GB2104078A - New amino acid isomers, their production and their medicinal use - Google Patents
New amino acid isomers, their production and their medicinal use Download PDFInfo
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- GB2104078A GB2104078A GB08223363A GB8223363A GB2104078A GB 2104078 A GB2104078 A GB 2104078A GB 08223363 A GB08223363 A GB 08223363A GB 8223363 A GB8223363 A GB 8223363A GB 2104078 A GB2104078 A GB 2104078A
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- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 150000001413 amino acids Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 230000002378 acidificating effect Effects 0.000 claims abstract description 3
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims abstract description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000003536 tetrazoles Chemical class 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- ISOLMABRZPQKOV-UHFFFAOYSA-N diethyl 2-acetamidopropanedioate Chemical compound CCOC(=O)C(NC(C)=O)C(=O)OCC ISOLMABRZPQKOV-UHFFFAOYSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 5
- -1 dibromo compound Chemical class 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 238000006114 decarboxylation reaction Methods 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 2
- 239000007859 condensation product Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 2
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical group CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- GSSVPYDPBHEDBM-UHFFFAOYSA-N 1-bromo-5-diethoxyphosphorylpentane Chemical compound CCOP(=O)(OCC)CCCCCBr GSSVPYDPBHEDBM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 2
- MYDMWESTDPJANS-LURJTMIESA-N (2s)-2-amino-7-phosphonoheptanoic acid Chemical compound OC(=O)[C@@H](N)CCCCCP(O)(O)=O MYDMWESTDPJANS-LURJTMIESA-N 0.000 description 1
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 1
- KOLIZYXDZOWUMT-UHFFFAOYSA-N 1-bromo-5-ethylheptane Chemical compound CCC(CC)CCCCBr KOLIZYXDZOWUMT-UHFFFAOYSA-N 0.000 description 1
- MYDMWESTDPJANS-UHFFFAOYSA-N 2-amino-7-phosphonoheptanoic acid Chemical compound OC(=O)C(N)CCCCCP(O)(O)=O MYDMWESTDPJANS-UHFFFAOYSA-N 0.000 description 1
- NTIGNJOEVBTPJJ-UHFFFAOYSA-N 3,3-dibromopentane Chemical compound CCC(Br)(Br)CC NTIGNJOEVBTPJJ-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 238000012505 colouration Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The (-)-D-isomers of compounds of the general formula <IMAGE> in which R stands for an optionally substituted C5 aliphatic radical, X stands for an acidic radical, especially a radical of phosphonic acid, sulphonic acid, boronic acid or tetrazole, and A and B independently of each other stand for a lipophilic radical, or salts thereof, or pharmaceutically acceptable bioprecursors thereof, are new and find use in the treatment of diseases of the central nervous system.
Description
SPECIFICATION
New aminoacid isomers, their production and their medicinal use
The present invention relates to certain new isomers which have use in the treatment of diseases of the central nervous system and to processes for their production.
The compounds of the invention can be administered by intracerebral injection. While this would be a means of administration of last resort in therapy, it has particular significance in research into diseases of the central nervous system. There is much interest currently in developing an understanding of the action of certain compounds produced by the body on the central nervous system (CNS) of vertebrate mammals. Certain receptors in the CNS are excited by amino acids or derivatives thereof. These excitors cause neuronal degeneration and are believed to be responsible for example for
Huntington's Chorea disease. Current research is directed at identifying antagonists which block the receptors against excitors. A problem, however, is in determining which receptors are blocked by which antagonists.We have now surprisingly found that (-)- D-amino phosphonoheptanoic acid is a blocker of ibotenic acid-excited receptors but not a blocker of Kainic acid-excited receptors. This compound is therefore of great value in CNS research as a means of blocking ibotenic acid-excited receptors while leaving Kainic acid-excited receptors free to be acted on by candidate antagonists.
According to the present invention we provide, as new compounds, the (-)-D-isomers of compounds of the general formula
in which
R stands for an aliphatic radical of 5 C atoms, which may be optionaily substituted,
X stands for an acidic radical, especially a radical of phosphonic acid, sulphonic acid, boronic acid or tetrazole, and
A and B independently of each other stand for a lipophilic radical, especially an ester radical, or one of A and B can stand for a hydrogen atom, or salts thereof, or pharmaceutically acceptable bioprecursors thereof.
Examples of lipophilic radicals A are an imine or substituted imine, e.g.
-N(CH3)2, -NHCH3 or-N+(CH3)3. Examples of lipophilic radicals B are pivaloyloxy, pivaloyloxymethyl, amide, benzyloxycarbonyl or ester (e.g. methyl or ethyl ester) radicals.
For the purpose of this specification the term 'pharmaceutically acceptable bioprecursor' of an active compound of the invention means a compound having a structural formula different from the active compound but which nonetheless, upon administration to an animal or human being is converted in the patient's body to the active compound.
In preferred compounds R represents C,H,,.
The present invention further relates to processes for the production of compounds of the present invention in which:
(a) if a compound of formula (I) in which X stands for a phosphonic acid radical is required,
a dibromo compound of the general formula Br-R-Br (II) in which
R has the abovementioned meaning, is reacted with a compound of the general formula
in which
R' stands for an alkyl group, preferably an ethyl group, Ms stands for an alkali metal cation, preferably a sodium cation, and the resulting compound of the general formula
is heated, preferably in ethanol, with diethyl acetamidomalonate, and the resulting condensation product of the general formula
is subjected to decarboxylation, preferably in boiling hydrochloric acid, or, especially, using iodotrimethyl silane, to give a compound according to the present invention of the general formula
or
(b) if a compound of formula (I) in which X stands for a sulphonic acid radical is required,
a compound of the general formula
in which R has the abovementioned meaning, is reacted with sodium sulphide, to give a compound of the general formula
which is then heated to give a compound of the general formula
which then is reacted with bromine to give a compound according to the present invention of the general formula
(c) if a compound of formula (I) in which X stands for a triazolyl radical is required, a compound of the general formula
is reacted with sodium azide to give a compound according to the present invention of the general formula
(d) if a compound of formula (I) in which X stands for a boronic acid radical is required,
a compound of the general formula MgBr-R-Br (X) in which R has the abovementioned meaning, is reacted with a trialkyl borate, especially triethyl borate, of the general formula (R1O)3B (Xl) in which R' represents an alkyl group, to give a compound of the general formula (R'O)2B-R-Br (ill) which is then reacted with a diethylacetamidomalonate and the product of the general formula
is then hydrolysed to give a compound according to the present invention of the general formula
and the product of reaction variant a), b), c) or d) of formula (lea), (lb), (Ic) or (Id), respectively is, before or after separation of the (-)-D-isomer, converted into a corresponding compound in which the amino group and/or carboxylic acid group carries lipophilic group and also, if desired, converted into a salt thereof.
Among the new salts of the isomers of the present invention, those salts that are pharmaceutically acceptable are particularly important and are preferred.
The new free isomers of the general formula (I) and their salts can be interconverted in any suitable manner; methods for such interconversion are known in the art.
The separation of the (-)-D-isomer may be carried out by generally known methods, such as reacting the racemic mixture with an optically active base and separating out the salts formed. An appropriate method of separation has been found to be reacting the racemic mixture produced by a process of the invention with L-lysine, thereby forming diastereomers, separating the salt containing the (--)-D-isomer by crystallisation, followed by decomposition of the salt to obtain the (-)-D-isomer.
The starting compounds used in the process variants according to the present invention are known compounds or can be produced by processes similar to those used for the production of such known compounds.
All the process variants are preferably carried out in the presence of an inert organic solvent as the diluent. It is preferred that the reactions are carried out at the boiling point of the solvent used, that is to say, at reflux temperature.
The following reaction schemes illustrate the processes according to the present invention:
lipophilic radicals are then added to the NH2 and COOH groups.
The isomers of the present invention have use in the treatment of diseases of the central nervous system, particularly Alzheimer's disease and also Huntingtons disease and certain forms of epilepsy.
Those isomers may be applied by conventional pharmaceutical administration routes such as parenteral administration, e.g. intravenous administration.
Accordingly the invention further provides pharmaceutical compositions comprising the isomers of the present invention in admixture with a pharmaceutical carrier or excipient.
The following Example illustrates a process for the production of an isomer of the present invention.
Example
(a) Synthesis of (-)2-amino-7-phospheneheptanoic acid 1 ,5-dibromopentane-tdiethyl-5- bromopentane phosphonate
Diethyl phosphite was dissolved in anhydrous diethyl ether, and an squimolar quantity of sodium added in small pieces over a period of E hr; hydrogen being given off during this reaction. Four mole equivalents of 1 ,5-dibromopentane were dissolved in anhydrous diethyl ether, and the sodium salt of diethyl phosphite added, as a suspension, with stirring. The mixture was stirred for 36 hours, then refluxed for 2 hours; during this process, the fine precipitate of NaBr flocculated, and was filtered off.
The ether was evaporated off to leave a colourless liquid. Excess dibromopentane was distilled off at 1 mm Hg, to leave a colourless oil which was taken up in 50/50 pet. ether/ether and columned on
Kieselgel 60 in 50/50 pet. ether/ether. The first fraction contained unreacted diethyl phosphite; the product came off in pure diethyl ether.
(b) Diethyl-5-bromopentane phosphonateeacetamido adduct
The sodium salt of diethyl acetamidomalonate, was prepared by dissolving sodium in a slight excess of ethyl alcohol, and adding an equimolar quantity of diethyl acetamido malonate. The mixture was refluxed until a brown colouration indicated the formation of the sodium salt. The ethyl alcohol was evaporated off at 800 C, in vacuo, to leave a tan syrup; the remaining alcohol was removed by successive distillations with dry toluene, to leave a tan solid. The sodium salt was suspended in dry toluene, and diethyl carbonate added; the diethyl-5-bromopentane phosphonate was added, and the mixture refluxed for 3 days. The resulting NaBr was filtered off, and the solvents evaporated to leave a sticky, dark brown syrup.This was taken up in diethyl ether and columned on Kieselgel 60. Unreacted diethyl acetamido malonate, and diethyl-5-bromopentane phosphonate, came off with diethyl ether, and were separated by crystallisation of diethyl acetamido malonate from ether solution. The product was eluted off the column with chloroform, as a light yellow viscous syrup.
(c) Acetamido adduct < (+)2-amino-7-phosphonoheptanoic acid
The acetamido adduct was refluxed together with 6 M HCI overnight, the solution was evaporated to dryness, and the solid taken up in 5% aqueous ethanol. The free acid was precipitated by careful addition of propylene oxide and filtered off. The acid was dissolved in water and passed down on "Dowex" 50x8 (H+) column. The acid was washed with 5 bed volumes of water followed by elution with 2 M aqueous pyridine. The amino acid containing fractions were evaporated to dryness, and the product recrystailised from water/ethanol.
(d) Resolution of 2-amino-7-phosphonoheptanoic acid.
Equimolar quantities of the phosphonic acid, and L-lysine, were dissolved in water and warmed for 2 hr at 600 C. Two volumes of hot methanol were then added and the mixture brought to room temperature. Diethyl ether was added carefully, until a slight cloudiness appeared in the solution, which was left to stand. The phosphonic acid/lysine salt was filtered off and dissolved in water. A "Dowex" 50x8 column was prepared by passed 2 M pyridine down it, and washing with water, the lysine salt solution was passed down the column and washed through with water, the phosphonic acid passing straight through.The amine acid containing fractions were collected and evaporated to dryness; a solution of known concentration was then made up, and the rotation of plane polarised light recorded on a "TBL" Automatic Polarimeter 1 43D using a mercury lamp. The first isomer to be precipitated was found to be (-), and circular dichroism studies indicated it to have the D configuration.
(e) Lipophilic radicals can then be added on to the product by conventional methods such as esterification.
It is surprising that the (-)-D-isomers of the present invention should exhibit activity as anticonvulsants. The required dosage levels compare favourably to those of known drugs used for epilepsy.
The spectrum of activity of the present compounds and the routes by which they can be administered are especially remarkable. In particular it is surprising that the active compounds can pass the bloodbrain barrier to permit intraperitoneal and intravenous administration in addition to intracerebroventricular administration. (Thus, even the possibility of oral administration seems worth investigating). Thus the compounds of this invention are an unexpected advance in the art.
Claims (11)
1. (-)-D-isomers of compounds of the general formula
in which
R stands for an aliphatic radical of 5 C atoms, which may optionally be substituted,
X stands for an acidic radical, and
A and B independently of each other stand for a lipophilic radical, or one of A and B can stand for a hydrogen atom, or salts thereof, or pharmaceutically acceptable bioprecursors thereof.
2. Compounds according to claim 1, in which X stands for a radical of phosphonic acid, sulphonic acid, boronic acid or tetrazole, and/or R stands for C5H,O.
3. Compounds according to claim 1 or 2, in which A and B independently of each other stand for an ester radical.
4. A process for the production of a compound according to any of claims 1 to 3, in which
(a) if a compound of formula (I) in which X stands for a phosphonic acid radical is required,
a dibromo compound of the general formula Br-R-Br (II) in which
R has the abovementioned meaning, is reacted with a compound of the general formula
in which
R' stands for an alkyl group, M@; stands for an alkali metal cation, and the resulting compound of the general formula
is heated with diethyl acetamidomalonate, and the resulting condensation product of the general formula
is subjected to decarboxylation, to give a compound according to the present invention the general formula
or
(b) if a compound of formula (I) in which X stands for a sulphonic acid radical is required,
a compound of the general formula
in which R has the abovementioned meaning, is reacted with sodium sulphide, to give a compound of the general formula
which is then heated to give a compound of the general formula
which then is reacted with bromine to give a compound according to the present invention of the qenernl formula
(c) if a compound of formula (I) in which X stands for a triazolyl radical is required, a compound of the general formula
is reacted with sodium azide to give a compound according to the present invention of the general formula
(d) if a compound for formula (I) in which X stands for a boronic acid radical is required,
a compound of the general formula MgBr-R-Br (X) in which R has the abovementioned meaning, is reacted with a trialkyl borate of the general formula (R'O)2B (Xl) in which R' represents an alkyl group, to give a compound of the general formula (R'O)2B-R-Br (Xll) which is then reacted with a diethylacetamidomalonate and the product of the general formula
is then hydrolysed to give a compound according to the present invention of the general formula
and the product of reaction variant a), b), c) or d) of formula (la), (Ib), (Ic) or (Id), respectively, is, before or after separation of the (-)-D-isomer, converted in a corresponding compound in which the amino group and carboxylic acid group carry a lipophilic group and/or also, if desired, is converted into a salt thereof.
5. A process according to claim 4a), in which R' stands for an ethyl group.
6. A process according to claim 4a) or 5, in which Me stands for a sodium cation.
7. A process according to any of claims 4a), 5 and 6, in which the compound of formula (IV) is heated with diethyl acetamidomalonate in ethanol.
8. A process according to any of claims 4a) and 5 to 7 in which the decarboxylation is carried out using boiling hydrochloric acid or iodotrimethylsilane.
9. A process according to claim 4d), in which the trialkyl borate is triethyl borate.
10. A compound according to claim 1, whenever produced by the process of any of claims 4 to 9.
11. A compound according to claim 1 or 10, for use in the treatment of diseases of the central nervous system.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08223363A GB2104078B (en) | 1981-08-14 | 1982-08-13 | New aminoacid isomers, their production and their medicinal use |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8124899 | 1981-08-14 | ||
| GB08223363A GB2104078B (en) | 1981-08-14 | 1982-08-13 | New aminoacid isomers, their production and their medicinal use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2104078A true GB2104078A (en) | 1983-03-02 |
| GB2104078B GB2104078B (en) | 1985-01-23 |
Family
ID=26280467
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08223363A Expired GB2104078B (en) | 1981-08-14 | 1982-08-13 | New aminoacid isomers, their production and their medicinal use |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2104078B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992001455A1 (en) * | 1990-07-25 | 1992-02-06 | Luedke Hans Werner | Medicament against degenerative brain performance diseases of the alzheimer type and cholinergic system disturbances |
| US5175153A (en) * | 1987-11-30 | 1992-12-29 | Warner-Lambert Company | Substituted alpha-amino acids having pharmaceutical activity |
| WO1993011138A1 (en) * | 1991-12-02 | 1993-06-10 | John Wyeth & Brother Limited | Amine derivatives containing a phosphonic, phosphonous or phosphinic acid moiety |
| US5238958A (en) * | 1990-02-26 | 1993-08-24 | Warner-Lambert Company | Substituted α-amino acids having selected acidic moieties for use as excitatory amino acid antagonists in pharmaceuticals |
| US5399693A (en) * | 1984-04-17 | 1995-03-21 | British Technology Group Limited | Substituted piperazine-2-carboxylic acids and derivatives thereof |
| WO2019012109A1 (en) | 2017-07-13 | 2019-01-17 | Paris Sciences Et Lettres - Quartier Latin | Probenecid for use in treating epileptic diseases, disorders or conditions |
-
1982
- 1982-08-13 GB GB08223363A patent/GB2104078B/en not_active Expired
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5399693A (en) * | 1984-04-17 | 1995-03-21 | British Technology Group Limited | Substituted piperazine-2-carboxylic acids and derivatives thereof |
| US5595983A (en) * | 1984-04-17 | 1997-01-21 | British Technology Group Limited | Substituted piperazine 2-carboxylic acids useful in the treatment of central nervous system disorders |
| US5175153A (en) * | 1987-11-30 | 1992-12-29 | Warner-Lambert Company | Substituted alpha-amino acids having pharmaceutical activity |
| US5238958A (en) * | 1990-02-26 | 1993-08-24 | Warner-Lambert Company | Substituted α-amino acids having selected acidic moieties for use as excitatory amino acid antagonists in pharmaceuticals |
| WO1992001455A1 (en) * | 1990-07-25 | 1992-02-06 | Luedke Hans Werner | Medicament against degenerative brain performance diseases of the alzheimer type and cholinergic system disturbances |
| WO1993011138A1 (en) * | 1991-12-02 | 1993-06-10 | John Wyeth & Brother Limited | Amine derivatives containing a phosphonic, phosphonous or phosphinic acid moiety |
| GB2276168A (en) * | 1991-12-02 | 1994-09-21 | Wyeth John & Brother Ltd | Amine derivatives containing a phosphonic,phosphonous or phosphinic acid moiety |
| GB2276168B (en) * | 1991-12-02 | 1995-09-20 | Wyeth John & Brother Ltd | Amine derivatives containing a phosphonic,phosphonous or phosphinic acid moiety |
| US5538956A (en) * | 1991-12-02 | 1996-07-23 | John Wyeth & Brother, Limited | Amine derivatives containing a phosphonic acid moiety |
| WO2019012109A1 (en) | 2017-07-13 | 2019-01-17 | Paris Sciences Et Lettres - Quartier Latin | Probenecid for use in treating epileptic diseases, disorders or conditions |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2104078B (en) | 1985-01-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |