PH26027A - A process for preparing (aryl or heteroaromatic methyl)-2,2'-bi-1H-imidazoles - Google Patents
A process for preparing (aryl or heteroaromatic methyl)-2,2'-bi-1H-imidazoles Download PDFInfo
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- PH26027A PH26027A PH39550A PH39550A PH26027A PH 26027 A PH26027 A PH 26027A PH 39550 A PH39550 A PH 39550A PH 39550 A PH39550 A PH 39550A PH 26027 A PH26027 A PH 26027A
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- carbon atoms
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- 125000003118 aryl group Chemical group 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- -1 amino, sulfhydryl Chemical group 0.000 claims description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 15
- 238000000034 method Methods 0.000 description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000003276 anti-hypertensive effect Effects 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229960002748 norepinephrine Drugs 0.000 description 3
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VMJOGHYLJSXTDW-UHFFFAOYSA-N 2-(bromomethyl)-1,3-thiazole Chemical compound BrCC1=NC=CS1 VMJOGHYLJSXTDW-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229940083608 sodium hydroxide Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CEFVCNWQCJCMHZ-UHFFFAOYSA-N 2-(bromomethyl)furan Chemical compound BrCC1=CC=CO1 CEFVCNWQCJCMHZ-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- ZCUJYXPAKHMBAZ-UHFFFAOYSA-N 2-phenyl-1h-imidazole Chemical compound C1=CNC(C=2C=CC=CC=2)=N1 ZCUJYXPAKHMBAZ-UHFFFAOYSA-N 0.000 description 1
- KBWHYRUAHXHHFO-UHFFFAOYSA-N 3-(bromomethyl)thiophene Chemical compound BrCC=1C=CSC=1 KBWHYRUAHXHHFO-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- DZGWFCGJZKJUFP-UHFFFAOYSA-N Tyramine Natural products NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical group BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- PPNAOCWZXJOHFK-UHFFFAOYSA-N manganese(2+);oxygen(2-) Chemical class [O-2].[Mn+2] PPNAOCWZXJOHFK-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical class [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 229960003732 tyramine Drugs 0.000 description 1
- DZGWFCGJZKJUFP-UHFFFAOYSA-O tyraminium Chemical compound [NH3+]CCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-O 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
A PROCESS FOR PREPARING ARYL OR HETERO-
AROMATIC METHYL)=2,2'~Bl~1H-IMIDAZOLES
This invention relates to novel {aryl or hetero- aromatic methyl)-2,2'-bi-lH-imidazoles, to a process for their production, to pharmaceutical compositions of said compounda, and to methods of treating hypertension with such compounds,
More specifically, this invention relates to methylated 2,2'~bi-1H-imidasoles of the general formula
N
~~ N
B ‘H fe (1) X wherein X is 2- or 3-thienyl, 2- or 3-furyl, 2- or 4 thiasolyl or phenyl with each of said groups optionally being substituted; the optional subatitution on said thienyl, furyl or thiaszolyl groups being 1 or 2 moieties selected from the group consisting of chloro, fluoro, bromo and lower alkyl of from 1 to 6 carbon atoms; the optional substitution on said phenyl group being 1 or 2 moieties selected from the group consisting of chloro, bromo, fluoro, lower alkyl of from 1 to 6 carbon atoms, alkoxy of from 1 to 6 carbon atoms, trifluoromethyl, amino, sulfhydryl, and 8(0) _R wherein m is O, 1 or 2 and R is lower alkyl s of from 1 to 6 carbon atoms; : the therapsutically scceptable acid addition salts thereof, and a process for preparing these compounds.
The compounds of this invention are dopamine p hydroXylase inhibitors, and as such are useful as antihypertensive agents., This invention also relates : to a process for preparing imidazole compounds.
The tera "C,=C¢ lower alkyl!" means a straight or branched-chain alkyl group containing from one to six carbon atoms, and includes methyl, ethyl, propyl, butyl, 18 pentyl and hexyl groups. The term "C,=C¢ alkoxy" refers to an -OR' group where R' is GC -C¢ lower alkyl as above.
When X is a mono-substituted group, the substituent oan be located at any of the available positions on the aro- matic or heteroaromatic ring. When X is a disubstituted group, the substituents can be the same or they can be different and they can be located at any of the available positions on the ring and oriented in any manner with } respect to each other, Preferably, X is an unsubstituted group or is a monosubstituted group. Preferred substituents 2% include chloro, fluoro and methoxy. The X-CH,~ moiety can - 3 a :
located at either the 1- or U- position of the imidasole ring and both positions are encompassed by the present invention,
Illustrative examples of compounds of this invention includes 1=(3-thienylmethyl~2,2'=bi-1H-imidazole 4-/Th-methoxyphenyl)methyl/-2,2'-bi-1H-imidasole be(3-thienylmethyl)=2,2'-bi-1H-imidaszole 1-(2-thienylmethyl)-2,2'<bi-1H-inidazole 1-(2-furylmethyl)=2,2'~bi-1H-inidazole b-(3-furylmethyl)=2,2'~bi-1H-imidasole l-(2-thiazolylmethyl)-2,2'-bi~1H-imidasole bo(4=thiasolylmethyl)=-2,2'-bi-1H-imidasole 4 /(3-5-dichlorophenyl)methyl/-2,2'~bi-1H-imidasole 1-(2,fluoro=%-thienylmethyl)=2,2'-bi-1H-imidasole ho(2-fluoro-t-thisenylmethyl)=2,2%=bi-1H-inidasole 4~(3~chloro-%-thienylmethyl)=2,2'~bi-1H-inidasole 4e(3-chloro-%-furylmethyl)-2,2'-bi-1H~imidasole 1-(2-methoxy=l-thisnylmethyl)-2,2'~bi-1H-imidasole : 20 4u(2-methoxy=5-furylmethyl)-2,2'-bi-1H-imidazole h=(b-chloro-2-thiazolylmethyl)-2,2'~bi-1H-4inidasole and the therapeutically acceptable acid addition salts thereof, oh a Representative salts are those salts formed with non-toxic organic or inorganic acids, such as, for example, those formed from the following acids: hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitrio, maleic, fumaric, benzoic, ascorbic, sucdinic, methanesul- fonic, ascetic, propionic, tartaric, citric, lactic, malic, mandelio, cinnamic, palmitic, itaconioc, bensenesulfonic and toluenesulfonic, ~ The biimidazoles of this invention can readily de prepared by the reaction depicted in reaction Scheme I:
REACTION SCHEME I
N
N N SL pa ~~ \ / NN base; st0ll; reflux \ /4 r——
XaCH, «By or Xe-CH_ =C1 i
N N— 2 2 ~~ vx : CH >: H H H 2 11
I X
11 : §
Sb : wherein X is as defined above, “5 a
In essence, Reaction Scheme I illustrates that the biimidazoles of formula I can be prepared by reacting the appropriate ot bromo or chloro compounds (III) with 2,2'~bi-1H-imidazole (II) in a solvent such as ethanol (EtOH) and in the presence of a base such as sodium hydro- xide (NaOH) under reflux conditions. The biimidasole starting aaterial (11) oan be obtained by a method of
Matthews, D.P., Whitten, J.P., and McCarthy, J.R., set forth in Synthesis, 4, 336, (1986).
When the desired product contains X as amino substituted phenyl, (III) would include Ahe amino group protected by a silyl protecting group or protected as a : phthalimide, and the resulting silylated compound or bi- imidasole-phthalimide would be appropriately deprotected to obtain the desired final product (I). Appropriate deprotecting agents for the silyl-protected compound would be, for example, ethanolic hydrochloric acid, or sodium fluoride. The phthalimide compound would be deprotected : by means of hydrazine and alcohol.
Examples 1 through 5 are illustrations of Resction
Scheme I.
The process described above can also be used for the . novel synthesis of known imidazole compounds wherein a readily available 2-substituted imidasole (IV) (wherein Y can be alkyl, aryl or trialkylsiyl, with the alkyl groups
\ . being straight- or branched-chain and containing up to ten carbon atoms, and the aryl groups being phenyl or naphthyl optionally substituted with groups such as alkyl of from 1 to 6 carbon atoms, halo, or alkoxy of from 1 to 6 carbon atoms) is reacted with the appropriate of bromo, or chloro compound (III), wherein X is as defined above, in a solvent such as ethanol (EtOH) in the presence of a base such as sodium hydroxide under reflux conditions to : readily yield a mixture of 1l- and b= and 4,%5-big- (X- : 10 sethyl)-1H-imidasoles (V) which can be separated by flash chromatography. This reaction is depicted in Reaction
Scheme II.
REACTION SCHEME II
A b EtOH3rafl N ase; EtOH raflux \ \ i > > (XaCH } / ¥
X-CH,-Br or X-CH_«C1 2'n 2 2 N
H H
111 v (1V) (111) (vX
I. . wherein X and Y are as defined above and n is 1 or 2 sad
: Example 6 isa 11lustrative of Reaction Scheme II.
The following examples are present to illustrate the present invention, but: they should not be constructed as limiting it in any way. 3 EXAMPLE 1 : 4={Tl-Methoxyphenyl) methy17-2,2"-bi-1H-iuidasole (1) and 1-/T4-Methoxyphenyl)methyl/-2,2'-bi-1H-imidazole (2) 2,2'-1H-Biimidazole was prppared by the method of
Matthews, D.P., Whitten, J.P., McArthy, J.R., ida . 10° Synthesis, 4, 336 (1986). A mixture of 10 g (0.75 nol) biimidazole, 17 ml 5 N sodium hydroxide, and 150 ml ethanol was refluxed for ona hour, After the mixture was cooled to room temperature, 8.6 g (0.055 mol) L- methoxybenzyl chloride was added and the reaction was refluxed for 24 hours, The mixture was cooled to room . temperature and was filtered to remove any unreacted 2,2'- biimidazole solid. The filtrate waa concentrated under reduced pressure to yield 14.7 g crude (1) and (2).
Purification by flash chromatography (35% acetone/CH,CR, then 50% acetone) yielded 3.0 g (31%)(1) and 2.0 g (20%) 2). © (1)1 mp 204-205%C (8, 2), 6.77-7.26 (m, 7)§ M8 EI at 70eV (8, 3)y 5.85 (8, 2), 6.70e7.43 (m, 8) MS (EI at 70e V)2s4(45) (M*), 147(100), 121(81). Anal. Calcd. for
Cyl N 0s Co 66.133 H, 5.55§ N, 22.03. Found: c, 66.03
H, 5.65; N, 21.73. _8-
(2)s mp 138-140 ( toluene/hexane) ; 1 NMR (DMSO-d) 3.7% (s, 3), 5.85% (=, 2), 6.71=7.43 (m, 8) MS (EX at 70e Vv) ’ n/3 254(6) (M*), 147(3), 121(100),
EXAMPLE 2 3 he(Phenylmethyl)=2,2'~bi=1H-inidazole (3) and 1- (Phenylmethyl)-2,2'-~bi-1H-imidasole (4) . The procedure described in Example 1 was followed, substituting benzyl bromide for the 4L-methoxybensyl chloride used in Example 1, to produce 16% (3), 23% (4) and 17% 1,1'dialkylated biimidagole. . (3)s mp 208-210%C (isopropanol); 1y (DMBO-d,) 3.9% (so, 2), 6.81-7.34 (=, 8)y M3 (EI at 70 eV) n/s 224 (30) (¥") 147(100), 91(33), ?77(44)., Anal, Caled for Cy 3H ay? C, 69.623 H, 5.39. Found: Cc, 69.673 H, 5.54, (5) mp 138-140°C (toluene/hexane); 'H NMR (DMSO-d¢) 5.81 (8, 2), 6.99=7.28 (m, 9); M8 (EI- at 70eV) n/s . 224(13) (M*), 147(40), 91(100), 77(9). Anal. Caled for
Cy ti aly Cc, 69.62; H, 5.39. Found C, 70.003 H, 5.49. The dibensylated material had md 132-134°¢4 M8 (EI at 70 eV) u/s 314(81) (M*), 237(23), 223(60), 91(100).
EXAMPLE 3 1-(2-Furylmethyl)=2,2'=bi-1H-inidagole (5) and 4-(2- furylmethyl)-2,2'=bi-1H~imidasole (6) :
If the procedure of Example 1 is repeated using 2- bromomethylfuran rather than 4-methoxybenayl chloride of
Exemple 1, the products obtained are title compounds (3) and (6).
EXAMPLE 4 1-(2-THiagolylmethyl)-2,2'~bi~1li-imidazole (7) and be (2
Thiagolylmethyl)-2,2'-1i~-imidazole (8) : If the procedure of Example 1 is repeated using 2- : : bromomethylthiazole rather than -methoxybenzyl chloride of Example 1, the products obtained are title compounds (7) and 18).
Similarly, if an appropriate halo- or methyle : substituted (bromomethyl) thiazole is used in the above procedure, the corresponding halo- or methyl-subastituted thiazole product is obtained. : An alternate route for making a compound of this invention is presented in Example 5.
EXAMPLE 5 1-(2-Thienylmethyl)~2,2'~bi~1H-imidasole (9)
Under nitrogen, a adlution of 6.1 g (0.05 nol) be dimethylaminopyridine in 100 ml dimethyl formamide was cooled to 10°C ant 5.3 g (0.05 mol) oyanogen bromide was : added. The reaction was warmed to 20°C and a precipitate of cyanogen bromide~dimethydaminopyridine complex formed,
Upon cooling to 10°C, 3.3g (0.02 mol) 1-(2-thienyl-
methyl)«lH-i{midasole (which may be produced in a manner set forth in German patent application 3,228,266, 29 July 1982) was added. The reaction was stirred at room tempergture for 6 hours and then quenched with 600 ml dilute sodium carbonate. The product was washed with } water, dried (sodium sulfate) and concentrated under reduced pressure to yield 3.7 g crude l-(2-thienylmethyl)- 1H-imidazole-2-carbonitrile a which was purified by flash chromatography (5% ethyl acetate/dichloromethane).
A mixture of 4,7 g (0.025 mol) a, 0.5 g sulfur, 20 ml methoxyethanol and 1.7 g (0.029 mol) ethylenediamine vas stirred at room temperature under nitrogen for 1% minutes.
The reaction was then heated and maintained at 120°C for 6 hours, after which it was cooled to room temperature.
After the addition, with stirring, of 300 ml water, 5.33 g (92%) off-white solid was collected and recrystallized (isopropanol) to yield 4',5'-dihydro-l-(2-thienylmethyl)- 2,2'~bi-1H-imidazole b (mp 101-103°C; Anal. Caled for: N, : 24.123 Found: N, 24.20).
A mixture of 3.0 g (0.0129 mol) of b, 7.2 g (0,083 mol) activated manganese oxide, and 200 ml dry dichloromethane was stirred at room temperatures for 13 days. The reaction was filtered hot and the solids washed again with hot dichloromethane. Concentration under 25% reduced pressure yielded 4.0 g crude (9). Purification by flash chromatography (ethyl acetate) resulted in 1.26 g (42%) of the title product (9). mp 153-155°C; Anal Caled for Cy H oN 88 Co 57.373 Hy 4.383 Ny 24.3%; Found: C, 37.25; H, 4.4%) N, 24.30.
EXAMPLE 6 2-Phenyl-b=(3-thienylmethyl)-1ii-inidasole (10), 2-Phenyl= lt 5=bis=(3-thienylaethyl)~1H-iaidasole (11) and 2-phenyl- 1-(3-thienylmethyl)=1i=inidasole (12).
A mixture of 7.2 g (0.0% mol) 2-phenylimidazole, 12 ml 5M NaOH, and 100 ml ethanol was refluxed for 1 hour.
After cooling to room temperature, 7.1 g (0.0h mol) 3- thienylmethyl bromide was added and the resotion was again heated to reflux, After 24 hours, the reaction was cooled and concentrated to give 23 g brown residue. The products were separated by flash chromatography (10% acetone/CH,C1,) to yield 3.1 g (10), 2.6 g (11), 0.3 g (12) and also 3,0 g 2-phenylimidaszole. (10): mp 166-168°C3 IR (XBr) 3100 oat brs y NMR (DMSO oo dg) 3.90 (8, 2), 6.85-7.96 (my, 9), 12.37 (br 8s, 1)3 MS (EX at 70 oF) m/z 240(100) (M'), 157(9), 136(62), 97(8). Anal.
Caled for Cp,H,,N,85 Co 69.973 H, 5.033 N, 11.66. Found c, 69.83; H, 5.13; N, 11.58. (11): mp 163-165°C; IR (KBr) 3100 on! bry YH NMR (DMSO- dg) 3.88 (8s, 4), 6.93-7.98 (m, 0), 12.20 (br 8, 1)§ M3 (EI at 70 aV) m/s 336 (870.7), 239(50), 97(100). Anal.
Calod for Gyg) N,8, 6, 67.82; H, b.79; X, 8.32, TYounds C, 67.60; H, 4.83; N, 8.35. (12): 1H NMR (DMSO-d) 5.42 (s, 2), 6.95-7.0 (m, 10); MS (EI at 70 eV) w/z 280(53) (M.%), 157(1), 136(2), 97(100).
The compounds of this invention inhibit the ensyme dopamine p-hydroxylase (DBH) and therefore are useful in the treatment of hypertension. An embodiment of this invention is a method of treating hypertension in a mammal which comprises administering to said mammal an effective antihypertensive amount of compound of formula I, Since
DBH is a major enzyme in the synthetic pathway of . norepinephrine (NE), the presence of an inhibitor should decrease the amount of NE produced, and thereby have an antihypertensive effect, 18 ~ The DBH inhibitory properties of the compounds of this invention can readily be determined by standard and well : known procedures. For example, inhibition of DBH was determined by a procedure wherein ensymatic activity was - ascertained in aqueous solution in the presence of molecular oxygen, an electron donor such as ascorbate, a a substrate such as tyramine, an inhibitor, and the necessary cofactors for the enzyme at a pil of 4.5 to 5.5, : preferably pH 5.0, and at a temperature of 20°C to 4°c, preferably 37°%c. The inhibitor was assayed over a range 29 of concentrations. Each reaction was followed by measuring oxygen uptake as an indication of encyme activity using a polarographic electrode and an oxygen monitor, following the method of S. May, et al., Jo Biole
Chem., 256, 2258 (1981). The DBH inhibitory aotivity of compounds of this invention is indicated in Table I.
TABLE I
DBH INHIBITORY ACTIVITY
Compound ICsod : 1-(3-thienylmethyl)- 29.0 pM +/~6.0pM 2,2'=-bi-1H-imidazole
Yu(3-thienylmethyl)= 8.8 pM +/=1.8pM 2,2'=bi-~1H-imidazole 1-(2-thienylmethyl) 65.5 pM +/=ho3pM 2,2'«bi-1H-imidazole *Concentration at which the reaction is inhibited by 50%. : Thus, based on this and ddther standard laboratory techniques used to evaluate DBH inhibitors, by standard toxicity tests and pharmacological assays for the determination of antihypertensive activity in mammals, and : by comparison of these results with the results of known antihypertensive agents, the effective antihypertensive dosage of the compounds of this invention can readily be oo determined. In general, effective antihypertensive
: 2060p, : results can be achieved at a dose of about $ to about 100 mg per kilogram body weight per day. Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the hypertension as determined by the attending diagnostician,
In their funotion as therapeutically useful compounds, it is advantageous to administer the compounds to the host animal in admixture with an acceptable and suitable : 10 pharmaceutical carrier. Such preparations may be in such forms as, for example, tablets, caplets and suppositories, or in liquid forms, as for example, elixirs, emulsions, sprays and injectables. In the formulation of phagmaceutical preparations, such subatances can be employed which do not react with active substances as, for ’ .- example, water, gelatin, lactose, starches, magnesium sterate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly and the like,
Claims (1)
1. A process for preparing compounds of the formula P (X-CH —IF Ny 2 n ~y - ) wherein X is 2- or 3-thienyl, 2- or 3-furyl, 2- or he thiszolyl or phenyl, with each of said groups optionally being substituted; the optional substitution on said thienyl, furyl or thiazolyl groups being 1 or 2 moieties selected from the group consisting of chlero, fluoro, ‘ promo and lower alkyl of from 1 to 6 carbon atoms the optional substitution on said phenyl group being 1 or 2 moieties selected from the group consisting of chloro, bromo, fluoro, lower alkyl of from 1 to 6 carbon atoms, " alkoxy of from 1 to 6 carbon atoms, trifluoromethyl, amino, sulfhydryl; and S(O) R wherein m is 0, Y or 2 and R is lower alkyl of from 1 to 6 carbon atoms and n is 1 or 2; and wherein Y ie alkyl, aryl, or trialkylailyl, the _ alkyl groups being atraight- or branched-chain and : containing one to ten carbon atoms, and the aryl groups being phenyl or naphthyl, optionally substituted with from 1 to 3 substituents selected from the group containing alkyl of from 1 to 6 carbon atoms, chloro, bromo, fluoro
\
: . \ 26027 and alkoxy of from 1 to 6 carbon atoms, which comprises readting a 2-substituted imidasole of the formula N C NY N } H with an appropriate debrominated or d-chlorinated : 5 methylated, substituted or non-substituted, monocaromatio ring of the formula X=-CH,=Br, or X=~CHg~C1 wherein X is defined above, in ethanol in the presence of sodium hydroxide under reflux conditions. \ i! DONALD P. MATTHEWS ~ JEFFREY P. WHITTEN JAMES R. Mo@ARTHY : Inventors
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/078,352 US4839375A (en) | 1987-07-28 | 1987-07-28 | (Aryl or heteroaromatic methyl)-2,2'-bi-1H-imidazoles and their use as anti-hypertensive agents |
| PH37306A PH26551A (en) | 1987-07-28 | 1988-07-28 | (Aryl or heteroaromatic methyl)-2,2'-bi-hi-imidazoles and their use as anti-hypertensive agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PH26027A true PH26027A (en) | 1992-01-29 |
Family
ID=26652380
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PH39550A PH26027A (en) | 1987-07-28 | 1989-11-17 | A process for preparing (aryl or heteroaromatic methyl)-2,2'-bi-1H-imidazoles |
| PH39549A PH26028A (en) | 1987-07-28 | 1989-11-17 | A process for preparing (aryl or heteroaromatic methyl)-2,2'-bi-1H-imidazoles |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PH39549A PH26028A (en) | 1987-07-28 | 1989-11-17 | A process for preparing (aryl or heteroaromatic methyl)-2,2'-bi-1H-imidazoles |
Country Status (1)
| Country | Link |
|---|---|
| PH (2) | PH26027A (en) |
-
1989
- 1989-11-17 PH PH39550A patent/PH26027A/en unknown
- 1989-11-17 PH PH39549A patent/PH26028A/en unknown
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| Publication number | Publication date |
|---|---|
| PH26028A (en) | 1992-01-29 |
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