CA1094097A - Cyclic amino acid derivatives - Google Patents
Cyclic amino acid derivativesInfo
- Publication number
- CA1094097A CA1094097A CA280,334A CA280334A CA1094097A CA 1094097 A CA1094097 A CA 1094097A CA 280334 A CA280334 A CA 280334A CA 1094097 A CA1094097 A CA 1094097A
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- Prior art keywords
- acetic acid
- cyclohexane
- cycloheptane
- prepared
- reacted
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
A B S T R A C T
There is disclosed compounds of the formula wherein R1 is hydrogen or methyl, R2 is lower alkyl of 1 to 8 carbon atoms or a cycloalkyl of from 3 to 8 carbon atoms, or benzyl, R3 is hydrogen or lower alkyl of 1 to 8 carbon atoms.
These compounds exhibit hypothermal and, in some cases, narcosis-potentiating or sedating properties.
There is disclosed compounds of the formula wherein R1 is hydrogen or methyl, R2 is lower alkyl of 1 to 8 carbon atoms or a cycloalkyl of from 3 to 8 carbon atoms, or benzyl, R3 is hydrogen or lower alkyl of 1 to 8 carbon atoms.
These compounds exhibit hypothermal and, in some cases, narcosis-potentiating or sedating properties.
Description
~ 1094097 The N-substituted cyclic amino acid derivatives accord-ing to the present invention are compounds of the general formula:
; Rl - N - CH2 - C - CH2 - COOR3 (I) (CH2)n wherein Rl is a hydrogen atom or a methyl radical, R2 is a lower alkyl or cycloalkyl radical, or a benzyl radical, the aromatic nucleus of which may be substituted, or a furfuryl-or thiophene-methyl radical, R3 is a hydrogen atom or a lower alkyl radical and n is 4,5, or 6; and the pharmacologically compatible salts thereof.
By lower alkyl radicals, there are to be understood straight-chained or branched alkyl radicals containing up to 8 and preferably up to 5 carbon atoms, especially the methyl, ethyl, isopropyl, n-butyl and isopentyl radicals.
Those compounds of formula (I) are preferred in which Rl is a hydrogen atom or a methyl radical, R2 is an alkyl radical containing up to 5 carbon atoms or a benzyl radical and R3 is a hydrogen atom or a methyl or ethyl radical.
The compounds encompassed by the genera1 formula (I) exhibit hypothermal and, in some cases, narcosis-potentiating or sedating properties. They are also characterized by an extremely low toxicity. In animal experiments, there was, surprisingly, also found a remarkable protective effect against cramp induced by thiosemicarbazide. Some of the compounds also possess a considerable protective action against cardiazole cramp. These new compounds (I) can be used for the therapy of certain cerebral diseases, for example, they are suitable for the treatment of certain forms of epilepsy, dizziness, of hypokinesia and cranial trauma. They also bring about an improvement of the cerebral functions. Consequently, they are also especially effective in the treatment of geri-atric patients.
The novel compounds of general formula (I) according to the present invention can be prepared by the reductive N-alkyl-ation of compounds of the general formula:
r ~ (II) (CH2)n wherein R4 is a hydrogen atom or a lower alkyl radical and n is 4,~, or 6, followed, ;f desired, by esterification or transesterification with an alcohol of the general formula:
H0 - R3 (III) wherein R3 is a hydrogen atom or a lower alkyl. If desired, the compounds thus obtained may be further converted into their pharmacologically compatible salts by reaction with appropriate acids or bases.
The N-alkylation according to the present invention is carried out by known processes (see Houben-Weyl, Vol. 11/2, p. 330) by first reacting the compounds of general formula (II) with a carbonyl compound which contains a number of carbon atoms corresponding to the radical Rl or R2 After the inter-mediate compound is obtained, it is then converted into the desired end product by means of a reducing agent.
-` 1094097 The reaction can be carried out in an inert solvent and, as reducing agent, there can be used, for example, formic acid, catalytically activated hydrogen, or a metal hydride, such as sodium borohydride or sodium cyanoborohydride.
Examples of carbonyl compounds which can be used include the aliphatic aldehydes, such as formaldehyde, acetaldehyde, propionaldehyde, isobutyraldehyde, butyraldehyde and valer-aldehyde, and the ketones, such as acetone, methyl ethyl ketone, methylpropyl ketone, diethyl ketone, cyclohexanone, cyclopent-anone and cycloheptanone.
Examples of aromatic aldehydes, which can be usedencompass benzaldehyde, halogenated aldehydes, such as chlorobenzaldehyde or bromobenzaldehyde, tolualdehyde, mono-and dihydroxybenzaldehyde, methoxybenzaldehyde, di- and tri-methoxybenzaldehydes, such as veratraldehyde, piperonal and 3, 4, 5-trimethoxybenzaldehyde, and hydroxymethoxybenzaldehydes, such as vanillin or isovanillin, as well as furfural or thio-phene-aldehyde.
When using the carbonyl compound formaldehyde, the corresponding N-methyl or N,N-dimethyl compounds are obtained, whereas the other aldehydes yield only the N-monosubstituted compounds. The N,N-mixed substituted compounds are, therefore, prepared by first carrying out a reductive alkylation with a -carbonyl compound which possess a number of carbon atoms cor-responding to the radical R2 and then introducing the methyl radical Rl by means of formaldehyde.
Compounds of general formula (I) in which Rl is a hydrogen atom and R2 is a methyl radical can be prepared by reductively N-methylating the N-benzyl compound by means of formaldehyde and subsequently splitting off the benzyl radical hydrogenolytically in the presence of a catalyst such as pal-ladium charcoal or platinum oxide.
~09409'7 For the preparation of the compounds of general formula (I), the compounds of formula (II) are reacted with equivalent or excess amounts of a carbonyl compound in an inert solvent.
The carbonyl compound may also serve as the solvent. The intermediate is then hydrogenated in the presence of a catalyst, such as palladium-charcoal or platinum oxide, at ambient or a moderately elevated temperature, preferably at 20 to 50C. The hydrogenation can be carried out at a hydrogen pressure of about 1 to 5 atmospheres. The reductive alkylation, especially the 10 methylation or benzylation, may be carried out in such a manner that the intermediate formed by the reaction with a compound of general formula (II) is reduced with sodium borohydride (see Helv. Chim. Acta., 46 327/1963) or sodium cyanoborohydride (see J. Org. Chem., 37, 1673/1972); the reaction is preferably carried out at a temperature of from O to 25C. and in a polar solvent such as water, methanol, ethanol, dioxan, tetrahydro-furan, acetonitrile or aqueous mixtures of these solvents.
N-methylation can also be accomplished by reductive alkylation of the monosubstituted amine with a carbonyl com-20 pound, such as formaldehyde, and formic acid or formamides asreducing agents. (See Houben-Weyl, vol. 11/2, p. 331).
When R3 is to be an alkyl radical, the carboxyl group of the amino acid obtained is esterified. The reaction is, most simply, carried out by dissolving the free amino acid of formula (I~ or a salt thereof in an excess of the esterifying alcohol and saturating the solution with hydrogen chloride.
The amino acid ester hydrochloride is thus directly obtained.
The compounds of general formula (II) used as starting materials can be prepared by one of the following methods:
(a) converting a compound of the general formula:
HOOC - CH2 ~ C - CH2 - COOR5 ~ (IV), (CH2)n wherein R5 is an alkyl radical containing up to 8 carbon atoms and n is 4,5, or 6, via a reactive acid derivative, into an azide and then subjecting this to the Curtius rearrangement; or ~b) subjecting a compound of the general formula:
(V) (CH2)n in which n is 4,5 or 6 to the Hofmann rearrangement, or (c) subjecting a compound of the general formula:
> N - CO - CH2 - C j CH2 - COOH
HO ~ (VI) (CH2)n wherein n is 4, 5, or 6, or a compound of the general formula:
HO - N \ \ C /'~~~(CH2)n (VIa) wherein n is 4, 5 or 6, to the Lossen rearrangement.
When a free amino acid is obtained, it may be ester-ified to give a corresponding lower alkyl ester and/or the product obtained may be converted into a pharmaceutically com-patible salt by reaction with an acid or a base.
The reaction of the compounds of general formula (IV) takes place according to the well-known Curtius rearrangement.
The free carboxyl group is first activated by conversion into a reactive derivative, for example an acid halide or a mixed anhydride, and subsequently reacted with an appropriate azide, for example, sodium azide. The acid azide thus obtained is then subjected to thermal decomposition in an organic solvent, for example, benzene, toluene or an alcohol, such as ethanol, during which nitrogen is split off and an introamolecular rearrangement to an isocyanate or, in the presence of an alco-hol, to a urethane takes place. The isocyanates and theureth-anes can easily be converted into the desired primary amines by basic or acidic hydrolysis.
The well-known Hofmann rearrangement of compounds of general formula (V) also takes place via isocyanates. In this case, the acid amides are reacted with alkali metal hypohalites.
Upon hydrolysis of the isocyanate formed by anionotropic re-arrangement, the desired amine is formed, together with carbon dioxide.
The Lossen rearrangement of the hydroxamic acids of general formula (VI) also takes a similar course. In this case, water is split off, the corresponding isocyanate first eing formed, hydrolysis of which gives the desired amine.
Usually the hydroxamic acids are reacted with bases via their 0-acyl derivatives as, for example, the 0-acetyl-, 0-benzoyl- and preferably 0-sulfonyl- derivatives.
The compounds of general formula (Vla) can be prepared 10!~4097 by reacting a hemiester of the general formula:
(CH2)n C (VIb) wherein R3 is an alkyl radical containing up to 5 carbon atoms and n is 4,5 or 6, with hydroxylamine at an elevated temper-ature, preferably of from 50 to 100C. (See ~.C.S., 1929, 713).
Since amino acids are amphoteric, pharmacologically compatible salts when R3 is a hydrogen atom, can be salts of appropriate inorganic or organic acids, for example, hydro-chloric acid, sulphuric acid, phosphoric acid, acetic acid, oxalic acid, latic acid, citric acid, malic acid, salicylic acid, malonic acid, maleic acid, succinic acid or ascorbic acid, but also, starting from the correspond;ng hydroxides or carbonates~ salts with alkali metals or alkaline earth metals, for example, sodium, potassium, magnesium or calcium.
Salts with quaternary ammonium ions can also be prepared with, for example, the tetramethyl-ammonium ion. Of course, when R3 is a lower alkyl radical, it is only possible to form salts with acids.
The compounds of general formula (IV) used as starting materials can be prepared by reacting an acid anhydride of the general formula:
ICl CH2 (VI I ) '-` 1094097 wherein n is 4, 5, or 6, either with water, or with one mole of an alcohol of the general formula:
~0 - R5 (VIII), wherein R~ has the same meaning as above.
The compounds of general formula (VII) are known (see J.C.S., 115, 686/1919; Soc., 99, 446; J.C.S., 117, 639/1920.
Some of the compounds of general formula (V), as well as processes for the preparation thereof, are known (see Austral J.C., 13, 127/1960). They can also be prepared, for example, by reacting compounds of general formula (VII) with ammonia.
In this case it is advantageous to operate at the lowest possible temperature. However, it is also possible, as des-cribed above, to prepare a hemiester and to react the free carboxyl group with, for example, ethyl chloroformate and subsequently with ammonia.
The hydroxamic acids of general formula (VI) can be obtained analogously by reaction of the anhydride (VII) with hydroxylamine.
Because of their low toxicity, the compounds of general formula (I) according to the present invention can be administered enterally or parenterally within wide dosage limits in solid or liquid form. As injection solution, water which contains the additives usual in the case of injection solutions, such as stabilizing agents, solubilizing agents or buffers is preferably employed.
Additives of this type include, for example, tartrate and citrate buffers, ethanol, complex-forming agents such as ethylenediamine-tetraacetic acid and the non-toxic salts there-of, as well as high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation. Sold carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids such as stearic acid, gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers such as polyethylene glycol. Compositions which are suitable for oral administration can, if desired, also contain flavoring and/or sweetening agents.
The individual dosage for the compounds according to the present invention are preferably 5 - 50 mg. parenterally and 20 - 200 mg. enterally.
Thus, the present invention also provides pharmaceutical compositions containing at least one compound of general formula (I) and/or at least one pharmaceutically compatible salt thereof in admixture with a solid or liquid pharmaceutical diluent or carrier.
The following Examples are given for the purpose of illustrating the present invention:
l-(n,N-Dimethylaminomethyl)-cyclohexane-acetic acid.
4.5 9. l-aminomethylcyclohexane-acetic acid are dis-solved in 150 ml. water and mixed with 8.5 ml. 37% aqueous formaldehyde solution. The reaction mixture is hydrogenated in the presence of palladium-charcoal (10%) at ambient temper-ature and atmospheric pressure. The calculated amount of hydrogen is taken up after 3 hours. The reaction mixture is filtered and the filtrate acidified to pH 2 with dilute hydro-chloric acid and then concentrated in a vacuum. By crystal-lisation of the residue from acetone/diethyl ether, there are obtained 4.9 9. (79% of theory) l-(N,N-dimethylaminoethyl)-cyclohexane-acetic acid in the form of its hydrochloride; m.p.
140 - 142C.
g ' 1094097 Analysis:
CllH21N02.HCl.l/4H20 calc. : C 54.99%; H 9.44%; N 5.83~; CI 14.76%
found : 54.90%; 9.36X; 6.22%; 15.05%
The l-aminomethylcyclohexane-acetic acid used as starting material is prepared as follows:
5.6 ml. triethylamine in 16 ml. anhydrous acetone is added dropwise, with stirring and cooling to 0C., to a solution of 7.28 9. l,l-cyclohexane-diacetic acid monomethyl ester in 60 ml. anhydrous acetone, followed by a solution of 3.6 ml. ethyl chloroformate in 16 ml. anhydrous acetone.
Stirring is continued for 30 minutes at 0C. and then a solution of 3.4 9. sodium azide in 12 ml. water is added there-to dropwise. The reaction mixture is further stirred for 1 hour at 0C., then poured into ice-water and extracted three times with 50 ml. amounts of ice-cold toluene. The combined extracts are dried at 0C. over anhydrous sodium sulphate and subsequently dropped into a flask pre-heated to 100C. The mixture is further heated under reflux for 1 hour and then ~0 evaporated in a vacuum. The crude methyl l-isocyanatomethyl-l-cyclohexane-acetate remaining behind is heated under reflux for 3 hours in 50 ml. 20% hydrochloric acid. After cooling the solution, the l-aminomethyl-l-cyclohexane-acetic acid lactam formed as a by-product is removed by extracting three times with 100 ml. amounts of chloroform, whereafter the aqueous hydrochloric acid solution is evaporated in a vacuum.
The l-aminomethyl-l-cyclohexane-acetic acid crystallises out as the hydrochloride; m.p. 123 - 132C., after recrystal-lisation from acetone/methanol/diethyl ether.
-` 1094097 l-(N,N-Dimethylaminomethyl)-cycloheptane-acetic acid In a manner analogous to that described in Example 1, by the catalytic hydrogenation of a solution of 5.5 9. 1-aminomethyl-cycloheptane-acetic acid and 9.6 ml. 37~ aqueous formaldehyde solution in 180 ml. water in the presence of 5.5 9. palladium-charcoal (10%) and corresponding working up, there are obtained 4.97 9. (67% of theory) l-(N,N-dimethyl-aminomethyl)-cycloheptane-acetic acid in the form of its hydro-chloride; m.p. 185 - 188C.
Analysis:
C12H23N02.HCl calc. : C 57.70%; H 9.68%; N 5.61%; Cl 14.19%
found : 57.75%; 9.60% 5.51%; 14.23%
The l-aminomethyl-cycloheptane-acetic acid used as starting material is prepared as follows:
13.7 9. l,l-cycloheptane-diacetic anhydride are mixed with 2.36 9. anhydrous methanol in 10 ml. benzene and the mixture boiled under reflux for 2 hours. After evaporating 20 the reaction mixture in a vacuum, there are obtained 15.~ 9.
l,l-cycloheptane-diacetic acid monomethyl ester. This is dissolved in 100 ml. anhydrous acetone and, in a manner anal-ogous to that described in Example 1, first mixed with 8.1 9.
triethylamine in 30 ml. acetone and thereafter with 9.8 9.
ethyl chloroformate in 30 ml. anhydrous acetone and finally with 6.5 9. sodium azide in 20 ml. water. After the reaction has taken place, the reaction mixture is extracted in the manner described in Example 1 and the solution obtained of l,1-cycloheptane-diacetic acid monomethyl ester azide in 30 toluene is rearranged to give the corresponding isocyanate.
The l-isocyanatomethyl-l-cycloheptane-acetic acid methyl ester obtained is then boiled under reflux for 3 hours with ~094097 20% hydrochloric acid. Upon concentrating the reaction mixture in a vacuum, l-aminomethyl-l-cycloheptane-acetic acid separates out in the form of its hydrochloride, which is re-crystallised from methanol/acetone/ethyl acetate; m.p. 69 -72C.
l-(N-Isopropylaminomethyl)-cyclohexane-acetic acid 5 9. l-aminomethylcyclohexaneacetic acid hydrochloride are hydrogenated at ambient temperature in a mixture of 60 ml.
water and 30 ml. acetone in the presence of 0.5 9. platinum oxide. The calculated amount of hydrogen is taken up after 5 hours. The catalyst is filtered off and the filtrate is evaporated in a vacuum. Crystallisation of the residue for isopropanol/acetone gives 5.2 g. (88% of theory) l-(N-iso-propylaminomethyl)-cyclohexaneacetic acid in the form of its hydrochloride; m.p. 175 - 180C.
Analysis:
C12H23N02.HCl calc. : C 57.70%; H 9.68%; H 5.61%; Cl 14.19%
found : 57.76%; 9.74%; 5.94%; 14.12%
l-(N-Isopropylaminomethyl)-cycloheptane-acetic acid In a manner analogous to that described in Example 3, 1.11 9. l-aminomethylcycloheptane-acetic acid hydrochloride is hydrogenated in a solution of 10 ml. water and 10 ml. ace-tone in the presence of 0.1 9. platinum oxide. After appropri-ate working up and crystallisation from isopropanol/acetone, there is obtained l-(N-isopropylaminomethyl~-cycloheptane-acetic acid in the form of its hydrochloride; m.p. 193 - 194C.
30 (sublimes ~150C.).
l-(N-n-Propylaminomethyl)-cyclohexane-acetic acid A solution of 0.86 g. l-aminomethylcyclohexane-acetic acid in 1.16 9. propionaldehyde in 100 ml. 95% ethanol is hydrogenated at ambient temperature in the presence of 0.85 9.
palladium-charcoal (10%). After 1 hour, the calculated amount of hydrogen is taken up. The catalyst is filtered off, the filtrate is acidified with dilute hydrochloric acid and then evaporated in a vacuum. Crystallisation from acetone/diethyl ether gives l-(N-n-propylaminomethyl)-cyclohexane-acetic acid in the form of its hydrochloride; m.p. 148 - 152C.
l-(N-n-Propylaminomethyl)-cycloheptane-acetic acid In a manner analogous to that described in Example 5, by the catalytic hydrogenation of 1.1 9. l-aminomethyl-cyclo-heptane-acetic acid and 1.16 9. propionaldehyde in 100 ml.
ethanol in the presence of 1.16 9. palladium-charcoal ~10~) at ambient temperature and appropriate working up, there is obtained l-(N-n-propylaminomethyl)-cycloheptane-acetic acid;
m.p. 182 - 183C.
l-(N-Ethylaminomethyl)-cyclohexane-acetic acid In a manner analogous to that described in Example 5, by the catalytic hydrogenation of a solution of 0~86 9.
l-aminomethylcyclohexane-acetic acid and 2.2 9. acetaldehyde in 100 ml. methanol in the presence of 0.85 9. palladium-charcoal and appropriate working up, there is obtained l-(N-ethylaminomethyl)-cyclohexane-acetic acid; m.p. 172 -173C., after recrystallisation from isopropanol/diethyl ether.
l-(N-Ethylaminomethyl`)-cycloheptane-acetic acid In a manner analogous to that described in Example 5, by the catalytic hydrogenation of 1.85 9. l-aminomethyl-cycloheptane-acetic acid and 2.2 9. acetaldehyde in 100 ml.
ethanol in the presence of 1.85 9. palladium-charcoal and appropriate working up, there is obtained l-(N-ethylamino-methyl)-cycloheptane-acetic acid in the form of its hydro-chloride; m.p. 168 - 170C.
l-(N-n-Butylaminomethyl)-cyclohexane-acetic acid In a manner analogous to that described in Example 5, by the catalytic hydrogenation of a mixture of 0.86 9.
l-aminomethylcyclohexane-acetic acid and 1.44 9. n-butyr-aldehyde in 50 ml. 95% ethanol in the presence of 0.8 9.
palladium-charcoal, there is obtained l-(N-n-butylaminomethyl) -cyclohexane-acetic acid; m.p. 142 - 154C.
l-(N-n-Butylaminomethyl)-cycloheptane-acetic acid In a manner analogous to that described in Example 5, 0.93 9. l-aminomethylcycloheptane-acetic acid are hydrogen-ated with 1.44 9. n-butyraldehyde in 50 ml. ethanol in the presencepresence of 0.9 9. palladium-charcoal. After appropri-ate working up and crystallisation from acetone/diethyl ether, there is obtained l-N-n-butylaminomethyl)-cycloheptane-acetic acid in the form of its hydrochloride; m.p. 158 - 165C.
10'34097 l-(N-Benzylaminome`thyl)-cyclohexane-acetic acid Variant A.
0.86 9. l-aminomethylcyclohexane-acetic acid are hydrogenated in 50 ml. 95% ethanol with 0.65 9. benzaldehyde in the presence of 0.1 q. platinum oxide. The reaction mixture is work up in the manner described in Example 5. After crystallisation from acetone/diethyl ether, there is obtained - l-N-benzylaminomethyl)-cyclohexane-acetic acid in the form of its hydrochloride; m.p. 125 - 135 C.
Variant B.
386 g. sodium l-aminomethylcyclohexane-acetate in 2 ml.
water, prepared from the free amino acid by the addition of an equivalent amount of sodium hydroxide in water, are mixed with 0.21 ml. benzaldehyde. The reaction mixture is stirred at ambient temperature until the solution is homogeneous.
Subsequently, 75 mg. sodium cyanoborohydride are introduced portionwise, while stirring. After stirring for one hour, the reaction mixture is acidified with dilute hydrochloric acid 20 and evaporated in a vacuum. After crystallisation of the residue from acetone/diethyl ether, there is obtained l-(N-benzylaminomethyl)-cyclohexane-acetic acid, the hydrochloride of which melts at 125 - 135C.
l-(N-Benzyl-N-methylaminomethyl)-cyclohexane-acetic acid 500 mg. l-(N-Benzylaminomethyl)-cyclohexane-acetic acid hydrochloride (cf. Example 11) are dissolved in 10 ml.
water and mixed with 1.68 ml. lN aqueous sodium hydroxide solution. This solution is introduced into a prehydroqenated ` 1094097 solution of 500 mg. platinum dioxide in 10 ml. water. After the addition of 1 ml. 37% aqueous formaldehyde solution, hydrogenation is carried out at ambient temperature and atmostpheric pressure. After about 2 hours, the take up of hydrogen ceases. The catalyst is filtered off and the fil-trate, after acidification with dilute hydrochloric acid, is evaporated in a vacuum. Excess formaldehyde is removed by repeated evaporation with water. Crystallisation of the residue from acetone/diethyl ether gives l-(N-benzyl-N-meth-ylaminomethyl)-cyclohexane-acetic acid hydrochloride; m.p.
150 - 157C.
l-(N-Methylaminomethyl)-cyclohexane-acetic acid 178 mg. l-(N-benzyl-N-methylaminomethyl)-cyclohexane-acetic acid hydrochloride are hydrogenated in 25 ml. ethanol in the presence of 0.2 9. palladium-charcoal at ambient temperature and atmospheric pressure. After 1 hour, the cata-lyst is filtered off and the filtrate evaporated ;n a vacuum at 20C. Crystallisation of the residue from acetone/diethyl ether gives l-(N-methylaminomethyl)-cyclohexane-acetic acid in the form of its hydrochloride; m.p. 160 - 162C.
l-(N-Ethyl-N-methylaminomethyl)-cycloheptane-acetic acid 1 9. l-(N-ethylaminomethyl)-cycloheptane-acetic acid hydrochloride (cf. Example 8) is dissolved in 60 ml. water and mixed with 4 ml. lN aqueous sodium hydroxide solution.
After the addition of 2 ml. 37% aqueous formaldehyde solution, the reaction mixture is hydrogenated in the presence of 1 9.
palladium-charcoal at ambient temperature and atmospheric pressure. After about 2 hours, the calculated amount of ~0~34097 hydrogen is taken up. The reaction mixture is then worked up in the manner described in Example 12 and, after recrystal-lisation from acetone/diethyl ether, there is obtained l-(N-ethyl-N-methylaminomethyl)-cycloheptane-acetic acid in the form of its hydrochloride; m.p. 148 - 153C.
l-(N-Cyclohexylaminomethyl)-cycloheptane-acetic acid A solution of 925 mg. l-aminomethylcycloheptane-acetic acid and 982 mg. cyclohexanone in 50 ml. 90% aqueous methanol is hydrogenated in the presence of 0.8 9. palladium-charcoal at ambient temperature and atmospheric pressure.
After working up the reaction mixture in the manner described in Example 5 and crystallising from aqueous methanol, there is obtained l-(N-cyclohexylaminomethyl)-cycloheptane-acetic acid hydrochloride; m.p. 198 - 204C.
Ethyl l-(N-ethylaminomethyl)-cycloheptane-acetate 166 mg. l-(N-ethylaminomethyl)-cycloheptane-acetic acid hydrochloride (cf. Example 8) are dissolved in 5 ml.
absolute ethanol. Gaseous hydrogen chloride is passed in and the solution is left to stand overnight at ambient temper-ature. After evaporation in a vacuum and crystallisation of the residue from ethyl acetate/diethyl ether/hexane, there is obtained ethyl l-(N-ethylaminomethyl)-cycloheptane-acetate in the form of its hydrochloride; m.p. 110 - 118C.
109~097 l-(N-benzylaminomethyl~-cycloheptaneOacetic acid A solution of 3 9. l-aminomethylcycloheptane-acetic acid hydrochloride and 13.86 ml. lM aqueous sodium hydroxide solution in 150 ml. ethanol is mixed with 3 g. freshly dis-tilled benzaldehyde and hydrogenated in the presence of 2.3 9.
platinum dioxide at ambient temperature and atmospheric pres-sure. After working up the reaction mixture as described in Example 5 and crystallisation from aqueous ethanol, there is obtained l-(N-benzylaminomethyl)-cycloheptane-acetic acid hydrochloride; m.p. 145 - 157C.
; Rl - N - CH2 - C - CH2 - COOR3 (I) (CH2)n wherein Rl is a hydrogen atom or a methyl radical, R2 is a lower alkyl or cycloalkyl radical, or a benzyl radical, the aromatic nucleus of which may be substituted, or a furfuryl-or thiophene-methyl radical, R3 is a hydrogen atom or a lower alkyl radical and n is 4,5, or 6; and the pharmacologically compatible salts thereof.
By lower alkyl radicals, there are to be understood straight-chained or branched alkyl radicals containing up to 8 and preferably up to 5 carbon atoms, especially the methyl, ethyl, isopropyl, n-butyl and isopentyl radicals.
Those compounds of formula (I) are preferred in which Rl is a hydrogen atom or a methyl radical, R2 is an alkyl radical containing up to 5 carbon atoms or a benzyl radical and R3 is a hydrogen atom or a methyl or ethyl radical.
The compounds encompassed by the genera1 formula (I) exhibit hypothermal and, in some cases, narcosis-potentiating or sedating properties. They are also characterized by an extremely low toxicity. In animal experiments, there was, surprisingly, also found a remarkable protective effect against cramp induced by thiosemicarbazide. Some of the compounds also possess a considerable protective action against cardiazole cramp. These new compounds (I) can be used for the therapy of certain cerebral diseases, for example, they are suitable for the treatment of certain forms of epilepsy, dizziness, of hypokinesia and cranial trauma. They also bring about an improvement of the cerebral functions. Consequently, they are also especially effective in the treatment of geri-atric patients.
The novel compounds of general formula (I) according to the present invention can be prepared by the reductive N-alkyl-ation of compounds of the general formula:
r ~ (II) (CH2)n wherein R4 is a hydrogen atom or a lower alkyl radical and n is 4,~, or 6, followed, ;f desired, by esterification or transesterification with an alcohol of the general formula:
H0 - R3 (III) wherein R3 is a hydrogen atom or a lower alkyl. If desired, the compounds thus obtained may be further converted into their pharmacologically compatible salts by reaction with appropriate acids or bases.
The N-alkylation according to the present invention is carried out by known processes (see Houben-Weyl, Vol. 11/2, p. 330) by first reacting the compounds of general formula (II) with a carbonyl compound which contains a number of carbon atoms corresponding to the radical Rl or R2 After the inter-mediate compound is obtained, it is then converted into the desired end product by means of a reducing agent.
-` 1094097 The reaction can be carried out in an inert solvent and, as reducing agent, there can be used, for example, formic acid, catalytically activated hydrogen, or a metal hydride, such as sodium borohydride or sodium cyanoborohydride.
Examples of carbonyl compounds which can be used include the aliphatic aldehydes, such as formaldehyde, acetaldehyde, propionaldehyde, isobutyraldehyde, butyraldehyde and valer-aldehyde, and the ketones, such as acetone, methyl ethyl ketone, methylpropyl ketone, diethyl ketone, cyclohexanone, cyclopent-anone and cycloheptanone.
Examples of aromatic aldehydes, which can be usedencompass benzaldehyde, halogenated aldehydes, such as chlorobenzaldehyde or bromobenzaldehyde, tolualdehyde, mono-and dihydroxybenzaldehyde, methoxybenzaldehyde, di- and tri-methoxybenzaldehydes, such as veratraldehyde, piperonal and 3, 4, 5-trimethoxybenzaldehyde, and hydroxymethoxybenzaldehydes, such as vanillin or isovanillin, as well as furfural or thio-phene-aldehyde.
When using the carbonyl compound formaldehyde, the corresponding N-methyl or N,N-dimethyl compounds are obtained, whereas the other aldehydes yield only the N-monosubstituted compounds. The N,N-mixed substituted compounds are, therefore, prepared by first carrying out a reductive alkylation with a -carbonyl compound which possess a number of carbon atoms cor-responding to the radical R2 and then introducing the methyl radical Rl by means of formaldehyde.
Compounds of general formula (I) in which Rl is a hydrogen atom and R2 is a methyl radical can be prepared by reductively N-methylating the N-benzyl compound by means of formaldehyde and subsequently splitting off the benzyl radical hydrogenolytically in the presence of a catalyst such as pal-ladium charcoal or platinum oxide.
~09409'7 For the preparation of the compounds of general formula (I), the compounds of formula (II) are reacted with equivalent or excess amounts of a carbonyl compound in an inert solvent.
The carbonyl compound may also serve as the solvent. The intermediate is then hydrogenated in the presence of a catalyst, such as palladium-charcoal or platinum oxide, at ambient or a moderately elevated temperature, preferably at 20 to 50C. The hydrogenation can be carried out at a hydrogen pressure of about 1 to 5 atmospheres. The reductive alkylation, especially the 10 methylation or benzylation, may be carried out in such a manner that the intermediate formed by the reaction with a compound of general formula (II) is reduced with sodium borohydride (see Helv. Chim. Acta., 46 327/1963) or sodium cyanoborohydride (see J. Org. Chem., 37, 1673/1972); the reaction is preferably carried out at a temperature of from O to 25C. and in a polar solvent such as water, methanol, ethanol, dioxan, tetrahydro-furan, acetonitrile or aqueous mixtures of these solvents.
N-methylation can also be accomplished by reductive alkylation of the monosubstituted amine with a carbonyl com-20 pound, such as formaldehyde, and formic acid or formamides asreducing agents. (See Houben-Weyl, vol. 11/2, p. 331).
When R3 is to be an alkyl radical, the carboxyl group of the amino acid obtained is esterified. The reaction is, most simply, carried out by dissolving the free amino acid of formula (I~ or a salt thereof in an excess of the esterifying alcohol and saturating the solution with hydrogen chloride.
The amino acid ester hydrochloride is thus directly obtained.
The compounds of general formula (II) used as starting materials can be prepared by one of the following methods:
(a) converting a compound of the general formula:
HOOC - CH2 ~ C - CH2 - COOR5 ~ (IV), (CH2)n wherein R5 is an alkyl radical containing up to 8 carbon atoms and n is 4,5, or 6, via a reactive acid derivative, into an azide and then subjecting this to the Curtius rearrangement; or ~b) subjecting a compound of the general formula:
(V) (CH2)n in which n is 4,5 or 6 to the Hofmann rearrangement, or (c) subjecting a compound of the general formula:
> N - CO - CH2 - C j CH2 - COOH
HO ~ (VI) (CH2)n wherein n is 4, 5, or 6, or a compound of the general formula:
HO - N \ \ C /'~~~(CH2)n (VIa) wherein n is 4, 5 or 6, to the Lossen rearrangement.
When a free amino acid is obtained, it may be ester-ified to give a corresponding lower alkyl ester and/or the product obtained may be converted into a pharmaceutically com-patible salt by reaction with an acid or a base.
The reaction of the compounds of general formula (IV) takes place according to the well-known Curtius rearrangement.
The free carboxyl group is first activated by conversion into a reactive derivative, for example an acid halide or a mixed anhydride, and subsequently reacted with an appropriate azide, for example, sodium azide. The acid azide thus obtained is then subjected to thermal decomposition in an organic solvent, for example, benzene, toluene or an alcohol, such as ethanol, during which nitrogen is split off and an introamolecular rearrangement to an isocyanate or, in the presence of an alco-hol, to a urethane takes place. The isocyanates and theureth-anes can easily be converted into the desired primary amines by basic or acidic hydrolysis.
The well-known Hofmann rearrangement of compounds of general formula (V) also takes place via isocyanates. In this case, the acid amides are reacted with alkali metal hypohalites.
Upon hydrolysis of the isocyanate formed by anionotropic re-arrangement, the desired amine is formed, together with carbon dioxide.
The Lossen rearrangement of the hydroxamic acids of general formula (VI) also takes a similar course. In this case, water is split off, the corresponding isocyanate first eing formed, hydrolysis of which gives the desired amine.
Usually the hydroxamic acids are reacted with bases via their 0-acyl derivatives as, for example, the 0-acetyl-, 0-benzoyl- and preferably 0-sulfonyl- derivatives.
The compounds of general formula (Vla) can be prepared 10!~4097 by reacting a hemiester of the general formula:
(CH2)n C (VIb) wherein R3 is an alkyl radical containing up to 5 carbon atoms and n is 4,5 or 6, with hydroxylamine at an elevated temper-ature, preferably of from 50 to 100C. (See ~.C.S., 1929, 713).
Since amino acids are amphoteric, pharmacologically compatible salts when R3 is a hydrogen atom, can be salts of appropriate inorganic or organic acids, for example, hydro-chloric acid, sulphuric acid, phosphoric acid, acetic acid, oxalic acid, latic acid, citric acid, malic acid, salicylic acid, malonic acid, maleic acid, succinic acid or ascorbic acid, but also, starting from the correspond;ng hydroxides or carbonates~ salts with alkali metals or alkaline earth metals, for example, sodium, potassium, magnesium or calcium.
Salts with quaternary ammonium ions can also be prepared with, for example, the tetramethyl-ammonium ion. Of course, when R3 is a lower alkyl radical, it is only possible to form salts with acids.
The compounds of general formula (IV) used as starting materials can be prepared by reacting an acid anhydride of the general formula:
ICl CH2 (VI I ) '-` 1094097 wherein n is 4, 5, or 6, either with water, or with one mole of an alcohol of the general formula:
~0 - R5 (VIII), wherein R~ has the same meaning as above.
The compounds of general formula (VII) are known (see J.C.S., 115, 686/1919; Soc., 99, 446; J.C.S., 117, 639/1920.
Some of the compounds of general formula (V), as well as processes for the preparation thereof, are known (see Austral J.C., 13, 127/1960). They can also be prepared, for example, by reacting compounds of general formula (VII) with ammonia.
In this case it is advantageous to operate at the lowest possible temperature. However, it is also possible, as des-cribed above, to prepare a hemiester and to react the free carboxyl group with, for example, ethyl chloroformate and subsequently with ammonia.
The hydroxamic acids of general formula (VI) can be obtained analogously by reaction of the anhydride (VII) with hydroxylamine.
Because of their low toxicity, the compounds of general formula (I) according to the present invention can be administered enterally or parenterally within wide dosage limits in solid or liquid form. As injection solution, water which contains the additives usual in the case of injection solutions, such as stabilizing agents, solubilizing agents or buffers is preferably employed.
Additives of this type include, for example, tartrate and citrate buffers, ethanol, complex-forming agents such as ethylenediamine-tetraacetic acid and the non-toxic salts there-of, as well as high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation. Sold carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids such as stearic acid, gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers such as polyethylene glycol. Compositions which are suitable for oral administration can, if desired, also contain flavoring and/or sweetening agents.
The individual dosage for the compounds according to the present invention are preferably 5 - 50 mg. parenterally and 20 - 200 mg. enterally.
Thus, the present invention also provides pharmaceutical compositions containing at least one compound of general formula (I) and/or at least one pharmaceutically compatible salt thereof in admixture with a solid or liquid pharmaceutical diluent or carrier.
The following Examples are given for the purpose of illustrating the present invention:
l-(n,N-Dimethylaminomethyl)-cyclohexane-acetic acid.
4.5 9. l-aminomethylcyclohexane-acetic acid are dis-solved in 150 ml. water and mixed with 8.5 ml. 37% aqueous formaldehyde solution. The reaction mixture is hydrogenated in the presence of palladium-charcoal (10%) at ambient temper-ature and atmospheric pressure. The calculated amount of hydrogen is taken up after 3 hours. The reaction mixture is filtered and the filtrate acidified to pH 2 with dilute hydro-chloric acid and then concentrated in a vacuum. By crystal-lisation of the residue from acetone/diethyl ether, there are obtained 4.9 9. (79% of theory) l-(N,N-dimethylaminoethyl)-cyclohexane-acetic acid in the form of its hydrochloride; m.p.
140 - 142C.
g ' 1094097 Analysis:
CllH21N02.HCl.l/4H20 calc. : C 54.99%; H 9.44%; N 5.83~; CI 14.76%
found : 54.90%; 9.36X; 6.22%; 15.05%
The l-aminomethylcyclohexane-acetic acid used as starting material is prepared as follows:
5.6 ml. triethylamine in 16 ml. anhydrous acetone is added dropwise, with stirring and cooling to 0C., to a solution of 7.28 9. l,l-cyclohexane-diacetic acid monomethyl ester in 60 ml. anhydrous acetone, followed by a solution of 3.6 ml. ethyl chloroformate in 16 ml. anhydrous acetone.
Stirring is continued for 30 minutes at 0C. and then a solution of 3.4 9. sodium azide in 12 ml. water is added there-to dropwise. The reaction mixture is further stirred for 1 hour at 0C., then poured into ice-water and extracted three times with 50 ml. amounts of ice-cold toluene. The combined extracts are dried at 0C. over anhydrous sodium sulphate and subsequently dropped into a flask pre-heated to 100C. The mixture is further heated under reflux for 1 hour and then ~0 evaporated in a vacuum. The crude methyl l-isocyanatomethyl-l-cyclohexane-acetate remaining behind is heated under reflux for 3 hours in 50 ml. 20% hydrochloric acid. After cooling the solution, the l-aminomethyl-l-cyclohexane-acetic acid lactam formed as a by-product is removed by extracting three times with 100 ml. amounts of chloroform, whereafter the aqueous hydrochloric acid solution is evaporated in a vacuum.
The l-aminomethyl-l-cyclohexane-acetic acid crystallises out as the hydrochloride; m.p. 123 - 132C., after recrystal-lisation from acetone/methanol/diethyl ether.
-` 1094097 l-(N,N-Dimethylaminomethyl)-cycloheptane-acetic acid In a manner analogous to that described in Example 1, by the catalytic hydrogenation of a solution of 5.5 9. 1-aminomethyl-cycloheptane-acetic acid and 9.6 ml. 37~ aqueous formaldehyde solution in 180 ml. water in the presence of 5.5 9. palladium-charcoal (10%) and corresponding working up, there are obtained 4.97 9. (67% of theory) l-(N,N-dimethyl-aminomethyl)-cycloheptane-acetic acid in the form of its hydro-chloride; m.p. 185 - 188C.
Analysis:
C12H23N02.HCl calc. : C 57.70%; H 9.68%; N 5.61%; Cl 14.19%
found : 57.75%; 9.60% 5.51%; 14.23%
The l-aminomethyl-cycloheptane-acetic acid used as starting material is prepared as follows:
13.7 9. l,l-cycloheptane-diacetic anhydride are mixed with 2.36 9. anhydrous methanol in 10 ml. benzene and the mixture boiled under reflux for 2 hours. After evaporating 20 the reaction mixture in a vacuum, there are obtained 15.~ 9.
l,l-cycloheptane-diacetic acid monomethyl ester. This is dissolved in 100 ml. anhydrous acetone and, in a manner anal-ogous to that described in Example 1, first mixed with 8.1 9.
triethylamine in 30 ml. acetone and thereafter with 9.8 9.
ethyl chloroformate in 30 ml. anhydrous acetone and finally with 6.5 9. sodium azide in 20 ml. water. After the reaction has taken place, the reaction mixture is extracted in the manner described in Example 1 and the solution obtained of l,1-cycloheptane-diacetic acid monomethyl ester azide in 30 toluene is rearranged to give the corresponding isocyanate.
The l-isocyanatomethyl-l-cycloheptane-acetic acid methyl ester obtained is then boiled under reflux for 3 hours with ~094097 20% hydrochloric acid. Upon concentrating the reaction mixture in a vacuum, l-aminomethyl-l-cycloheptane-acetic acid separates out in the form of its hydrochloride, which is re-crystallised from methanol/acetone/ethyl acetate; m.p. 69 -72C.
l-(N-Isopropylaminomethyl)-cyclohexane-acetic acid 5 9. l-aminomethylcyclohexaneacetic acid hydrochloride are hydrogenated at ambient temperature in a mixture of 60 ml.
water and 30 ml. acetone in the presence of 0.5 9. platinum oxide. The calculated amount of hydrogen is taken up after 5 hours. The catalyst is filtered off and the filtrate is evaporated in a vacuum. Crystallisation of the residue for isopropanol/acetone gives 5.2 g. (88% of theory) l-(N-iso-propylaminomethyl)-cyclohexaneacetic acid in the form of its hydrochloride; m.p. 175 - 180C.
Analysis:
C12H23N02.HCl calc. : C 57.70%; H 9.68%; H 5.61%; Cl 14.19%
found : 57.76%; 9.74%; 5.94%; 14.12%
l-(N-Isopropylaminomethyl)-cycloheptane-acetic acid In a manner analogous to that described in Example 3, 1.11 9. l-aminomethylcycloheptane-acetic acid hydrochloride is hydrogenated in a solution of 10 ml. water and 10 ml. ace-tone in the presence of 0.1 9. platinum oxide. After appropri-ate working up and crystallisation from isopropanol/acetone, there is obtained l-(N-isopropylaminomethyl~-cycloheptane-acetic acid in the form of its hydrochloride; m.p. 193 - 194C.
30 (sublimes ~150C.).
l-(N-n-Propylaminomethyl)-cyclohexane-acetic acid A solution of 0.86 g. l-aminomethylcyclohexane-acetic acid in 1.16 9. propionaldehyde in 100 ml. 95% ethanol is hydrogenated at ambient temperature in the presence of 0.85 9.
palladium-charcoal (10%). After 1 hour, the calculated amount of hydrogen is taken up. The catalyst is filtered off, the filtrate is acidified with dilute hydrochloric acid and then evaporated in a vacuum. Crystallisation from acetone/diethyl ether gives l-(N-n-propylaminomethyl)-cyclohexane-acetic acid in the form of its hydrochloride; m.p. 148 - 152C.
l-(N-n-Propylaminomethyl)-cycloheptane-acetic acid In a manner analogous to that described in Example 5, by the catalytic hydrogenation of 1.1 9. l-aminomethyl-cyclo-heptane-acetic acid and 1.16 9. propionaldehyde in 100 ml.
ethanol in the presence of 1.16 9. palladium-charcoal ~10~) at ambient temperature and appropriate working up, there is obtained l-(N-n-propylaminomethyl)-cycloheptane-acetic acid;
m.p. 182 - 183C.
l-(N-Ethylaminomethyl)-cyclohexane-acetic acid In a manner analogous to that described in Example 5, by the catalytic hydrogenation of a solution of 0~86 9.
l-aminomethylcyclohexane-acetic acid and 2.2 9. acetaldehyde in 100 ml. methanol in the presence of 0.85 9. palladium-charcoal and appropriate working up, there is obtained l-(N-ethylaminomethyl)-cyclohexane-acetic acid; m.p. 172 -173C., after recrystallisation from isopropanol/diethyl ether.
l-(N-Ethylaminomethyl`)-cycloheptane-acetic acid In a manner analogous to that described in Example 5, by the catalytic hydrogenation of 1.85 9. l-aminomethyl-cycloheptane-acetic acid and 2.2 9. acetaldehyde in 100 ml.
ethanol in the presence of 1.85 9. palladium-charcoal and appropriate working up, there is obtained l-(N-ethylamino-methyl)-cycloheptane-acetic acid in the form of its hydro-chloride; m.p. 168 - 170C.
l-(N-n-Butylaminomethyl)-cyclohexane-acetic acid In a manner analogous to that described in Example 5, by the catalytic hydrogenation of a mixture of 0.86 9.
l-aminomethylcyclohexane-acetic acid and 1.44 9. n-butyr-aldehyde in 50 ml. 95% ethanol in the presence of 0.8 9.
palladium-charcoal, there is obtained l-(N-n-butylaminomethyl) -cyclohexane-acetic acid; m.p. 142 - 154C.
l-(N-n-Butylaminomethyl)-cycloheptane-acetic acid In a manner analogous to that described in Example 5, 0.93 9. l-aminomethylcycloheptane-acetic acid are hydrogen-ated with 1.44 9. n-butyraldehyde in 50 ml. ethanol in the presencepresence of 0.9 9. palladium-charcoal. After appropri-ate working up and crystallisation from acetone/diethyl ether, there is obtained l-N-n-butylaminomethyl)-cycloheptane-acetic acid in the form of its hydrochloride; m.p. 158 - 165C.
10'34097 l-(N-Benzylaminome`thyl)-cyclohexane-acetic acid Variant A.
0.86 9. l-aminomethylcyclohexane-acetic acid are hydrogenated in 50 ml. 95% ethanol with 0.65 9. benzaldehyde in the presence of 0.1 q. platinum oxide. The reaction mixture is work up in the manner described in Example 5. After crystallisation from acetone/diethyl ether, there is obtained - l-N-benzylaminomethyl)-cyclohexane-acetic acid in the form of its hydrochloride; m.p. 125 - 135 C.
Variant B.
386 g. sodium l-aminomethylcyclohexane-acetate in 2 ml.
water, prepared from the free amino acid by the addition of an equivalent amount of sodium hydroxide in water, are mixed with 0.21 ml. benzaldehyde. The reaction mixture is stirred at ambient temperature until the solution is homogeneous.
Subsequently, 75 mg. sodium cyanoborohydride are introduced portionwise, while stirring. After stirring for one hour, the reaction mixture is acidified with dilute hydrochloric acid 20 and evaporated in a vacuum. After crystallisation of the residue from acetone/diethyl ether, there is obtained l-(N-benzylaminomethyl)-cyclohexane-acetic acid, the hydrochloride of which melts at 125 - 135C.
l-(N-Benzyl-N-methylaminomethyl)-cyclohexane-acetic acid 500 mg. l-(N-Benzylaminomethyl)-cyclohexane-acetic acid hydrochloride (cf. Example 11) are dissolved in 10 ml.
water and mixed with 1.68 ml. lN aqueous sodium hydroxide solution. This solution is introduced into a prehydroqenated ` 1094097 solution of 500 mg. platinum dioxide in 10 ml. water. After the addition of 1 ml. 37% aqueous formaldehyde solution, hydrogenation is carried out at ambient temperature and atmostpheric pressure. After about 2 hours, the take up of hydrogen ceases. The catalyst is filtered off and the fil-trate, after acidification with dilute hydrochloric acid, is evaporated in a vacuum. Excess formaldehyde is removed by repeated evaporation with water. Crystallisation of the residue from acetone/diethyl ether gives l-(N-benzyl-N-meth-ylaminomethyl)-cyclohexane-acetic acid hydrochloride; m.p.
150 - 157C.
l-(N-Methylaminomethyl)-cyclohexane-acetic acid 178 mg. l-(N-benzyl-N-methylaminomethyl)-cyclohexane-acetic acid hydrochloride are hydrogenated in 25 ml. ethanol in the presence of 0.2 9. palladium-charcoal at ambient temperature and atmospheric pressure. After 1 hour, the cata-lyst is filtered off and the filtrate evaporated ;n a vacuum at 20C. Crystallisation of the residue from acetone/diethyl ether gives l-(N-methylaminomethyl)-cyclohexane-acetic acid in the form of its hydrochloride; m.p. 160 - 162C.
l-(N-Ethyl-N-methylaminomethyl)-cycloheptane-acetic acid 1 9. l-(N-ethylaminomethyl)-cycloheptane-acetic acid hydrochloride (cf. Example 8) is dissolved in 60 ml. water and mixed with 4 ml. lN aqueous sodium hydroxide solution.
After the addition of 2 ml. 37% aqueous formaldehyde solution, the reaction mixture is hydrogenated in the presence of 1 9.
palladium-charcoal at ambient temperature and atmospheric pressure. After about 2 hours, the calculated amount of ~0~34097 hydrogen is taken up. The reaction mixture is then worked up in the manner described in Example 12 and, after recrystal-lisation from acetone/diethyl ether, there is obtained l-(N-ethyl-N-methylaminomethyl)-cycloheptane-acetic acid in the form of its hydrochloride; m.p. 148 - 153C.
l-(N-Cyclohexylaminomethyl)-cycloheptane-acetic acid A solution of 925 mg. l-aminomethylcycloheptane-acetic acid and 982 mg. cyclohexanone in 50 ml. 90% aqueous methanol is hydrogenated in the presence of 0.8 9. palladium-charcoal at ambient temperature and atmospheric pressure.
After working up the reaction mixture in the manner described in Example 5 and crystallising from aqueous methanol, there is obtained l-(N-cyclohexylaminomethyl)-cycloheptane-acetic acid hydrochloride; m.p. 198 - 204C.
Ethyl l-(N-ethylaminomethyl)-cycloheptane-acetate 166 mg. l-(N-ethylaminomethyl)-cycloheptane-acetic acid hydrochloride (cf. Example 8) are dissolved in 5 ml.
absolute ethanol. Gaseous hydrogen chloride is passed in and the solution is left to stand overnight at ambient temper-ature. After evaporation in a vacuum and crystallisation of the residue from ethyl acetate/diethyl ether/hexane, there is obtained ethyl l-(N-ethylaminomethyl)-cycloheptane-acetate in the form of its hydrochloride; m.p. 110 - 118C.
109~097 l-(N-benzylaminomethyl~-cycloheptaneOacetic acid A solution of 3 9. l-aminomethylcycloheptane-acetic acid hydrochloride and 13.86 ml. lM aqueous sodium hydroxide solution in 150 ml. ethanol is mixed with 3 g. freshly dis-tilled benzaldehyde and hydrogenated in the presence of 2.3 9.
platinum dioxide at ambient temperature and atmospheric pres-sure. After working up the reaction mixture as described in Example 5 and crystallisation from aqueous ethanol, there is obtained l-(N-benzylaminomethyl)-cycloheptane-acetic acid hydrochloride; m.p. 145 - 157C.
Claims (26)
1. Process for the preparation of compounds of the general formula:
wherein R1 is hydrogen or methyl, R2 is lower alkyl of 1 to 8 carbon atoms or a cycloalkyl of 3 to 8 carbon atoms, or benzyl, R3 is hydrogen or lower alkyl of 1 to 8 carbon atoms and n is 4, 5 or 6, which comprises:
a) when R3 is hydrogen: Reacting under reductive conditions a compound of the formula:
i) with a ketone of the formula in which case R1 may not be hydrogen;
ii) or with formaldehyde when R1 and R2 are both to be methyl;
iii) or with an aldehyde of the formula when R1 is to be hydrogen;
iv) or first with an aldehyde of the formula followed by reaction with formaldehyde when R1 is to be methyl and R2 is to be other than methyl, wherein R2 is as defined above; or b) when R3 is lower alkyl, reacting the compounds obtained in step (a) with a loweralkanol having 1 to 8 carbon atoms.
wherein R1 is hydrogen or methyl, R2 is lower alkyl of 1 to 8 carbon atoms or a cycloalkyl of 3 to 8 carbon atoms, or benzyl, R3 is hydrogen or lower alkyl of 1 to 8 carbon atoms and n is 4, 5 or 6, which comprises:
a) when R3 is hydrogen: Reacting under reductive conditions a compound of the formula:
i) with a ketone of the formula in which case R1 may not be hydrogen;
ii) or with formaldehyde when R1 and R2 are both to be methyl;
iii) or with an aldehyde of the formula when R1 is to be hydrogen;
iv) or first with an aldehyde of the formula followed by reaction with formaldehyde when R1 is to be methyl and R2 is to be other than methyl, wherein R2 is as defined above; or b) when R3 is lower alkyl, reacting the compounds obtained in step (a) with a loweralkanol having 1 to 8 carbon atoms.
2. The process of Claim 1, wherein l-aminomethyl-cyclohexane-acetic acid is reacted with formaldehyde and the reaction mixture is reduced to form the l-(N,N-dimethylamino-methyl)-cyclohexane-acetic acid.
3. The process of Claim 1, wherein l-aminomethyl-cycloheptane-acetic acid is reacted with formaldehyde and the reaction mixture is reduced to form the l-(N,N-dimethylamino-methyl)-cycloheptane-acetic acid.
4. The process of Claim 1, wherein l-aminomethyl-cyclohexane-acetic acid is reacted with acetone under reductive conditions to form the l-(N-isopropylaminomethyl)-cyclohexane-acetic acid.
5. The process of Claim 1, wherein l-aminomethyl-cycloheptane-acetic acid is reacted with acetone under reductive conditions to form the l-(N-isopropylaminomethyl)-cycloheptane-acetic acid.
6. The process of Claim 1, wherein l-aminomethyl-cyclohexane-acetic acid is reacted with propionaldehyde under reductive conditions to form the l-(N-n-propylaminomethyl)-cyclohexane-acetic acid.
7. The process of Claim 1, wherein l-aminomethyl-cycloheptane-acetic acid is reacted with propionaldehyde under reductive conditions to form the l-(N-n-propylaminomethyl)-cycloheptane-acetic acid.
8. The process of Claim 1, wherein l-aminomethyl-cyclohexane-acetic acid is reacted with acetaldehyde under reductive conditions to form the l-(N-ethylaminomethyl)-cyclohexane-acetic acid.
9. The process of Claim l, wherein the l-amino-methylcycloheptane-acetic acid is reacted with acetaldehyde under reductive conditions to form the l-(N-ethylaminomethyl)-cycloheptane-acetic acid.
10. The process of Claim l, wherein the l-amino-methylcyclohexane-acetic acid is reacted with n-butyraldehyde under reductive conditions to form the l-(N-n-butylamino-methyl)-cyclohexane-acetic acid.
11. The process of Claim l, wherein the l-amino-methylcycloheptane-acetic acid is reacted with n-butyraldehyde under reductive conditions to form the l-(N-n-butylamino-methyl)-cycloheptane-acetic acid.
12. The process of Claim 1, wherein l-aminomethyl-cyclohexane-acetic acid is reacted with benzaldehyde under reductive conditions to form the l-(N-benzylaminomethyl)-cyclohexane-acetic acid.
13. The process of Claim 12, wherein the l-(N-benzyl-aminomethyl)-cyclohexane-acetic acid is reacted with formalde-hyde under reductive conditions to form the l-(N-benzyl-N-methylaminomethyl)-cyclohexane-acetic acid.
14. The compounds of the general formula:
wherein Rl is hydrogen or methyl, R2 is lower alkyl of 1 to 8 carbon atoms or a cycloalkyl of 3 to 8 carbon atoms, or benzyl, R3 is hydrogen or lower alkyl of l to 8 carbon atoms and n is 4, 5 or 6, when prepared by the process defined in Claim l or by an obvious chemical equivalent.
wherein Rl is hydrogen or methyl, R2 is lower alkyl of 1 to 8 carbon atoms or a cycloalkyl of 3 to 8 carbon atoms, or benzyl, R3 is hydrogen or lower alkyl of l to 8 carbon atoms and n is 4, 5 or 6, when prepared by the process defined in Claim l or by an obvious chemical equivalent.
15. The 1-(N,N-dimethylaminomethyl)-cyclohexane-acetic acid, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.
16. The 1-(N,N-dimethylaminomethyl)-cycloheptane-acetic acid, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.
17. The 1-(N-isopropylaminomethyl)-cyclohexane-acetic acid, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.
18. The 1-(N-isopropylaminomethyl)-cycloheptane-acetic acid, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.
19. The 1-(N-n-propylaminomethyl)-cyclohexane-acetic acid, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.
20. The 1-(N-n-propylaminomethyl)-cycloheptane-acetic acid, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.
21. The 1-(N-ethylaminomethyl)-cyclohexane-acetic acid, when prepared by the process defined in Claim 8 or by an obvious chemical equivalent.
22. The 1-(N-ethylaminomethyl)-cycloheptane-acetic acid, when prepared by the process defined in Claim 9 or by an obvious chemical equivalent.
23. The 1-(N-n-butylaminomethyl)-cyclohexane-acetic acid, when prepared by the process defined in Claim 10 or by an obvious chemical equivalent.
24. The l-(N-n-butylaminomethyl)-cycloheptane-acetic acid, when prepared by the process defined in Claim 11 or by an obvious chemical equivalent.
25. The l-(N-benzylaminomethyl)-cyclohexane-acetic acid, when prepared by the process defined in Claim 12 or by an obvious chemical equivalent.
26. The l-(N-benzyl-N-methylaminomethyl)-cyclohexane-acetic acid, when prepared by the process defined in Claim 13 or by an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2626467A DE2626467C2 (en) | 1976-06-12 | 1976-06-12 | 1- (N-Isopropylaminomethyl) -cyclohexaneacetic acid, process for the preparation thereof and medicaments containing this compound |
| DEP2626467.5 | 1976-06-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1094097A true CA1094097A (en) | 1981-01-20 |
Family
ID=5980432
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA280,334A Expired CA1094097A (en) | 1976-06-12 | 1977-06-10 | Cyclic amino acid derivatives |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS52153946A (en) |
| AU (1) | AU508229B2 (en) |
| CA (1) | CA1094097A (en) |
| DE (1) | DE2626467C2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5091567A (en) * | 1989-08-25 | 1992-02-25 | Godecke Aktiengesellschaft | Process for the preparation of 1-aminomethyl-1-cyclohexaneacetic acid |
| GB2362646A (en) * | 2000-05-26 | 2001-11-28 | Warner Lambert Co | Cyclic amino acid derivatives useful as pharmaceutical agents |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02132299A (en) * | 1988-11-14 | 1990-05-21 | Tokai Rubber Ind Ltd | Waterproof construction method |
| FI107914B (en) * | 1989-08-25 | 2001-10-31 | Warner Lambert Co | An improved process for the preparation of cyclic amino acid compounds and an intermediate used in the process |
| KR100512506B1 (en) * | 1996-03-14 | 2005-12-21 | 워너-램버트 캄파니 엘엘씨 | Novel Substituted Cyclic Amino Acids as Pharmaceutical Agents |
-
1976
- 1976-06-12 DE DE2626467A patent/DE2626467C2/en not_active Expired
-
1977
- 1977-06-10 JP JP6874277A patent/JPS52153946A/en active Granted
- 1977-06-10 CA CA280,334A patent/CA1094097A/en not_active Expired
- 1977-06-10 AU AU26024/77A patent/AU508229B2/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5091567A (en) * | 1989-08-25 | 1992-02-25 | Godecke Aktiengesellschaft | Process for the preparation of 1-aminomethyl-1-cyclohexaneacetic acid |
| GB2362646A (en) * | 2000-05-26 | 2001-11-28 | Warner Lambert Co | Cyclic amino acid derivatives useful as pharmaceutical agents |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS52153946A (en) | 1977-12-21 |
| DE2626467C2 (en) | 1984-11-22 |
| DE2626467A1 (en) | 1977-12-29 |
| AU508229B2 (en) | 1980-03-13 |
| JPS5633385B2 (en) | 1981-08-03 |
| AU2602477A (en) | 1978-12-14 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |