CA1254230A - Cycloalkane-indene- carboximidamide derivatives - Google Patents
Cycloalkane-indene- carboximidamide derivativesInfo
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- CA1254230A CA1254230A CA000482008A CA482008A CA1254230A CA 1254230 A CA1254230 A CA 1254230A CA 000482008 A CA000482008 A CA 000482008A CA 482008 A CA482008 A CA 482008A CA 1254230 A CA1254230 A CA 1254230A
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- pharmaceutically acceptable
- acceptable salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/16—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/16—Benz[e]indenes; Hydrogenated benz[e]indenes
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
CYCLOALRANE-INDENE-CARBOXIMIDAMIDE DERIVATIVES
The present invention is dealing with cycloalkane-indene-carboximidamide derivatives having the general formula:
wherein Rx together with either Ry1 or Ry2 represent the moiety
CYCLOALRANE-INDENE-CARBOXIMIDAMIDE DERIVATIVES
The present invention is dealing with cycloalkane-indene-carboximidamide derivatives having the general formula:
wherein Rx together with either Ry1 or Ry2 represent the moiety
Description
~L25423(3 CYCLOALKANE-INDENE-CARBOXIMIDAMIDE DERIVATIVES
The present invention is dealing with cycloalkane-indene-carboximidamide derivatives and to a pharmaceutical preparation which contains these novel compounds as the active constituent.
More especially, the invention relates to carboximidamide derivatives having the general foxmula:
Rx ~ ` NHR2 ~herein ~x together with either Ryl or RY2 represent the moiety ~ n R
(the other Ry being hydrogen), n represents the number 1, 2 or 3, R represents hydrogen or a (1-4 C)-alkyl group, Rl represents hydrogen, (1-4 C)-alkyl, hydroxyl, (1-4 C)-alkoxy or anamino groupwhich-isunsubstituted or substituted by (1-4 C)-alkyl and R2 is hydrogen, hydroxyl or (1-4 C)-alkyl, as well as the pharmaceutically acceptable salts thereof.
The present compounds and salts thereof exhibit powerful blood platelet aggregation-inhibiting activity, as a result of ~-hich they are useful in combating certain cardiovascular conditions. They have relatively few side-effects.
The compounds according to the general formula I can be prepared in a manner usual for analogous compounds.
These compounds I can, for example, be prepared by ~f ~254230
The present invention is dealing with cycloalkane-indene-carboximidamide derivatives and to a pharmaceutical preparation which contains these novel compounds as the active constituent.
More especially, the invention relates to carboximidamide derivatives having the general foxmula:
Rx ~ ` NHR2 ~herein ~x together with either Ryl or RY2 represent the moiety ~ n R
(the other Ry being hydrogen), n represents the number 1, 2 or 3, R represents hydrogen or a (1-4 C)-alkyl group, Rl represents hydrogen, (1-4 C)-alkyl, hydroxyl, (1-4 C)-alkoxy or anamino groupwhich-isunsubstituted or substituted by (1-4 C)-alkyl and R2 is hydrogen, hydroxyl or (1-4 C)-alkyl, as well as the pharmaceutically acceptable salts thereof.
The present compounds and salts thereof exhibit powerful blood platelet aggregation-inhibiting activity, as a result of ~-hich they are useful in combating certain cardiovascular conditions. They have relatively few side-effects.
The compounds according to the general formula I can be prepared in a manner usual for analogous compounds.
These compounds I can, for example, be prepared by ~f ~254230
-2- 23804-206 condensing a o- or S-alkyliso(thio)amide having the general formula II:
RX~ ~ NR2 II
RYl~/ ZRo or an acid addition salt thereof, with ammonia or a hydroxylamine, hydrazine or amine derivative having the formula III:
~ Rl H - N III
or an acid addition salt thereof, wherein Rx, Ryl, Ry2~ R, n and Rl have the meanings given above, R21 has the same meaning as R2 but can also be an amino group which is unsubstituted or sub-stituted by (1-4 C)-alkyl, æ represents an oxygen or sulphur atom and Ro represents a lower alkyl group, preferably methyl or ethyl.
The compounds I wherein R2 represents hydrogen or hydroxyl can moreover be prepared by condensatlon of the nitrile of the general formula IV:
Ry~ ~> CN IV
wherein RX, Ryl and RY2 have the above-mentioned meaning~ with a compound of the general formula III described above, or an acid addition salt thereof.
The starting materials of the general formulae II and IV
required for the above condensation reactions can be prepared in a manner customary for analogous compounds.
~L25~23~
RX~ ~ NR2 II
RYl~/ ZRo or an acid addition salt thereof, with ammonia or a hydroxylamine, hydrazine or amine derivative having the formula III:
~ Rl H - N III
or an acid addition salt thereof, wherein Rx, Ryl, Ry2~ R, n and Rl have the meanings given above, R21 has the same meaning as R2 but can also be an amino group which is unsubstituted or sub-stituted by (1-4 C)-alkyl, æ represents an oxygen or sulphur atom and Ro represents a lower alkyl group, preferably methyl or ethyl.
The compounds I wherein R2 represents hydrogen or hydroxyl can moreover be prepared by condensatlon of the nitrile of the general formula IV:
Ry~ ~> CN IV
wherein RX, Ryl and RY2 have the above-mentioned meaning~ with a compound of the general formula III described above, or an acid addition salt thereof.
The starting materials of the general formulae II and IV
required for the above condensation reactions can be prepared in a manner customary for analogous compounds.
~L25~23~
-3- 23804-206 The attached flow sheets show a number of methods for the preparation of these starting materials.
Compounds according to the general formula III needed in the above-mentioned condensation reactions include, inter alia, ammonia (NH3), methylamine, ethylamine, propylamine, isobutylamine, butylamine, hydroxylamine, hydroxylamine methyl ether, hydroxylamine ethyl ether, hydroxylamine propyl ether, hydrazine, l-methylhydra-zine and l,l-dimethylhydrazine, as well as the acid addition salts thereof.
Preferably, the substituents on the nitrogen atoms (Rl R2) should already be present in either starting material mentioned.
However, it is also possible to modify or introduce one or more substituents after the above-mentioned condensation reactions.
~54230 For example, one of the nltrogen atoms of a compound I (Rl or R2 ~ H) can be alkylated in a known manner, for example by maans of alkyl halides, by means of an Eschweiler-Clarke reaction or by acylation followed by reduction. The N-hydroxyl group which may be present in the compound of formula I ~Rl or R2 is hydroxyl~ will also be alkylated during such an alkylation. Moreover, this N-hydroxyl group can be specifically alkylated by means of, for example, dimethyl sulphate.
The compounds of the formula I contain an alkaline group. They can, depending on the medium in which they are prepared, be obtained as free base or as an acid addition salt. However, if desired the free base I can be prepared from the salt, for example by reaction with an alkaline compound or by means of an ion exchanger, while the free base I can be converted in a simple manner into an acid addition salt.
Pharmaceutically acceptable acid addition salts are obtained by allowing the free base I to react with acids, such as hydrochloric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, fumaric acid, malonic acid. succinic acid, tartaric acid, lactic acid, citric acid, ascorbic acid or salicylic acid.
It follows from the general formula I of the end products that the compounds according to the invention may contain an asymetric carbon, as a result of whlch not only racemic mixtures I but also optically active compounds I are possible. These optically active compounds I are also to be included among the compounds according to the invention. They can be prepared directly from an optically active starting material (II, IV) or be obtained by resolving the racemate I
into its optical antipodes in a manner customary for such resolutions.
12$42310 The present compounds accordlng to the invantlon can be administered orally, locally or parenterally, preferably in a daily dose of between O.Ol and 50 mg per kilogram of body weight. The compounds are, for this purpose, converted in a customary manner into a form suitable for oral, local or parenteral admlnistration, for example a tablet, pill, capsule, 301ution, suspension, emulsion, paste or spray.
An administration form for oral use is preferred.
Compounds I which are preferred are compounds whersin the carboximidamide group has the following structure3:
,i ~ NOH ~NOH 1~
--C ~ , C\
NH2 NHOH 1 j NOC~3 //NH
-C \ and -C \
More especially that compound of formula I is preferred wherein R
represents hydrogen, n represents the number 1 or 2, R2 is hydrogen and Rl represents a hydroxyl group, as well as acid addition salts thereof.
The position of the double bond between the nitrogen and carbon atom in the carboximidamide group of formula I csnnot be specified unam~iguously since an equilibrium will set up betwsen the groups:
~ NRl NHR
-C \ and -C ~
Both tautomeric forms are included in the invention.
~2S4L~30 Prepar _ ion of startlng materlAl A. Ethyl 2-cyano-2~3,5,6~7,8-hexahydro-lH-ben~ indene-2-carboxylate NaOC2Hs was prepared in a 10 litre 3-necked flask by adding small pieces of sodium (1.68 moles) to absolute ethanol (900 ml) over a period of about 1 hour. The temperature was kept at 60-70C by controlling the speed of addition.
After all sodium had reacted, the mixture was cooled to room temperature and thereafter dry THF (1650 ml) and ethyl cyanoacetate (1.68 moles) were added all at once. After 5 minutes, a precipitate began to form and slowly thickened. Afte} 30 minutes' stirring, the reaction mixture was cooled with ica water to 10-15C and thereafter a solution of 2,3-bis-(bromoethyl~-5,6,7,8-tetrahydro-naphthalene (0.84 mole~ in dry THF (1000 ml) was added as rapidly as possible (2 to 3 minutes). As a result of the exothermic character of the reaction, the temperature rose to about 35C; thereafter the mixture was cooled to room temperature and stirred for a further hour.
The reaction mixture was then evaporated as far as possible and the residue was partitloned between methylene chlaride (750 ml) and water (about 400 ml). The layers were separated and the water layer was extracted twice wlth methyle~e chloride (250 ml). The combined methylene chloride extracts were washed once with water (200 ml) and dried over Na2S04. After the drying agent had been filtered off, the filtrate was evaporated. This gave about 300 g of a yellow oil.
300 ~1 of ether were added to the residue and after seeding 80.5 g of the desired compound crystallised out.
B. 2,3,5,6,7,8-Hexahydro-lH-benzlflindene-2-carbonitrile -The product (0.29 mole) obtained in A. was suspended in DMS0 tl60 ml). Distilled water (12 ml) and iodine-free sodium chloride t5.6 g) were added. Theresfter the reaction mlxture was heated to 170C for about 3 hours, with stirring, until the C02 evolution had ceased.
- 1~254230 After it had cooled to room temperature, the reaction mixture was poured out slowlyl with stirring, into distilled water (1000 ml). The precipitate was extracted with methylene chloride (4 x 200 ml) and the combined extracts were washed with water (200 ml), dried over Na2S04 and evaporated. The reYidue was filtered over silica gel.
Melting point 102C.
C.. In a corresponding manner as described in A. and B. was prepared:
2,3,4,5,6,7-hexahydro-lH-benzle~indene-2-carbonitrile; m.p. 48C.
Example 1 2,3,5,6,7,8-Hexahydro-N-hydroxy-lH-benzlfJindene-2-carboximidamide.HCl 29.2 g of sodium were dissolved in 560 ml of dry methanol and a warm solution of 88 g of hydroxylamine hydrochlorlde in 110 ml of dry methanol was thereafter added to this solution. The solution obtained had a pH of 8 to 10. Thereafter, the NaCl precipitate formed was filtered off.
The filtrate obtained was added at room tenperature, under nitrogen, to a solution of 25 g (127 millimoles) of 2,3,5,6,7,8-hexahydro-lH-benzlflindene-2-carbonitrile in 560 ml of dry methanol.
The reaction mixture was stirred for 3 x 24 hours at 50C under nitrogen and was then evaporated.
The residue was thereafter stirred with 400 ml of water, after which the precipitate was filtered off, again washed with water and dried. Yield 28 g.
The precipitate was then dissolved in 120 ml of 5N methanolic HCl 301ution. The solution was evaporated to a volume of about 100 ml after which 250 ml of diethyl ether were added.
The precipitate formed after some time at 0C waY filtered off and dried.
Yleld: 26 g of the compound shown in the title.
Rf in methylene chloride:methanol (9~ 0.44 on SiO2; melting point: 213C (with decomposition).
~254230 Example 2 The followlng are prepared in a manner analogous to Example 1:
2,3,5,6,7,8-hexahydro-N-hydroxy-o-methyl-lH-benzlf~indene-2-carboximidamide.HCl, melting point 205C (with decomposition~;
1,2,3,5,6,7-hexahydro-N-hydroxy-~-indacene-2-carboximidamide.
HCl, melting point: 215C (with decomposition);
1,2,3,5,6,7-hexahydro-N-hydroxy-6-methyl-s-indacene-2-carboximidamide.HCl, melting point: 194-195C
1,2,3,5,6,7,8,9-octahydro-N-hydroxy-cycloheptlflindene-2-ca}boximidamide;
2,3,4,5,6,7-hexahydro-N-hydroxy-lH-benzle~indene-2-carboximidamide.HCl, melting point: 194C (dec.);
2,3,4,5,6,7-hexahydro-N-hydroxy-5-methyl-lH-benz[elindene-2-carboximidamide.HCl;
1,2,3,4,5,6-hexahydro-N-hydroxy-as-indacene-2-carboximidamide.HCl;
1,2,3,4,5,6-hexahydro-N-hydroxy-6-methyl-a~-indacene-2-carboximidamide.HCl;
1,2,3,4,5,6,7,8-octahydro-N-hydroxy-cyclohept~e]indene-2-carboximidamide.
Example 3 2,3,5,6,7,8-Hexahydro-N-methoxy-lH-benzlfJindene-2 carboximidamide.HCl Method A
A sodium methanolate solution prepared by di3solving 3.45 g (150 millimoles) of sodium in 50 ml of methanol, was added to a solution of 12.5 g (150 millimoles) of hydroxylamine methyl ether hydrochloride in 60 ml of methanol.
After the mixture had been stirred for about 5 minutes, the sodium chloride formed was filtered off and the filtrate was added to 10 g (50 mi:llimoles) of 2~3~5~6~7~8-hexahydro-lH-benzlfJindene-2 carbonitrile.
125423C~
After 15 hours' atirring at 50C, the methanol was removed and the residue W83 stirred with 250 ml of water.
After the precipitnte had been filtered off, washed neutral with water and dried to constant weight, the amidoxime was suspended in 35 ml of methanol and acidified wlth 2N methanolic HCl solution.
After addition of 165 ml of ether to the solution, the hydrochloride crystallised out. Yield 10.6 g.
Method B
0.5 ml of water, 0.53 g (2 millimoles) of 2,3,5,6,7,8-hexahydro-N-hydroxy-lH-ben~lfJlndene-2-carboxlmidamide hydrochloride and, after a few mlnutes' stirrlng, 0.3 ml (about 3 millimoles) of dimethyl sulphate, were added successively to a solution of g2 mg
Compounds according to the general formula III needed in the above-mentioned condensation reactions include, inter alia, ammonia (NH3), methylamine, ethylamine, propylamine, isobutylamine, butylamine, hydroxylamine, hydroxylamine methyl ether, hydroxylamine ethyl ether, hydroxylamine propyl ether, hydrazine, l-methylhydra-zine and l,l-dimethylhydrazine, as well as the acid addition salts thereof.
Preferably, the substituents on the nitrogen atoms (Rl R2) should already be present in either starting material mentioned.
However, it is also possible to modify or introduce one or more substituents after the above-mentioned condensation reactions.
~54230 For example, one of the nltrogen atoms of a compound I (Rl or R2 ~ H) can be alkylated in a known manner, for example by maans of alkyl halides, by means of an Eschweiler-Clarke reaction or by acylation followed by reduction. The N-hydroxyl group which may be present in the compound of formula I ~Rl or R2 is hydroxyl~ will also be alkylated during such an alkylation. Moreover, this N-hydroxyl group can be specifically alkylated by means of, for example, dimethyl sulphate.
The compounds of the formula I contain an alkaline group. They can, depending on the medium in which they are prepared, be obtained as free base or as an acid addition salt. However, if desired the free base I can be prepared from the salt, for example by reaction with an alkaline compound or by means of an ion exchanger, while the free base I can be converted in a simple manner into an acid addition salt.
Pharmaceutically acceptable acid addition salts are obtained by allowing the free base I to react with acids, such as hydrochloric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, fumaric acid, malonic acid. succinic acid, tartaric acid, lactic acid, citric acid, ascorbic acid or salicylic acid.
It follows from the general formula I of the end products that the compounds according to the invention may contain an asymetric carbon, as a result of whlch not only racemic mixtures I but also optically active compounds I are possible. These optically active compounds I are also to be included among the compounds according to the invention. They can be prepared directly from an optically active starting material (II, IV) or be obtained by resolving the racemate I
into its optical antipodes in a manner customary for such resolutions.
12$42310 The present compounds accordlng to the invantlon can be administered orally, locally or parenterally, preferably in a daily dose of between O.Ol and 50 mg per kilogram of body weight. The compounds are, for this purpose, converted in a customary manner into a form suitable for oral, local or parenteral admlnistration, for example a tablet, pill, capsule, 301ution, suspension, emulsion, paste or spray.
An administration form for oral use is preferred.
Compounds I which are preferred are compounds whersin the carboximidamide group has the following structure3:
,i ~ NOH ~NOH 1~
--C ~ , C\
NH2 NHOH 1 j NOC~3 //NH
-C \ and -C \
More especially that compound of formula I is preferred wherein R
represents hydrogen, n represents the number 1 or 2, R2 is hydrogen and Rl represents a hydroxyl group, as well as acid addition salts thereof.
The position of the double bond between the nitrogen and carbon atom in the carboximidamide group of formula I csnnot be specified unam~iguously since an equilibrium will set up betwsen the groups:
~ NRl NHR
-C \ and -C ~
Both tautomeric forms are included in the invention.
~2S4L~30 Prepar _ ion of startlng materlAl A. Ethyl 2-cyano-2~3,5,6~7,8-hexahydro-lH-ben~ indene-2-carboxylate NaOC2Hs was prepared in a 10 litre 3-necked flask by adding small pieces of sodium (1.68 moles) to absolute ethanol (900 ml) over a period of about 1 hour. The temperature was kept at 60-70C by controlling the speed of addition.
After all sodium had reacted, the mixture was cooled to room temperature and thereafter dry THF (1650 ml) and ethyl cyanoacetate (1.68 moles) were added all at once. After 5 minutes, a precipitate began to form and slowly thickened. Afte} 30 minutes' stirring, the reaction mixture was cooled with ica water to 10-15C and thereafter a solution of 2,3-bis-(bromoethyl~-5,6,7,8-tetrahydro-naphthalene (0.84 mole~ in dry THF (1000 ml) was added as rapidly as possible (2 to 3 minutes). As a result of the exothermic character of the reaction, the temperature rose to about 35C; thereafter the mixture was cooled to room temperature and stirred for a further hour.
The reaction mixture was then evaporated as far as possible and the residue was partitloned between methylene chlaride (750 ml) and water (about 400 ml). The layers were separated and the water layer was extracted twice wlth methyle~e chloride (250 ml). The combined methylene chloride extracts were washed once with water (200 ml) and dried over Na2S04. After the drying agent had been filtered off, the filtrate was evaporated. This gave about 300 g of a yellow oil.
300 ~1 of ether were added to the residue and after seeding 80.5 g of the desired compound crystallised out.
B. 2,3,5,6,7,8-Hexahydro-lH-benzlflindene-2-carbonitrile -The product (0.29 mole) obtained in A. was suspended in DMS0 tl60 ml). Distilled water (12 ml) and iodine-free sodium chloride t5.6 g) were added. Theresfter the reaction mlxture was heated to 170C for about 3 hours, with stirring, until the C02 evolution had ceased.
- 1~254230 After it had cooled to room temperature, the reaction mixture was poured out slowlyl with stirring, into distilled water (1000 ml). The precipitate was extracted with methylene chloride (4 x 200 ml) and the combined extracts were washed with water (200 ml), dried over Na2S04 and evaporated. The reYidue was filtered over silica gel.
Melting point 102C.
C.. In a corresponding manner as described in A. and B. was prepared:
2,3,4,5,6,7-hexahydro-lH-benzle~indene-2-carbonitrile; m.p. 48C.
Example 1 2,3,5,6,7,8-Hexahydro-N-hydroxy-lH-benzlfJindene-2-carboximidamide.HCl 29.2 g of sodium were dissolved in 560 ml of dry methanol and a warm solution of 88 g of hydroxylamine hydrochlorlde in 110 ml of dry methanol was thereafter added to this solution. The solution obtained had a pH of 8 to 10. Thereafter, the NaCl precipitate formed was filtered off.
The filtrate obtained was added at room tenperature, under nitrogen, to a solution of 25 g (127 millimoles) of 2,3,5,6,7,8-hexahydro-lH-benzlflindene-2-carbonitrile in 560 ml of dry methanol.
The reaction mixture was stirred for 3 x 24 hours at 50C under nitrogen and was then evaporated.
The residue was thereafter stirred with 400 ml of water, after which the precipitate was filtered off, again washed with water and dried. Yield 28 g.
The precipitate was then dissolved in 120 ml of 5N methanolic HCl 301ution. The solution was evaporated to a volume of about 100 ml after which 250 ml of diethyl ether were added.
The precipitate formed after some time at 0C waY filtered off and dried.
Yleld: 26 g of the compound shown in the title.
Rf in methylene chloride:methanol (9~ 0.44 on SiO2; melting point: 213C (with decomposition).
~254230 Example 2 The followlng are prepared in a manner analogous to Example 1:
2,3,5,6,7,8-hexahydro-N-hydroxy-o-methyl-lH-benzlf~indene-2-carboximidamide.HCl, melting point 205C (with decomposition~;
1,2,3,5,6,7-hexahydro-N-hydroxy-~-indacene-2-carboximidamide.
HCl, melting point: 215C (with decomposition);
1,2,3,5,6,7-hexahydro-N-hydroxy-6-methyl-s-indacene-2-carboximidamide.HCl, melting point: 194-195C
1,2,3,5,6,7,8,9-octahydro-N-hydroxy-cycloheptlflindene-2-ca}boximidamide;
2,3,4,5,6,7-hexahydro-N-hydroxy-lH-benzle~indene-2-carboximidamide.HCl, melting point: 194C (dec.);
2,3,4,5,6,7-hexahydro-N-hydroxy-5-methyl-lH-benz[elindene-2-carboximidamide.HCl;
1,2,3,4,5,6-hexahydro-N-hydroxy-as-indacene-2-carboximidamide.HCl;
1,2,3,4,5,6-hexahydro-N-hydroxy-6-methyl-a~-indacene-2-carboximidamide.HCl;
1,2,3,4,5,6,7,8-octahydro-N-hydroxy-cyclohept~e]indene-2-carboximidamide.
Example 3 2,3,5,6,7,8-Hexahydro-N-methoxy-lH-benzlfJindene-2 carboximidamide.HCl Method A
A sodium methanolate solution prepared by di3solving 3.45 g (150 millimoles) of sodium in 50 ml of methanol, was added to a solution of 12.5 g (150 millimoles) of hydroxylamine methyl ether hydrochloride in 60 ml of methanol.
After the mixture had been stirred for about 5 minutes, the sodium chloride formed was filtered off and the filtrate was added to 10 g (50 mi:llimoles) of 2~3~5~6~7~8-hexahydro-lH-benzlfJindene-2 carbonitrile.
125423C~
After 15 hours' atirring at 50C, the methanol was removed and the residue W83 stirred with 250 ml of water.
After the precipitnte had been filtered off, washed neutral with water and dried to constant weight, the amidoxime was suspended in 35 ml of methanol and acidified wlth 2N methanolic HCl solution.
After addition of 165 ml of ether to the solution, the hydrochloride crystallised out. Yield 10.6 g.
Method B
0.5 ml of water, 0.53 g (2 millimoles) of 2,3,5,6,7,8-hexahydro-N-hydroxy-lH-ben~lfJlndene-2-carboxlmidamide hydrochloride and, after a few mlnutes' stirrlng, 0.3 ml (about 3 millimoles) of dimethyl sulphate, were added successively to a solution of g2 mg
4 millimoles) of sodium in 5 ml of ethanol.
After the mlxture had been stirred for 1 hour at room temperature, 2 millimoles of sodium ethanolate solution and 0.2 ml (0.2 millimole) of dimethyl sulphate were furthermore added.
After this mixture had been stirred for some time at room temperature, the solvent was evaporated off. The residue was then taken up in ethyl acetate and washed 3 times with water. The organic layer was dried over sodium sulphate and then evaporated to dryness, and the residue was subsequently converted to the hydrochloric acid salt by suspending lt ln 3 ml of methanol and acldifying wlth 2N
methanolic HCl.
Addition of 3 ml of ether to the solution caused the hydrochlorlde to crystallise out. Yleld 355 mg.
~25423(~
Example 4 2,3,5,6,7,8-Hexahydro-N,N'-dihydroxy-lH-benz¦f~indene-2-carboximidamide.
Small portions of about 7.5 millimoles of a sodium methanolate solution were added, with stirring, to a suspension of 10 g (50 millimoles) of 2,3,5,6,7,8-hexahydro-lH-benz~flindene-2-carbonitrile and 10.5 g (150 millimoles) of hydroxylamine hydrochloride in 80 ml of methanol, at 45C. In total, about 40 millimoles of sodium methanolate were used, spread over 48 hours.
After the mixture had cooled to room temperature, 80 ml of ether were added and the precipitate was filtered off. This precipitate was subsequently stirred twice with 50 ml of water to remove salts, and was then recrystallised from methanollether. Yield 7.0 g, melting point 151 C.
Example 5 2,3,5,6,7,8-Hexahydro-N-hydroxy-lH-benzlf¦indene-2-carboximidamide.HCl A solution of 20.3 millimoles of 2,3,5,6,7,8-hexahydro-lH-benz[f~indene-2-carbonitrile in 16 ml of methylene chloride and 6 ml of ethanol was saturated wlth HCl gas at 0C. After leaving the mixture in a refrigerator for 24 hours, the solvents were removed and the iminoethyl ether hydrochloride was dissolved in 100 ml of water.
This solution was treated with a sodium bicarbonate solution and then extracted with methylene chloride, and the organic layer was washed with water until neutral. Thereafter, the solvent was removed.
To this residue timincethyl ether) there was subsequently added a hydroxylamine solution which was prepared by adding a solution of 120 millimoles of sodium in 10 ml of methanol to 120 millimoles of hydroxylamine hydrochloride in 10 ml of methanol. After 45 minutes' qtirring at room temperature, the solvent was removed and the residue was stirred with water.
~L25~23~
The precipitate was filtared off, washed neutral with water and dried to constant weight, giving 3.5 g of amidoxime.
A suspension of this amidoxime in 20 ml of methanol, when acidified with 2N methanolic HCl, gave a solution of the hydrochloride which after concentration to about 20 ml and addition of 150 ml of ether started to crystallise. Yield 3.9 g, melting point 213C (with decomposition).
Example 6 2,3,5,6,7,8-Nexahydro-lH-benzlf¦lndene-2-carboximidamide.HCl 4 g (20.3 millimoles) of 2,3,5,6,7,8-hexahydro-lH-benzlf~indene-2-carbonitrile were converted to the corresponding lminoethyl ether in the same manner as described in Example 5.
The residue obtained (iminoethyl ether) was dissolved in 14 ml of dry methanol, after which 1.03 g of NH4Cl were added.
The reaction mixture was then stirred for some time at 40C and then set aside at room temperature for 24 houra.
After the mixture had been evaporated and chromatographed with methylene chloride:methanol (1:1) as eluant over a short silica gel column, it was acidified with ethanolic HCl solution and again evaporated. The residue was recrystallised f~om ethanol:ether (1:3).
Yield 3.7 g, melting point 279C (dec.).
Example 7 The following compounds are prepared in a corresponding manner to that described in Example 6:
1,2,3,5,6,7-hexahydro-s-indacene-2-carboximidamide.HCl, melting point 282 C (dec.);
2,3,4,5,6,7-hexahydro-lH-benzle~indene-2-carboximidamide.HCl, melting point 222 C (dec.).
~254~30 In an analogous manner as described in Example 6 but replaclng ammoniumchloride by methylamine the following compound~ are prepared:
2,3,5,6,7,8-hexahydro-N-methyl-lH-benz¦f~indene-2-carboximidamide;
2,3,4,5,6,7-hexahydro-N-methyl-lH-benz~elindene-2-carboximidamide.
Example_8 2,3,5,6,7,8-Hexahydro-~-hydroxy-N'-methyl-lH-benz~flindene-2-carboximidamide 720 mg of a 60~ dispersion of sodium hydride in oil (18 millimoles of sodium hydride) were freed from the oil with hexane after which 13 ml of dimethylformamide were added, followed by 1.3 g (18 millimoles) of hydroxylamine hydrochloride added over 20 minutes.
The mixture was stirred for 20 minutes, the precipitate was filtered off, and the filtrate was added to 3.5 g (9 millimoles) of methyl-2,3,5,6,7,8-hexahydro-N-methyl-lH-benz¦f]indene-2-carboximidothioate hydriodide.
The reaction mixture was stirred for a further 45 minutes at room temperature, poured out into 600 ml of water and brought to pH 9 with 4N sodium hydroxide, after which the precipitate formed was filtered off and washed neutral. Drying to constant weight gave 1.8 g of the carboximidamide in ~uestion, melting point 161 C.
The following compounds are prepared in an analogous manner but using hydrazine hydrate in place of hydroxylamine hydrochloride:
2,3,5,6,7,8-Hexahydro-N-amino-N'-methyl-lH-benzlflindene-2-carboximidamide;
2,3,4,5,6,7-hexahydro-N-amino-N'-methyl-lH-benz[e]indens-2-carboximidamide.
Flow sheet C~h. 0~
¦ cooE~ ~yL~
,, l isOcyan~te CN r O~COOC~ CN
~ ' ~ ~ ~0~t ¦ h~e~
O~CUO~ X} C ~H
(X~
(~ C--Nll~, C~ C -- N ~;
~ ~advv Flow sheet C~ Ce-CH;Ci~-~O-C~p ~r~~S~
-- C.~ ( i')" ~ L - OC
o o ~'~ C~ ~
I
~N
~, c_ NP~
After the mlxture had been stirred for 1 hour at room temperature, 2 millimoles of sodium ethanolate solution and 0.2 ml (0.2 millimole) of dimethyl sulphate were furthermore added.
After this mixture had been stirred for some time at room temperature, the solvent was evaporated off. The residue was then taken up in ethyl acetate and washed 3 times with water. The organic layer was dried over sodium sulphate and then evaporated to dryness, and the residue was subsequently converted to the hydrochloric acid salt by suspending lt ln 3 ml of methanol and acldifying wlth 2N
methanolic HCl.
Addition of 3 ml of ether to the solution caused the hydrochlorlde to crystallise out. Yleld 355 mg.
~25423(~
Example 4 2,3,5,6,7,8-Hexahydro-N,N'-dihydroxy-lH-benz¦f~indene-2-carboximidamide.
Small portions of about 7.5 millimoles of a sodium methanolate solution were added, with stirring, to a suspension of 10 g (50 millimoles) of 2,3,5,6,7,8-hexahydro-lH-benz~flindene-2-carbonitrile and 10.5 g (150 millimoles) of hydroxylamine hydrochloride in 80 ml of methanol, at 45C. In total, about 40 millimoles of sodium methanolate were used, spread over 48 hours.
After the mixture had cooled to room temperature, 80 ml of ether were added and the precipitate was filtered off. This precipitate was subsequently stirred twice with 50 ml of water to remove salts, and was then recrystallised from methanollether. Yield 7.0 g, melting point 151 C.
Example 5 2,3,5,6,7,8-Hexahydro-N-hydroxy-lH-benzlf¦indene-2-carboximidamide.HCl A solution of 20.3 millimoles of 2,3,5,6,7,8-hexahydro-lH-benz[f~indene-2-carbonitrile in 16 ml of methylene chloride and 6 ml of ethanol was saturated wlth HCl gas at 0C. After leaving the mixture in a refrigerator for 24 hours, the solvents were removed and the iminoethyl ether hydrochloride was dissolved in 100 ml of water.
This solution was treated with a sodium bicarbonate solution and then extracted with methylene chloride, and the organic layer was washed with water until neutral. Thereafter, the solvent was removed.
To this residue timincethyl ether) there was subsequently added a hydroxylamine solution which was prepared by adding a solution of 120 millimoles of sodium in 10 ml of methanol to 120 millimoles of hydroxylamine hydrochloride in 10 ml of methanol. After 45 minutes' qtirring at room temperature, the solvent was removed and the residue was stirred with water.
~L25~23~
The precipitate was filtared off, washed neutral with water and dried to constant weight, giving 3.5 g of amidoxime.
A suspension of this amidoxime in 20 ml of methanol, when acidified with 2N methanolic HCl, gave a solution of the hydrochloride which after concentration to about 20 ml and addition of 150 ml of ether started to crystallise. Yield 3.9 g, melting point 213C (with decomposition).
Example 6 2,3,5,6,7,8-Nexahydro-lH-benzlf¦lndene-2-carboximidamide.HCl 4 g (20.3 millimoles) of 2,3,5,6,7,8-hexahydro-lH-benzlf~indene-2-carbonitrile were converted to the corresponding lminoethyl ether in the same manner as described in Example 5.
The residue obtained (iminoethyl ether) was dissolved in 14 ml of dry methanol, after which 1.03 g of NH4Cl were added.
The reaction mixture was then stirred for some time at 40C and then set aside at room temperature for 24 houra.
After the mixture had been evaporated and chromatographed with methylene chloride:methanol (1:1) as eluant over a short silica gel column, it was acidified with ethanolic HCl solution and again evaporated. The residue was recrystallised f~om ethanol:ether (1:3).
Yield 3.7 g, melting point 279C (dec.).
Example 7 The following compounds are prepared in a corresponding manner to that described in Example 6:
1,2,3,5,6,7-hexahydro-s-indacene-2-carboximidamide.HCl, melting point 282 C (dec.);
2,3,4,5,6,7-hexahydro-lH-benzle~indene-2-carboximidamide.HCl, melting point 222 C (dec.).
~254~30 In an analogous manner as described in Example 6 but replaclng ammoniumchloride by methylamine the following compound~ are prepared:
2,3,5,6,7,8-hexahydro-N-methyl-lH-benz¦f~indene-2-carboximidamide;
2,3,4,5,6,7-hexahydro-N-methyl-lH-benz~elindene-2-carboximidamide.
Example_8 2,3,5,6,7,8-Hexahydro-~-hydroxy-N'-methyl-lH-benz~flindene-2-carboximidamide 720 mg of a 60~ dispersion of sodium hydride in oil (18 millimoles of sodium hydride) were freed from the oil with hexane after which 13 ml of dimethylformamide were added, followed by 1.3 g (18 millimoles) of hydroxylamine hydrochloride added over 20 minutes.
The mixture was stirred for 20 minutes, the precipitate was filtered off, and the filtrate was added to 3.5 g (9 millimoles) of methyl-2,3,5,6,7,8-hexahydro-N-methyl-lH-benz¦f]indene-2-carboximidothioate hydriodide.
The reaction mixture was stirred for a further 45 minutes at room temperature, poured out into 600 ml of water and brought to pH 9 with 4N sodium hydroxide, after which the precipitate formed was filtered off and washed neutral. Drying to constant weight gave 1.8 g of the carboximidamide in ~uestion, melting point 161 C.
The following compounds are prepared in an analogous manner but using hydrazine hydrate in place of hydroxylamine hydrochloride:
2,3,5,6,7,8-Hexahydro-N-amino-N'-methyl-lH-benzlflindene-2-carboximidamide;
2,3,4,5,6,7-hexahydro-N-amino-N'-methyl-lH-benz[e]indens-2-carboximidamide.
Flow sheet C~h. 0~
¦ cooE~ ~yL~
,, l isOcyan~te CN r O~COOC~ CN
~ ' ~ ~ ~0~t ¦ h~e~
O~CUO~ X} C ~H
(X~
(~ C--Nll~, C~ C -- N ~;
~ ~advv Flow sheet C~ Ce-CH;Ci~-~O-C~p ~r~~S~
-- C.~ ( i')" ~ L - OC
o o ~'~ C~ ~
I
~N
~, c_ NP~
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Cycloalkane-indene-carboximidamide derivative having the general formula I
I
wherein Rx together with either Ry1 or RY2 represent the moiety (the other Ry being hydrogen), n represents the number 1, 2 or 3, R represents hydrogen or a C1-C4-alkyl group, R1 represents hydrogen, C1-C4-alkyl, hydroxyl, C1-C4-alkoxy or an amino group which is unsubstituted or substituted by C1-C4-alkyl and R2 is hydrogen, hydroxyl or C1-C4-alkyl, or a pharmaceutical acceptable salt thereof.
I
wherein Rx together with either Ry1 or RY2 represent the moiety (the other Ry being hydrogen), n represents the number 1, 2 or 3, R represents hydrogen or a C1-C4-alkyl group, R1 represents hydrogen, C1-C4-alkyl, hydroxyl, C1-C4-alkoxy or an amino group which is unsubstituted or substituted by C1-C4-alkyl and R2 is hydrogen, hydroxyl or C1-C4-alkyl, or a pharmaceutical acceptable salt thereof.
2. Compound of the formula:
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
3. Compound of the formula:
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
4. Compound of the formula:
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient in association with a pharma-ceutically acceptable diluent or carrier.
6. A pharmaceutical composition comprising a compound according to claim 2, 3 or 4 or a pharmaceutically acceptable salt thereof as an active ingredient in association with a pharmaceutic-ally acceptable diluent or carrier.
7. A process for preparing a compound of formula I as defin-ed in claim 1 or a pharmaceutically acceptable salt thereof which process comprises:
(a) condensing a compound of formula II or an acid addition salt thereof II
wherein Rx, Ry1 and RY2 are as defined in claim 1, Ro denotes lower alkyl R'2 denotes hydrogen, hydroxyl, C1-C4-alkyl or amino or amino substituted by C1-C4-alkyl, Z denotes oxygen or sulphur with a compound of formula III or an acid addition salt thereof III
wherein R1 is as defined in claim 1, or, (b) condensing a compound of formula IV
IV
wherein Rx, Ry, and Ry2 are as defined in claim 1 with a compound of formula III, as defined above, or an acid addition salt thereof, and, if required, alkylating the product of step (a) or step (b) at the nitrogen or the hydroxyl group, and, if required, resolving the product into separate optical enantiomers, and, if required, forming a pharmaceutically acceptable salt thereof.
(a) condensing a compound of formula II or an acid addition salt thereof II
wherein Rx, Ry1 and RY2 are as defined in claim 1, Ro denotes lower alkyl R'2 denotes hydrogen, hydroxyl, C1-C4-alkyl or amino or amino substituted by C1-C4-alkyl, Z denotes oxygen or sulphur with a compound of formula III or an acid addition salt thereof III
wherein R1 is as defined in claim 1, or, (b) condensing a compound of formula IV
IV
wherein Rx, Ry, and Ry2 are as defined in claim 1 with a compound of formula III, as defined above, or an acid addition salt thereof, and, if required, alkylating the product of step (a) or step (b) at the nitrogen or the hydroxyl group, and, if required, resolving the product into separate optical enantiomers, and, if required, forming a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL84.01653 | 1984-05-24 | ||
| NL8401653 | 1984-05-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1254230A true CA1254230A (en) | 1989-05-16 |
Family
ID=19843996
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000482008A Expired CA1254230A (en) | 1984-05-24 | 1985-05-22 | Cycloalkane-indene- carboximidamide derivatives |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS617244A (en) |
| KR (1) | KR850008665A (en) |
| CA (1) | CA1254230A (en) |
| ES (1) | ES8704884A1 (en) |
| ZA (1) | ZA853764B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5205971B2 (en) * | 2006-01-27 | 2013-06-05 | 宇部興産株式会社 | Method for producing tetrahydropyran compound |
-
1985
- 1985-05-17 ZA ZA853764A patent/ZA853764B/en unknown
- 1985-05-22 JP JP60110090A patent/JPS617244A/en active Pending
- 1985-05-22 CA CA000482008A patent/CA1254230A/en not_active Expired
- 1985-05-23 ES ES543440A patent/ES8704884A1/en not_active Expired
- 1985-05-24 KR KR1019850003600A patent/KR850008665A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS617244A (en) | 1986-01-13 |
| ES8704884A1 (en) | 1987-04-16 |
| KR850008665A (en) | 1985-12-21 |
| ZA853764B (en) | 1986-01-29 |
| ES543440A0 (en) | 1987-04-16 |
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