NO156370B - Analogifremgangsmaate ved fremstilling av terapeutisk virksomme polyolefiniske-a- alfa-alkyl-carboxylsyrer. - Google Patents
Analogifremgangsmaate ved fremstilling av terapeutisk virksomme polyolefiniske-a- alfa-alkyl-carboxylsyrer. Download PDFInfo
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- NO156370B NO156370B NO832333A NO832333A NO156370B NO 156370 B NO156370 B NO 156370B NO 832333 A NO832333 A NO 832333A NO 832333 A NO832333 A NO 832333A NO 156370 B NO156370 B NO 156370B
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- compounds
- carbon atoms
- alkyl
- trimethyl
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- 239000002253 acid Substances 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000007513 acids Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 230000002207 retinal effect Effects 0.000 claims description 7
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 abstract description 4
- 101100294102 Caenorhabditis elegans nhr-2 gene Proteins 0.000 abstract 1
- 125000000392 cycloalkenyl group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 125000000468 ketone group Chemical group 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 8
- 235000020945 retinal Nutrition 0.000 description 7
- 239000011604 retinal Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 210000001339 epidermal cell Anatomy 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229930002330 retinoic acid Natural products 0.000 description 3
- 229960001727 tretinoin Drugs 0.000 description 3
- LHAGMERYGJOTAS-UHFFFAOYSA-N 2,5,9-trimethyl-11-(2,6,6-trimethylcyclohexen-1-yl)undeca-2,4,6,8,10-pentaenoic acid Chemical compound OC(=O)C(C)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C LHAGMERYGJOTAS-UHFFFAOYSA-N 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 240000007711 Peperomia pellucida Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000002995 comedolytic effect Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-OFKYTIFKSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(tritiooxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO[3H])O[C@H]1N1C(=O)NC(=O)C(C)=C1 IQFYYKKMVGJFEH-OFKYTIFKSA-N 0.000 description 1
- -1 2,6,6-trimethyl-1-cyclohexen-1-yl Chemical group 0.000 description 1
- WEPCGUIBKXFDIH-UHFFFAOYSA-N 2,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid Chemical compound OC(=O)C(C)=CC=CC=C(C)C=CC1=C(C)CCCC1(C)C WEPCGUIBKXFDIH-UHFFFAOYSA-N 0.000 description 1
- DDNRJQYJWNEUQS-UHFFFAOYSA-N 2-ethyl-5,9-dimethyl-11-(2,6,6-trimethylcyclohexen-1-yl)undeca-2,4,6,8,10-pentaenoic acid Chemical compound CCC(C(O)=O)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C DDNRJQYJWNEUQS-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- CWAIPBKZSWRXCS-UHFFFAOYSA-N 5,9-dimethyl-11-(2,6,6-trimethylcyclohexen-1-yl)undeca-2,4,6,8,10-pentaenoic acid Chemical compound OC(=O)C=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C CWAIPBKZSWRXCS-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- NCYCYZXNIZJOKI-OVSJKPMPSA-N Retinaldehyde Chemical compound O=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 description 1
- 229940008309 acetone / ethanol Drugs 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001339 alkali metal compounds Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- AFVLVVWMAFSXCK-VMPITWQZSA-N alpha-cyano-4-hydroxycinnamic acid Chemical group OC(=O)C(\C#N)=C\C1=CC=C(O)C=C1 AFVLVVWMAFSXCK-VMPITWQZSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003540 anti-differentiation Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000003178 carboxy group Chemical class [H]OC(*)=O 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000006003 cornification Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000036566 epidermal hyperplasia Effects 0.000 description 1
- BVSRWCMAJISCTD-UHFFFAOYSA-N ethyl 2-diethoxyphosphorylpropanoate Chemical compound CCOC(=O)C(C)P(=O)(OCC)OCC BVSRWCMAJISCTD-UHFFFAOYSA-N 0.000 description 1
- KVSSDQQYBSLCMD-UHFFFAOYSA-N ethyl 2-ethyl-5,9-dimethyl-11-(2,6,6-trimethylcyclohexen-1-yl)undeca-2,4,6,8,10-pentaenoate Chemical compound CCOC(=O)C(CC)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C KVSSDQQYBSLCMD-UHFFFAOYSA-N 0.000 description 1
- MEESBSKHHKLXAW-UHFFFAOYSA-N ethyl 5,9-dimethyl-2-propyl-11-(2,6,6-trimethylcyclohexen-1-yl)undeca-2,4,6,8,10-pentaenoate Chemical compound CCOC(=O)C(CCC)=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C MEESBSKHHKLXAW-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/04—Dandruff
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Foreliggende oppfinnelse angår en analogifremgangs-
måte for fremstilling av nye polyolefiniske a-alkyl-carboxyl-
syrer fra retinal (3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclo-hexen-l-yl)-2,4,6,8-nonatetraenal; vitamin-A-aldehyd) som har strukturformelen
En syntese av retinal fra 6-ionon og propargylhalo-
genid beskrives i US patentskrift nr. 3 060 229.
En rekke polyolefiniske a-substituerte carboxylalde-
hyder,-syrer og-estere er beskrevet i den videnskapelige litteratur. I japansk patentskrift nr. 10 124 (1964), CA.
62, 2798 g (1965), beskrives 2,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraensyre og 2,7,11-trimethyl-13-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10,12-trideca-
hexansyre, i Machleidt, et al., Justus Liebigs Ann. Chem., 679,20
(1964) beskrives a-fluorpolyolefiniske syrer og estere, i Chan,
et al., J.A.C.S. 96, 3642 (1974) beskrives polyolefiniske carboxaldehyder, i Haeck, et al., Recuil 85 (1966) sidene 334-
338 beskrives 5,9-dimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaensyre og tilsvarende 2,4,6,8,10,12-tridecahexanensyrer og de tilsvarende a-cyano og a-carboxysub-
stituerte forbindelser. I Buchta, et al., Naturwissenschaften 46, 74 (1959) beskrives methyl-2-methyl-7-fenyl-2,4,6-hepta-
trienoat.
Den foreliggende oppfinnelse angår fremstilling av
nye polyolef iniske ot-alkyl-carboxylsyrer og derivater av disse med den generelle formel
hvor R og hver er hydrogen eller en alkylgruppe med fra 1 til 5 carbonatomer, R2 er en alkylgruppe med fra 1 til 5 carbonatomer, R^ er hydroxyl eller alkoxy med fra 1 til 5 carbonatomer, og Z er en cyclohexenyl-gruppe substituert med fra 0 til 5 alkylgrupper med 1-5 carbonatomer, og farma-søytisk akseptable salter av disse. Fremstillingen omfatter forbindelser hvori dobbeltbindingene er i cis- eller trans-konfigurasjon.
De foregående forbindelser er alle funnet å være effek-tive ved behandling av psoriasis, acne og cellulære og humorale immunologiske mangeltilstander.
Blant forbindelsene med den omtalte generelle formel foretrekkes de hvor R^ er methyl og Z er en cyclohexenyl-gruppe substituert med fra 0 til 3 alkylgrupper, eller kombinasjoner av de foregående, inkludert de forbindelser hvori én eller flere av dobbeltbindingene er i cis-konfigurasjon. Innen denne foretrukne gruppe forbindelser foretrekkes særskilt forbindelser hvori Z er gruppen 2,6,6-trimethyl-l-cyclohexen-l-yl, og særlig foretrukket er 2,5,9-trimethyl-ll-(2,6,6-tri-methyl-l-cyclohexen-l-yl)-2,4,6,8,10-undecapentaensyre, som har spesielt fordelaktig terapeutisk virkning.
Forbindelsene fremstilles ut fra den kjente polyolefiniske forbindelse retinal ved bruk av i og for seg kjent syntetisk fremgangsmåte. Således fremstilles forbindelsene ved at retinal kondenseres med et keton med formelen
hvor R2 og R^ er som angitt i krav 1, i nærvær av
en sterk base, hvoretter de erholdte forbindelser eventuelt overføres til tilsvarende forbindelser med formel I ved hydrolyse og/eller forestring ifølge kjente fremgangsmåter, og det eventuelt dannes salter av de forbindelser hvor R^ er
OH.
Således resulterer kondensasjon av aldehydgruppen i retinal med den aktive methylengruppe i egnede syrer eller syredérivater med formelen i det tilsvarende derivat av undecapentaensyre.
Kondensasjonsreaksjonen utføres vanligvis ved å om-sette utgangsmaterialet i et egnet løsningsmiddel, og ved at det som sterk base anvendes natriumhydrid, natriumamid, natriumethoxyd eller lignende alkalimetallforbindelser. Reak-sjonen er vanligvis eksoterm og avkjøles følgelig for å kontrollere reaksjonshastigheten. Etter at den innledende reaksjon er over, oppvarmes reaksjonsblandingen til temperaturen for koking med tilbakeløp for å oppnå fullstendig om-setning.
En rekke forskjellige løsningsmidler kan anvendes, inkludert dioxan, tetrahydrofuran (THF), dimethylformamid, dimethylacetamid og tilsvarende organiske løsningsmidler som er blandbare med vann. Det anvendes fortrinnsvis vannfrie løsningsmidler, særlig ved bruk av alkalimetallbaser, for å unngå bireaksjoner.
Fremstillingen og virkningen av forbindelsene illu-streres nærmere ved hjelp av henholdsvis eksemplene og sammen-ligningsforsøket nedenunder.
Eksempel 1
Ethyl-2,5,9-trimethyl-11 -(2,6,6-trimethyl-1-cyclohexen-1-yl)-2, 4, 6, 8, 1O- undecapentaenoat
4,03 g natriumhydrid (50% dispersjon i mineralolje) ble vasket tre ganger med tørt pentan og suspendert i 50 ml vannfritt THF under nitrogenatmosfære. Den omrørte blanding ble avkjølt i et bad med isvann, og 20,6 g triethyl-2-fosfono-propionat ble tilsatt dråpevis. Den resulterende blanding ble omrørt i ytterligere to timer, mens temperaturen ble tillatt å øke til romtemperatur. Blandingen ble så avkjølt i et bad med isvann, og en løsning av 16 g retinal i 50 ml vannfritt THF ble tilsatt dråpevis. Den resulterende mørkerøde blanding ble omrørt i fire timer ved romtemperatur, 700 ml kaldt vann
ble tilsatt, og løsningen ble ekstrahert med tre 200 ml's etherporsjoner. De samlede etherløsninger ble vasket med 100 ml vann og tørket over natriumsulfat. Etter fjerning av
løsningsmidlet forelå råproduktet av esteren (20 g, 97%) som et mørkerødt, oljeaktig stoff. Dette ble benyttet til fremstilling av den frie syre i eksempel 2 uten ytterligere opp-arbeiding .
Eksempel 2
2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2, 4, 6, 8, 10- undecapentaensvre
20 g uren ester fra eksempel 1 ble oppløst i 50 ml ethanol, og en løsning av 5,12 g kaliumhydroxyd i 45 ml ethanol og 5 ml vann ble tilsatt dråpevis under omrøring under nitrogenatmosfære. Den resulterende løsning ble omrørt i 12 timer ved romtemperatur. Reaksjonsblandingen ble delvis konsentrert under redusert trykk og så blandet med 500 ml vann. Den resulterende blanding ble ekstrahert med tre 150 ml's etherporsjoner. Etherlaget ble kastet; det vandige lag ble surgjort til pH 3 med 10 N vandig saltsyre. Det resulterende produkt ble ekstrahert i ether. Etherløsningen ble vasket med vann og tørret over natriumsulfat. Konsentrering og filtrering av denne løs-ning ga det ønskede produkt som et orangerødt pulver. Omkrys-tallisering i aceton/ethanol ga 9,3 g (50,6%) av det rene produkt, smp. 197-199°C, UV spektrum (methanol) maks 380 nm.
Følgende forbindelser ble fremstilt ifølge prosedy-rene beskrevet i eksemplene 1 og 2: ethyl-2-ethyl-5,9-dimethyl-11 -(2,6,6-trimethyl-1-cyclohexen-1- yl)-2,4,6,8,10-undecapentaenoat (én olje), ethyl-2-propyl-5,9-dimethyl-11(2,6,6-triméthyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaénoat (en olje),
2- ethyl-5,9-dimethyl-11 -(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaensyre (smp. 162-165°C),
2-propyl-5,9-dimethyl-11 -(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,1O-undecapentaensyre (smp. 172-175°C).
Sammenligningsforsøk
På grunnlag av forsøk ifølge modeller ansett som predikative for kliniske tilstander hos mennesket, har det vist seg at forbindelsene er virksomme mot forskjellige hudlidelser, slik som acne og psoriasis. Som modeller ble anvendt rhino-mus-metoden (Klingman, et al., J. Investigative Dermatology, 73, 354 (1979)), den comedolytiske metode utført på kaniner (Mills OH, Klingman AM: Assay of Comedolytic Agents in the Rabbit Ear, Animal Models in Dermatology, Relevance to Human Dermatopharmacology and Dermatotoxicology, utgitt av H.I. Maibach, New York Churchill-Livingston, 1975, sidene 176-183) og metoden med dyrking av epidermalceller fra mus (Marcelo, et al., J. Cell Biol., 79, 356 (1978)). Som sammenlignings-grunnlag for forsøkene ble det benyttet standard retinoider som er kjent for å være virksomme mot disse lidelser, og et kjent a-methylretinoid (2,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetransyre, angitt som DTCNA).
2,5,9-trimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,1O-undecapentaensyre (TTCUA) oppviste en aktivitet som var lik eller større enn aktiviteten av standardstoffene og den kjente forbindelse. Således hadde den, i en konsentrasjon på 0,05%, samme evne som trans-retinsyren (TRA) til å
redusere comedonstørrelsen i kaninøremodellen. Ved samme konsentrasjon var den, ifølge rhino-mus-modellen, lik med TRA med hensyn til evne til å gi signifikant reduksjon i størrelsen av utriculi (pseudocomedoner) og i mengden av forhorning i utriculi. Huden til disse mus viste moderat epidermal hyperplasia og betydelig mindre skrukkethet enn hos ubehandlede kontrolldyr.
I en konsentrasjon på 12 ug/ml reduserte den celle-formeringen i cellekulturen av epidermalceller fra mus, målt ved inhibering av opptaket av tritiert thymidin i DNA. Tabell I viser det prosentvise opptak relativt til kontrollbæreren (100%).
I sammenligning med de to standarder sees det prosentvise op tak med TTCUA å være inntil fem ganger mindre på ethvert tid punkt. Den kjente forbindelse, DTCNA, sees som kontrast å g omtrent det samme prosentvise opptak som standardmedikamente på alle tre tidspunkter. Likeledes viste TTCUA høy antidif-ferensieringsvirksomhet ved 12 ug/ml i kulturen av epidermal celler fra mus, som angitt i tabell II.
Forholdstallene i tabellen representerer resultatene av 2 må parametre, kulturfarging ved Kreyberg-teknikken (maksimal di ferensiering 10) og kjerneopptelling (maksimal differensieri 0). Den høyest mulige anti-differensierende aktivitet vil således være gitt ved forholdet 0/10. TTCUA sees å være mer virksom, uansett parameter, enn de to standarder, mens den kjente forbindelse er omtrent som standardene.
Claims (2)
1. Analogifremgangsmåte for fremstilling av terapeutisk virksomme polyolefiniske forbindelser med den generelle formel:
hvor R og R^ hver er hydrogen eller en alkylgruppe med 1-5 carbonatomer, er en alkylgruppe med 1-5 carbonatomer, R^ er hydroxyl eller alkoxy med 1-5 carbonatomer, og Z er en cyclohexenylgruppe som er substituert med 0-5 alkylgrupper med 1-5 carbonatomer, samt farmasøytisk akseptable salter derav,
karakterisert ved at retinal kondenseres
med et keton av formelen R0CH0CR-, hvor R„ og R_ er som oven-2 2 (i 3 2^3 0
for angitt, i nærvær av en sterk base, hvoretter de erholdte forbindelser eventuelt overføres til tilsvarende forbindelser av formel I ved hydrolyse og/eller forestring etter i og for seg kjente fremgangsmåter, og det eventuelt dannes salter av forbindelser hvor R^ er OH.
2. Analogifremgangsmåte ifølge krav 1, karakterisert ved at 2,5,9-trimethyl-ll-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4,5,8,10-undecapentaensyre fremstilles.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/392,837 US4472430A (en) | 1982-06-28 | 1982-06-28 | Alpha-alkyl polyolefinic carboxylic acids and derivatives thereof useful in the treatment of psoriasis |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO832333L NO832333L (no) | 1983-12-29 |
| NO156370B true NO156370B (no) | 1987-06-01 |
| NO156370C NO156370C (no) | 1987-09-09 |
Family
ID=23552199
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO832333A NO156370C (no) | 1982-06-28 | 1983-06-27 | Analogifremgangsmte ved fremstilling av terapeutisk virksomme polyolefiniske-alfa-alkyl-carboxylsyrer. |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4472430A (no) |
| EP (1) | EP0100433B1 (no) |
| JP (1) | JPS5920266A (no) |
| KR (1) | KR840005066A (no) |
| AT (1) | ATE33133T1 (no) |
| AU (1) | AU1611583A (no) |
| CA (1) | CA1278308C (no) |
| DE (1) | DE3376068D1 (no) |
| DK (1) | DK294883A (no) |
| EG (1) | EG16055A (no) |
| ES (1) | ES523553A0 (no) |
| FI (1) | FI832353L (no) |
| IL (1) | IL69036A (no) |
| NO (1) | NO156370C (no) |
| NZ (1) | NZ204704A (no) |
| ZA (1) | ZA834679B (no) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4694023A (en) * | 1982-06-28 | 1987-09-15 | Usv Pharmaceutical Corporation | Alpha-alkyl polyolefinic carboxylic acids and derivatives thereof useful in the treatment of psoriasis and allergic responses |
| US4722939A (en) * | 1983-07-29 | 1988-02-02 | Usv Pharmaceutical Corporation | Derivatives of alpha-alkyl polyolefinic carboxylic acid useful in the treatment of psoriasis |
| US4523042A (en) * | 1983-07-29 | 1985-06-11 | Usv Pharmaceutical | Derivatives of alpha-alkyl polyolefinic carboxylic acid useful in the treatment of psoriasis |
| DE3443627A1 (de) * | 1984-11-29 | 1986-05-28 | USV Pharmaceutical Corp., Tuckahoe, N.Y. | Polyolefinische (alpha)-alkylcarbonsaeuren und deren derivate, sowie diese verbindungen enthaltende arzneimittel |
| US5721103A (en) * | 1994-12-30 | 1998-02-24 | Ligand Pharmaceuticals Incorporated | Trienoic retinoid compounds and methods |
| US7314953B2 (en) * | 2001-03-27 | 2008-01-01 | Errant Gene Therapeutics, Llc | Treatment of lung cells with histone deacetylase inhibitors |
| US8026280B2 (en) | 2001-03-27 | 2011-09-27 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
| US6495719B2 (en) * | 2001-03-27 | 2002-12-17 | Circagen Pharmaceutical | Histone deacetylase inhibitors |
| US7312247B2 (en) | 2001-03-27 | 2007-12-25 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
| US7842727B2 (en) | 2001-03-27 | 2010-11-30 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
| CA2486303C (en) | 2002-05-22 | 2013-04-30 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors based on alpha-ketoepoxide compounds |
| CA2587013A1 (en) * | 2004-11-08 | 2006-05-18 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1271491A (fr) * | 1959-08-06 | 1961-09-15 | Hoffmann La Roche | Procédé pour la préparation d'esters polyènecarboxyliques et de leurs produits de saponification |
| GB1402999A (en) * | 1972-07-13 | 1975-08-13 | Univ California | Higher homologue of retinoic acid |
| JPS4931645A (no) * | 1972-07-24 | 1974-03-22 | ||
| US4021573A (en) * | 1974-04-22 | 1977-05-03 | The Regents Of The University Of California | Psoriasis treatment with retinoic acid analogs |
| US3934028A (en) * | 1974-04-22 | 1976-01-20 | The Regents Of The University Of California | Acne and psoriasis treatment with retinoic acid analogs |
-
1982
- 1982-06-28 US US06/392,837 patent/US4472430A/en not_active Expired - Fee Related
-
1983
- 1983-06-21 AU AU16115/83A patent/AU1611583A/en not_active Abandoned
- 1983-06-21 IL IL69036A patent/IL69036A/xx unknown
- 1983-06-23 ES ES523553A patent/ES523553A0/es active Granted
- 1983-06-27 ZA ZA834679A patent/ZA834679B/xx unknown
- 1983-06-27 DK DK294883A patent/DK294883A/da unknown
- 1983-06-27 NZ NZ204704A patent/NZ204704A/en unknown
- 1983-06-27 NO NO832333A patent/NO156370C/no unknown
- 1983-06-28 AT AT83106298T patent/ATE33133T1/de not_active IP Right Cessation
- 1983-06-28 EG EG392/83A patent/EG16055A/xx active
- 1983-06-28 EP EP83106298A patent/EP0100433B1/en not_active Expired
- 1983-06-28 KR KR1019830002926A patent/KR840005066A/ko not_active Application Discontinuation
- 1983-06-28 CA CA000431328A patent/CA1278308C/en not_active Expired - Lifetime
- 1983-06-28 DE DE8383106298T patent/DE3376068D1/de not_active Expired
- 1983-06-28 FI FI832353A patent/FI832353L/fi not_active Application Discontinuation
- 1983-06-28 JP JP58115332A patent/JPS5920266A/ja active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| ATE33133T1 (de) | 1988-04-15 |
| IL69036A (en) | 1986-01-31 |
| JPS5920266A (ja) | 1984-02-01 |
| EP0100433A2 (en) | 1984-02-15 |
| ES8507092A1 (es) | 1985-09-16 |
| NO832333L (no) | 1983-12-29 |
| CA1278308C (en) | 1990-12-27 |
| FI832353L (fi) | 1983-12-29 |
| DE3376068D1 (en) | 1988-04-28 |
| EP0100433B1 (en) | 1988-03-23 |
| AU1611583A (en) | 1984-01-05 |
| NO156370C (no) | 1987-09-09 |
| US4472430A (en) | 1984-09-18 |
| FI832353A0 (fi) | 1983-06-28 |
| DK294883D0 (da) | 1983-06-27 |
| ZA834679B (en) | 1984-03-28 |
| NZ204704A (en) | 1985-11-08 |
| JPH0449533B2 (no) | 1992-08-11 |
| DK294883A (da) | 1983-12-29 |
| KR840005066A (ko) | 1984-11-03 |
| EG16055A (en) | 1987-03-30 |
| ES523553A0 (es) | 1985-09-16 |
| IL69036A0 (en) | 1983-10-31 |
| EP0100433A3 (en) | 1985-06-26 |
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