PH27109A - N-Úsubstituted alkylidine¾ fused-bicycloalkyldine and hetero-alkylidine quinolinamides a process for their preparation and their use as medicaments - Google Patents
N-Úsubstituted alkylidine¾ fused-bicycloalkyldine and hetero-alkylidine quinolinamides a process for their preparation and their use as medicaments Download PDFInfo
- Publication number
- PH27109A PH27109A PH39197A PH39197A PH27109A PH 27109 A PH27109 A PH 27109A PH 39197 A PH39197 A PH 39197A PH 39197 A PH39197 A PH 39197A PH 27109 A PH27109 A PH 27109A
- Authority
- PH
- Philippines
- Prior art keywords
- tetrahydro
- amine
- phenylmethylene
- compounds
- acridinamine
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title description 6
- 238000000034 method Methods 0.000 title description 4
- 239000003814 drug Substances 0.000 title description 2
- ZEXKKIXCRDTKBF-UHFFFAOYSA-N quinoline-2-carboxamide Chemical class C1=CC=CC2=NC(C(=O)N)=CC=C21 ZEXKKIXCRDTKBF-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
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- 230000003287 optical effect Effects 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
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- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 15
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- 230000007074 memory dysfunction Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
- 229940012189 methyl orange Drugs 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- SPZVKYOVPXXVMX-UHFFFAOYSA-N oct-6-en-4-one Chemical compound CCCC(=O)CC=CC SPZVKYOVPXXVMX-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002913 oxalic acids Chemical class 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Description
H-Subgtituted alkylidene fused-bicycloalkylidene : and heteroalkylidene quinolinamines, a process for their preparatioh and their use as medicaments
This invention relates to compounds having the formula n
PN
Ry : N A \
X
Y
N(CH) n
R) wherein n is 1-4; R, is hydrogen, alkyl, aryl, arylloweralkyl, naphthyl, furyl, thienyl, pyridinyl or pyrrolyl; A is a direct bond or (CHRz) ps m being 1-33 X is hydrogen, loweralkyl, cycloalkyl, lower- alkoxy, kalogen, hydroxy, nitro, trifluoromethyl, formyl, loweralkylcarbonyl, arylcarbonyl, -SH, loweralkylthio, -NHCOR,, or -NRcRg, R, being hydrogen or loweralkyl, and Rg and Rg being independently hydrogen, loweralkyl or cycloalkyl; Y is CH,, O
S or NRq 3 and each Ry» each Ry and Ro, are independently hydrogen, loweralkyl or arylloweralkyl or taken two at a time form a methylene or ethylene bridge constituting a part of a five-membered or larger ring, with the proviso that when Y is CH,, R, and Ry must together constitute a methylene or ethylene bridge; stereo, optical and geometrical isomers thereof, and pharmaceutically acceptable acid addition galts thereof, which are useful for enhancing memory. : Throughout. the specification and the appended claims, given chemical formula or name shall encom- pass all stereo and optical isomers thereof where such isomers exist, a well as pharmaceutically accep- table acid addition salts thereof and solvates thereof such as for instance hydrates. : The following definitions shall apply throughout the specification and the appended claims.
Unless otherwise stated or indicated, the term alkyl denotes a strajght or branched alkyl group having from 1 to 8 carbon atoms. Examples of said _u alkyl include methyl, n-propyl, iso-butyl, heptyl, decyl, dodecyl, hexadecyl and octadecyl.
Unless otherwise stated or indicated, the term loveralkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said loweralkyl include methyl, ethyl, n-propyl, iso-butyl, pentyl and hexyl.
Unless otherwise stated or indicated, the term cycloalkyl denotes a saturated ring containing 3 to 7 carbon atoms. Examples of said cycloalkyl include ¢yclopropyl, cyclohexyl and cycloheptyl.
Unless otherwise stated or indicated, the term halogen shall mcan fluorine, chlorine, or bromine or iodine.
Unless otherwise stated or indicated, the term aryl shall mean an unsubstituted phenyl group, & phenyl grcup substituted with 1, 2 or 3 substituents each of which being independently loweralkyl, lower- alkoxy, halogen, hydroxy, trifluromethyl, phengxy or benzyloxy.
The phrase "each R," appearing in the definition of group R, refers to the fact that when n is greater than 1, there are more than one R, group in the molecule, in which case they may or may not be the same. Similarly, the phrase "each R3" appearing in the definition of group Ry refers to the fact that : when m is greater than 1, there are more than one
R, group in the molecule in which case they may or may not be the sane.
The compounds of this invention are prepared by utilizing the synthetic scheme described below.
In order to simplify the description of the synthetic scheme, the description will be presented with specific reference to the situation where A is
CHR, Y is CH,, (CHR,) is CHR CH, and R, and Ry together form a methylene bridge, but it will readily be understood that the synthetic scheme can also be applied to the other oi tuations by making obvious modifications where necessary.
Synthetic Scheme
Compounds of Formula Ia can be prepared by reacting a 1,4-methano-1,2,3,4-tetrahydro-9-acridi- namines of formula II with an aldehyde of formula III where the definitions of X and Ry» are as given earlier. Typically, said reaction is conducted in a suitable solvent such as benzene, toluene or xylene at a temperature of about 80-150°C in the presence of a base such as piperidine, morpholine, diethylamine or diisopropylamine.
NH, 7D + R,CHO —>
N
(11) (III)
H
PN oo “1
X
8 (Ia)
The compounds of Formula I of the present invention are useful in the treatment of various memory dysfunctions characterized by decreased cholinergic function, such as Alzheimer's disease.
This utility is manifested by the ability of these compounds to inhibit the enzyme cholinesterase and thereby increase acetylcholine levels in the brain. Further, the compounds of this invention are in general less toxic and have a broader therapeutic window than heretofore known compounds such as tacrine and physostigmine, making them more therapeutically acceptable.
The ability to inhibit acetylcholinesterhse } was determined by the photometric method of Ellman et al., Biochem. Pharmacol. 7,88 (1961). Results of acetylcholinesterase inhibition for some of the compounds of this invention are presented in Table 1 along with those for reference compounds.
Acetylcholinesterase Inhibition Agsay
Table 1 ————
Acetylcholinesterase : Inhibition
Compound ICgo(molar)
FO
1,4-Methano-N-( phenylmethylene)-T1,2,3,4- 1.2 x 10°? tetrahydro-9-acridinamine 1,4-Methano-N~-(phenylmethylene)-6- trifluoromethyl-1,2,3,4-tetrahydro-9- -5 2.2 x 10 acridinamine (Reference Compounds)
Pacrine(9-amino-1,2,3,4-tetrahydroacridine) 3.1 x 10™7
Fhysostigmine 6.0 x 1079 — ’ } .
This utility is further demonstrated by the ability of these compounds to restore cholinergically deficient memory in the Dark Avoidance Assay, where they are in general active over a broader dose range than heretofore known compounds, a distinct therapeutic advantage. In this assay mice are tested for their ability to remember an unpleasant stimulus for a period of 24 hours. . A mouse is placed in a chamber that contains a dark compartment; a strong incandescent light drives it to the dark compartment, where an electric shock is administered through metal plates on the floor. The animal is removed from the testing appratus and tested again, 24 hours later, for the ability to remember the electric shock.
If scopolamine, an anticholinergic that is known to cause memory impairment, is administered before an animal's initial exposure to the test : chamber, the animal re-enters the dark compartment shortly after being placed in the test chamber 24 hours later. Lhis effect of scopolamine is blocked by an : active test compound, resulting in a greater interval before re-entry into the dark compartment.
The test results are expressed as the percent of a group of animals in which the effect of scopolamine is blocked, as manifested by an increased interval : between being placed in the test chamber and re- entering the dark compartment. Results of Dark
Avoidance Assay for a representative compound of this invention and ghysostigmine(Teference compound) are presented in Table 2.
Dark Avoidance Assay
Table 2 —
Dose (mg/kg of % of Animals body weight, sc) with Bcopolamine
Compound Induced Memory : Deficit Revers: 1, 4-Methano-N-(phenylmethylene)- "0. 1,2,%,4-tetrahydro-9-acridinamine 0.3%1 27% (Reference Compound)
Physostigmine : 0.31 20%
: Effective quantities of the compounds of the invention may be administered to a patient by any of the various methods, for example, orally as in capsules or tablets,parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions.
The free base final products, while effective themselves, : may be formulated and adbinistered in the form of their pharmaceutically acceptable acid addition salts for purposes of stability, convenience of crysta- llization, increased solubility and the like.
Acids useful for preparing the pharmaceutically acceptable acid addition salts of the invention include inorgahic acids such as hydrochloric, hydrobromic, sulfuric, hitric, phosphoric and perchloric acids, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids.
The ,ctive compounds of the present invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they : may be enclosed in gelatin capsules, or they may be compressed into talbets. For the purpose of oral therapeutic administration, the active compounds of the invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least 0.5% of active compounds, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
The amount of active compound in such compositions is seh that a suitable dosage will be obtained.
Preferred compositions and preparations according to : the present invention are prepared so that an oral dosage unit form contains between 1.0-300 milligr,ms of active compound.
The tablets, pills, capsules, troches and the like may also contain the following .ingredients a binder such as micro-crystalline cellulose, gum
Co tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, cornstarch and the like; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materiels of the above type , a liquid carrier such as a fatty oil. Other dosage unit forms may contain cther various materials which modify the physical form of the dosage unit, for example, as coatings. Thus tablets or pills may be coated with sugar, shellac, or other enteric coating coatings. A syrup may contain, in addition to the active compounds, sucrose : as a sweetening agent and certain preservatives, dyes, coloring and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purpose of parenteral therapeutic administratin, the acitve compounds of the invention may be incorporated into a solutior or suspension.
These preparations should contain at least 0.1% of -active compound, but may be varied between 0.2 and about 30% of the weight thereof. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present inventions are prepared go .that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound.
The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents ‘such as benzyl alcohol or methyl parabens; anti- oxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, cftrates or phosphates "10 and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral prepa- rations can be enclosed in disposable syringes or multiple dose vials made of glass or plastic.
Examples of the compounds of this invention include: -
N-(phenylmethylene)-3,4-dihydro-1H-thiopyrano/ 4 ,3-b7 - quinolin-10-amine;
N-ethylidene-3,4-dihydro-1H-thiopyrano/ #,3-b7quinolin- © 10-amine;
N-decylidene-3,4-dihydro-1H-thiopyrano/ #,3-b7quinolin- 10-amine; .
N-(phenylmethylene)-3,4-dihydro-1H-pyrano/ 4, 3-bquinolin- : 10-amine;
N-/ 4-fluorophenyl)methylene/-3,4~dihydro-1H-pyreno re
/ #,3-b7quinolin-10-gmine;
N-hexylidene-3,4-dihydro-1H-pyrano/ 4,3-b/ quinolin- 10-amine;
N-(phenylmethylene)-2, 3-dihydrothieno/ 3,2-b7quinolin-
O-amine;
N-/(2-thienyl)methylene7-2,3-dihydrothieno/” 3,2-b/ quinolin-9-amine;
N-dodecylidene-2,3-dihydrothieno/ 3-2-b/quinolin-9- amine;
N-(phenylm-thylene)-1,3-dihydrothieno/ 3,4-b/quinolin- 9-amine; : : 1,4-methano-6-methyl-N-(phenylmethylene)-1,2,3,4-tetrahydro- 9-acridinsmine; 1,4-methanol-N~-(phenylmethylene)-6-trifluoromethyl- 1,2,3,4-tetrahydro-9-acridinamine; }
N-/ #-pyridinyl)methylene/-1,3-dihydrothieno/”3,4-b/- quinolin-9-amine;
N-tegradecylidene-1,3-dihydrothieno/ 3,4-b7quinolin-
Q-amine} 1-phenylmethyl-N-(phenylmethylene)-2,3-dihydro-2H- pyrrolo/ 3,2-b/-quinolin-9-amine;
N-(phenylmethylene)-2,3-dihydro-1H-pyrrolo/ 3,2-b7 quinolin-9-amine;
2-phenylmethyl-N-(phenylmethylene)-1,3-dihydro-2H- pyrrolo/ 3,4-b7quinolin-9-amine;
N-(phenylmethylene)-1,3-dihydro-2H-pyrrolo/ 3,4-b/ quinolin-9-amine; 1,4-methano. -N-(phenylmethylene)-1,2,3,4-tetrahydro-9- acridinamine;
N-ethylidene-1,4-methano-1,2,3,4-tetrahydro-9-acridi- namine;
N-hexadecylidene-1,4-methanox1,2,3,4~-tetrahydro-9- acridinamine; 1,4-ethano-H-(phenylmethylene)-1,2,3,4-tetrahydro-9- acridinamine; 1,4-ethano-N-J~ (4-fluorophenyl)methylene/-1,2,3,4- tetrahydro-9-acridinamine; and
N-decylidene-1,4-ethano-1,2,3,4-tetrahydro-9- acridinamine. '
The following examples are presented in order to illustrate this invention.
EXAMPLE 1 1,4-Methano-N-(phenylmethylene)-1,2,3,4-tetrahydro- 9-agcridinamine 1,4-Methano-1,2,3,4-tetrahydro-9-acridinamine (8.40 g) was refluxed in 300 ml of toluene which contained 7.0 g of morpholine and 6.4 g of benzaldehyde which had been freshly washed with aqueous K,C05%.
The reaction mixture was refluxed overnight and then concentrated and purified by flash chromatography (20% ethyl acetate/CH,C1,) to give 9.51 g of chroma-~ tographically pure product. Analytically pure material was obtained by recrystallization from benzene-pentane, mp 128-130°C.
ANALYSIS:
Calculated for C,H, glN,: 84. 53%C 6.08%H 9.39%N
Found: 84. 49%C 6.02%H 9. 31%N
EXAMPLE 2
N-(Fhenylmethylene)-3,4-dihydrothiopyrano-1H-/"4, 3-b/~ a quinolin-10-amine 3,4-Dihydrothiopyrano-1H-/"4,3-b/quinolin-10- amine(8.64 g) was suspended in 300 ml of toluene to which morpholine (7.0 g) and benzaldehyde were then added. This reaction mixture was then refluxed overnight with the separation of H,0 (Dean-Stark trap) and then concentrated and purified by flash chroma- tography (20% ethyl acetate/CH,C1,). The product- containing fractions were concentrated to give 7.30 g chromatographically pure product, mp 171-173°C.
Analytically pure material was obtained by recrys- tallisation from CH,C1l,/pentane, mp 175-176°C.
ANALYSIS: : Calculated for Crofq elas: 74, 96%C 5.30%H 9.20%N
Found: a 74, 97%C 5.25%6H 9.18%N : ‘he benzaldehyde was freshly washed with aqueous
ECO solution.
EXAMPLE 3 1,4-Methano-6-methyl-1,2,3,4-tetrahydro- ~ 9-scridinamine
A solution of 2-amino-4-methylbenzonitrile (16.0g) and zinc chloride (24.7 g) in 70 ml of ‘nitrobenzene w s heated at 50°C for 1 hour. To this was added norcamphor (20.0 g) and the mixture was stirred at 130°C for 3 hours. The reaction mixture was cooled and diluted with ether and the zinc complex was filtered. This complex was partitioned if Tn hg
To a Lit ali 400 roe EE uh Cha NEL : oo Coa - between aqueous NH, OH and 2-butanone (MME) and the aqueous phase was extracted with MiK. The organics were washed with water, dried (saturated NaCl, MgSO, ) and concentrated to an 0il which was triturated with ether to give 12.f gg of white powder, m.p. 159-162°C. : A 4.0 g portion was recrystallized from isopropyl ether to give 2.5 pg of anelytically pure “hite solid, Bh m.p. 162-164°C. : i ATALYST . : 10 Calculated for CoN: A0.32KC 7.19%H T12.89%N . Found: 80.2902 7.05% AR. 5PHN oo { n } Te = - SES 4 Cy ta EXAMILE 4 eo : oo . 1,4-i et) ano-6-methyl-N-(phenyluethylene)- a i | | s 1,7,3,4-tetrahydro-9-acridinaning
Pow = . Co 5 io : bo 4,95 A solution prepared from _ nl x CE 1,4-nethaho-6-methyl-1,?, b-tetrahydro-9-ncridnanine : 3 fn Th (8.68), benzaldehyde (6.3 g, freshly washed with - 3 Sw K,00,, solution), morpholine (6.9 ml) and toluerie 3 : : “x (300 1) was refluxed, with removal of water: for eighteen Le
Ei | 20 (18) hours. At this time, 6.3 g of benzaldeliyde was : ~
Le . A “added. and reflux was continued for twenty-four (24) 0 ) : : hoursi* The solvent was then removed in vacuo Jand the Cn oo ot imine was purified via flash chromatography (DCM) to
T i give 7.3 g of an organish solid, m.p. 144-147. A . - 25 3.5 g portion was recrystallized from tsopropyl, ether CT a Te : ; to give 2.54 g of light yellow crystals, n.ps 49- she Tk A “i | 152°C, aE hp a TET . ; ~20- ALGO - BAP onan J, Go
ANALYSIg:
Calculated for C,H, Ns: 84, 58%C 6.45% 8.97%N
Found 84, 46%C 6.42%H 9.00%N
EXAMPLE 5 5 . 1,4-Methano-1,2,3,4-tetrahydro-6- trifluoromethyl-9-acridinamine
To a solution of 2-amino-4-trifluoromethyl- : benzonitrile (12.8g) in 50 ml of nitrobenzene was : added freshly fused and pulverized ZnCl, (14.18).
This was heated at 50°C for 1. hour and to this mixture was.added norcamphor (11.4 g).The reaction mixture was heated at 130°C for 3 hours, after which it was cooled, diluted with ethyl ether and filtered. The resulting solid was partitioned between 2-butanone (MEEK) and aqueous NH, OH and the aqueous portion was extracted : with MEK. The combined organics were washed with water, dried (saturated NaCl, MgSO, ) and concentrated to a solid which was triturated with ether/hexane to : give 10.3 g of a white powder, m.p. 174-179°C. A 4,0 g portion was recrystallized from methanol/water —21- BAD ORIGINAL dN aoe to give 3.5 g of an analytically pure white powder, m.p. 175-178°C.
ANALYSIS: ,
Calculated for Chol zF No: 64, 74%C 4, 71%H 10. 07%N
Found 64. 70%C 5.88%H 10.09%N
EXAMPLE 6 1,4-Methano-N-(phenylmethylene)-6- trifluoromethyl-1,2,3,4~-tetrahydro-9-acridinamine
A mixture prepared from 1,4-methanol-1,2,3,4,- tetrahydro-6-trifluoromethyl-9-acridinamine (7.65), . benzaldehyde (4.4 g, freshly washed with R,C05), morpholine (4.8 ml) and toluene 300 ml) was refluxed with removal of water for eighteen (18) hours. At this point, an additional 4.4 g of benzaldehyde was added and reflux was continued for twenty-four (24) hours.
The reaction was then concentrated to a solid and the residue was chromstograhbhed (DCM) to give 8.3 g of an orangish solid, m.p. 120-126°C. A 4.07 8 portion was recrystallized from cyclohexane to give
2.56 g of an off-white solid, m.p. 127-130°C.
ANALYSIS: :
Calculated for Copy nF3l,: 72.12%C 4.68%H 7.65%N
Found: 72.15%C 4.83%H 7.61%N
EXAMPLE 7 3,4-Dihydro-1H-thiopyrano/ 4,3/quinolin- 10-amine :
Tetrahydrothiopyran-4-cne(10.0g) was mixed with anthranilonitrile (5.08g) and the mixture warmed at 60°C until a homogeneous solution was obtained.
Freshly fused ZnC1,(8.2g) was then added portionwise and the temperature of the reaction mixture raised to 120°C. After two (2) hours it was cooled and distributed between 10% NaOH ahd 2-butanone. The organic phase was separated, dried and concentrated, and the crude product triturated with Et,0 snd then passed over a silica gel column (5% Et N/ethyl acetate).
The product-containing fractions were concentrated and the product recrystallized from toluene to give 3.66 g, m.p. 214-216°C.
ANALYSIS:
Calowlated for C,H, N.S: 66.63%C S5.59%H 12.95%N
Found: 66. 74%C 5.71%H 12. 79%N
EXAMPLE 8
N-(Phenylmethylmne)-3,4-dihydrothiopyrano=- 1H-/"4,3-b/quinolin-10amine 3,4-Dihydrothiopyrano-1K-/"4,3-b7quinolin-10- amine (8.64 g) was suspended in 300 ml of toluene to which morpholine (7.0 g) and benzaldehyde (freshly washed with aqueous K,C0;4 solution, 8.50 g) were then added. The reaction mixture was refluxed overnight with removal of water (Dean-Stark trap) and then concentrated and purified by flash chromatography (20% EtOAc/CH,CL,). The product-containing fractions were concentrated to give 7.30 g of chromatographically pure product, m.p. 171-173°C. Analytically pure
So material was obtained by recrystallization from
CH,Cl,/pentane, m.p. 175-176°C. : ANALYSIS: ~oh- .
Calculated for PL PTPER 74, 96%C 5. 30%H 9. 20%N
Found: 74. ,97%C 5.25%H 9.18%N
EXAMPLE 9 1,4-Dihydro-1,4-ethano-9-acridinamine
A mixture prepared from anthranilonitrile (4.18 g), freshly fused zinc chloride (7.2 g) and 15 ml of nitrobenzene was heated at 50°C for 45 minutes. To the resulting suspension was added : bicyclo / 2.2.27 oct-2-en-5-one(6.5g) and this was heated at 130°C for 1.5 hours.
The reaction mixture was cooled and treated with ethyl ether, and the precipitate was filtered, rinsed with ether and then partitioned between 2-butanone : (MEK) nad aqueous NH, OH solution. The aqueous phase was extracted with MEK and the combined organics were washed with water and dried (saturated NaCl,
MgSO, ) - Removal of the solvents gave 5.7 g of an off-white powder which was recrystallized from methanol/ water to give 4.76 g of an off-white solid, m.p. 218-220°Cd.
ANALYSIS:
Calculated for C cH, Ny: 81.05%C 6.35%H 12.60%N
Found: 80.96%C 6. 34%H 12.65%N 1,4-Dihydro-1,4-ethano-N-(phenylmethylene) - 9-acridinamine :
A mixture of 1,4-dihydro-1,4-ethano-9-acridinamine (11.4 g), benzaldehyde(8.2 g, freshly washed with
K 005 solution) and morpholine (9.0 ml) in 350 ml toluene was refluxed with removal of water for eighteen (18)hours. An additional 6 g of benzaldehyde was added and reflux was continued for twelve (12) hours with removal of water.
The reaction mixture was concentrated, passed through a column of florisil (DCM) and the imine was purified via flaBh chromatography (DCM then 5%
EtOAc/DCM) to give 13.4 g of an orangish solid. A 32.0 g portion was recrystallized from methanol/water to give 2.54 g of light yellow crystals, m.p. 178-180°C.
ANALYSIS:
: | Calculated for PPLIPLPY 85.13%C 5.85%H 9.02%N
Found: ~~ 85.03%C 6.05%H 8.94%N
Claims (3)
1. A compound of the formula I H A I A A = df) n Ro wherein n=1o0r 2, R, is unsubstituted phenyl; Ais (CHRz) ps wherein m is 1 or 2; Ry and R, are hydrogen , ’ Y is 8, X is hydrogen and al} stereo, optical or geometrical isomers thereof, and all pharmaceutically acceptablé acid addition salts thereof.
2. A compound as defined. in Claim 1, wherein 4 is CH,, Y is S, R, is hydrogen and n is 2.
3. A compound as defined in claim 1 or 2 wherein R, is phenyl.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PH39197A PH27109A (en) | 1987-09-08 | 1989-09-01 | N-Úsubstituted alkylidine¾ fused-bicycloalkyldine and hetero-alkylidine quinolinamides a process for their preparation and their use as medicaments |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US9418187A | 1987-09-08 | 1987-09-08 | |
US22384888A | 1988-07-25 | 1988-07-25 | |
PH3751388 | 1988-09-06 | ||
PH39197A PH27109A (en) | 1987-09-08 | 1989-09-01 | N-Úsubstituted alkylidine¾ fused-bicycloalkyldine and hetero-alkylidine quinolinamides a process for their preparation and their use as medicaments |
Publications (1)
Publication Number | Publication Date |
---|---|
PH27109A true PH27109A (en) | 1993-03-16 |
Family
ID=27353995
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PH39197A PH27109A (en) | 1987-09-08 | 1989-09-01 | N-Úsubstituted alkylidine¾ fused-bicycloalkyldine and hetero-alkylidine quinolinamides a process for their preparation and their use as medicaments |
Country Status (1)
Country | Link |
---|---|
PH (1) | PH27109A (en) |
-
1989
- 1989-09-01 PH PH39197A patent/PH27109A/en unknown
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