GB2217706A - alpha -Amino-alkanoic acid derivatives and process for their preparation with anti-inflammatory, analgesic, sedative, hypnotic, anxiolytic, spasmolytic, anaesthetic, muscle relaxant and cardiovascular activity - Google Patents

alpha -Amino-alkanoic acid derivatives and process for their preparation with anti-inflammatory, analgesic, sedative, hypnotic, anxiolytic, spasmolytic, anaesthetic, muscle relaxant and cardiovascular activity Download PDF

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GB2217706A
GB2217706A GB8809871A GB8809871A GB2217706A GB 2217706 A GB2217706 A GB 2217706A GB 8809871 A GB8809871 A GB 8809871A GB 8809871 A GB8809871 A GB 8809871A GB 2217706 A GB2217706 A GB 2217706A
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W A Gibbons
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Abstract

<IMAGE> Therapeutic compositions of anti-inflammatory, analgesic, sedative, hypnotic, anxiolytic, spasmolytic, anaesthetic, muscle relaxant and cardiovascular activity, where at least one component is the active compound with the general formula 1 in which: R1=linear, branched or substituted, saturated or unsaturated radical of 1-24 carbon atoms, aryl, aralkyl, substituted aryl or aralkyl, carbohydrate group, heterocyclic ring or ring system. R2=-, alkyl substituent with 1-24 carbon atoms. R1, R2=cycloalkyl or substituted cycloalkyl group. R3=H, acyl, tosyl or mesyl group. R4=H, alkyl, aryl, substituted alkyl or aryl group. X= 0 or S. Z= linear, branched or substituted alkylene group.

Description

0: - AMINO g - ALKANOIC ACID DERIVATIVE AND PROCESSES FOR ....
CHEMISTRY This invention relates to a-amino alkanoic acid derivatives with antiinflammatory, analgesic, sedative, hypnotic, anxiolytic, spasmolytic, anaesthetic, muscle relaxant and cardiovascular activity and their therapeutic compositions. The compounds are of the general formula 1, in which: R 1= linear, branched or substituted, saturated or unsaturated radical of 1-24 carbon atoms, aryl, aralkyl, substituted aryl, aralkyl, carbohydrate group, heterocyclic rings or ring systems.
R2=-, alkyl substituent with 1-24 carbon atoms.
R1,R2= cycloalkyl or substituted cycloalkyl group.
R3= H, acyl, tosyl or mesyl group.
R4=H, alkyl, aryl, substituted alkyl or aryl group.
X= O or S.
Z= linear, branched or substituted alkylene group.
This invention also relates to the different salts of the compound of Formula 1.
Preferred designations for X = O or S.
Preferred designations for R1 = alkyl, alkanyl radical with 1-24 carbon atoms, adenosyl, adenyl or sugar moiety (fructyl, lactyl or ribosyl).
Preferred designations for R2 = alkyl radical with 1-6 carbon atoms.
Preferred designations for R3 = H or tosyl group.
Preferred designations for R4 = H or methyl group.
Preferred designations for Z = linear alkyl group with 1-10 carbon atoms.
Preferred of salts of compounds of formula 1 are: chloride, acetate, sulfate, tartrate, citrate and methane sulfonate.
The literature syntheses of a-amino alkanoic acid derivatives are poor.
In most cases, a Williamson synthesis is used following protection of the w-halogen a-amino alkanoic acid. [Park, W.K. and Kim, S. Protein methylation (1980) John Wiley and Sons, Chichester (New York), Legraver and M. Ibanez et al., Eur. J. Med. Chem. 12, 105, (1977)].
We have developed two new methods of a-amino alkanoic acid synthesis.
In the first method, we use the knowledge that Y-butyrolactone forms butyric acid derivatives at very high temperatures in the presence of a strong base.
Hence, a-amino butyrolactone or tosylated a-aminobutyrolactone is reacted with different alcohols and thiols (such as dodecyl mercaptan, eicosanyl alcohol, N-secadecyl mercaptan, l-thio-a-d-glucose tetracetate, 2'3'- isopropyridine-adenosine or 2',3'-isopropylide-5'-thioadenosine) in toluene, tetralin or decalin in the presence of base (KOH, NaSH or NaOH) and a phase transfer catalyst (tetrabutyl ammonium sulfate) to give the appropriately substituted a-amino butyric acid derivative. The temperature of the reaction is between 1000 and 240"C and the reaction time is between 5 and 40 hours.
In the second method, alcohols and thiols (2),
(where R1 and X are as defined for general formula 1), are first reacted with dihalogen compounds 3 (where Z is as defined for general formula 1, Y=C1 or I) in the presence of strong base to yield monohalogenated compounds 4.
Alternatively, the monohalogenated thio ethers 7 can be obtained (Venkatachalam Eswarakrishnan and Lamar Field: J. Org. Chem. 1981, 46,
4182-4187) starting from the 5 mesylate or tosylate and 6 thiol.
The 4 or 7 halogen compounds are subsequently reacted with diethyl acetamidomalonate in the presence of sodium-ethanoate, followed by HC1/H20 hydrolysis and decarboxylation (Albertson, N.F.: J. Ann. Chem. Soc. 1946, 68, 450), yielding the appropriate a-amino alkanoic acid derivatives. BIOLOGY The biological function of the compounds described in this patent is to inhibit enzymes using the S-adenosylhomocysteine/S-adenosylmethionine. These coenzymes are involved in transfer of (a) methyl groups, (b) adenosyl-ribose moieties and (c) CH2CH2-CH-NH2-C02 moieties. The preferred of these three biological reactions is the methylation of lipids, including phospholipids, sphingolipids, plasmalogens, lysolipids and neutral lipids that contain an ethanolamine or choline moiety.The enzymatic reaction can be depicted as follows: Lipid + n(SAM) ' lipid(CH3) +nSAH where n=1,2,3 depending upon the lipid to be methylated.
The organic molecules and enzymes involved in equation 1 have been established in this patent to have the following biological functions.
(1) Methylated lipids are the endogenous gating and blocking molecules for membrane bound ion channels for translocation of sodium, potassium, calcium, chloride, and protons.
(2) SAH is the endogenous benzodiazepine.
(3) Lipid methyl transferases are identified as components of or associated with the GABA superfamily of receptors that includes the CABA, Gly and nicotinic acetylcholine receptors. Additional receptors and enzymes that utilise purine-riboside containing cofactors can also be inhibited. These include the purinergic receptors and membrane-bound ATPases, GTPases and adenylate cyclases.
(4) The mechanism of. ligand-gating of ion channels involves generation of methylated lipids by the methyl transferase enzyme (i.e. receptor) which therefore closes the channel. The latter can be opened by (a) inhibition of the lipid methylase or (b) enzymatic destruction of the methylated lipid by lipases or demethylases or (c) inhibition of the recycling of SAM, SAH or lipid recycling or (d) lipid mobility.
The therapeutic activities of the compounds are widespread and based upon the novel biochemical mechanisms depicted in (1) to (4) above. These therapeutic activities include: (a) Sedative and hypnotic (b) Anxiolytic (c) Spasmolytic (d) Anaesthetic (e) Muscle relaxant (f) Drug and alcohol dependence and withdrawal (g) Anti-inflammatory, including anti-asthmatic and antiallergic (h) Cardiovascular (i) Analgesic Examples of specific clinical disorders to be cured and biomedical uses based upon inhibition of lipid methylases by substrate and product analogues or gating of ion channels by endogenous lipid-gating and blocking molecules and their analogues include: : (1) Sleep apnea, narcolepsy and insomnia (2) Cerebral palsy (3) Epilepsy (4) Cystic fibrosis (5) Parkinson's disease (6) Schizophrenia (7) Depression (8) Anxiety (9) Allergy (10) Asthma (11) Alzheimer's disease (12) Huntingdon's chorea (13) Anaesthesia Diagnostic applications include diagnosis of disease by (a)- the levels of lipid methyl transferases, (b) the levels of SAM and SAH in body fluids and tissues, (c) the levels of endogenous lipids in cells, tissues and body fluids.
Diagnostic methods include measurement by (a) enzyme-linked immunoassay with monoclonal and polyclonal antibodies to the methylases and/or their endogenous substrates and cofactors, (b) lipid methylase activity, (c) lipid methylase mRNA levels, and (d) lipid methylase gene structure, occurrence and expression.
EXAMPLE 1 S-OCTADECYL-HOMOCYSTEINE (1A) In a 50ml round bottom flask equipped with magnetic stirrer and Dien Stark apparatus, octadecyl mercaptan (1.Og, 3.49mmol) potassium hydroxide (586mg, 10.46mmol) and a-amino-g-butyrolactone hydrobromide (728mg, 4.0mmol) were refluxed in toluene (15ml) in the presence of tetrabutyl ammoniumsulphate (2mg) for 5 hours. The water was removed continously.
The solvent was removed in vacuo and the residue triturated with ether (2x20ml) and filtered.
The dry precipitate was stirred in 5% acetic acid-water, filtered and washed with water.
Yield: 1.3g (95.9%) mp. 218 C.
Anal. C22H45NO9S (387.66) Calc. C 68.15 H 11.70 N 3.61 Found C 67.78 H 11.58 N 3.42 IR(KBR): 3200, 2960, 2915, 2865, 2650, 2340, 2100, 1660, 1625, 1590, 1510, 1350cm-1 .
NMR(CD30D): 3.85(1H,m, -CH), 2.60(4H,m,2xSCH2), 9.20(2H,m,CH2), 1.60(2H,m,CH2), 1.35(32H,m,16xCH2), 0.85(3H,t,CH3).
MS, m/e (%): 388[M+H] + (100), 342(29), 313(48), 299(45), 283(20), 178(30), 134(30), 198(22), 119(26), 108(23), 105(33), 103(21), 95(43), 91(70), 90(61), 89(85), 83(35), 79(47), 78(42), 77(89), 65(37), 57(45).
EXAMPLE 2 S-DODECYL-HOMOCYSTEINE (1B) Dodecyl mercaptan was reacted with a-amino-X-butyrolactone using the method described in Example 1.
Yield: 77% mp. 202-2040C.
Anal. C16H33NO2S(303.5) Calc. C 63.31 H 10.96 N 4.62 Found C 63.08 H 10.71 N 4.60 IR(KBr): 2960, 2920, 2840, 1660, 1640, 1620cm .
NMR(OD3OD): 3.78(1H,m, -CH), 2.50(4H,m,2xSCH2), 1.70, 1.60(2H,m,CH2).
1.38(18H,m,9xCH2), 0.85(3H,t,CH3).
MS, m/e (%): 304 [M+H] + (9), 265(13), 230(15), 229(100), 215(6), 201(14), 199(22), 129(6), 101(15), 97(18), 95(93), 87(25), 83(28), 81(22), 69(47), 55(69), 43(59), 29(15).
EXAMPLE 3 N-P-TOLUERE-SULPHONYL-S-BENZYL-HOMOCYSTEINE (1C) In a 50ml round bottom flask, equipped with magnetic stirrer and Dien Stark apparatus, benzyl mercaptan (1.0g, 0.945ml,- 8.05mmol), N-p-toluene sulphonyl-a-amino-Y-butyrolactone (2.5g, 8.05mmol), potassium hydroxide (450mg, 8.95mmol), sodium hydrogen sulphide H20 (569mg, 8.05mmol) and tetrabutyl ammonium sulphate (5mg) in tetralin (20ml) were stirred at 2000C for 10 hours. The tetralin was decanted and the yellow residue washed with ether, stirred in water (5ml), the pH adjusted to 7 with 10% hydrochloric acid and the precipitate filtered and washed with water.
Yield: 2.1g (68.7%) Anal. C18H2lNO4S2 (379.4) Calc. C 56.98 H 5.58 N 3.69 Found C 56.58 H 5.50 N 3.57 NMR(CDCl3): 7.75, 7.72, 7.31, 7.28(4H,s,aromatic H), 6.90(5H,m,aromatic H), 4.0(1H,m, -CH), 2.8(2H,m,SCH2), 2.5(2H,m,SCH2), 2.42(3H,s,CH3), 2.0(2H,m,CH2).
EXAMPLE 4 S-(5-DEOXY-ADENOSINE-5)-HOMOCYSTEINE (1D) 5'-Deoxy-5'-mercapto-adenosine and a-amino-Y-butyrolactone hydro bromide were reacted using the method described in Example 1. The crude compound was purified by FPLC using a Mono S cation exchange column.
Solvent system: ammonium-formate 0.25M (pH=2.5). Isocratic elution (lyophilised for 24 hours).
Yield: 23% The compound was authenticated by comparison with SAH [Sigma] using mp. TLC, IR, NMR and MS.
EXAMPLE 5 2-P-TOLUENE-SULPHONYL-AMINO-4-(2',3'-ISOPROPYLIDENE ADENOSYL-5')-BUTANOIC ACID (1E) 2',3'-Isopropylidene adenosine and N-p-toluene-sulphonyl-a-amino-Y- butyrolactone were reacted using the method described in Example 3. The compound was purified by TLC (dichloromethane:methanol).
Yield: 58% Anal. C24H30N6 8S (562.60) Calc. C 51.23 H 5.37 N 14.94 Found C 51.51 H 5.47 N 14.52 NMR(DMSO-d6): 8.25, 8.40(2H,s,adenine CH), 7.78, 7.75, 7.35, 7.32(4H,s,aromatic H), 5.94(1H,m,C1-H), 4.78(1H,m,C2-H), 4.22(1H,m,C3-H), 4.20(1H,m,C4-H), 4.09(2H,m,NH2), 3.42(1H,m, -CH), 2.96(2H,m,2xC5-H), 2.58(2H,m, -CH2), 2.40(3H,s,CH3), 1.92(2H,m, -OH2).
EXAMPLE 6 S-(1'-DEOXY-TETRAACETO-a-D-GLUCOSYL)-HOMOCYSTEINE (1G) 1-Thio-a-D-glucose tetraacetate and a-amino- < - butyrolactone hydrobromide were reacted using the method described in Example 1.
Yield: 67% Anal. C18H27NOllS (465.48) Calc. C 46.44 H 5.85 N 3.01 Found C 46.52 H 5.61 N 2.67 NMR(DMSO-d6): 5.15(1H,m,Cl -H), 4.0-5.0(3H,m,C2,3,5-H), 4.15(2H,m,2xC6-H), 3.95(1H,m,C4-H), 3.70(1H,t, -CH), 2.87(2H,m, -CH2), 2.12(2H,m, -CH2), 2.0, 2.02, 2.10, 2.l2(12H,s,4xOOOH3).
EXAMPLE 7 S-ADENOSYL-METHIONINE (IODINE SALT) (5F) 5'-Deoxy-5'mercapto-adenosine and a-amino-Y-butyrolactone were reacted using the method described in Example 4. Compound 1D (100mg, 0.26mmol) was dissolved in acetic acid (lml) and together with methyl iodide (lllmg, 0.78mmol) added to the reaction mixture and stirred for 3 days at room temperature. Ether (45ml) was added to the solution and the precipitated product was filtered and purified by FPLC.
Yield: 69% The compound was authenticated by comparison with SAM [Sigma] using mp. TLC, IR, NMR and MS.
EXAMPLE 8 S-OCTADECYL HOMOCYSTEINE (1A) a) l-Bromo-ethyl-( 2)-octadecyl-sulphide.
In a 100 ml round bottom flask equipped with magnetic stirrer and reflux condenser, octadecyl-mercaptan (2 g, 6.98 mmol) was dissolved in absolute tetrahydrofuran (20 ml). Sodium hydride (50% oil dispersion, 335 mg, 6.98 mmol) was added to the solution and the mixture stirred for 3 hours at room temperature. 1,2-dibromo-ethane (6.6 g, 3.03 ul, 35 mmol) was then added and the mixture refluxed for 24 hours. The soluent was evaporated in vacuo and the residue stirred with water (50 ml) and extracted with dichloromethane (3x30 ml). The organic phase, after drying (Mg SO4) was evaporated, the residue triturated with methanol (20 ul) and the precipitated white 1-bromo-ethyl-2-octadecyl sulphide (CH3(CH2)17S(CH2)2Br) filtered and washed with methanol.
Yield: 2.7 g (98.3%) mp. 48-50 C.
Anal. C20H41S Br (392.52) Calc. C 61.04 H 10.50 Br 20.31 Found C 60.95 H 10.44 Br 20.01 NMR(CDCl3): 3.55(2H,t,SCH2), 2.72(2H,t,CH2-S), 2.55(2H,t,BrCH2), 1.60(2H,m, CH2), 1.40(2H,m, CH2), 1.28(30H,m,NCH2), 0.89(3H,t,CH3).
MS, m/e (%): 393[M+H] , 314(23), 313(100), 311(10), 285(15), 97(15), 95(12), 87(13), 85(16), 83(25), 81(16), 71(96), 69(33), 67(16), 57(14), 55(47), 43(37), 41(26).
b) In a 50 ml round bottom flask equipped with magnetic stirrer and reflux condenser sodium (87.6 mg, 3.8 mmol) was reacted with absolute ethanol (3 ml). Diethylacetamidomalonate (825 mg, 3.8 mmol) was then added to the solution and the reaction mixture stirred for 30 min at room temperature. 1-Bromo-(2)-octadecyl sulphide (1.5 g, 3.8 mmol) was added to the clear solution and the mixture refluxed for 24 hours. Water was added to the reaction mixture and the precitated product collected by filtration.
OH3(CH2)17S-(CH2)2O(C00C2H5)2NHO0OH3 mp. 67-69 C Anal. C29H55NO5S (529.81) Calc. C 65.74 H 10.46 N 2.64 Found C 65.66 H 10.46 N 2.55 MS, m/e (%), 530[H] (24), 488(7), 414(6), 299(21), 245(13), 244(100), 217(36), 171(24), 128(10), 100(4), 84(2.7), 69(3.7), 55(5).
IR (KMCB): 3400, 3300, 2950, 2850, 1740.
NMR (CDCl3): 6.80(1H,s,NH), 4.20(4H,2g,OCH2CH3), 2.65(2H,t,SCH2), 2.45(2H,t,SCH2), 2.30(2H,t,C-CH2), 2.05(3H,s,COCH3), 1.5(2H,m, OH2), 1.35(2H,m, CH2), 1.25(30H,m,15xCH2), 1.24(6H,t, OCH2CH3), 0.9(3H,t,CH3).
This compound was then refluxed in concentrated hydrochloric acid (10 ml) for 10 hours. Ethanol (20 ml) was added to the mixture at room temperature and the pH adjusted to 8-9 with concentrated ammonium hydroxide. The white precipitate (IA) was filtered and washed with 80% ethanol-water.
Yield: 1.33 g (90%) The compound was identical to the product in Example 1.
EXAMPLE 9 2-AMINO-5-OCTADECYLTHIO-PENTANOIC ACID (1H) Octadecyl-mercaptan (2 g, 6.98 mmol) was reacted with 1,3-dibromopropane, using the method described in Example 8.
Yield: 2.27 g (81.2%) mp. 199-201 C.
Anal. C23H47NO2S (401.76) Calc. C 68.77 H 11.79 N 3.49 Found C 66.58 H 11.61 N 3.37 IR(KMCB): 2900, 2960, 2840, 1660, 1620cm 1.
MS m/e (%): 402[M+H)+ (30), 327(42), 192(25), 171(68), 116(100), 102(28), 91(60), 70(72), 55(55), 43(20).
3(CH2)17(cH2)3Br mp. 37-390C Anal. C21H43BrS (407.54) Calc. C 61.89 H 10.63 Br 19.61 Found C 61-81 H 10.59 Br 19.57 NMR CDCl3): 3.49(2H,t,BrCH2), 2.65(2H,t,SCH2), 2.5(2H,t,SCH2), 2.1(2H,2t,CH2), 1.55(2H,m, CH2), 1.35(2H,m, CH2), 1.2(30H,m,15xCH2), 0.9(3H,t,CH3).
MS, m/e (%): 409(16), 408(14), 407(30), 406(12), 405(18), 327(28), 285(16), 283(10), 109(10), 97(25), 95(22), 89(11), 87(23), 85(22), 83(44), 81(32), 71(38), 69(69), 67(37), 57(77), 55(100), 43(8), 41(65), 29(16).
CH3(CH2)17S-(CH2)3-C(000C2H5)2HC0CH3.mp. 65-66 C Anal. C30H57No5S(543.84) Calc. C 66.25 H 10.57 N 2.58 Found C 66.09 H 10.51 N 2.57 NMR(CDCl3): 6.8(1H,s,NH), 4.2(4H,q,2x0OH2CH3), 2.45(4H,m,2xSCH2), 2.0(3H,s,COCH3), 1.6(2H,m, CH2), r.45(2H,m, CH2), 1.25(38H,m,16xCH,+2xOCH2CH3), 0.9(3H,t,CH3).
MS, m/e (%): 544[M+H] +(31), 502(13), 470(12), 428(13), 354(10)', 327(42), 299(12), 258(50), 216(31), 214(34), 186(16), 159(14), 142(100), 114(18), 97(20), 95(21), 87(23), 85(21), 83(31), 81(23), 71(43), 69(47), 67(29), 57(54), 55(54), 43(74), 41(70), 29(29).
EXAMPLE 10 S-BENZYL-HOMOCYSTEINE (1I) Benzyl-mercaptan (5 g, 40.26 mmol) was reacted with 1,2 dibromo-ethane using the method described in Example 8.
Yield: 7.71 g (85%) mp. 245 C 1I HCl mp. 210 C Anal. C 11H15N02S (225.31) Calc. C 58.63 H 6.71 N 6.22 Found C 58.51 H 6.59 N 6.17 MS, m/e (%): 226[M+H]+ (100), 222(69), 180(24), 148(25), 134(35), 102(33), 91(63), 90(22), 56(23).
IR (Nujol): 2960, 2940, 2880, 1660, 1640, 1620, 1500cm 1.
H CH2-S-CH2CH2-Br oil Anal. C9H11SBr (231.17) Calc. C 46.76 H 4.80 Br 34.57 Found C 46.71 H 4.85 Br 34.29 NMR(CDC13): 7.25(5H,s,aromatic H), 3.8(2H,s,C6H5CH2), 3.35(2H,t,SCH2), 2.9(2H,t,BrCH2).
C6H5CH2S(CH)2C(COOC2H5)2NHCOCH3 oil Anal. C18H25-NO5S (367.46) Calc. C 58.83 H 6.86 N 3.81 Found C 58.67 H 6.79 N 3.69 MS, m/e (5): 368[.H+H] (47), 326(18), 252(13), 245(14), 244(100), 217(23), 174C1S), 171(17), 151(12), 137(12), 128(21), 100(11), 91(87) 43(12), 29(5).
NMR(CDC13)): 7.20, 7.25(S,5H, aromatic H), 6.65(1H,m,NH), 4.22(4H,m,2x0OH2OH3), 3.68(2H,s,C6H5CH2), 2.60(2H,t,SCH2), 2.22(2H,t,CCH2), 1.98(3H,s,COCH3), 1.25(6H,t,OCH2CH3).
EXAMPLE 11 2-AMINO-8-DODECYLTHIO-OCTANOIC ACID (1J) Dodecylmercaptan was reacted with 1,6 dibromohexane using the method described in Example 8.
Yield: 72% mp. 260 C (d') Anal. C20H41NO2S (359.61) Calc. C 66.79 H 11.49 N 3.89 Found C 66.85 H 11.27 N 3.67 MS, m/e (%): 360[MH + (30), 358(12), 314(15), 285(34), 166(10), 150(9), 136(24), 129(10), 124(21), 118(9), 117(15), 115(24), 112(24), 108(16), 107(16), 97(15), 91(38), 81(41), 77(51), 69(56), 67(38), 61(49), 55(100), 29(19).
CH3(CH2)1lS(CH2)6Br mp. 380C Anal. C18H37SBr (365.47) Calc. C 59.15 H 10.21 Br 21.87 Found C 59.01 H 10.22 Br 21.51 367[M+H]+81 +81 Br(22), 365[M+H] +79 +81 MS, m/e (%): 367[M+H] Br(22), 365 Br, [M+H] Br(43), 363(27), 317(5), 287(10), 286(15), 285(58), 283(15), 215(11), 201(6), 199(11), 115(15), 109(13), 101(12), 97(19), 95(25), 87(24), 85(18), 83(47), 81(50), 69(55), 57(53), 55(100), 43(65), 41(54), 29(17).
NMR(CDC13): 3.40(2H,t,BrCH2), 2.50(4H,2t,2xSCH2), 1.86(2H,m,CH2), 1.58(4H,m,2xCH9), 1.40(2H,m,CH2), 1.25(20H,m,10xCH2), 0.88(3H,t,CH3).
CH3(CH2)11SCCH2)6CCC00O2H5)2NHCOCH3. mp. 35-37 C Anal. C27H51NO5S (501.76) Calc. C 64.63 H 10.25 N 2.79 Found C 64.61 H 10.21 N 2.65 MS m/e (%): 502[M+H] (70), 500(15), 461(10), 460(37), 386(31), 382(13), 266(9), 218(12), 217(64), 184(30), 182(19), 171(55), 128(11), 116(10), 115(10), 112(17), 110(31), 101(10), 95(11), 87(14), 83(22), 81(21), 71(21), 69(42), 57(48), 55(64), 43(100), 41(47), 29(23).
NMR(CDC13): 6.8(1H,s,NH), 4.25(4H,2g,2x0CH2OH3), 2.50(2H,m,SCH2), 2.25(2H,m,SCH2), 2.05(3H,s,CH2CO), 1.85(2H,m, CH2), 1.55(4H,m,2xCH2), 1.35(4H,m,2xCH2), 1.25(30H,m,2xCH3,12xCH2), 0.85(3H,t,CH3).
EXAMPLE 12 S-DODECYL-HOMOCYSTEINE (1B) Dodecyl mercaptan was reacted with 1,2-dibromoethane using the method described in Example 8.
Yield: 89%.
The product is identical to the product in Example 2.
CH3(CH2)11SCH2)CH2Br Anal. C14H29SBr (309.36) Calc. C 54.35 H 9.45 Br 25.83 Found C 54.32 H 9.44 Br 25.59 NMR(CDC13): 3.48(2H,t,SCH2), 2.92(2H,t,BrCH2), 2.55(2H,t,SCH2), 1.6(2H,m, CH2), 1.40(2H ,m, CH2), 1.30(16H,m,8xCH2), 0.9(3H,t,CH3).
311[M+H]+81 +81 311[M*H] Br(9), 309[M-H] +71 +81 +79 Ms, m/e (%): 311[MtH] Br(23), 309 Br (17), 299(100), 199(22), 97(25), 95(29), 87(29), 83(40), 71(37), 69(69), 57(74), 55(93), 43(71), 41(53).
CH3(CH2)11S(CO2)2C(CooC2H5)2NHO0CH3.
Anal. C23H43NO5S (445.65) Calc. C 61.98 H 9.27 N 3.14 Found C 61.77 H 9.38 N 3.19 MS m/e (%): 446[M+H+](48), 402(40), 374(42), 215(45), 172(100), 145(43), 98(20), 56(20), 43(18).
NMR(CDCl3): 6.18(1H,d, H), 4.20(4H,2g,2x0CH2CH2), 2.5(4H,m,2xSCH2), 2.1(2H,m,CH2), 9 .02(3H,s,COCH2), 1.90(2H,m, CH2), 1.50(2H,m, CH2), 1.30(22H,m,8xCH2+2x0CK2CH2), 0.9(3H,t,CH3).
EXAMPLE 13 S-(5-DEOXY-ADENOSINE-5)-HOMOCYSTEINE (1D) 5'-Deoxy-5'-mercapto-2' ,3 1-isopropylidene-adenosine was reacted with 1,2 dibromo-ethane using the method described in Example 8.
Yield: 71%.
The compound was authenticated by comparison with SAH (Sagma).
EXAMPLE 14 S-OCTADECYL-HOMOCYSTEINE (1A) In a 50 ml round bottom flask equipped with magnetic stirrer triethylamine (2.02 g, 10 mmol) and methane sulphonylchloride (1.15 g, 10 mmol) were added to octadecanol (2 g, 7.4 mmol), in dichloromethane (10 ml) at OOC. The reaction mixture was stirred for 0.5 hour at 0 C and 0.5 hour at room temperature. The reaction mixture was quenched with water and extracted with dichloromethane. The organic phase was dried (MgSO4) and evaporated.
Yield: 2.47 g (96%). CH3(CH)17OSO2CH3 In a 50 ml round bottom flask equipped with magnetic stirrer and drying tube, sodium (230 mg, 10 mmol) was reacted with abs. ethanol (5 ml).
2-Bromo-ethylmercaptan (1.41 g, 10 mmol), was added to the solution and this mixture added to the previously prepared mesylate in ethanol (5 ml). The reaction mixture was stirred to room temperature overnight. Dichloromethane (30 ml) was added to the reaction mixture and washed with 5% sodium hydroxide (3x20 ml). The organic layer after drying (!gSO4) was evaporated, methanol (20 ml) added to the residue. The precipitated product was filtered and washed with methanol.
Yield: 2.3 g (79%).
The product was identical to the product in Example 8a.
From the resulting l-bromo-ethyl-(2)-octadecyl-sulphide we have synthesised the S-octadecyl-homocystein (1A) using the procedure described in Example 8b.
EXAMPLE 15 2-AMIN0-4-ETHOXY-BUTANOIC ACID (1K) 2-Bromo-ethylether ( 5g, 32.7 mmol) was reacted with diethylacetamidomalonate (7.16 g, 33 mmol), in a solution of sodium (752 mg, 33 mmol) in ethanol (25 ml) using the procedure described in Example 8b.
The product was extracted with ether and the solvent evaporated.
2H50(CH2)2C(COOC2H5)2NHCOCH3.
Yield: 7.9 g (83.5%) oil.
Anal. C 13H23N06 (289.32) Calc. C 53.96 H 8.01 N 4.84 Found C 53.91 H 7.97 N 4.59 IR (Nujol): 3420, 3380, 3300, 2980, 2940, 2920, 2880, 2805, 1740, 1680, -1 1660 cm NMR(CDC13): 4.15(4H,m,CH20OH2), 3.30(4H,2g,0CH2CH2), 2.60(2H,t,CH2), 2.0(3H,s,COCH3), 1.1(6H,t,2xCH3CH2O), 1.05C3H,t,OH3).
The product was refluxed in concentrated hydrochloric acid (30 ml) for 25 hours. The solvent was evaporated, the residue dissolved in water, the pH adjusted to 8 with concentrated ammonium hydroxide, and the solution extracted with dichloromethane. The organic layer was dried (MgS04) and evaporated.
Yield: 4.3 g (89.3%).
Anal. C6H13NO3 (147.17) Calc. C 48.96 H 8.90 N 9.52 Found C 48.59 H 8.61 N 9.27 NMR(CDC13): 8.6(2H,bs,NH2), 8.5(1H,bs,OH), 4.35(1H,u, CH), 3.8(2H,t,OCH2), 3.45(2H,g, OCH2), 2.3(2H,t,CH2CH), 1.15(3H,t,CH3).

Claims (15)

  1. The embodiments of the invention for which an exclusive property and privilege is claimed are defined as follows: 1. a. Racemic and optically active compounds, their salts and their therapeutic compositions of general formula 1 to be used for (i) their actions on the central nervous system, including:: sedation and hypnosis anxiolysis spasmolysis anaesthesia analgesia (ii) their actions on the peripheral nervous system, including muscle relaxation analgesia (iii)the treatment of inflammatory disorders, including asthma arthritis (iv) the treatment of cardiovascular disorders (v) the treatment of drug and alcohol dependence and withdrawal where R 1=linear, branched or substituted saturated or unsaturated radical of 1-24 carbon atoms, aryl, aralkyl, substituted aryl, aralkyl or carbohydrate group, heterocyclic ring or ring system alkyl alkyl group with 1-24 carbon atoms R1,R2 cycloalkyl or substituted cycloalkyl group R3=H, acyl, tosy or mesyl group R4=H, alkyl, aryl, substituted alkyl or aryl groups Z=linear, branched or substituted alkylene X=O or S The use of the inhibition of lipid methyl transferases as a means of discovering, designing lead compounds or medicines which have the therapeutic activities described above.
    b. Processes for producing compounds with general formula 1, whereby the synthesis ofa-amino alkanoic acid derivatives is achieved by either of two methods: (i) from the reaction ofa-amino--butyrolactone or N-p toluene-sulphonyl-a-amino-Y-butyrolactone with different alcohols and thiols in the presence of a strong base and phase transfer catalyst at high temperature, (ii) from the reaction of the Williamson products of various alcohols and thiols with Brdihalogeno-alkanes or from the products of the reaction of various mesylated and tosylated alcohols with -halogeno-thiols, with diethylacetamidomalonate in sodium ethoxide and subsequent acidcatalysed hydrolysis and decarboxylation.
  2. 2. Processes as claimed in Claim lb(i) wherein for the reaction, nonpolar, high boiling, organic solvents, preferably toluene, xylene, tetralin, decalin or paraffin oil, were used.
  3. 3. Processes as claimed in Claim lb(i) wherein for the reaction a catalytic amount of a phase transfer catalyst, preferably tetraalkyl ammonium salts, were used.
  4. 4. Processes as claimed in Claim lb(i) wherein for the reaction strong base, preferably potassium hydroxide, sodium hydroxide or sodium hydrogen sulphide, were used.
  5. 5. Processes as claimed in Claim lb(i) wherein the reaction was performed at high temperature, preferably between 100200CC.
  6. 6. Compounds and processes as claimed in Claim lb(i) wherein as a reagent a-amino-t-butyrolactone or N protected-a-amino-ç-butyrolactone preferably N-acetyl- or N-p-toluene-sulphonyl-a-amino-Y-butyrolactone were used.
  7. 7. Compounds and processes as claimed in Claim lb(ii) wherein as a reactant -dihalogeno-alkanes, preferably the -dihalogen derivatives of methane, ethane, propane, butane, hexane, octane and dodecane, were used.
  8. 8. Compounds and processes as claimed in Claim 1B(ii) wherein as a reactant -halgeno-thiols, preferably such derivatives of ethane, propane, butane, hexane, octane and dodecane were used.
  9. 9. Compounds and processes as claimed in Claim 1 wherein as a reactant alcohols and thiols and their p-toluene-sulphonyl and methyl-p-toluenesulphonyl derivatives, preferably dodecyl mercaptan, benzyl mercaptan, 5' deoxy-5 '-thic-adenosine, benzyl mercaptan, adenosine, 1-thio-a-D-glucose- tetraacetate, and 2'-3'-isopropyl-adenosine were used.
  10. 10. Compounds and processes as claimed in Claim 1 wherein compounds of general formula 1 form salts with inorganic or organic acid salts or ions (hydrochloric acid, citric acid, tartaric acid, sodium ion, etc).
  11. 11. Compounds and processes as claimed in Claim 1 wherein the compounds of general formula 1 are to be used as agents for their actions on the central nervous system, including sedation, hypnosis, anxiolysis, spasmolysis, anaesthesia and analgesia.
  12. 12. Compounds and processes as claimed in Claim 1 wherein the compounds of general formula 1 are to be used as agents for their actions on the periperal nervous system, including muscle relaxation and analgesia.
  13. 13. Compounds and processes as claimed in Claim 1 wherein the compounds of general formula 1 are to be used for the treatment of inflammatory disorders, including asthma and arthritis.
  14. 14. Compounds and processes as claimed in Claim 1 wherein the compounds of general formula 1 are to be used as agents for the treatment of cardiovascular disorders.
  15. 15. Compounds and processes as claimed in Claim 1 wherein the compounds of general formula 1 are to be used as agents for the treatment of drug and alcohol dependence and withdrawal.
GB8809871A 1988-07-07 1988-07-07 alpha -Amino-alkanoic acid derivatives and process for their preparation with anti-inflammatory, analgesic, sedative, hypnotic, anxiolytic, spasmolytic, anaesthetic, muscle relaxant and cardiovascular activity Withdrawn GB2217706A (en)

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EP0424543A1 (en) * 1989-04-28 1991-05-02 Fuji Kagaku Kogyo Kabushiki Kaisha New s-adenosylmethionine derivative
WO2002022569A1 (en) * 2000-09-14 2002-03-21 Grünenthal GmbH Method for producing chiral compounds

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GB1003176A (en) * 1961-04-20 1965-09-02 Organon Labor Ltd Butyl ethers of hydroxy amino acids and peptides and derivatives thereof
GB1199613A (en) * 1966-10-12 1970-07-22 Nippon Kayaku Kk Process for Producing 2-Amino-4-Substituted Butyric Acids and their Corresponding Nitriles
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Publication number Priority date Publication date Assignee Title
EP0424543A1 (en) * 1989-04-28 1991-05-02 Fuji Kagaku Kogyo Kabushiki Kaisha New s-adenosylmethionine derivative
EP0424543A4 (en) * 1989-04-28 1991-07-03 Fuji Kagaku Kogyo Kabushiki Kaisha New s-adenosylmethionine derivative
US5166328A (en) * 1989-04-28 1992-11-24 Fuji Kagaku Kogyo Kabushiki Kaisha S-adenosylmethionine derivatives
WO2002022569A1 (en) * 2000-09-14 2002-03-21 Grünenthal GmbH Method for producing chiral compounds

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