979-05-30 ES ES481102A patent/ES481102A0/en active Granted
- 1979-05-30 DK DK225279A patent/DK225279A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DE2964198D1 (en) | 1983-01-13 |
| EP0005821B1 (en) | 1982-12-08 |
| EP0005821A1 (en) | 1979-12-12 |
| ES8101539A1 (en) | 1980-12-16 |
| ES481102A0 (en) | 1980-12-16 |
| DK225279A (en) | 1979-12-01 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |