WO1995014006A1 - OCTAHYDROBENZO[f]QUINOLINE-BASED RECEPTOR AGONISTS AND ANTAGONISTS - Google Patents
OCTAHYDROBENZO[f]QUINOLINE-BASED RECEPTOR AGONISTS AND ANTAGONISTS Download PDFInfo
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- WO1995014006A1 WO1995014006A1 PCT/US1993/011302 US9311302W WO9514006A1 WO 1995014006 A1 WO1995014006 A1 WO 1995014006A1 US 9311302 W US9311302 W US 9311302W WO 9514006 A1 WO9514006 A1 WO 9514006A1
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- trans
- quinoline
- octahydrobenzo
- phenethyl
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- 0 *C(CC1)=C(*)C(CC2)C1C1C2N(*)CCC1 Chemical compound *C(CC1)=C(*)C(CC2)C1C1C2N(*)CCC1 0.000 description 2
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
Definitions
- a medicament to be effective in vivo to effectively interact with CNS receptors depends upon many factors, including the binding affinity of the medicament for a receptor, the medicaments ability to cross the blood-brain barrier, and the selectivity of the medicament for a targeted receptor.
- a medicament would be a selective antagonist for the D4 dopamine receptor.
- many medicaments with good binding affinities for a particular CNS receptor also bind to non-targeted receptors, often resulting in undesirable side-effects.
- common side-effects of anti- psychotic drugs include extrapyra idal side-effects.
- some atypical anti-psychotic drugs such as clozapine which is selective for the D4 receptor, have not exhibited extrapyramidal side-effects but have had severe effects upon the patient's white blood cells, such as agranulocytosis.
- compositions are needed that can cross the blood-brain barrier to act in vivo and selectively target a CNS receptor without causing severe extrapyramidal side-effects, agranulocytosis or other side-effects associated with current medicaments.
- the present invention relates to a composition, and method of use, of an octahydrobenzo[f]quinoline-based compound represented by the following structural formula:
- R 1 is -OH or -OCH 3 and R 2 is -H, - OH or -OCH 3 .
- R 3 is a CI to C4 alkyl group.
- R 4 is an aryl group, wherein examples of suitable aryl groups, as defined herein, include phenyl and thienyl groups.
- the method of this invention relates to the use of the claimed compositions to treat psychotic disorders, to treat Parkinson's disease, or to sedate a mammal by administering an effective amount of a claimed composition.
- the benefits of this invention include the ability to treat psychotic disorders without causing extrapyramidal side-effects or agranulocytosis associated with other anti-psychotic medicaments.
- Figures la and lb are plots of (a) the horizontal activity counts per 10 minute interval, and (b) the average horizontal activity counts per 10 minute period averaged over the first 30 minutes of the test, for mice treated with 0.003 mg/kg, 0.01 mg/kg, 0.03 mg/kg or 0.1 mg/kg doses of ( ⁇ )-trans-7,8-dihydroxy-4-phenethyl- 1,2,3,4a,5,6,10b-octahydrobenzo[f]quinoline or with a saline control.
- Figures 2a and 2b are plots of (a) the horizontal activity counts per 10 minute interval, and (b) the average horizontal activity counts per 10 minute period averaged over the first 30 minutes of the test, for mice treated with 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg or 10.0 mg/kg doses of ( ⁇ )-cis-7,8-dihydroxy-4-phenethyl- l,2,3,4a,5,6,10b-octahydrobenzo[fjquinoline or with a saline control.
- the present invention relates to a composition, and method of use, of an octahydrobenzo[f]quinoline-based compound which is useful as a receptor binding-affinity composition.
- a receptor binding- affinity composition is a composition with a binding affinity for a receptor, wherein said composition can act as an agonist, an antagonist or a mixed agonist/antagonist to the receptor.
- Examples of receptors, for which the compositions of this invention are useful include D2, D4, 5HT1, 5HT1A, 5HT2, ⁇ l and ⁇ 2 receptors.
- the octahydrobenzo[f]quinoline- based receptor binding-affinity composition comprises a composition represented by structural formula I. Structural formula I is as follows:
- R 1 is -OH or -OCH 3 and R 2 is - H, -OH or -OCH 3 .
- R 3 is a CI to C4 alkyl group, such as an ethyl group.
- R 4 is an aryl group. Examples of suitable aryl groups, as defined herein, include phenyl and thienyl groups.
- the receptor binding- affinity composition has a significant affinity to bind to ⁇ l-adrenergic, ⁇ 2-adrenergic and D2 dopamine receptors.
- This receptor binding-affinity composition is represented by structural formula II. Structural formula II is as follows:
- R 2 is -H or -OH
- R 3 is a CI to C4 alkyl group
- R 4 is an aryl group.
- the binding affinities of the receptor binding-affinity compositions of this invention for the ⁇ l, ⁇ 2 and D2 receptors are further described in Examples 16-18.
- the receptor binding- affinity compositions are dopamine receptor agonists which are effective agonists Parkinson's disease.
- Receptor binding-affinity compositions suitable to act as dopamine receptor agonists include the trans- enantiomers of dihydroxy compositions represented by structural formula II, such as trans-7,8-dihydroxy-4- phenethyl-1,2,3,4a,5, 6,lOb-octahydrobenzo[f]quinoline and trans-7,8-dihydroxy-4-thienylethyl-l,2,3,4a,5,6,10b- octahydrobenzo[f]quinoline.
- Dopamine receptor binding with an agonist results in stereotypic activity. Description of the stereotypic effects of receptor binding-affinity compositions of this invention are provided in Example 25. Details of the evaluation of receptor binding-affinity compositions, as dopamine agonists or antagonists, are provided in Examples 25 and 28.
- the receptor binding- affinity compositions produce a sedative effect.
- Receptor binding-affinity compositions suitable to produce a sedative effect are represented by structural formula II.
- a sedative effect will result in a reduction in locomotor activity. Description of the sedative effect of receptor binding-affinity compositions of this invention is provided in Example 24.
- the sedative compositions include trans-7,8-dihydroxy-4-phenethyl- l,2,3,4a,5,6,10b-octahydrobenzo[f]quinoline and cis-7,8- dihydroxy-4-phenethyl-l,2,3,4a,5,6,10b- octahydrobenzo[f]quinoline.
- the receptor binding- affinity compositions are D2 and/or for D4 agonists, or mixed agonists/antagonists, and therefore have an anti- psychotic effect.
- Suitable anti-psychotic compositions include the cis-enantiomers and of the composition represented by structural formula II, and also the trans-enantiomers of the monohydroxy compositions of structural formula II.
- the receptor binding- affinity composition is a preferentially selective antagonist for the D4 receptor over the D2 receptor.
- D4 selective antagonists have less extrapyramidal side- effects than do non-selective dopamine antagonists.
- Receptor binding-affinity compositions suitable for D4 selectivity include cis-enantiomers of compounds represented by structural formula II.
- the D4 selective receptor binding- affinity composition comprises cis-7,8-dihydroxy-4- phenethyl-1,2,3,4a,5 ,6,lOb-octahydrobenzo[f]quinoline. Further description of receptor binding-affinity compositions selectivity as an antagonist, or mixed agonist/antagonist, for D4 over D2 is provided in Examples 26 and 27.
- receptor binding- affinity compositions of this invention are suitable to selectively bind with 5HT1, 5HT1A and/or 5HT2 serotonin receptors.
- Examples of receptor binding-affinity compositions suitable to bind with the 5HT1 receptor include trans-7,8-dihydroxy-4-phenethyl- 1,2,3,4a,5,6,10b-octahydrobenzo[f]quinoline and trans- (-)-7-hydroxy-4-phenethyl-l , 2,3 ,4a,5,6 ,10b- octahydrobenzo[f]quinoline.
- Receptor binding-affinity compositions suitable to bind with the 5HT1 receptor include trans-(-)-7,8- dihydroxy-4-phenethyl-l,2,3,4a,5,6,10b- octahydrobenzo[f]quinoline, trans-(-)-7-hydroxy-4- phenethyl-1,2,3,4a,5,6,lOb-octahydrobenzo[f]quinoline, trans-7 ,8-dihydroxy-4-thienylethyl-l,2,3,4a,5,6,10b- octahydrobenzoffjquinoline, and trans-7-hydroxy-4- thienylethyl-1,2,3,4a,5,6,lOb-octahydrobenzo- [f]quinoline.
- receptor binding-affinity compositions suitable to bind with the 5HT1 receptor include trans-(- )-7,8-dihydroxy-4-phenethyl-l,2,3,4a,5,6,10b- octahydrobenzo[f]quinoline, trans-(-)-7-hydroxy-4- phenethyl-1,2,3,4a,5,6,lOb-octahydrobenzo[f]quinoline, trans-7-hydroxy-4-phenethyl-l,2,3,4a,5,6,10b- octahydrobenzo[f]quinoline, trans-7 ,8-dihydroxy-4- thienylethyl-l,2,3,4a,5,6,10b- octahydrobenzo[f]quinoline, and trans-7-hydroxy-4- thienylethyl-1,2,3,4a,5,6,10b- octahydrobenzo[f]quinoline.
- arylalkyl- OHBQ mono- or di-methoxy-4-arylalkyl-l,2,3,4,4a,5,6,10b- octahydrobenzo[f]quinoline
- an agent suitable to convert a methoxy group into a hydroxyl group examples include acids and boron tribromide.
- phenylalkyl- OHBQ mono- or di-methoxy-4-phenylalkyl-l,2,3,4,4a,5,6,10b- octahydrobenzo[f]quinoline
- phenylalkyl- OHBQ an inert gas, such as nitrogen or argon
- a suitable amount of an acid preferably HBr
- Suitable proportions of reagents are about 17 L to about 35 mL of approximately 48% acid, such as HBR, per mmole of phenylalkyl-OHBQ.
- the volume of acid used can vary approximately proportionally with changes in the concentration of the acid.
- the preferred ratio of acid to phenylalkyl-OHBQ is about 25 mL to about 30 mL acid per mmole of phenylalkyl-OHBQ.
- a suitable combination of time and temperature is about 1-6 hours at about 100 to 150 °C.
- Suitable phenylalkyl-OHBQ compounds can be synthesized as described in Examples 1, 2 and 8, or as is known in the art.
- thienylalkyl- OHBQ mono- or di-methoxy-4-[2-(2- thienyl)alkyl-1,2,3,4,4a,5,6,10b- octahydrobenzo[f]quinoline
- the preferred ratio of boron tribromide to thienylalkyl-OHBQ is about 3 mmole boron tribromide per mmole thienylalkyl-OHBQ.
- Suitable thienylalkyl-OHBQ compounds can be synthesized as described in Examples 14 and 15.
- the syntheses of compositions of this invention are further described in Examples 3-15.
- the method of this invention relates to the use of the receptor binding-affinity compositions claimed.
- the method of use comprises a method for treating psychotic disorders, such as schizophrenia, by administering an effective amount of a cis-enantiomer of the composition represented by structural formula II or a trans-enatiomer of a monohydroxy composition of structural formula II.
- an effective amount of cis-7,8-dihydroxy-4-phenethyl- 1,2,3,4a,5,6,lOb-octahydrobenzo[f]quinoline is administered.
- the method of use is a method for sedating a mammal comprising administering an effective amount of a composition represented by structural formula II.
- a composition represented by structural formula II In a preferred embodiment, the cis and/or trans enantiomers of 8-dihydroxy-4-phenethyl- 1,2,-3,4a,5,6,10b-octahydrobenzo[f]quinoline are administered.
- the method use is a method for treating Parkinson's disease, comprising administering an effective amount of trans-enantiomers of a dihydroxy composition represented by structural formula II.
- the composition administered is trans-7,8-dihydroxy-4-phenethyl- l,2,3,4a,5,6,10b.
- the receptor binding-affinity compositions of this invention, as well as the pharmaceutically acceptable salts can be used as medicaments, for example, in the form of pharmaceutical preparations.
- the pharmaceutical preparations can be administered, for example, orally, rectally or parenterally.
- Oral administration can be in various forms, such as tablets, coated tablets, dragees, hard and soft gelation capsules, solutions, emulsions or suspensions. Rectal administration can include, for example, suppositories.
- Parenteral administration can include, for example, intramuscular, intravenous or subcutaneous injection of solutions, syrups, suspensions, etc.
- the pharmaceutical composition containing the receptor binding-affinity composition, can also include pharmaceutically inert organic or inorganic excipients, such as lactose, corn starch, talc, stearic acid, vegetable oils, waxes, fats, sugars, and the like.
- pharmaceutically inert organic or inorganic excipients such as lactose, corn starch, talc, stearic acid, vegetable oils, waxes, fats, sugars, and the like.
- these pharmaceutical preparations can contain preserving agents, solubilizing agents, viscosity-increasing substances, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying osmotic pressure, buffers, coating agents or antioxidants. They can also contain or be mixed with other therapeutic agents. It is also to be understood that the compositions of this invention can be administered in the form of a pro-drug such that upon metabolizing in vivo, the therapeutically effective composition will be formed.
- 7,8-dimethoxy-4-phenethyl-l,2,4a,5,6, 10b- octahydrobenzo[F]quinoline can be administered as a pro- drug which then metabolizes to form 7,8-dihydroxy-4- phenethyl-1,2 ,3,4a,5,6,lOb-octahydrobenzo[f]quinoline.
- the dosage administered can vary within wide limits and will depend upon the individual requirements in each particular case. In general, for oral administration a dose of about 1-500 mg/day or for parenteral administration a dose of about .1-50 mg/day, dispensed in one or more individual doses, should be sufficient.
- Compound 2 2-(2,3- dimethoxyphenyl) -ethylmethylsulfinyl methylketone
- Compound 2 (21.6 g (0.0799 mole)) and 18 g of trifluoroacetic acid were refluxed in 860 mL of benzene for 1.5 hours. The cooled reaction mixture was washed with 5% Na 2 C0 3 and volatiles were removed under reduced pressure to leave 21 g of oil, comprising 3,4-dihydro-l- methylthio-5 ,6-dimethoxy-2(IH)-naphthalenone, (hereinafter, "Compound 3”) which was then utilized without further purification.
- Compound 3 3,4-dihydro-l- methylthio-5 ,6-dimethoxy-2(IH)-naphthalenone
- Compound 4 3,4-Dihydro-5,6-dimethoxy-2 (IH)-naphthalenone (hereinafter, "Compound 4”) was obtained by treating the bisulfite addition compound with excess 10% Na 2 C0 3 and extracting the resulting mixture with benzene. The extract was washed with 10% HC1 and then with water and subsequently dried over Na 2 S0 4 . Volatiles were removed under reduced pressure to leave a residue which was crystallized from cyclohexane to afford 2.61 g (45% yield) of white needles with melting point of 62 °C. J.G. Cannon et al.. J. Med. Chem.. 20(9) :111 (1977) cites Compound 4 as having a melting point range of 61-64 °C.
- trans-6 white crystal trans-7,8-Dimethoxy-l ,4 ,4a ,5,6 ,lOb-hexahydro- benzo[f]quinoline-3 (2H)-one (hereinafter, "trans-6") .
- Melting point 239-240 °C. Cannon, et al.. Synthesis. 494 (1986) cites trans-6 as having a melting point range of 232-233 °C (ether) .
- l K NMR (CDC1 3 ) shifts observed were l.64-1.85(m,2H aliph) ; 1.99-2.07(m,lH aliph);
- trans-7 a trans-7,8-Dimethoxy-l,2,3,4,4a,5, 6,10b- octahydrobenzo[f]quinoline (hereinafter, "trans-7") solidified. Solidified trans-7 was utilized in the next step without purification.
- trans-8 white solid trans-7,8-Dimethoxy-(phenethyl-1,2,3,4,4a,-5,6,10b- octahydrobenzo[f]quinoline (hereinafter, "trans-8") . Melting point 110-111 °C.
- the *H NMR (CDC1 3 ) shifts observed were 1.17, 3.13(m,16H,-CH 2 -,>CH-) , 3.81, 3.85 (2S,6H OCH 3 ), 6.76-7.33 (m,7H,ArH) . Elemental analysis gave C Q H ⁇ O J (C,H,N) .
- Example 4 Separation of Isomers of trans-7,8-Dlmethoxy-4- phenethyl-1.2.3.4.4a.5.6.lOb-octahydrobenzorf1quinoline Trans-8 (94 mg) was dissolved in 1.5 mL of EtOH. This solution (200 ⁇ L) was applied to a J.T. Baker semi- preparative HPLC column (chiralcel OD, J.T. Baker Inc. 10 mm inner diameter, mobile phase: EtOH) using a flow rate of 1.7 mL/minute. Seven fractions were collected, using UV detection to indicate the start of sample collection.
- trans-(+)-8 solid (+)-isomer of trans-8 (hereinafter, "trans-(+)-8") with [ ⁇ ] D (20 °C) of +89.9 (c 0.28, MeOH).
- trans-(-)-8 The seventh fractions were pooled from consecutive runs and gave after solvent removal 40 mg of the solid (-)-isomer of trans-8 (hereinafter, "trans-(-)-8") with [ ⁇ ] D (20 °C) of -89.4 (C 0.16, MeOH).
- trans-(+)- 9 was prepared in 74% yield from 40 mg (0.11 mmole) of trans-(+)-8 by the method described for trans-9 as described in Example 3.
- trans-(-)- 9 The melting point observed was 253-4 °C (dec.) and [ ⁇ ] D (20 °C) was +74.6 (c 0.17, MeOH) .
- Example 6 Synthesis of trans-(-)-7.8-Dihydroxy-4- phenethyl-1.2,3,4.4a,5.6. lOb-octahvdrobenzo ⁇ f)quinoline Trans-(-)-7,8-Dihydroxy-4-phenethyl-l,2,3,4,4a,5,6, 10b-octahydrobenzo[f]quinoline (hereinafter, "trans-(-)- 9") was prepared in 72% yield from 40 mg (0.11 mole) of trans-(-)-8 by the method described for trans-9 in Example 3. The melting point observed was 253-4 °C (dec.) and [ ⁇ ] D (20 °C) was -68.0 (c 0.25, MeOH).
- Cis-7,8-dimethoxy-l,2,3,4,4a,5,6,10b- octahydrobenzo[f]quinoline (hereinafter, "cis-7") was prepared in 88% yield; from 0.58 g (2.22 mmole) of cis-6 by the method described to form trans-7 in Example 2.
- the melting point was 252-4 °C (B «HC1) .
- Cis-7 is cited by J.G. Cannon et al.. J. Med. Chem.. 22(4) :341 (1979) as having a melting point of 243-5 °C (B «HC1) .
- the jH NMR (CDCl j ) shifts observed were 1.56-3.30 (m,12H,aliph. ) ; 3.81; 3.85(2s,6H,OCH 3 ) ; 6.77-
- Cis-7,8-dimethoxy-4-phenethyl-l,2,3,4,4a,5,6,10b- octahydrobenzo-[f]quinoline (hereinafter, "cis-8") was prepared from cis-7 using the method described to form trans-8 in Example 2. The melting point was 75-76 °C.
- Cis-7,8-Dihydroxy-4-phenethyl-l,2,3,4,4a,5,6,10- octahydrobenzo-[f]quinoline (hereinafter, "cis-9") was prepared from cis-8 by the method described to form trans-9 in Example 3. The melting point observed was
- (+) and (-)-isomers of cis-9 were then formed from cis-8 by the methods described in Examples 4-6 for forming the (+) and (-)-isomers of trans-9.
- Example 8 Synthesis of trans-7-hvdroxy-4-phenethyl-l.2.3.4.4a. 5.6,lOb-octahvdrobenzoff
- Compound 21 7-Methoxy-l,4,5,6-tetrahydrobenzo[f]quinoline- 3(2H)-one (hereinafter, "Compound 21") was prepared from Compound 20 by the method described for synthesizing Compound 5 in Example 1.
- the *H NMR (CDC1 3 ) shifts observed were 2.32-2.37 (m,2H) ; 2.62-2.73 (m,4H) ; 2.88- 2.93(t,2H); 3.83(5,3H); 6.71-6.78(q,2H) ; 7.14-7.19 (t,lH) ; 7.98(s,lH,NH) .
- Trans-22 Trans-7-methoxy-l,4,4a,5 , 6,10b-hexahydrobenzo[f] quinolin-3 (2H)-one (hereinafter, "trans-22”) was prepared from Compound 21 by the method described for synthesizing Compound 6 as described in Example 2. The melting point observed was 274-5 °C.
- Trans-23 Trans-7-methoxy,1,4,4a,5,6,10b-octahydrobenzo[f] quinoline (hereinafter, "trans-23”) was prepared from Compound 22 by the method described for Compound 7 in Example 2.
- Trans-24 Trans-7-methoxy-4-phenethyl-l,2,3,4,4a,5,6,10b- octahydrobenzoff]quinoline (hereinafter, "trans-24") was prepared from trans-23 by the method described for synthesizing Compound 8 as described in Example 2.
- the ⁇ NMR (CDC1 3 ) shifts observed were 1.17- 3.13 (m,16H,aliph.) ; 3.81(s,3H,OCH 3 ) ; 6.68- 6.95(2d,2H, rH) ; 7.13-7.32( ,6H,ArH) .
- Elemental analysis (hydrochloride) gave C 22 H 2 gClNO•%H 2 0 (C,H,N) .
- trans-25 Trans-7-hydroxy-4-phenethyl-l,2,3,4,4a,5,6,10b- octahydrobenzo[f]quinoline (hereinafter, "trans-25") was prepared from 0.25 g (0.78 mole) of trans-24 by the method described for synthesizing trans-9 as described in Example 3. The melting point observed was 284-5 °C. Elemental analysis gave C 21 H 26 BrNO•*;H 2 0 (C,H,N) .
- Trans-24 (218 mg) was dissolved in 4.5 mL of ethanol. Separation was then performed as described to separate trans-(+)-8 and trans-(-)-8 in Example 4. Fractions 1 and 2 were pooled from consecutive runs and gave after solvent removal 100 mg of solid (+)-isomer of trans-24 (hereinafter, "trans-(+)-24") with [ ⁇ ] D ( 20 °C) of +100.9 (c 0.34, MeOH).
- trans-(-)-24 solid (-)-isomer of trans-24 (hereinafter "trans-(-)-24") with [ ⁇ ] D (20 °C) of -95.2 (c 0.23, MeOH) .
- Cis-7-methoxy,1,4,4a,5,6,lOb-octahydrobenzo[f] quinoline (hereinafter, "cis-23") was prepared from Compound 22 by the method described for trans-23 in Example 8.
- Cis-7-methoxy-4-phenethy1-1,2,3,4,4a,5,6,10b- octahydrobenzo[f]quinoline (hereinafter, "cis-24") was prepared in 73% yield form 0.67 g (3.08 mmole) of cis-23 by the method described for synthesizing trans-24 as described in Example 8. The melting point observed was 226-7 °C.
- the *H NMR (CDC1 3 ) shifts observed were 1.61- 3.24(m,16H,aliph.) ; 3.81(s,3H,OCH 3 ) ; 6.64-
- Cis-7-hydroxy-4-phenethyl-l,2,3,4,4a,5,6,10b- octahydrobenzo[f]quinoline (hereinafter, "cis-25") was prepared in 60% yield from 0.25 g (0.78 mole) of cis-24 by the method described for synthesizing trans-25 as described in Example 8. The melting point observed was 261-2 °C. Elemental analysis gave C 2 ,H 26 BrNO (C,H,N) .
- Cis-24 120 mg was dissolved in 2.9 mL of ethanol. Separation was then performed as described to separate (+)-trans-8 and (-)-trans- ⁇ in Example 4. Fractions 1 and 2 were pooled from consecutive runs and gave after solvent removal 40 mg of solid (-)-isomer of cis-24 (hereinafter, "cis-(-)-24") with [ ⁇ ] D (20 °C) of -9.33 (c 0.20, MeOH).
- Cis-(+)-7-hydroxy-4-phenethyl-l,2,3,4,4a,5,6, 10b-octahydrobenzo[f]quinoline (hereinafter, "cis-(+)- 25") was prepared in 50% yield from 37 mg (0.12 mmole) of cis-(+)-24 by the method of forming trans-9 as described in Example 3.
- the melting point observed was 194 °C and [ ⁇ ] D (20 °C) was +6.05 (c 0.22, MeOH).
- Cis-(-)-7-hydroxy-4-phenethyl-l,2,3,4,4a,5,6, 10b-octahydrobenzo[f]quinoline (hereinafter, "cis-(-)- 25") was prepared in 46% yield from 34 mg (0.11 mmole) of cis-(-)-24 by the method described for trans-9 in Example 3.
- the melting point observed was 196 °C and [ ⁇ ] D (20 °C) was -6.0 (c 0.20, MeOH).
- trans-30 was 103 mg (91%) .
- the *H NMR (CDC1 3 ) shifts observed were 1.17-3.14(m,16H, aliph); 3.82(S,3H,0CH 3 ) ; 6.70, 6.83(2d,2H,ArH) ; 6.92- 6.98(m,2H,ArH) ; 7.13-7.18(m,2H,ArH) .
- Elemental analysis results were C 20 H 2 sNOS (C,H,N) with 73.35C 7.70H 4.28N predicted and 73.56C 7.74H 4.27N found.
- Trans-7 8-dimethoxy-4-[2-(2-thienyl)ethyl- 1,2,3,4,4a,5,6,lOb-octahydrobenzo[f]quinoline (hereinafter "trans-32”) was prepared in 69% yield from 410 mg (1.65 mmole) of trans-2 by the method described for trans-30 in Example 15.
- the *H NMR (CDC1 3 ) shifts observed were 1.17-3.15(m,16H, aliph); 3.80, 3.84(2s,6H,OCH 3 ) ; 6.76- 7.15(m,5H,ArH) .
- Elemental analysis results were C ⁇ H ⁇ NO j S (C,H,N) with 70.55C 7.61H 3.92N 8.97S predicted and 70.47C 7.68H 3.91N 8.79S found.
- Trans-7,8-dihydroxy-4-[2-(2-thienyl)ethyl- 1,2,3,4,4a,5, 6,10b-octahydrobenzo[f]quinoline (hereinafter "trans-33") was prepared in from trans-7,8- dimethoxy-1,2,3,4,4a,5,6,lOb-octahydrobenzo[f]quinoline according to the method of Example 15.
- binding affinities of the compositions of this invention were assayed for various receptors.
- the binding reaction was initiated by the addition of varying concentrations of the potential binding composition and a radioligand to an appropriate tissue.
- the assay was then incubated to allow binding. Binding was then terminated by dilution of the assay with a cold buffer, followed by rapid vacuum filtration onto Whatman GI/C filters that were presoaked in 0.1% polyethylene i ine for at least 3 hours. Radioactivity trapped onto the filters was determined and compared to control values in order to ascertain any interactions of test compound with the binding sites. Binding affinity analyses were performed by Novascreen, Division of the Adheron Corporation, Hanover, MD.
- DOPAMINE (Dl AND O2 ) CENTRAL BINDING ASSAYS Dopamine (Dl) binding assays were performed on rat striatal membranes according to the method described by Billard, et al.. Life Sciences . 3_5:1885-1893 (1984). Incubation was conducted in 50 nM HEPES containing 1.0 mM EDTA, 4.0 mM MgS0 4 , and 10 ⁇ M Ketanserin (pH 7.4) at 37°C for 60 minutes.
- the radioligand used was [ 3 H]SCH 23390 (70-87 Ci/mmol) .
- the final radioligand concentration was 0.5 nM.
- the reference compound and the positive control was SCH 23390.
- the assay was characterized by a binding affinity (K;) of 0.53 nM, a receptor number (B ⁇ ) of 69 fmol/g wet weight of tissue, and 90% non-specific binding as determined using 1.0 ⁇ M SCH 23390.
- K; binding affinity
- B ⁇ receptor number
- the values for binding affinity of the reference compounds for dopamine Dl receptors are provided in Table I.
- Dopamine (D2) binding assays were performed on rat striatal membranes according to the method described by
- Incubation was conducted in 50 mM TRIS-HC1 (pH 7.5) containing 100 mM NaCl at 25°C for 60 minutes.
- the radioligand used was [ 3 H]Sulpiride (60-80 Ci/mmol) .
- the final ligand concentration was 0.5 nM.
- the reference compound and the positive control was sulpiride.
- the assay was characterized by a Kj of 3.0 nM, a B ⁇ - of 348 fmol/g wet weight of tissue, and 90% non-specific binding as determined using 10 ⁇ M sulpiride.
- dopamine Dl and D2 receptor binding affinities for the compositions of this invention are provided in Table III, as either the K ; (in nM) or for compositions with lesser binding affinities, the percent binding by a concentration of 10 "5 .
- Table III The values for dopamine Dl and D2 receptor binding affinities for the compositions of this invention are provided in Table III, as either the K ; (in nM) or for compositions with lesser binding affinities, the percent binding by a concentration of 10 "5 .
- Example 17 ALPHA1-ADRENERGIC (NON-SELECTIVEl BINDING ASSAY Alphal-adrenergic binding assays were performed on rat forebrain membranes according to the method described by Timmermans, et al.. Molecular Pharmacology. 2J):295-301 (1981).
- the reference compound was phentolamine and the positive control was prazosin.
- the assay was characterized by a K ; of 0.2 nM, a B ⁇ of 95 fmol/g wet weight of tissue, and 95% non-specific binding as determined 3 x 10" 7 M prazosin.
- Alpha2-adrenergic binding assays were performed on rat cortical membranes according to the method described by Doxy, et al.. British Journal of Pharmacology. j ⁇ ():155-161 (1983). Incubation was conducted in 50 mM TRIS-HCl (pH 7.4) at 0 °C for 90 minutes. The radioligand used was [ 3 H]RX 781094 (40-60 Cl/mmol) . The final ligand concentration was 1.5 nM. The reference compound was phentolamine and the positive control was clonidine. The assay was characterized by a Kj of 0.5 nM, a B_, complaint of 142.7 fmol/g wet weight of tissue, and 90% non-specific binding as determined using 10 ⁇ M phentolamine.
- Example 19 BETA-ADRENERGIC NON-SELECTIVE- BINDING ASSAY Beta-adrenergic binding assays were performed on rat cortical membranes according to the method described by Marco, et al.. Molecular Pharmacology . l ⁇ '201-210 (1989). Incubation was conducted in 50 mM TRIS-HCl (pH 7.4) at 37°C for 30 minutes. The radioligand used was [ 3 H]DHA (90-120 Ci/mmol). The final ligand concentration was 2.0 nM.
- the reference compound and positive control was alprenolol.
- the assay was characterized by a K; of 1.74 nM, a B,- discipline of 2.33 fmol/g wet weight of tissue, and 70% non-specific binding as determined using 10"* M alprenolol.
- compositions of this invention are provided in Table III. These results show that none of the compositions of this invention had significant binding affinity for the ⁇ -adrenergic receptor.
- Example 20 SEROTONIN (5m--n BINDING ASSAY Serotonin (5HT j ) binding assays were performed on rat cortical membranes according to the method described by Bennett et al.. Molecular Pharmacology. 32:373-389 (1976). Incubation was conducted in 50 mM TRIS-HCl (pH 7.4) at 45 minutes for 37°C. The radioligand used was [ 3 H]Hydroxytryp amine binoxalate (15-30 Ci/mmol). The final ligand concentration was 3.0 nM.
- the reference compound was serotonin and the positive control was LSD.
- the assay was characterized by a K j of 2.8 nM, a B ⁇ of 9.2 fmol/g wet weight of tissue, and 60% non-specific binding as determined using 10 ⁇ M serotonin.
- Serotonin (5HT1A) binding assays were performed on bovine hippocampus according to the method described by Hall et al.. Journal of Neurochemistr ⁇ . 44:1685-1696 (1985) . Incubation was conducted at 10 minutes for 37°C.
- the radioligand used was [ 3 H]-8-OH-DPAT (> 100 Ci/mmol). The final ligand concentration was 1.0 nM.
- the reference compound was 8-OH-DPAT and the positive control was serotonin.
- the assay was characterized by a Kj of 2. nM, a B mMX of 1626 fmol/g wet weight of tissue, and 90% non-specific binding as determined [10 ⁇ M serotonin].
- Ketanserin > 10,000.0
- Example 22 SEROTONIN (5HT2 ⁇ BINDING ASSAY Serotonin (5HT2) binding assays were performed on rat cortical membranes according to the method described by Leysen, et al.. Molecular Pharmacolog . 21:301-314 (1982). Incubation was conducted in 50 mM TRIS-HCl (pH 7.5) at 36°C) for 15 minutes. The radioligand used was [ 3 H]Ketanserin (60-90 Ci/mmol) . The final ligand concentration was 1.0 nM. The reference compound and positive control was methysergide.
- the assay was characterized by a Kj of .43 nM, a B ⁇ of 30.9 fmol/g wet weight of tissue, and 65% non-specific binding as determined using lO ⁇ M methysergide.
- the values for binding affinity of the.reference compounds for the serotonin receptor are provided in Table IX.
- Serotonin (5HT3) binding assays were performed on NIE-115 neuroblastoma cells according to the method described by Lummis, et al.. European Journal Pharmacol og ⁇ . 189:223-227 (1990). Incubation was conducted in 20 mM HEPES (pH 7.4) containing 150 mM
- the radioligand used was [ 3 H]GR65630 (30-50 Ci/mmol) .
- the final ligand concentration was 0.7 nM.
- the reference compound and positive control was MDL-72222 .
- the assay was characterized by a K; of 0.3 nM, a B ⁇ ,- of 233 fmol/108 cells, and 80-90% non-specific binding as determined using l ⁇ M MDL-72222.
- Locomotor activity was measured in photocell cages. A panel of infrared beams was located in the horizontal direction along all 4 sides of each activity cage.
- Non-habituated male Swiss-Webster served as subjects in this experiment.
- the mice were injected via the intraperitoneal (IP) route with a ethylcellulose vehicle or a test compound, comprising trans-9 or cis-9, and placed singly in cages for 20 minutes. After this 20 minute period, mice were injected with saline IP, placed in individual photocell cages and testing for effects upon locomotor activity was begun. Eight mice were tested at each dose level. Experimental sessions were 60 minutes in duration with horizontal locomotor activity recorded in 10 minute intervals. Within each 10 minute interval, the data from all subjects are averaged.
- IP intraperitoneal
- Figures la, lb, 2a and 2b show the average horizontal activity counts for each successive 10 minute time period for the different doses of the compounds tested.
- Figure lb shows the average horizontal activity counts per 10 minute period during the first 30 minutes of the test session. Data were analyzed by a one-way ANOVA computed across doses using a log, 0 transformation of the horizontal activity counts. Comparisons between vehicle and each dose of the compounds tested were made by a priori contrasts. Doses of the compounds tested, which produced a statistically significant (p ⁇ 0.05) decrease in locomotor activity relative to vehicle control, are denoted with an asterisk.
- ED 50 50% maximal depressant activity
- Cis-9 was much weaker than expected when compared to its dopamine D2 receptor affinity. Cis-9 caused dose-related suppression of locomotor activity at 10 mg/kg. Two of eight mice died at 10 mg/kg.
- COMPOUND ED 50 (mg/kg) trans-9 0. 038 cis-9 2 . 1
- D2 or D4 receptor selectivity competition binding assays were performed using membranes from fibroblast cell lines transfected with D2444 (rat) , D3 (human) or D4 (rat) receptors. All cell lines were maintained in Dulbecco's modified Eagle's media (DMEM) supplemented with 10% fetal bovine serum at 37 °C with 5% C0 2 . Transfected cells were maintained in DMEM containing 300 ⁇ g/mL of the antibiotic G418 (Gibco) .
- DMEM Dulbecco's modified Eagle's media
- Membranes were prepared from the cell lines and the assays were performed as described in Tang et al. Journal of Pharmacology and Experimental Therapeutics (in press 1993) . Briefly, nearly confluent cells were harvested by scraping, washed twice in phosphate- buffered saline (PBS; 145 mM NaCl, 5 mM KC1, 0.7 mM CaCl 2 , 0.5 mM MgCl 2 , 10 mM phosphate, pH 7.4), resuspended in distilled water and homogenized with a Brinkman Polytron. Nuclei were removed by centrifugation for five minutes at 600 g at 4 °C, membranes were pelleted for 25 minutes at 50,000 g.
- PBS phosphate- buffered saline
- Membrane protein was resuspended in homogenization buffer (0.32 M sucrose, 0.0025 M Tris, pH 6.9 at 20 °C) and incubated at 37 °C for 15 minutes. Membrane protein was pelleted, resuspended in water and stored at -70 °C.
- the D2 assay was prepared from pig anterior pituitary tissue as described in Seeman et al.. Molecular Pharmacology. 28.:391 (1985).
- the D4 assay contained membranes prepared from COS-7 cells transfected with a 3.9 kb cDNA-gene fusion construct as described in H.H.M. Vantol. Nature, 350:610 (1991).
- Binding assays were done using the methods described in by Seeman and Vantol. [ 3 H]-spiperone (New England Nuclear, Boston, MA) . The compositions were tested varying concentrations. After addition of all components, the samples were incubated for 15 minutes at 37 °C, terminated with 50 mM Tris-HCl (pH 7.4 at 20 °C) and collected on glass- fiber filters on a Brandel cell harvester. Radioactivity retained on the filters was counted on a Beckman LS 1701 scintillation counter and data were analyzed by non-linear least squares regression methods. The receptor binding results (K ; in nM) of these tests are provided in Table XIV.
- Example 28 D2 Receptor Agonist Evaluation To determine whether or not compounds of this invention were D2 receptor agonists, a membrane binding assay, utilizing the D2 cell line described in Example 26, was performed in the presence and absence of the non-hydrolyzable guanine nucleotide (GTP analogue) Gpp(NH)p. A shift in K ; (nM) with Gpp(NH)p would be indicative of G-protein coupling and would therefor suggest the compound was an agonist. The effects of GTP on receptor binding (nM) of these tests are provided in Table XV.
- trans-9 and trans-25 appear to be agonists as D2 receptor binding was enhanced by the addition of GTP, while cis-9 and cis-25 appear to be an antagonist as the addition of GTP did not significantly affect receptor binding affinity.
Abstract
Description
Claims
Priority Applications (7)
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CA002177046A CA2177046A1 (en) | 1993-11-19 | 1993-11-19 | Octahydrobenzo[f]quinoline-based receptor agonists and antagonists |
EP94901631A EP0729458A1 (en) | 1993-11-19 | 1993-11-19 | OCTAHYDROBENZO[f]QUINOLINE-BASED RECEPTOR AGONISTS AND ANTAGONISTS |
PCT/US1993/011302 WO1995014006A1 (en) | 1993-11-19 | 1993-11-19 | OCTAHYDROBENZO[f]QUINOLINE-BASED RECEPTOR AGONISTS AND ANTAGONISTS |
AU56153/94A AU684730B2 (en) | 1993-11-19 | 1993-11-19 | Octahydrobenzo{f}quinoline-based receptor agonists and antagonists |
JP7514411A JPH09509398A (en) | 1993-11-19 | 1993-11-19 | Octahydrobenzo [f] quinoline receptor agonists and antagonists |
US08/666,286 US5863928A (en) | 1993-11-19 | 1993-11-19 | Octahydrobenzo f!quinoline-based receptor agonists and antagonists |
US09/237,390 US6262064B1 (en) | 1993-11-19 | 1999-01-26 | Octahydrobenzo[f]quinoline-based receptor agonists and antagonists |
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PCT/US1993/011302 WO1995014006A1 (en) | 1993-11-19 | 1993-11-19 | OCTAHYDROBENZO[f]QUINOLINE-BASED RECEPTOR AGONISTS AND ANTAGONISTS |
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US08/666,286 Continuation US5863928A (en) | 1993-11-19 | 1993-11-19 | Octahydrobenzo f!quinoline-based receptor agonists and antagonists |
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JP (1) | JPH09509398A (en) |
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Cited By (3)
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WO1997040015A1 (en) * | 1996-04-23 | 1997-10-30 | Neurogen Corporation | Tricyclic aminoalkylcarboxamides; novel dopamine d3 receptor subtype specific ligands |
WO1997047602A1 (en) * | 1996-06-11 | 1997-12-18 | Smithkline Beecham Plc | Tricyclic amine derivatives |
WO2010097087A1 (en) * | 2009-02-25 | 2010-09-02 | H. Lundbeck A/S | Catecholamine derivatives and prodrugs thereof |
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UA73981C2 (en) * | 2000-03-10 | 2005-10-17 | Merck Patent Gmbh | (r)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane for treatment of extrapyramidal movement disorders (variants), pharmaceutical composition and kit |
Citations (2)
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EP0059553A2 (en) * | 1981-03-02 | 1982-09-08 | Smithkline Beckman Corporation | Octahydrobenzo(f)quinoline compounds |
WO1984004303A1 (en) * | 1983-04-27 | 1984-11-08 | Astra Laekemedel Ab | NEW OCTAHYDROBENZO (f) QUINOLINE DERIVATIVES |
-
1993
- 1993-11-19 WO PCT/US1993/011302 patent/WO1995014006A1/en not_active Application Discontinuation
- 1993-11-19 EP EP94901631A patent/EP0729458A1/en not_active Withdrawn
- 1993-11-19 AU AU56153/94A patent/AU684730B2/en not_active Ceased
- 1993-11-19 CA CA002177046A patent/CA2177046A1/en not_active Abandoned
- 1993-11-19 JP JP7514411A patent/JPH09509398A/en active Pending
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EP0059553A2 (en) * | 1981-03-02 | 1982-09-08 | Smithkline Beckman Corporation | Octahydrobenzo(f)quinoline compounds |
WO1984004303A1 (en) * | 1983-04-27 | 1984-11-08 | Astra Laekemedel Ab | NEW OCTAHYDROBENZO (f) QUINOLINE DERIVATIVES |
Non-Patent Citations (3)
Title |
---|
HAKAN WIKSTRÖM ET AL: "Monophenolc octahydrobenzo[f}quinolines:central dopamine and serotonin-receptor stimulating activity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 25, no. 8, August 1982 (1982-08-01), WASHINGTON US, pages 925 - 931 * |
HAKAN WIKSTRÖM ET AL: "N-substituted 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines and 3-phenyl piperidines:effects on central dopamine and delta-receptors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 30, no. 12, December 1987 (1987-12-01), WASHINGTON US, pages 2169 - 2174 * |
JOSEPH G. CANNON ET AL: "Rigid congeners of dopamine based on octahydrobenzo[f]quinoline:Peripheral and central effects", JOURNAL OF MEDICINAL CHEMISTRY, vol. 22, no. 4, April 1979 (1979-04-01), WASHINGTON US, pages 341 - 347 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997040015A1 (en) * | 1996-04-23 | 1997-10-30 | Neurogen Corporation | Tricyclic aminoalkylcarboxamides; novel dopamine d3 receptor subtype specific ligands |
WO1997047602A1 (en) * | 1996-06-11 | 1997-12-18 | Smithkline Beecham Plc | Tricyclic amine derivatives |
US6080752A (en) * | 1996-06-11 | 2000-06-27 | Smithkline Beecham Plc | Tricyclic amine derivatives |
WO2010097087A1 (en) * | 2009-02-25 | 2010-09-02 | H. Lundbeck A/S | Catecholamine derivatives and prodrugs thereof |
US20120196889A1 (en) * | 2009-02-25 | 2012-08-02 | H. Lundbeck A/S | Catecholamine derivatives and prodrugs thereof |
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AU684730B2 (en) | 1998-01-08 |
EP0729458A1 (en) | 1996-09-04 |
CA2177046A1 (en) | 1995-05-26 |
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