WO2001060781A2 - Diphenyl compounds, formulations and uses thereof - Google Patents
Diphenyl compounds, formulations and uses thereof Download PDFInfo
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- WO2001060781A2 WO2001060781A2 PCT/GB2001/000686 GB0100686W WO0160781A2 WO 2001060781 A2 WO2001060781 A2 WO 2001060781A2 GB 0100686 W GB0100686 W GB 0100686W WO 0160781 A2 WO0160781 A2 WO 0160781A2
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- alkyl
- nitrophenyl
- group
- halide
- formula
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- 0 *c1ccc(*c(cc2)ccc2O)cc1 Chemical compound *c1ccc(*c(cc2)ccc2O)cc1 0.000 description 11
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Clc1ccccc1 Chemical compound Clc1ccccc1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Nc1ccccc1 Chemical compound Nc1ccccc1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- LFQDUTOHQSEIKI-UHFFFAOYSA-N [O-][N+](c1ccc(C(CC(c2ccccc2)O2)C2=O)cc1)=O Chemical compound [O-][N+](c1ccc(C(CC(c2ccccc2)O2)C2=O)cc1)=O LFQDUTOHQSEIKI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/19—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
- C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
- C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/43—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
Definitions
- the present invention is concerned with diphenyl compounds, pharmaceutical formulations containing the same and uses thereof.
- the present invention is concerned with the use of diphenyl compounds in the inhibition of retinoic acid metabolism.
- Retinoic acid supports cellular growth and differentiation (Roop, et al . , Retinoids : 10 Years On
- Retinoic acid is also implicated in cell proliferation in skin conditions.
- Synthetic retinoids have shown promise in the treatment of oral leukoplakia and head and neck cancer, although their use may be associated with significant toxicity (Armstrong, et al . , The Retinoids : Biology, Chemistry and Medi cine (Sporn et al (eds) ) 2 nd Edition: 545-72 (1994)).
- Retinoids have also been used topically and orally for the treatment of skin diseases, i.e. actinic keratoses (Lotan, FASEB J.
- Vitamin A retinol
- dehydrogenases Rost al . , Mol . Pharmacol . 49: 515-22
- RA trans-retinoic acid
- RA has a short half life (c. 1 hour) (Muindi, et al . , Proc . A er. Soc . Clin . Oncol . 10: 92
- P450-RA The specific P450s responsible for 4 -hydroxylation of RA in the human liver have not been characterised, but several reconstituted P450s CYP1A2/2B6/2C8/2D6/2E1/3A4 , can catalyse the reaction (Nadin and Murray, Br. J. Clin . Pharmacol . 41: 609-12 (1996)).
- hP450RAI mRNA expression is highly induced by RA in certain human tumour cell lines and RA- metabolism may correlate with P450RAI expression (White, et al . , J. Biol . Chem. 272: 18538-41 (1997)).
- a drug which can potentiate the action of endogenous RA on the cell by inhibiting P450-RA metabolising enzymes would have potential as a clinical agent in the treatment of certain skin conditions and cancer.
- Ketoconazole lacks specificity towards P450 17 ⁇ and inhibits several other cytochrome P450 enzymes on the steroidogenic pathway of androgen synthesis and has a poor pharmacokinetic profile and hepatic toxicity has been noted.
- Liarozole (R75251) also inhibits testicular (but not adrenal) P450 17 ⁇ and similarly lowers testosterone levels in human volunteers, but its effect on androgen-independent carcinoma has been partially attributed to inhibition of P450-RA with an associated increase in RA levels (Dockx, et al . , Br. J. Dermatol . 133: 426-32 (1995)) (Roseeuw, et al . , 18 th World Congress of Dermatology, June 12th-18th : P194A (1992) (ketoconazole is also an inhibitor of this enzyme) .
- RA-metabolising enzyme inhibitors intended for topical use for skin diseases should show little unwanted systemic effects due to the involvement of other enzymes, e.g. steroidogenic P450 enzymes such as P450 17 , CSCC, 21- hydroxylase. This objective should be achievable due to either poor sub-dermal penetration or, should this occur, low dose effects due to plasma dilution of the small load of drug placed on a restricted area of skin.
- R 1 and R 2 are independently selected from the group consisting of H, CH 2 0H, OH , halide and C0 2 C 1 -4 alkyl ;
- R 3 is H and R 4 is OH or OT where T is O 0
- R 10 is C 1 . 4 alkyl , aryl (C 1-4 ) alkyl , di -aryl (C 1-4 ) alkyl or aryl ; or
- R 1 and R 2 are C0 2 C 1-4 alkyl ;
- R 1 and R 3 together are 0 0
- R 5 and R 6 are selected from the group consisting of H, halide, NH 2 , N (C ⁇ alkyl) 2 , NH (C ⁇ alkyl) and N0 2 , with the proviso that R 5 and R s are not both H;
- R 7 is H, or R 7 is halide when R s is halide
- each of R 8 and R 9 is H or halide
- n 0 or 1
- y and z are both 0, or one of y and z is 1 and the other of y and z is 0.
- R 1 and R 2 are independently selected from the group consisting of H , CH 2 0H, OH, halide and C0 2 C 1-4 alkyl ;
- R 3 is H and R 4 is OH or OT where T is O O
- R 10 is C 1-4 alkyl , aryl (C 1-4 ) alkyl , di - aryl (C 1-4 ) alkyl or aryl ; or
- R 5 and R 6 are selected from the group consisting of H, halide, NH 2 , N (C 1-4 alkyl) 2 , NH (C 1-4 alkyl) and N0 2 , with the proviso that R 5 and R 6 are not both H;
- R 7 is H, or R 7 is halide when R 5 is halide;
- each of R 8 and R 9 is H or halide
- n 0 or 1
- y and z are both 0, or one of y and z is 1 and the other of y and z is 0.
- R 1 and R 2 in compounds of Formula (I) are selected from the group consisting of H, OH, Br, C0 2 Me and CH 2 0H; or
- R 1 and R 2 together 0 or
- R 4 in compounds of Formula (I) can represent OT, where T is O
- R 10 typically represents di-aryl (C 1-4 ) alkyl .
- R 10 represents di-aryl (C 2-4 ) alkyl and more preferably R 10 represents di-phenyl (C 2 _ 4 ) alkyl .
- the present invention further includes for use in therapy, a compound of general Formula (IA) or (IB) , or a pharmaceutically acceptable salt or prodrug thereof
- R 2 is H , CH 2 OH , OH , hal ide or C0 2 C 1-4 alkyl ;
- R 5 and R 6 are selected from the group consisting of H, halide, NH 2/ N (C 1-4 alkyl) 2 , NH (C 1-4 alkyl) and N0 2 , with the proviso that R 5 and R 6 are not both H;
- R 7 is H, or halide when R 5 is halide
- each of R 8 and R 9 is H or halide.
- Alk represents C x _ 4 alkyl
- R 2 is H , CH 2 OH, OH, halide or C0 2 C 1-4 alkyl ;
- R 5 and R 6 are selected from the group consisting of H, halide, NH 2 , N (C ⁇ alkyl) 2 , NH (C ⁇ alkyl) and N0 2 , with the proviso that R 5 and R 6 are not both H;
- R 7 is H, or halide when R 5 is halide
- each of R 8 and R 9 is H or halide .
- the present invention further provides for use in therapy, a compound of general Formula (IC) or a pharmaceutically acceptable salt or prodrug thereof,
- R a is selected from the group consisting of N0 2 , NH 2 , NH(C 1 _ 4 alkyl) and N(C 1 . 4 alkyl) 2 ;
- R b is selected from the group consisting of H, halide and N0 2 and b is 1 or 2 ;
- X can be selected from the group consisting of -C(R C ) (R d )C(R e ) (R £ ) -,
- R c and R d can be independently selected from the group consisting of H, halide, OH, CH 2 OH and
- R e and R f can be selected from the group consisting of
- R g is H or C 1-4 alkyl; and d is an integer selected from 1 to 4; or
- R a is selected from the group consisting of N0 2 , NH 2 , NH(C 1 _ 4 alkyl) and N (C 1-4 alkyl) 2 ;
- R b is selected from the group consisting of H, halide and N0 2 and b is 1 or 2 ;
- X can be selected from the group consisting of
- R c and R d can be independently selected from the group consisting of H, halide, OH, CH 2 OH and C0 2 C 1-4 alkyl ; or
- R e and R f can be selected from the group consisting of
- R h represents (diaryl) alkyl
- R g is H or C 1-4 alkyl ; and
- d is an integer selected from 1 to 4; or
- a compound of general Formula (IC) is selected from the following :
- R a , R b and X are as hereinbefore described in relation to general Formula (IC) .
- R a m compounds of Formula (IC) is selected from the group consisting of N0 2 , NH 2 and N(CH 3 ) 2 .
- R b compounds of Formula (IC) is selected from the group consisting of H, Br, Cl and N0 2 .
- X in compounds of Formula (IC) is selected from the group consisting of
- X in compounds of Formula (IC) may be -CH(CH 2 0H) (CH 2 ) d CH(0H) - wherein d is as hereinbefore described in relation to general Formula (IC) .
- X is -CH (CH 2 0H) CH 2 CH (OH) - .
- X in compounds of Formula (IC) may be
- Particular compounds for use in therapy or in the manufacture of a medicament for the inhibition of retinoic acid metabolism according to the present invention may include at least one of the following compounds:
- the preferred compounds may advantageously be achiral, readily available and potentially metabolically stable in vivo. It is advantageous in some embodiments to have achiral compounds, as resolution into specific enantiomers and/or stereoselective synthesis is not then required.
- compounds according to the present invention can be chiral and one of the resolved enantiomers may possess most of the activity in accordance with general findings for inhibition of P450s.
- the present invention therefore encompasses both racemic mixtures of such chiral compounds, and resolved enantiomers thereof.
- a method of treating a disease state ameliorated by the presence of retinoic acid comprises administering to a patient suffering from or susceptible to such a disease state a therapeutically effective amount of a compound as hereinbefore described in connection with use according to the present invention, or a pharmaceutically acceptable salt or prodrug thereof.
- the present invention further provides a compound of the general Formula (I) , or a pharmaceutically acceptable salt or prodrug thereof
- R 1 and R 2 are independently selected from the group consisting of H, CH 2 0H, OH, halide and C0 2 C 1-4 alkyl ;
- R 3 is H and R 4 is OH or OT where T is O O
- R 1 and R 3 together are 0 0
- R 7 is H, or R 7 is halide when R 5 is halide;
- each of R 8 and R 9 is H or halide
- n 0 or 1 ;
- y and z are both 0, or one of y and z is 1 and the other of y and z is 0.
- R 1 and R 2 are selected from the group consisting of H, OH, Br, C0 2 Me and CH 2 OH; or
- R 1 and R 2 together 0 or
- R 10 typically represents di-aryl (C 1-4 ) alkyl .
- R 10 represents di-aryl (C 2-4 ) alkyl , most preferably R 10 represents di-phenly (C 2 _ 4 ) alkyl .
- a further embodiment of the present invention is a compound of general Formula (IA) or (IB) , or a pharmaceutically acceptable salt or prodrug thereof
- Alk represents C 1-4 alkyl
- R 2 is H, CH 2 0H, OH, halide or C0 2 C 1-4 alkyl;
- R 7 is H, or halide when R 5 is halide
- each of R 8 and R 9 is H or halide.
- the present invention further provides a compound of general Formula (IC) or a pharmaceutically acceptable salt or prodrug thereof ,
- R a is selected from the group consisting of N0 2 , NH 2 , NH(C 1 . 4 alkyl) and N (C 1-4 alkyl) 2 ;
- R b is selected from the group consisting of H, halide and N0 2 and b is 1 or 2;
- X can be selected from the group consisting of
- R c and R d can be independently selected from the group consisting of H, halide, OH, CH 2 OH and
- R e and R f can be selected from the group consisting of H, OH and OC0 2 R h , where R h represents (diaryl) alkyl ; or
- R e and R f together 0 or ethylenedioxy
- R g is H or C 1-4 alkyl; and d is an integer selected from 1 to 4; or
- X can represent a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by
- R a and R b do not both represent N0 2 when X represents
- a compound of general Formula (IC) is selected from the following:
- R a , R b and X are as hereinbefore described in relation to a compound of general Formula (IC) .
- R a is selected from the group consisting of N0 2 , NH 2 and N(CH 3 ) 2 .
- R b is selected from the group consisting of H, Br, Cl and N0 2 .
- X is selected from the group consisting of -C(R C ) (R d )C(R e ) (R f ) - , -C(R C ) (R d ) (CH 2 ) d C(R e ) (R f ) - , -C(R C ) (R d ) (CH 2 ) d C(R e ) (R f )N(R g )- and -C(R C ) (R a ) (CH 2 ) d N(R g )C(R e ) (R f ) - , wherein R c , R d , R e , R f , R g and d are as hereinbefore disclosed in relation to compounds of general Formula (IC) .
- X may represent -CH (CH 2 0H) (CH 2 ) d CH (OH) - , wherein d is as hereinbefore disclosed in relation to compounds of general Formula (IC) .
- X is preferably -CH (CH 2 0H) CH 2 CH (OH) - .
- compounds of Formula (I) can be prepared following reaction of a known substituted benzaldehyde derivative of Formula (II)
- Y can represent hydrogen or another suitable group, whereby compounds of Formula (III) can react with either the aldehyde moiety of benzaldehyde derivatives of Formula (II) in a first preferred method according to the present invention or the phenyl ring substituent X-CH 2 -C (R 3 ) (R 4 ) - of compounds of Formula (VII) in a second preferred method according to the present invention substantially as hereinafter described.
- Benzaldehyde derivatives of Formula (II) are generally known compounds.
- Compounds of Formula (III) can also be known compounds or may be prepared from compounds of
- Benzaldehyde derivatives of Formula (II) are typically reacted with compounds of Formula (III) , in a first preferred method according to the present invention, in the presence of an alkali metal hydroxide and an inert solvent, such as dimethylformanide or the like, to yield compounds of Formula (I) according to the present invention.
- Het suitably represents a heterocyclic moiety and X a suitable leaving group, typically a halide (bromide, chloride, fluoride or iodide) or the like.
- X a suitable leaving group, typically a halide (bromide, chloride, fluoride or iodide) or the like.
- Compounds of Formula (I) are typically obtained from compounds of Formula (IV) via a number of intermediates following reaction of compounds of Formula (II) and (IV) (substantially as hereinafter described in greater detail in the accompanying Examples) , suitably by elimination followed by reduction or reaction with an alkylene glycol or the like.
- R 5a can either represent R 5 substantially as hereinbefore described with reference to Formula (I) or a precursor thereof that can readily be converted to R 5 .
- R 5a can represent CH 3 CONH that can be converted to NH 2 -, suitably by reflux under acidic conditions followed by addition of a base, such as an alkali metal hydroxide, to release the free amine .
- (V) is typically carried out under reflux in the presence of an alkali metal cyanide (e.g. potassium cyanide) and an alcohol (e.g. ethanol) .
- an alkali metal cyanide e.g. potassium cyanide
- an alcohol e.g. ethanol
- Benzaldehyde derivatives of Formula (V) are generally known compounds.
- compounds of Formula (I) can be prepared by reaction of a compound of Formula (III) substantially as hereinbefore described and a compound of Formula (VII)
- X is a suitable leaving group, such as a halide (bromide, chloride, fluoride or iodide) or the like.
- Compounds of Formula (III) and (VII) are typically reacted under reflux, with stirring, in the presence of an anhydrous solvent, such as an alkali metal (typically potassium) carbonate or the like.
- X in Formula (VII) represents halide substantially as hereinbefore described, suitably in the presence of a catalyst, such as aluminium chloride or the like.
- Formula (III) are typically obtained from compounds of
- Formula (IX) by reaction of the latter with an alkylating agent, such as a trialkyl orthoformate or the like, in the presence of a catalytic amount of a mineral acid, such as hydrochloric acid or the like.
- an alkylating agent such as a trialkyl orthoformate or the like
- Compounds of Formula (I) obtained by a second preferred method according to the present invention can typically form a subgroup of compounds according to the present invention that can suitably be represented by Formula (IA) substantially as hereinbefore described.
- compounds of Formula (I) substantially as hereinbefore described obtained by a method according to the present invention can be converted into further compounds of Formula (I) by suitable interconversion techniques.
- R 1 represents C0 2 Alk
- R 1 can be converted into corresponding alcohol derivatives where R 1 can represent -CH 2 OH
- suitable reducing conditions such as reaction in the presence of a reducing agent, typically a borohydride (for example, sodium borohydride) or the like.
- compounds of Formula (I) can be subjected to oxidative conditions, for example where the moiety -CH(OH)- [represented by either -C(R 1 ) (R 2 ) - or C(R 3 ) (R 4 ) - in Formula
- R a , R b , R c and R d are as hereinbefore described in relation to a compound of general Formula (IC) ;
- R al represents R a or a precursor thereof that can readily be converted to R a .
- X is a leaving group; and R a , R b , R c , R d , R e , R f/ b and d are as hereinbefore described in relation to a compound of general Formula (IC) .
- the present invention further includes within its scope prodrugs of compounds of Formula (I) and in general such prodrugs will be functional derivatives of compounds of Formula (I) which are readily convertible in vivo into the required compound. Conventional procedures for selection and preparation of suitable prodrug derivatives are well known in the art .
- Compounds according to the present invention are inhibitors of retinoic acid metabolism substantially as hereinbefore described and are, therefore, useful as therapeutic agents for potentiating the action of endogenous retinoic acid.
- the compounds according to the invention generally have low activity against other P450 enzymes involved in cortisol production, which is indicative of low toxicity on oral dosing or should systemic absorption occur.
- compounds according to the present invention are useful as therapeutic agents for treating disease states ameliorated by the presence of retinoic acid, such as skin diseases, (including actinic keratoses, nonmelanoma skin cancer, acne vulgaris, psoriasis, orders of keratinisation and the like, substantially as hereinbefore described) , oncogenic conditions (including oral leukoplakia, head and neck cancer and the like, substantially as hereinbefore described) and other disease states that can be associated with a lack of retinoic acid.
- retinoic acid such as skin diseases, (including actinic keratoses, nonmelanoma skin cancer, acne vulgaris, psoriasis, orders of keratinisation and the like, substantially as hereinbefore described)
- oncogenic conditions including oral leukoplakia, head and neck cancer and the like, substantially as hereinbefore described
- treatment includes both the amelioration of the symptoms of an established disease state and the prophylaxis of such a disease state.
- a compound of Formula (I) substantially as herein before described for use in therapy. More particularly, there is further provided by the present invention a compound of Formula (I) substantially as hereinbefore described, for use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, substantially as herein before described.
- compositions according to the present invention are included in pharmaceutical Formulations.
- a pharmaceutical Formulation comprising a compound of Formula (I) , substantially as herein before described, together with at least one acceptable carrier, diluent or excipient therefor.
- the carriers must be "acceptable” in the sense of being compatible with the other ingredients of the Formulation and not deleterious to a recipient thereof.
- Formulations according to the present invention include those suitable for oral, parenteral and topical administration, although the most suitable route will generally depend upon the condition of a patient and the specific disease state being treated.
- the precise amount of a compound of Formula (I) to be administered to a patient will be the responsibility of an attendant physician, although the dose employed will depend upon a number of factors, including the age and sex of the patient, the specific disease state being treated and the route of administration substantially as described above.
- a method of treating a disease state ameliorated by the presence of retinoic acid substantially as hereinbefore described comprises administering to a patient suffering from or susceptible to a such disease a therapeutically effective amount of a compound of Formula (I), or a prodrug thereof.
- Table 1 lists exemplary compounds according to the present invention, together with their respective values for inhibition of retinoic acid metabolism
- Example 2 The title compound of Example 1 (4.6 g; 0.015 mol.) in dry dichloromethane (40 ml) was added to a suspension of pyridinium chlorochromate (6.5 g; 0.03 mol.) in dichloromethane (40 ml) , after which the solution turned dark brown. After 1.5 hours stirring at room temperature, with the reaction followed by TLC, diethyl ether (40 ml) was added and the supernatant liquid was decanted from a black gum. The insoluble residue was washed with diethyl ether and the combined (decolourised) organic solution filtered through Celite (Trade Mark) and the solvent removed under vacuum.
- Phenyltrimethylammonium tribromide (3.76 g; 0.01 mol.) was added in small portions to a solution of Intermediate 1 (3.12 g; 0.01 mol.) in tetrahydrofuran (20 ml), with stirring. After 30 minutes the resultant white precipitate (phenyltrimethylammonium bromide) was removed by filtration. The filtrate was concentrated in vacuo and the yellow residue dissolved in chloroform and washed with water, dried (MgS0 4 ) and evaporated to leave a yellow oil, which solidified on standing. Crystallization (ethanol) gave Intermediate 2 (3.34 g; 86%), as cream crystals, m.p. 89-90°C.
- Freshly ground sodium hydroxide (0.2 g) was added to a solution of 4-nitrotoluene (20.57 g; 0.15 mol.) and 2,4- dichlorobenzaldehyde (8.75 g; 0.05 mol.) in dry N, N- dimethylformamide (100 ml), and the reaction stirred under nitrogen at room temperature. The reaction mixture turned dark green within several minutes . After 2 hours the reaction mixture was acidified with concentrated hydrochloric acid (1 ml) , diluted with toluene and washed with water.
- Example 2a The title compound of Example 2a was isolated as yellow crystals (ethanol) , following oxidation of the title compound of Example 1 when the reaction proceeded beyond 1.5 hours, m.p. 133-134°C. Found: C, 51.86; H, 2.09; ⁇ ,
- nitric acid (30 ml, S.G. 1.42) was poured onto the title compound of Example 1 (5 g; 0.016 mol.) in a round- bottomed flask fitted with an air condenser.
- the reaction mixture was heated on a boiling water bath for 2.5 hours until the evolution of brown fumes of nitric oxide ceased, whereupon the solution was poured onto ice and stirred.
- the resulting gum obtained after decantation gave yellow crystals after crystallization (ethanol) , of the title compound of Example 2b (2.90 g, 55.9%), m.p. 132-134°C, with analytical data as shown in Example 2a and a mixed m.p. 132-134°C.
- Example 15 The title compound of Example 15 was obtained from Intermediates 8 and 12 as yellow crystals (56%) .
- Example 17 The title compound of Example 17 was obtained from Intermediates 8 and 14 as yellow crystals (47%) .
- Example 11 To a solution of the title compound of Example 11 (1.01 g, 3.2 mmol) in diglyme (50 cm 3 ) was added soldium borohydride (0.5 g, 13 mmol), and the mixture stirred overnight at room temperature. The purple solution was added to ice water (50 cm 3 ) , ethyl acetate (50 cm 3 ) and then acidified (2M HC1) . The organic layer was separated and washed with water (2 x 50 cm 3 ) , saturated sodium bicarbonate (50 cm 3 ) , water (50 cm 3 ) , then dried (MgSO .
- soldium borohydride 0.5 g, 13 mmol
- Example 20 The title compound of Example 20 was obtained from the title compound of Example 12.
- M.P. 127.2-128.4°C (Found: C, 53.59; H, 3.44; N, 3.57.
- C 16 H 17 N0 4 requires C, 53.42; H, 3.42; N, 3.66%) ; n ⁇ .
- Example 21 The title compound of Example 21 was obtained from the title compound of Example 13. Column chromatography with ethyl acetate: petroleum ether (6:4 v:v) , pale yellow
- Example 23 The title compound of Example 23 was obtained as a solid from the title compound of Example 15. (79%) . m.p. 124. - 125.3°C. V max KBr disc/cm "1 3525.9 and 3356.8 (OH) , 1506.
- Example 26 The title compound of Example 26 was obtained from the title compound of Example 18. m.p. 121.8 - 123.7°C. (Found: C, 53.59; H, 3.44; N, 3.57. C 16 H 16 N 2 0 6 requires C, 53.42; H, 3.42; N, 3.66%) ; V max KBr disc/cm "1 3518.7 and 3395.1 (OH) , 1510.3 and 1352.8 (N0 2 ) .
- Example 11 The title compound of Example 11 (1.38g, 4.40mmol) in 70% ethanol/water (50 cm 3 ) was stirred at room temperature with sodium borohydride (0.2g, 7.40mmol) for 8 hours. The resulting purple reaction mixture was added to ice water (50 cm 3 ) and ethyl acetate (50 cm 3 ) and then acidified (2M HC1) . The organic layer was separated and washed with water (2 x 50 cm 3 ) , saturated sodium bicarbonate (50 cm 3 ) , water (50 cm 3 ) and then dried (MgSO . The volatile components were removed to leave a brown oil .
- Example 28 According to the procedure described in Example 27, the title compound of Example 28 was prepared as yellow crystals from the title compound of Example 12 (25%) .
- Example 16 The title compound of Example 16 was employed according to the procedure described in Example 27, whereby a pale yellow oil was formed. Column chromatography with ethyl acetate : petroleum ether (3:7) gave pale yellow crystals of the title compound of Example 29 (48%). m.p. 148.7 - 153.9°C. (Found: C, 54.39; H, 3.32, N, 3.71. C ⁇ H ⁇ C ⁇ NG, requires C, 54.56; H, 3.15; N, 3.98%); V max KBr disc/cnr 1
- Example 31 (0.15g, 5.6%) . m.p. 124.3 - 125.7°C.
- the enzyme reaction was initiated by addition of rat liver microsomes (lO ⁇ l of lOmg/ml) and the mixture incubated at 37°C for 25 minutes.
- the enzyme action was arrested by addition of lOO ⁇ l of 1% formic acid and the tubes were placed in ice for 5 minutes.
- 3ml of ethyl acetate containing 0.02% butylated hydroxy anisole was added and the tubes vortexed for 10 seconds.
- the tubes were then left for another 5 minutes at room temperature and the organic layer (2ml) was removed from each tube and transferred to another set of tubes .
- the ethyl acetate extracts were evaporated using a univap centrifuge connected to a vacuum pump and a multitrap at -80°C.
- Percentage inhibition was calculated from the conversion rate of the samples containing inhibitors to that of control samples which contained absolute ethanol instead of inhibitor solution. Ketoconazole was used as a standard.
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Abstract
For use in the inhibition of retinoic acid metabolism, diphenyl compounds of formula (I).
Description
Diphenyl Compounds, Formulations And Uses Thereof
The present invention is concerned with diphenyl compounds, pharmaceutical formulations containing the same and uses thereof. In particular, the present invention is concerned with the use of diphenyl compounds in the inhibition of retinoic acid metabolism.
Retinoic acid (RA) supports cellular growth and differentiation (Roop, et al . , Retinoids : 10 Years On
(Saurat J-H (ed) ) : 28-30 (1991)) and has been shown to attenuate or completely reverse the malignant phenotype for many cell lines (Kaburagi, et al . , J. Steroid Biochem . 26:
739-42 (1987)). Retinoic acid is also implicated in cell proliferation in skin conditions. Synthetic retinoids have shown promise in the treatment of oral leukoplakia and head and neck cancer, although their use may be associated with significant toxicity (Armstrong, et al . , The Retinoids : Biology, Chemistry and Medi cine (Sporn et al (eds) ) 2nd Edition: 545-72 (1994)). Retinoids have also been used topically and orally for the treatment of skin diseases, i.e. actinic keratoses (Lotan, FASEB J. 10: 1031-9 (1996)) (precursors to squamous cell carcinoma) , nonmelanoma skin cancer (Lotan, FASEB J. 10: 1031-9 (1996)), acne vulgaris (Peck, et al . , N. Engl . J. Med . 300: 329-33 (1979)), psoriasis (Dockx, et al . , Br. J. Dermatol . 133: 426-32
(1995)) orders of keratinisation (Futoryan, et al . ,
Nutri tion Rev. 52: 299-310 (1994)). More recently, the benefit of retinoids to photodamaged skin has led to their use in anti-wrinkle cosmetic preparations.
Vitamin A (retinol) is oxidised through retinal by dehydrogenases (Raner, et al . , Mol . Pharmacol . 49: 515-22
(1996) ) in the cytoplasm of target cells in low yield to all trans-retinoic acid (RA) . RA is at least 100 fold more active than retinol (Williams and Napoli, Proc . Natl . Acad .
Sci . 82: 4658-62 (1985)) and is considered to account for its biological action. RA has a short half life (c. 1 hour) (Muindi, et al . , Proc . A er. Soc . Clin . Oncol . 10: 92
(1991) ) and therefore the potency of RA is reduced when administered systemically due to metabolism by human liver and intestine cytochrome P450s to the inactive 4-hydroxy-RA and thence by dehydrogenases to the partially active 4- keto-RA and inactive polar metabolites (Williams and Napoli, Proc. iVatl. Acad. Sci . 82: 4658-62 (1985)) (Van Wauwe, et al., Biochem . Pharmacol . 47: 737-41 (1994)). The specific P450s (P450-RA) responsible for 4 -hydroxylation of RA in the human liver have not been characterised, but several reconstituted P450s CYP1A2/2B6/2C8/2D6/2E1/3A4 , can catalyse the reaction (Nadin and Murray, Br. J. Clin . Pharmacol . 41: 609-12 (1996)).
Repeated exogenous administration of RA leads to a lowering of RA levels due to induction of the metabolising enzymes
(Muindi, et al . , Blood . 70: 299-303 (1992)). Recent work has shown that RA induces a RA-inducible RA-metabolising P450 (hP450RAl) , which belongs to a novel class of mammalian cytochromes (CYP26) , which gives the RA- metabolites previously described (Ray, et al . , J. Biol . Chem . 272: 18702-8 (1997)) (White, et al . , J. Biol . Chem . 272: 18538-41 (1997)) (AbuAbed, et al . , J. Biol . Chem. 273:
2409-15 (1998)) (Haque, et al . , Nutri tional Rev. 56: 84-5
(1998) ) Furthermore hP450RAI mRNA expression is highly induced by RA in certain human tumour cell lines and RA- metabolism may correlate with P450RAI expression (White, et al . , J. Biol . Chem. 272: 18538-41 (1997)).
A drug which can potentiate the action of endogenous RA on the cell by inhibiting P450-RA metabolising enzymes would have potential as a clinical agent in the treatment of certain skin conditions and cancer.
The imidazoles, ketoconazole and liarozole, were reported as inhibitors of RA-metabolising enzymes whilst being studied as inhibitors of 17α-hydroxylase : 17,20-lyase (P450 17 ) as agents for the treatment of androgen-dependent prostatic cancer by lowering testosterone levels (Vander Bosche and Willemsens, Retinoids : 10 Years On (Saurat J- H (ed) ) : 79-88 (1991)). Ketoconazole lacks specificity towards P450 17α and inhibits several other cytochrome P450 enzymes on the steroidogenic pathway of androgen synthesis and has a poor pharmacokinetic profile and hepatic toxicity has been noted.
Liarozole (R75251) , a related compound, also inhibits testicular (but not adrenal) P450 17α and similarly lowers testosterone levels in human volunteers, but its effect on androgen-independent carcinoma has been partially attributed to inhibition of P450-RA with an associated increase in RA levels (Dockx, et al . , Br. J. Dermatol . 133: 426-32 (1995)) (Roseeuw, et al . , 18th World Congress of Dermatology, June 12th-18th : P194A (1992) (ketoconazole is
also an inhibitor of this enzyme) . This view has been confirmed by experiments showing that RA metabolism in epidermal cells is inhibited (IC50-2μM) and also that endogenous RA levels are increased and the elimination rate from the plasma of injected RA is reduced (Roseeuw, et al . , 18th World Congress of Dermatology, June 12th-18th : P194A (1992) . Liarozole has also been in trials for the treatment of severe psoriasis (oral) and acne (topical and oral) and it seems likely that this action is due to inhibition of epidermal P450-RA. The ability of oral liarozole to act as a useful drug in the treatment of hormone-resistant prostate cancer, ichthyosis, psoriasis (Dockx, et al . , Br. J. Derma tol . 133: 426-32 (1995)) and acne (Roseeuw, et al . , 18th World Congress of Dermatology, June 12th-18th : P194A (1992) has been established by certain workers .
RA-metabolising enzyme inhibitors intended for topical use for skin diseases should show little unwanted systemic effects due to the involvement of other enzymes, e.g. steroidogenic P450 enzymes such as P450 17 , CSCC, 21- hydroxylase. This objective should be achievable due to either poor sub-dermal penetration or, should this occur, low dose effects due to plasma dilution of the small load of drug placed on a restricted area of skin.
It is therefore the aim of the present invention to provide a P450-RA inhibitor of low activity towards other steroidogenic P450 enzymes and therefore low inherent toxicity to alleviate some of the aforementioned problems. We have now discovered compounds that are inherently less
active inhibitors of P450 17α, the main target of liarozole and ketoconazole, and yet are inhibitors of retinoic acid metabolism with potency comparable with that of ketoconazole. This selectivity for inhibition of retinoic acid metabolism is useful in the treatment of the skin conditions mentioned above and cancer.
According to the present invention, there is provided for use in therapy, a compound of the general Formula (I) :
where R1 and R2 together are =0 or
or R1 and R2 are independently selected from the group consisting of H, CH20H, OH , halide and C02C1 -4alkyl ;
R3 is H and R4 is OH or OT where T is O 0
OR1 or - C R1 where R10 is C1.4alkyl , aryl (C1-4) alkyl , di -aryl (C1-4) alkyl or aryl ; or
R3 and R4 together are =0 :
(i) when R1 and R2 together are =0; or
(ii) when R1 and R2 are both halide; or
(iii) at least one of R1 and R2 is is C02C1-4alkyl ; or
each of R3 and R4 is H when R1 and R2 together are not =0; or
R1 and R3 together are 0 0
- C - 0 or - C - NH -
when n is 1, z is 0 and R2 and R4 are each H;
R5 and R6 are selected from the group consisting of H, halide, NH2, N (C^alkyl) 2, NH (C^alkyl) and N02, with the proviso that R5 and Rs are not both H;
R7 is H, or R7 is halide when Rs is halide;
each of R8 and R9 is H or halide;
n is 0 or 1;
y and z are both 0, or one of y and z is 1 and the other of y and z is 0.
There is further provided by the present invention, use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, a compound of the general Formula (I) :
where R1 and R2 together are =0 or
O ) c o
\ /
or R1 and R2 are independently selected from the group consisting of H , CH20H, OH, halide and C02C1-4alkyl ;
R3 is H and R4 is OH or OT where T is O O
OR1 or C - R1
where R10 is C1-4alkyl , aryl (C1-4 ) alkyl , di - aryl (C1-4 ) alkyl or aryl ; or
R3 and R4 together are =0: (i) when R1 and R2 together are =0; or (ii) when R1 and R2 are both halide; or (iii) at least one of R1 and R2 is is C02C1-4alkyl ,- or
each of R3 and R4 is H when R1 and R2 together are not =0 ; or
R1 and R3 together are
0 0
II II
- C - 0 or - C - NH
when n is 1, z is 0 and R2 and R4 are each H;
R5 and R6 are selected from the group consisting of H, halide, NH2, N (C1-4alkyl) 2, NH (C1-4alkyl) and N02, with the proviso that R5 and R6 are not both H;
R7 is H, or R7 is halide when R5 is halide;
each of R8 and R9 is H or halide;
n is 0 or 1;
y and z are both 0, or one of y and z is 1 and the other of y and z is 0.
Suitably for use according to the present invention, R1 and R2 in compounds of Formula (I) are selected from the group consisting of H, OH, Br, C02Me and CH20H; or
R1 and R2 together are =0 or
O 0
II II
- C - 0 or - C - NH -
when n is 1, z is 0 and R2 and R4 are each H,
More preferably for use according to the present invention, R2 in compounds of Formula (I) represents H when R1 is selected from H, C02Me and CH2OH. Even more preferably for use according to the present invention in compounds of Formula (I) R1 represents C02Me, R2 represents H and R3 and R4 together are =0; or in compounds of Formula (I) R1 represents CH20H, R2 represents H, R3 represents H and R4 represents OH.
For use according to the present invention where R4 in compounds of Formula (I) can represent OT, where T is O
- C - OR10 R10 typically represents di-aryl (C1-4) alkyl . Preferably R10 represents di-aryl (C2-4) alkyl and more preferably R10 represents di-phenyl (C2_4) alkyl .
It is particularly desirable for use according to the present invention that R5 and R6 in compounds of Formula (I) are selected from the group consisting of H, halide, NH2, N(C1-4alkyl)2/ NH (C1-4alkyl) and N02, with the proviso that at least one of R5 and Rδ is NH2, N (C1.4alkyl) 2, NH (C1-4alkyl) and
N02 and that both R5 and R6 are not N02 when R1 and R2 together are =0, R3 is H, R4 is OH, R7 is H, R8 is H, R9 is H, n is 1, y is 0 and z is 0. It is preferred for use according to the present invention that R5 and R6 in compounds of Formula (I) are selected from the group consisting of H, Br, Cl , NH2, N(Me)2 and N02, with the proviso that at least one of R5 and R6 is NH2, N(Me)2 and N02 and that both R5 and R6 are not N02 when R1 and R2 together are =0, R3 is H, R4 is OH, R7 is H, R8 is H, R9 is H, n is 1, y is 0 and z is 0.
The present invention further includes for use in therapy, a compound of general Formula (IA) or (IB) , or a pharmaceutically acceptable salt or prodrug thereof
(IA)
(IB)
where Alk represents C1-4 alkyl;
R2 is H , CH2OH , OH , hal ide or C02C1-4 alkyl ;
R5 and R6 are selected from the group consisting of H, halide, NH2/ N (C1-4alkyl) 2, NH (C1-4alkyl) and N02, with the proviso that R5 and R6 are not both H;
R7 is H, or halide when R5 is halide; and
each of R8 and R9 is H or halide.
There is further provided by the present invention, use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, a compound of general Formula (IA) or (IB) , or a pharmaceutically acceptable salt or prodrug thereof
(IA)
(IB)
where Alk represents Cx_4 alkyl ;
R2 is H , CH2OH, OH, halide or C02C1-4 alkyl ;
R5 and R6 are selected from the group consisting of H, halide, NH2, N (C^alkyl) 2, NH (C^alkyl) and N02, with the proviso that R5 and R6 are not both H;
R7 is H, or halide when R5 is halide; and
each of R8 and R9 is H or halide .
The present invention further provides for use in therapy, a compound of general Formula (IC) or a pharmaceutically acceptable salt or prodrug thereof,
where (IC) Ra is selected from the group consisting of N02, NH2, NH(C1_4alkyl) and N(C1.4alkyl) 2;
Rb is selected from the group consisting of H, halide and N02 and b is 1 or 2 ;
X can be selected from the group consisting of -C(RC) (Rd)C(Re) (R£) -,
-C(Rc) (Rd) (CH2)dC(Re) (Rf) -,
-C(RC) (Rd) (CH2)dC(Re) (Rf)N(Rg)- and
-C(RC) (R«j) (CH2)dN(Rg)C(Re) (Rf)-; wherein Rc and Rd can be independently selected from the group consisting of H, halide, OH, CH2OH and
C02C1_4alkyl ; or
Rc and Rd together represent =0 or ethylenedioxy;
Re and Rf can be selected from the group consisting of
H, OH and OC02Rh, where Rh represents (diaryl) alkyl ; or Re and Rf together represent =0 or ethylenedioxy;
Rg is H or C1-4alkyl; and d is an integer selected from 1 to 4; or
X can represent a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =0.
There is further provided by the present invention, use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, a compound of general Formula (IC) or a pharmaceutically acceptable salt or prodrug thereof,
(IC) where
Ra is selected from the group consisting of N02, NH2, NH(C1_4alkyl) and N (C1-4alkyl) 2;
Rb is selected from the group consisting of H, halide and N02 and b is 1 or 2 ;
X can be selected from the group consisting of
-C(Rc) (Rd)C(Re) (Rf)-, -C(RC) (Rd) (CH2)dC(Re) (Rf)-,
-C(Rc) (Ra) (CH2)dC(Re) (Rf)N(Rg)- and
-C(RC) (Rd) (CH2)dN(Rg)C(Re) (Rf)-; wherein Rc and Rd can be independently selected from the group consisting of H, halide, OH, CH2OH and C02C1-4alkyl ; or
Rc and Rd together represent =0 or ethylenedioxy;
Re and Rf can be selected from the group consisting of
H, OH and 0C02Rh, where Rh represents (diaryl) alkyl ; or
Re and Rf together represent =0 or ethylenedioxy; Rg is H or C1-4alkyl ; and d is an integer selected from 1 to 4; or
X can represent a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =0.
Suitably, for use according to the present invention a compound of general Formula (IC) is selected from the following :
(IC)
(IC)
(IC)
(IC)
wherein Ra, Rb and X are as hereinbefore described in relation to general Formula (IC) .
Suitably for use according to the present invention Ra m compounds of Formula (IC) is selected from the group consisting of N02, NH2 and N(CH3)2.
Suitably for use according to the present invention Rb compounds of Formula (IC) is selected from the group consisting of H, Br, Cl and N02.
In a first embodiment for use according to the present invention X in compounds of Formula (IC) is selected from the group consisting of
-C(RC) (Rd)C(Re) (Rf) - ,
-C(RC) (Rd) (CH2)dC(Re) (Rf)- ,
-C(RC) (Rd) (CH2)dC(Re) (Rf)N(Rg)- and -C(RC) (Rd) (CH2)dN(Rg)C(Re) (Rf) - , wherein Rc, Rd, Re, Rf, Rg and d are as hereinbefore described in relation to general Formula (IC) .
Typically for use according to the present invention X may be selected from the group consisting of -CH2CH(OH)-, -C(=0)C(=0) -, C (halide) 2C (=0) -, -CH2C (ethylenedioxy) - , -CH2CH(OC02Rh) - where Rh is as hereinbefore described in relation to general Formula (IC) , -CH(OH)CH2-, -C (ethylenedioxy) CH2- and -C (=0) CH (OH) - . Preferably for use according to the present invention X can be selected from the group consisting of -CH2CH(OH)-, -C (=0) C (=0) - , -C (Br) 2C (=0) - , -CH2C (ethylenedioxy) - ,
-CH2CH[OC02-CHR1R;ι] - where R, is 2 , 4-dichlorophenyl and R: is 4-nitrobenzyl, -CH(0H)CH2- , -C (ethylenedioxy) CH2- and -C(=0)CH(0H) -.
Alternatively, for use according to the present invention X may be -CH (C02C1.4alkyl) (CH2) dC (=0) - , wherein d is as hereinbefore described in relation to general Formula (IC) . Preferably for use according to the present invention X in compounds of Formula (IC) is -CH (C02Me) CH2C (=0) - .
Alternatively, for use according to the present invention X in compounds of Formula (IC) may be -CH(CH20H) (CH2)dCH(0H) - wherein d is as hereinbefore described in relation to general Formula (IC) . Preferably for use according to the present invention X is -CH (CH20H) CH2CH (OH) - .
Alternatively, for use according to the present invention X in compounds of Formula (IC) may be -CH(C02C1-4alkyl) (CH2) dC (=0) NH- , wherein d is as hereinbefore described in relation to general Formula (IC) . Preferably for use according to the present invention X in compounds of Formula (IC) is -CH (C02Me) CH2C (=0) NH- .
Alternatively, for use according to the present invention X in compounds of Formula (IC) may be
-CH(C02C1_4alkyl) (CH2) dNHC (=0) - , wherein d is as hereinbefore described in relation to general Formula (IC) . Preferably X is -CH(C02Me)CH2NHC(=0) -.
In a second embodiment of general Formula (IC) for use according to the present invention, X represents a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =0. The 5 or 6 membered heterocyclic ring preferably contains an oxygen or
nitrogen heteroatom, which ring is preferably substituted by =0. It is most preferred that the heterocyclic ring is either tetrahydrofuran or pyrrolidine.
Suitably in the case of following Formula (IC) for use according to the present invention
(IC)
Ra and Rb do not both represent N02 when X represents -CH(OH)CH2C(=0) -.
Particular compounds for use in therapy or in the manufacture of a medicament for the inhibition of retinoic acid metabolism according to the present invention may include at least one of the following compounds:
1- (2 , 4-Dichlorophenyl) -2- (4-nitrophenyl) -1-ethanol ; 1 - (2 , 4 -Dichlorophenyl ) -2 - (4 -nitrophenyl ) - 1 , 2 - ethandione;
2 , 2-Dibromo-l- (2, 4 -dichlorophenyl) -2- (4-nitrophenyl) -
1-ethanone;
1 - (2,4 -Dichlorophenyl ) - 1 , 1 -ethylenedioxy- 2 - (4 - nitrophenyl) ethane;
Di (1- (2 , 4 -dichlorophenyl) -2 - (4-nitrophenyl) ethyl )
carbonate;
2- (2 , 4 -Dichlorophenyl) -1- (4-nitrophenyl) -1-ethanol ;
2 - (2,4 -Dichlorophenyl ) - 1 , 1 -ethylenedioxy- 1 - ( 4 nitrophenyl ) ethane ; 2- (2 , 4 -Dichlorophenyl) -1- (4-dimethylaminophenyl) -2 hydroxy- 1 -ethanone ;
1- (2 , 4 -Dichlorophenyl) -2- (4-dimethylaminophenyl) -1,2 ethandione;
2 - (4 -Aminophenyl ) -1- (2,4-dichlorophenyl) -1,2 ethandione;
Methyl 2- (4-nitrophenyl) -4-oxo-4-phenylbutanoate;
Methyl 4- (4 -bromophenyl ) -2- (4-nitrophenyl) -4 oxobutanoate ;
Methyl 4- (2 -chlorophenyl) -2- (4-nitrophenyl) -4 oxobutanoate;
Methyl 4- (3 -chlorophenyl) -2- (4-nitrophenyl) -4 oxobutanoate ;
Methyl 4- (4 -chlorophenyl ) -2- (4-nitrophenyl) -4 oxobutanoate ; Methyl 4- (2 , 4 -dichlorophenyl) -2- (4-nitrophenyl) -4 oxobutanoate ;
Methyl 4- (3 , 4 -dichlorophenyl) -2- (4-nitrophenyl) -4 oxobutanoate ;
Methyl 4- (4-nitrophenyl) -2- (4-nitrophenyl) -4 oxobutanoate;
3- (4 -Nitrophenyl) -1-phenyl-l, 4-butanediol;
1- (4-bromophenyl) -3- (4-nitrophenyl) -1 , 4-butanediol ;
1- (2 -chlorophenyl) -3- (4-nitrophenyl) -1 , 4-butanediol
1- (3 -chlorophenyl) -3- (4-nitrophenyl) -1 , 4-butanediol 1- (4 -chlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol
1 - (2,4 -dichlorophenyl ) - 3 - (4 -nitrophenyl ) - 1 , 4
butanediol ;
1- (3,4-dichlorophenyl) -3- (4-nitrophenyl) -1,4- butanediol ;
1- (4-nitrophenyl) -3 - (4-nitrophenyl) -1 , 4-butanediol ; 3- (4-nitrophenyl) -5-phenyltetrahydro-2-furanone;
5 - (4 -Bromophenyl ) - 3 - (4 -nitrophenyl ) tetrahydro-2 - f uranone ;
5- (2 , 4 -dichlorophenyl) -3- (4-nitrophenyl) tetrahydro-2- f uranone ; 5- (2, 4-dichlorophenyl) -3- (4-aminophenyl) - 2 - pyrrolidinone ;
Methyl 4- (2,4 -dichlorophenylamino) -4-oxo-2 - (4- nitrophenyl) butanoate; and
Methyl 3- ( 2 , 4 - dichlorophenyloxoamino) -2- (4- nitrophenyl) propanoate .
The preferred compounds may advantageously be achiral, readily available and potentially metabolically stable in vivo. It is advantageous in some embodiments to have achiral compounds, as resolution into specific enantiomers and/or stereoselective synthesis is not then required.
In some instances, however, compounds according to the present invention can be chiral and one of the resolved enantiomers may possess most of the activity in accordance with general findings for inhibition of P450s. The present invention therefore encompasses both racemic mixtures of such chiral compounds, and resolved enantiomers thereof.
There is further provided by the present invention a method of treating a disease state ameliorated by the presence of
retinoic acid, which method comprises administering to a patient suffering from or susceptible to such a disease state a therapeutically effective amount of a compound as hereinbefore described in connection with use according to the present invention, or a pharmaceutically acceptable salt or prodrug thereof.
The present invention further provides a compound of the general Formula (I) , or a pharmaceutically acceptable salt or prodrug thereof
where R1 and R2 together are =0 or
or R1 and R2 are independently selected from the group consisting of H, CH20H, OH, halide and C02C1-4alkyl ;
R3 is H and R4 is OH or OT where T is O O
- C - OR10 or - C - R10 where R10 is C^alkyl, aryl (C1-4) alkyl , di-aryl (C1-4) alkyl or aryl; or
R3 and R4 together are =0 : ( i ) when R1 and R2 together are =0 ; or ( ii ) when R1 and R2 are both hal ide ; or ( iii ) at least one of R1 and R2 i s is C02C1-4alkyl ; or
each of R3 and R4 is H when R1 and R2 together are not =0 ; or
R1 and R3 together are 0 0
II II
- C - 0 or - C - NH
when n is 1, z is 0 and R2 and R4 are each H;
R5 and R6 are independently selected from the group consisting of H, halide, NH2, N (C1-4alkyl) 2, NH (C^alkyl) and N02, with the proviso that at least one of R5 and R6 is NH2, N(C1_4alkyl)2, NH (C1-4alkyl) and N02 and that both R5 and R6 are not N02 when R1 and R2 together are =0, R3 is H, R4 is OH, R7 is H, R8 is H, R9 is H, n is 1 , y is 0 and z is 0.
R7 is H, or R7 is halide when R5 is halide;
each of R8 and R9 is H or halide;
n is 0 or 1 ;
y and z are both 0, or one of y and z is 1 and the other of y and z is 0.
Suitably, in compounds of Formula (I) R1 and R2 are selected
from the group consisting of H, OH, Br, C02Me and CH2OH; or
R1 and R2 together are =0 or
or R1 and R3 together are
O O
II II
- C - 0 or - C - NH -
when n is 1, z is 0 and R2 and R4 are each H.
R2 in compounds of Formula (I) preferably represents H when R1 is selected from H,C02Me and CH2OH. More preferably in compounds of Formula (I) , R1 represents C02Me, R2 represents H and R3 and R4 together are =0; or in compounds of Formula (I) R1 represent CH20H, R2 represent H, R3 represent H and R4 represent OH.
In compounds of Formula (I) where R4 can represent OT, where T is
0 II
- C - OR10
R10 typically represents di-aryl (C1-4) alkyl . Preferably R10 represents di-aryl (C2-4) alkyl , most preferably R10 represents di-phenly (C2_4) alkyl .
Suitably, R5 and R6 are selected from the group consisting
of H, Br, Cl, NH2, N(Me)2 and N02 , with the proviso that at least one of R5 and R6 is NH2, N(Me)2 and N02 and that both R5 and R6 are not N02 when R1 and R2 together are =0, R3 is H, R4 is OH, R7 is H, R8 is H, R9 is H, n is 1, y is 0 and z is 0.
A further embodiment of the present invention is a compound of general Formula (IA) or (IB) , or a pharmaceutically acceptable salt or prodrug thereof
(IA)
OH
(IB)
where Alk represents C1-4 alkyl;
R2 is H, CH20H, OH, halide or C02C1-4 alkyl;
R5 and R6 are selected from the group consisting of H, halide, NH2, N (C1-4alkyl) 2, NH (C1-4alkyl) and N02, with the proviso that at least one of R5 and R6 is NH2 , N (C1-4alkyl) 2, NH (C1-4alkyl) and N02 and that compounds of Formulae (IA) and (IB) do not include within their scope compounds of Formula (I) where both R5 and R6 are N02/ when R1 and R2 together are =0, R3 is H, R4 is OH, R7 is H, R8 is H, R9 is H, n is 1, y is 0 and z is 0 ;
R7 is H, or halide when R5 is halide; and
each of R8 and R9 is H or halide.
The present invention further provides a compound of general Formula (IC) or a pharmaceutically acceptable salt or prodrug thereof ,
(IC)
where
Ra is selected from the group consisting of N02, NH2, NH(C1.4alkyl) and N (C1-4alkyl) 2;
Rb is selected from the group consisting of H, halide and N02 and b is 1 or 2;
X can be selected from the group consisting of
-C(RC) (Rd)C(Re) (Rf) -,
-C(Rc) (Rd) (CH2)dC(Re) (Rf)-,
-C(RC) (Rd) (CH2)dC(Re) (Rf)N(Rg)- and -C(RC) (Rd) (CH2)dN(Rg)C(Re) (Rf)-; wherein Rc and Rd can be independently selected from the group consisting of H, halide, OH, CH2OH and
C02C1-4alkyl ; or
Rc and Rd together represent =0 or ethylenedioxy; Re and Rf can be selected from the group consisting of H, OH and OC02Rh, where Rh represents (diaryl) alkyl ; or
Re and Rf together represent =0 or ethylenedioxy;
Rg is H or C1-4alkyl; and d is an integer selected from 1 to 4; or
X can represent a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by
=0, with the proviso that in the case of following Formula (IC)
(IC)
Ra and Rb do not both represent N02 when X represents
-CH(OH)CH2C(=0) -.
Suitably, a compound of general Formula (IC) is selected from the following:
(IC)
(IC) wherein
Ra, Rb and X are as hereinbefore described in relation to a compound of general Formula (IC) .
Suitably, Ra is selected from the group consisting of N02, NH2 and N(CH3)2.
Suitably, Rb is selected from the group consisting of H, Br, Cl and N02.
In a first preferred embodiment of the present invention, there is provided compounds of general Formula (IC) , where X is selected from the group consisting of
-C(RC) (Rd)C(Re) (Rf) - , -C(RC) (Rd) (CH2)dC(Re) (Rf) - , -C(RC) (Rd) (CH2)dC(Re) (Rf)N(Rg)- and -C(RC) (Ra) (CH2)dN(Rg)C(Re) (Rf) - , wherein Rc, Rd, Re, Rf , Rg and d are as hereinbefore disclosed in relation to compounds of general Formula (IC) .
Typically, X may be selected from the group consisting of -CH2CH(OH)-, -C(=0)C(=0) -, C (halide) 2C (=0) -, -CH2C (ethylenedioxy) -, -CH2CH (OC02Rh) - where Rh is as hereinbefore disclosed in relation to compounds of general Formula (IC) , -CH(0H)CH2-, -C (ethylenedioxy) CH2- and -C (=0) CH (OH) - . X is preferably selected from the group consisting of -CH2CH(OH)-, -C (=0) C (=0) - , -C (Br) 2C (=0) - , -CH2C (ethylenedioxy) -, -CH2CH [OCC CHRiR-,] - where R, is 2, 4-dichlorophenyl and R3 is 4-nitrobenzyl , -CH(0H)CH2- , -C (ethylenedioxy) CH2- and -C (=0) CH (OH) - .
Alternatively, X may represent -CH (C02C1-4alkyl) (CH2) dC (=0) - , wherein d is as hereinbefore disclosed in relation to compounds of general Formula (IC) . X is preferably -CH(C02Me)CH2C(=0) -.
Alternatively, X may represent -CH (CH20H) (CH2) dCH (OH) - , wherein d is as hereinbefore disclosed in relation to compounds of general Formula (IC) . X is preferably -CH (CH20H) CH2CH (OH) - .
Alternatively, X may represent-CH (C02C1_4alkyl) (CH2) dC (=0) NH- , wherein d is as hereinbefore disclosed in relation to compounds of general Formula (IC) . X is preferably
-CH (C02Me) CH2C (=0) NH- .
Alternatively, X may represent-CH (C02C1_4alkyl) (CH2) dNHC (=0) - , wherein d is as hereinbefore disclosed in relation to compounds of general Formula (IC) . X is preferably -CH (C02Me) CH2NHC (=0) - .
In a second preferred embodiment of the present invention, there is provided compounds of general Formula (IC), where X represents a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =0. X preferably represents a 5 membered heterocyclic ring containing an oxygen or nitrogen heteroatom, which ring is substituted by =0. It is most preferred that the heterocyclic ring is either tetrahydrofuran or pyrrolidine.
According to the present invention, there is further provided one or more of the following compounds:
1- (2 , 4 -Dichlorophenyl) -2- (4-nitrophenyl) -1-ethanol;
1- (2 , 4 -Dichlorophenyl) -2- (4-nitrophenyl) -1, 2 -ethandione;
2 , 2-Dibromo-l- (2 , 4 -dichlorophenyl ) -2- (4-nitrophenyl) -1- ethanone ; 1- (2 , 4 -Dichlorophenyl) -1 , 1-ethylenedioxy-2- (4-nitrophenyl) ethane ;
Di ( 1 - (2,4 -dichlorophenyl ) - 2 - (4 -nitrophenyl ) ethyl ) carbonate;
2- (2, -Dichlorophenyl) -1- (4-nitrophenyl) -1-ethanol; 2- (2,4-Dichlorophenyl) -1, 1-ethylenedioxy-l- ( 4 - nitrophenyl ) ethane ;
2- (2, 4-Dichlorophenyl) -1- (4-dimethylaminophenyl) -2-hydroxy-
1-ethanone;
1- (2,4 -Dichlorophenyl) -2- (4-dimethylaminophenyl) -1,2- ethandione;
2- (4-Aminophenyl) -1- (2, 4-dichlorophenyl) -1 , 2 -ethandione;
Methyl 2- (4-nitrophenyl) -4-oxo-4-phenylbutanoate;
Methyl 4- (4 -bromophenyl) -2- (4-nitrophenyl) -4 -oxobutanoate ;
Methyl 4- (2 -chlorophenyl) -2- (4-nitrophenyl) -4 -oxobutanoate;
Methyl 4- (3 -chlorophenyl) -2- (4-nitrophenyl) -4 -oxobutanoate,■
Methyl 4- (4 -chlorophenyl) -2- (4-nitrophenyl) -4 -oxobutanoate;
Methyl 4- (2 , 4 -dichlorophenyl ) -2- (4-nitrophenyl) -4- oxobutanoate ;
Methyl 4- (3 , 4 -dichlorophenyl ) -2- (4-nitrophenyl) -4- oxobutanoate ;
Methyl 4- (4-nitrophenyl) -2- (4-nitrophenyl) -4 -oxobutanoate;
3- (4-Nitrophenyl) -1-phenyl-l, 4-butanediol;
1- (4 -bromophenyl) -3- (4-nitrophenyl) -1 , 4-butanediol ;
1- (2 -chlorophenyl) -3- (4-nitrophenyl) -1 , 4-butanediol ,
1- (3 -chlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol, 1- (4 -chlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol
1- (2 , 4 -dichlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol ;
1- (3 , 4 -dichlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol ;
1- (4-nitrophenyl) -3- (4-nitrophenyl) -1, 4-butanediol;
3- (4-nitrophenyl) -5-phenyltetrahydro-2-furanone ; 5- (4 -Bromophenyl) -3- (4-nitrophenyl) tetrahydro-2-furanone ;
5- (2 , 4 -dichlorophenyl) -3 - (4-nitrophenyl) tetrahydro-2 - furanone ;
5- (2 ,4 -dichlorophenyl) -3- (4-aminophenyl) -2-pyrrolidinone;
Methyl 4- (2 , 4-dichlorophenylamino) -4-oxo-2- (4-nitrophenyl) but noate; or
Methyl 3- (2 , 4 -dichlorophenyloxoamino) -2- (4-nitrophenyl)
propanoate .
There is further provided by the present invention, methods of preparing compounds of Formula (I) .
According to a first preferred method according to the present invention, compounds of Formula (I) can be prepared following reaction of a known substituted benzaldehyde derivative of Formula (II)
(H)
with any of compounds of Formulae (III) , (IV) or (V)
(HI)
(IV)
(V)
where in the resulting compounds of Formula (I) each of n, y and z is 0.
In compounds of Formula (III) substantially as hereinbefore described Y can represent hydrogen or another suitable group, whereby compounds of Formula (III) can react with either the aldehyde moiety of benzaldehyde derivatives of Formula (II) in a first preferred method according to the present invention or the phenyl ring substituent X-CH2-C (R3) (R4) - of compounds of Formula (VII) in a second preferred method according to the present invention substantially as hereinafter described.
Benzaldehyde derivatives of Formula (II) are generally known compounds. Compounds of Formula (III) can also be known compounds or may be prepared from compounds of
Formula (IX) substantially as hereinafter described in a second preferred method according to the present invention.
Benzaldehyde derivatives of Formula (II) are typically reacted with compounds of Formula (III) , in a first preferred method according to the present invention, in the
presence of an alkali metal hydroxide and an inert solvent, such as dimethylformanide or the like, to yield compounds of Formula (I) according to the present invention.
In compounds of Formula (IV) , Het suitably represents a heterocyclic moiety and X a suitable leaving group, typically a halide (bromide, chloride, fluoride or iodide) or the like. Compounds of Formula (I) are typically obtained from compounds of Formula (IV) via a number of intermediates following reaction of compounds of Formula (II) and (IV) (substantially as hereinafter described in greater detail in the accompanying Examples) , suitably by elimination followed by reduction or reaction with an alkylene glycol or the like.
Compounds of Formula (IV) can suitably be obtained from reaction of a heterocyclic group with known benzyl derivatives of Formula (VI)
(VI)
where X is a leaving group substantially as hereinbefore described with reference to Formula (IV) . Typically the reaction is carried out in the presence of an inert solvent, at a temperature below about 30°C.
In benzaldehyde derivatives of Formula (V) , R5a can either represent R5 substantially as hereinbefore described with reference to Formula (I) or a precursor thereof that can readily be converted to R5. For example, R5a can represent CH3CONH that can be converted to NH2-, suitably by reflux under acidic conditions followed by addition of a base, such as an alkali metal hydroxide, to release the free amine .
Coupling of benzaldehyde derivatives of Formulae (II) and
(V) is typically carried out under reflux in the presence of an alkali metal cyanide (e.g. potassium cyanide) and an alcohol (e.g. ethanol) . Initially a diphenyl intermediate having a -C (=0) -CH (OH) - linker between the substituted end phenyl rings can be formed and this can subsequently be converted into a compound of Formula (I) having a dicarbonyl linker -C (=0) - (C=0) - between the phenyl rings.
Benzaldehyde derivatives of Formula (V) are generally known compounds.
According to a second preferred method according to the present invention, compounds of Formula (I) can be prepared by reaction of a compound of Formula (III) substantially as hereinbefore described and a compound of Formula (VII)
(Nil)
where in the resulting compounds of Formula (I) , n is 1 and each of y and z is 0. Substantially as hereinbefore described, X is a suitable leaving group, such as a halide (bromide, chloride, fluoride or iodide) or the like. Compounds of Formula (III) and (VII) are typically reacted under reflux, with stirring, in the presence of an anhydrous solvent, such as an alkali metal (typically potassium) carbonate or the like.
Compounds of Formula (VII) can be obtained from known acetophenone derivatives of Formula (VIII)
(Nm)
typically by halogenation where X in Formula (VII) represents halide substantially as hereinbefore described, suitably in the presence of a catalyst, such as aluminium chloride or the like.
Compounds of Formula (III) where R1 or R2 represents -C02Alk substantially as hereinbefore described with reference to Formula (I) can be prepared from known phenyl acetic acid derivatives of Formula (IX)
(IX)
whereby the carboxylic acid group of compounds of Formula (IX) can be converted into the corresponding ester group
- C02Alk represented by R1 in Formula (I) . Compounds of
Formula (III) are typically obtained from compounds of
Formula (IX) by reaction of the latter with an alkylating agent, such as a trialkyl orthoformate or the like, in the presence of a catalytic amount of a mineral acid, such as hydrochloric acid or the like.
Compounds of Formula (I) obtained by a second preferred method according to the present invention can typically form a subgroup of compounds according to the present invention that can suitably be represented by Formula (IA) substantially as hereinbefore described.
Compounds of Formula (I) substantially as hereinbefore described obtained by a method according to the present invention can be converted into further compounds of Formula (I) by suitable interconversion techniques. For example, compounds of Formula (I) where R1 represents C02Alk can be converted into corresponding alcohol derivatives where R1 can represent -CH2OH, employing suitable reducing conditions, such as reaction in the
presence of a reducing agent, typically a borohydride (for example, sodium borohydride) or the like. Alternatively, compounds of Formula (I) can be subjected to oxidative conditions, for example where the moiety -CH(OH)- [represented by either -C(R1) (R2) - or C(R3) (R4) - in Formula
(I) ] can be oxidised, suitably to yield corresponding carbonyl , carbonate or alkylenedioxy derivatives as allowed by Formula (I) . In a further interconversion reaction, compounds of Formula (I) where R3 and R4 together represent =0 and both y and z are 0 can be converted via an imino intermediate into further compounds of Formula (I) , for example compounds where R1 and R3 together represent
0
II - C - NH - substantially as hereinbefore described and y and z are both 0 , or compounds where R3 and R4 together represent =0 and either y or z is 1.
It will of course be appreciated that compounds of Formula
(IC) substantially as hereinbefore described can be prepared by techniques substantially as hereinbefore described for compounds of Formula (I) . More particularly, therefore, processes of preparing compounds of Formula (I) substantially as hereinbefore described are also provided by the present invention for the preparation of compounds of Formula (IC) . The following processes giving specific reference to Formula (IC) are, therefore, essentially as described for compounds of Formula (I) and the further details and preferences substantially as hereinbefore
described for the preparation of compounds of Formula (I) are similarly applicable for the preparation of compounds of Formula (IC) substantially as hereinafter described.
There is, therefore, further provided by the present invention a process of preparing a compound of Formula (IC) according to the first embodiment of the present invention substantially as hereinbefore described, which process comprises reacting a substituted benzaldehyde derivative of Formula (X)
(X)
with any one of compounds of Formulae (XIa) , (Xlb) and (XIc)
(XIc)
where Y in Formula (XIa) is hydrogen or a group reactive with the aldehyde moiety of benzaldehyde derivatives of Formula (X) ;
in Formula (Xlb) Het is a heterocyclic moiety and X is a leaving group;
Ra, Rb, Rc and Rd are as hereinbefore described in relation to a compound of general Formula (IC) ; and
Ral represents Ra or a precursor thereof that can readily be converted to Ra.
There is further provided by the present invention, a process of preparing a compound of Formula (IC) according to the first embodiment of the present invention, wherein a compound of Formula (XIa) is reacted with a compound of Formula (XII)
X-
(XTJ)
where in Formula (XIa) Y is hydrogen or a group reactive with the phenyl ring substituent
X-CH2-C(Re) (Rf) - of a compound of Formula (XII);
in Formula (XII) X is a leaving group; and
Ra, Rb, Rc, Rd, Re, Rf/ b and d are as hereinbefore described in relation to a compound of general Formula (IC) .
Compounds of Formula (IC) according to the second embodiment of the present invention where X represents a 5 or 6 membered heterocyclic ring substantially as hereinbefore described can be prepared by interconversion techniques substantially as hereinbefore described with reference to compounds of Formula (I) .
The present invention further includes within its scope prodrugs of compounds of Formula (I) and in general such prodrugs will be functional derivatives of compounds of Formula (I) which are readily convertible in vivo into the required compound. Conventional procedures for selection and preparation of suitable prodrug derivatives are well known in the art .
Compounds according to the present invention are inhibitors of retinoic acid metabolism substantially as hereinbefore described and are, therefore, useful as therapeutic agents for potentiating the action of endogenous retinoic acid. The compounds according to the invention generally have low activity against other P450 enzymes involved in cortisol production, which is indicative of low toxicity on oral dosing or should systemic absorption occur. For example, compounds according to the present invention are useful as therapeutic agents for treating disease states ameliorated by the presence of retinoic acid, such as skin diseases, (including actinic keratoses, nonmelanoma skin cancer, acne vulgaris, psoriasis, orders of keratinisation and the like,
substantially as hereinbefore described) , oncogenic conditions (including oral leukoplakia, head and neck cancer and the like, substantially as hereinbefore described) and other disease states that can be associated with a lack of retinoic acid. The term "treatment" as used herein includes both the amelioration of the symptoms of an established disease state and the prophylaxis of such a disease state.
According to a further aspect of the present invention there is provided a compound of Formula (I) substantially as herein before described, for use in therapy. More particularly, there is further provided by the present invention a compound of Formula (I) substantially as hereinbefore described, for use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, substantially as herein before described.
While it is possible for compounds according to the present invention to be administered as the substantially pure chemicals, it is preferable that such compounds are included in pharmaceutical Formulations. There is, therefore, still further provided by the present invention a pharmaceutical Formulation comprising a compound of Formula (I) , substantially as herein before described, together with at least one acceptable carrier, diluent or excipient therefor. The carriers must be "acceptable" in the sense of being compatible with the other ingredients of the Formulation and not deleterious to a recipient thereof.
Formulations according to the present invention include
those suitable for oral, parenteral and topical administration, although the most suitable route will generally depend upon the condition of a patient and the specific disease state being treated. The precise amount of a compound of Formula (I) to be administered to a patient will be the responsibility of an attendant physician, although the dose employed will depend upon a number of factors, including the age and sex of the patient, the specific disease state being treated and the route of administration substantially as described above.
Finally, there is further provided by the present invention a method of treating a disease state ameliorated by the presence of retinoic acid substantially as hereinbefore described which method comprises administering to a patient suffering from or susceptible to a such disease a therapeutically effective amount of a compound of Formula (I), or a prodrug thereof.
The following Table 1 lists exemplary compounds according to the present invention, together with their respective values for inhibition of retinoic acid metabolism
(according to the protocol described herein under the heading "In vitro inhibition studies") . This shows that the compounds according to the invention have potency comparable to that of ketoconazole:
Table 1. Inhibition of P450-RA
Example Number % Inhibition (lOOμM)
Example Number % Inhibition (lOOμM)
31 51 4
32 59 3
Example Number % Inhibition (lOOμM)
Ketoconazole 85
The present invention will now be further illustrated by the following intermediates and examples and exemplary methods for the preparation of compounds according to the present invention, and their biological screening, will, therefore, now be described. Primes on aromatic substituents as used in the following intermediates and examples are for the purposes of identifying the relevant peaks in the NMR spectra. The following intermediates and examples do not limit the scope of the invention in any way.
Intermediate 1
1- (2 , 4 -Dichlorophenyl) -2- (4 ' nitrophenyl) -1-ethanone
The title compound of Example 1 (4.6 g; 0.015 mol.) in dry dichloromethane (40 ml) was added to a suspension of pyridinium chlorochromate (6.5 g; 0.03 mol.) in dichloromethane (40 ml) , after which the solution turned dark brown. After 1.5 hours stirring at room temperature, with the reaction followed by TLC, diethyl ether (40 ml) was added and the supernatant liquid was decanted from a black gum. The insoluble residue was washed with diethyl ether and the combined (decolourised) organic solution filtered through Celite (Trade Mark) and the solvent removed under vacuum. The solid residue was dissolved in chloroform, and insoluble unreacted title compound of Example 1 removed by filtration. The chloroform solution was evaporated under vacuum to give a crude cream solid, which yielded upon crystallization (ethanol) Intermediate 1 (4.2 g; 90.3%) as crystalline material. Further crystallization furnished Intermediate 1 as fine colourless needles, m.p. 101°C. Found: C, 54.27; H, 3.04; N, 4.53.
C14H9C12N03 requires C, 54.22; H, 2.93; N, 4.52%. v m,ax
(KBrJ/cπr1 1719 (C = 0) , 1515 and 1348 (N02) . δH (300 MHz; CDC13) 4.40 (2H, s, CH2) , 7.31 (1H, dd, J = 1.7 Hz, J = 8.3 Hz, Ar C(5))H) , 7.40 (2H, ά, J = 9.3 Hz, Ar C(2')H and C(6')H) , 7.45 (2H, m, Ar C (3 ) H and C6) H) , 8.19 (2H, d, J = 9 Hz, Ar C(3') (H) and C(5')H) .
Intermediate 2
2-Bromo-l- (2 , 4 -dichlorophenyl) -2- (4 ' -nitrophenyl) -1- ethanone
Phenyltrimethylammonium tribromide (3.76 g; 0.01 mol.) was added in small portions to a solution of Intermediate 1 (3.12 g; 0.01 mol.) in tetrahydrofuran (20 ml), with stirring. After 30 minutes the resultant white precipitate (phenyltrimethylammonium bromide) was removed by filtration. The filtrate was concentrated in vacuo and the yellow residue dissolved in chloroform and washed with water, dried (MgS04) and evaporated to leave a yellow oil, which solidified on standing. Crystallization (ethanol) gave Intermediate 2 (3.34 g; 86%), as cream crystals, m.p. 89-90°C. Found: C, 43.01; H, 1.99; N, 3.49. C14H8BrCl2N03 requires C, 43.22; H, 2.07; N, 3.60%. nmax (KBr) /cm'1 1708 (C = O) , 1520 and 1345 (N02) . dH (300MHz; CDC13) 6.32 (1H, s, CHBr) , 7.41 (1H, dd, J" = 8.3 Hz, J" = 1.5 Hz, Ar C(5)H) , 7.52 (1H, d, J= 1.7 Hz, Ar (3)H) , 7.53 (1H, d, J" = 8.0 Hz, Ar C(6)H), 7.77 (2H, d, j = 8.7 Hz, Ar C (2')H) and C(6')H), 8.19 (2H, d, J = 8.7 Hz, Ar C(3')H and C(5' )H) .
Intermediate 3
4-Nitrobenzylpyridinium bromide
Pyridine (16.2 ml, 0.2 mol) was added dropwise to a solution of 4-nitrobenzyl bromide (21.6 g, 0.1 mol) in dry dichloromethane (200 ml) with maintenance of the reaction temperature below 30°C. After 30 minutes a heavy white precipitate was formed, and 2 hours later was filtered off, washed with dichloromethane and dried under vacuum to give Intermediate 3 (24 g, 83%) as a dense white solid, m.p. 221-222°C [Lit.m.p., 219-221°C] . A second crop was obtained after standing overnight, to give a total yield of 97%. nmax (KBr) /cm"1 1518 and 1349 (N02) . dH (300 MHz; CDC13) (6.21 (2H, s, CH2) , 7.88 (2H, d, J = 8.9 Hz, Ar C(2)H and C(6)H), 8.2 (2H, d, J = 8.9 Hz, Ar C(3)H and C(5)H), 8.41 (2H, dd, J = 7.3 Hz, J" = 8.0 Hz Pyr C(3")H and C(5")HJ_, 8.7 (1H, t, J" = 8.1 Hz, Pyr C(4")H), 9.4 (2H, ά , J = 7.2 Hz, Pyr C(2")H and C(6")H) .
Intermediate 4
N- [2- (2' , 4 ' -Dichlorophenyl) -1- (4-nitrophenyl) -1-ethenyl] pyridinium bromide
A mixture of Intermediate 3 ( 24.0 g, 0.08 mol.), 2,4- dichlorobenzaldehyde (14.0 g, 0.08 mol), anhydrous potassium acetate (6.4 g) , acetic acid (10 ml), and acetic anhydride (120 ml) was refluxed at 75-80°C for 48 hours, allowed to cool to room temperature, and the excess potassium acetate removed by filtration. The filtrate was diluted with water (100 ml) and allowed to stand at room temperature for 48 hours with stirring. The mixture was
washed with diethyl ether to remove unreacted materials and the aqueous layer acidified with hydrobromic acid (33% in glacial acetic acid), before concentrating. The bright yellow crystals which precipitated from the solution were filtered off, and the mother liquors concentrated to obtain further crops. The crops were combined and recrystallized (ethanol) to yield Intermediate 4 (5.8 g; 16%), as yellow crystals, m.p. > 250°C. nmax {KBr) / -cm~ 1 1514 and 1346 (N02) . dH (300MHz; CDCl3) 6.94 (1H, d, J" = 8.4 Hz, Ar C(6')H]_, 7.31 (1H, dd, J = 8.4 Hz, J = 2.1 Hz, Ar C(5')H), 7.79 (1H, d, J = 2.2 Hz, Ar C(3' )H) , 7.81 (2H, d, J = 8.9 Hz, Ar C(2)H) and C(6)H) , 8.12 (1H, s, =CH-) , 8.32 (2H, d, J = 8.9 Hz, Ar C(3)H) and C(5)H) . 8.34 (2H, t , J = 6.4 Hz, Pyr C(3")H and C(5")H), 8.89 (1H, t, J= 7.9 Hz, Pyr C(4")H), 9.24 (2H, d, J = 5.5 Hz, Pyr C(2")H_ and C(6")H) .
Intermediate 5
2- (2' , 4 ' -Dichlorophenyl) -1- (4-nitrophenyl) -1-ethanone
Intermediate 4 (4.52 g, 0.01 mol.), pyridine (40 ml), piperidine (8 ml) , and water (16 ml) were combined and heated at 80 °C for 1 hour. The resulting deep red solution was cooled, evaporated, and ethanol (14 ml) added to the residue. The resulting mixture was then diluted with water
(40 ml), acidified with hydrobromic acid (50 ml, 33% in glacial acetic acid) and shaken for 2 minutes. The solid material was filtered off and dried. Crystallization
(ethanol) furnished pure Intermediate 5 as white crystals
(2.77 g; 89.3%), m.p. 141-142°C. Found: C, 53.61; H, 2.98;
N, 4.19. C14H9C12N03 requires C, 54.22; H, 2.93; N, 4.52%. n^ (KBrJ/ctrr1 1692 (C = 0), 1520 and 1348 (N02) . dH
(300MHz; CDC13) 4.51 (2H, s, CH2) , 7.26 (1H, d, J = 8.2 Hz,
Ar C(6')H), 7.31 (1H, dd, J = 2.1 Hz, J" = 8.2 Hz, Ar
C(5' )H) , 7.50 (1H, d, J = 2.0 Hz, Ar C(3' )H) , 8.23 (2H, d,
J" = 8.9 Hz, Ar C(2)H and C(6)H]_, 8.40 (2H, d, J = 8.8 Hz, Ar C ( 3 ) H and C ( 5 ) H) .
Intermediate 6
N- (4- (2- (2' ,4' -Dichlorophenyl) -2- hydroxyacetyl)phenyl) acetamide
Potassium cyanide (1 g) dissolved in water (10 ml) was added to a solution of 4-acetylaminobenzaldehyde, (1.63 g; 0.01 mol.) and 2 , 4-dichlorobenzaldehyde (1.76 g, 0.01 mol.) in ethanol (30 ml), and the mixture refluxed for 2 hours. On cooling, the mixture was diluted with water, when an orange oily residue separated. The aqueous phase was decanted off, and the residue dissolved in dichloromethane, washed with water several times, and dried (MgS04) . On evaporating the solvent, a dark orange oil was obtained which on standing gave a yellow solid. Crystallization
(ethanol) gave Intermediate 6 (1.94 g; 57.4%) as a yellow crystalline solid, m.p. 180-181°C. Found C: 56.78; H,
3.88; N 3.97. C16H13C12N03 requires C, 56.82; H, 3.87; N,
4.14%. nmax (KBrJ/cm-1 3352 (OH), 1673 and 1654 (C=0) . dH
(300MHz; DMSO-d 2.11 (3H, s, COCH3) , 6.23 (1H, d, J = 7.0
Hz, CHOH or CHOH), 6.52 (1H, d, J" = 7.0 Hz, CHOH or CHOH), 7.45 (1H, dd, J = 8.4 Hz, J = 1.1 Hz, Ar C(5' )H) , 7.52 (1H, d, J = 8.4 Hz, Ar C(6')H) , 7.59 (1H, d, J = 1.7 (Ar C(3' )H) , 7.71 (2H, d, J = 8.5 Hz, Ar C(3)H and C(5)HJ_, 7.97 (2H, d, J = 8.4 Hz, Ar C(2)H and C(6)H) , 10.38 (1H, s, NH) , m/e (APCI, low resolution) 162 and 163 (CH3CONHC6H4CO+) 175
and 177 ( C6H3C12CH0H+ ) .
Intermediate 7
N- (4- (2- (2 ' .4 ' -Dichlorophenyl) -2 -oxoacetyl) phenyl) acetamide
Copper sulphate (1.5 g) , pyridine (3 ml) and water (1 ml) were heated for 10 minutes, until a homogeneous solution was obtained, when Intermediate 6 (0.84 g; 0.0025 mol.) was added and the mixture heated at 100°C for 2 hours with stirring. On pouring onto water a yellow oil separated which was extracted with dichloromethane, which was washed with HCl (2M) and water. After drying (MgS04) , the solvent was removed in vacuo to give a yellow powder. Crystallization (ethanol) gave Intermediate 7 (0.44 g; 52.4%) as fine yellow crystals, m.p. 177°C. Found C: 57.20; H, 3.44; N 4.01. C16H11C12N03 requires C, 57.17; H,
3.30; N, 4.17%. nmax (KBr) cm"1 1681 and 1661 (C=0) . dH
(300MHz; DMSO-dg) 2.13 (3H, s, COCH3) , 7.69 (1H, dd, J= 8.4
Hz, J = 1.8 Hz, Ar C(5')H), 7.82 (2H, d, J = 8.4 Hz, Ar
C(3) H and C(5)H), 7.87 (1H, d, J = 1.6 Hz, Ar C(3')H), 7.92 (1H, d, J = 8.6 Hz, Ar C(6')Hj_,7.96 (2H, d, J = 8.3 Hz, Ar C(2)H and C(6)H), 10.49 (1H, s, NH) .
Intermediate 8
Methyl 4-nitrophenyl acetate
A solution of 4-nitrophenyl acetic acid (5.03 g, 27.7 mmol) in methanol (200 cm3) , was refluxed with trimethyl orthoformate (10 cm3, 9.7 g) and a catalytic amount of concentrated hydrochloric acid (1 cm3) for 3 hours. The reaction mixture was left to cool, and the methanol removed
under vacuum. The residue was taken up in ethyl acetate
(70 cm3), and washed with saturated sodium bicarbonate (50 cm3) and then water (3 x 50 cm3) . The organic layer was dried (MgS04) and evaporated to give cream coloured crystals of Intermediate 8 (5.30 g, 98%). M.P. = 52.7-53.8°C.
(Found: C, 55.48; H, 4.73; N, 6.86. C9H9N04 calculated C,
55.38; H, 4.65; N, 7.18%). n^ KBr/cπr1 1724 (C02CH3) , 1512 and 1339 (N02) ; dH 8.1 (2H, d, J 8.8 Hz Ph-H), 7.4 (2H, d,
J 8.1 Hz Ph-H), 3.75 (2H, s, CH2) , 3.65 (3H, s, OCH3) .
Intermediate 9
2 -Bromo-1-phenyl-l-ethanone
A catalytic amount of aluminium chloride (O.lg) was added to a solution of acetophenone (lg, 8.3 mmol) in ether (50 cm3), and stirred at 0°C. Bromine (1.33g, 8.3 mmol, 0.41 cm3) was added dropwise to the solution over a period of 20 minutes and the solution stirred for a further 30 minutes. The reaction mixture was then quenched with water (10 cm3) and stirred for 10 minutes. The water was separated from the ether and the organic layer dried (MgS04) , filtered and evaporated to give Intermediate 9 as white crystals. Recrystallised (methanol) (1.33g, 81%). M.P. 46.5-48.7°C. nmax KBr/cm"11701.4 (C=0) ; dH 8.05 (2H, d, J = 7 , 1 Hz Ph.H), 7.66 (1H, dt, J=7.4 J = Hz = 1.1 Ph-H), 7.55 (2H, t, J=7.3 Hz, PhH) , 4.52 (2H, s, CH2) .
Intermediate 10
2-Bromo-l- (2 -chlorophenyl) -1-ethanone
A dark red oil was obtained with 2 -Chloroacetophenone . Purification by column chromatography on silica gel gave Intermediate 10 as a yellow oil, (62%) . Rf = 0.62 (dichloromethane :petroleum ether 4:1 v/v) . n^/crrr1 1700.3 (C=0) ; dH 7.66 (1H, m, Ph-H), 7.55 (2H, m, Ph-H), 7.46 (1H, m, Ph-H), 4.62 (2H, s, CH2) .
Intermediate 11
2-Bromo-l- (3 -chlorophenyl) -1-ethanone
Intermediate 11 (68%) was obtained as a yellow solid with 3 -chloroacetophenone. M.P. 35.6-37°C. nmax KBr /cm11686.9 (C=0) ; dH 8.00 (1H, t, J=l .8 Hz Ph-H), 7.89 (1H, dt , J=l .3 Hz, J=7.9 Hz, Ph-H), 7.62 (1H, dq, J=l .1 Hz, J=2.1 Hz, J=7.9, Ph-H), 7.47 (1H, t, J=7.9 Hz, Ph-H), 4.46 (2H, s, CH2) .
Intermediate 12
2-Bromo-l- (4-chlorophenyl) -1-ethanone
Intermediate 12 was obtained from 4-chloroacetophenone and on recrystallisation (ether) gave white crystals (71%) . M.P. 93.7-94.2°C. nmax KBr/crrr1 1685.0 (C=0) ; dH 7.98 (2H, d, J=8.6 Hz, Ph-H), 7.52 (2H, d, J=8.6 Hz, PhH) , 4.46 (2H, s, CH2) .
Intermediate 13
2-Bromo-l- (2 , 4 -dichlorophenyl) -1-ethanone
Intermediate 13 was obtained from 2 , 4-dichloroacetophenone and on purification by column chromatography on silica with dichloromethane: petroleum ether (4:1 v:v) as eluent gave a clear oil (82%). Rf = 0.62. (Found: C, 35.92; H, 1.93.
C18H5BrCl20 requires C, 35.86; H, 1.88%) ; nmax KBr/crrr1 1695.8
(C=0) ; dH 7.59 (1H, d, J=8 Hz, Ph-H) , 7.49 (1H, d, J=l .8
Hz, Ph-H) , 7.38 (1H, dd, J=8.3 Hz, J=1.8 Hz , Ph-H) , 4.55 (2H, s, CH2) .
Intermediate 14
2-Bromo-l- (3 , 4 -dichlorophenyl) -1-ethanone
Intermediate 14 was obtained from 3 , 4-dichloroacetophenone and on recrystallisation (ether) gave green crystals (75%) . M.P. 51.7-52.6°C. nmax KBr/crrr1 1687.1 (C=0) ; dH 8.10 (1H, d, J=2.03, Hz Ph-H), 7.85 (1H, dd, J=2.02, Hz, J=8.42 Hz Ph- H) , 7.64 (1H, d, J=8.38 Hz, Ph-H), 4.44 (2H, s, CH2) .
Intermediate 15
Methyl 4 - (2,4 -dichlorophenyl) -4 -hydroxyimino-2 - (4 - nitrophenyl) butanoate
A mixture of Example 16 (2.02 g, 5.09mmol) and ethanol
(50cm3) , and a mixture of hydroxylamine hydrochloride (1.53g, 22mmol) and sodium acetate (1.80g, 22mmol) in water
(50 cm3) were combined and refluxed with stirring for 6 hours. The reaction mixture was left to cool, and then poured into ice water mixture (50 cm3) and left in the
fridge overnight. A waxy green sold formed, and the water/ethanol mixture was decanted. The remaining slush was taken up in ethyl acetate (50 cm3) , dried (MgS04) and concentrated to leave a brown oil (1.23g, 61%) . Purified by preparative TLC with CH2Cl2:MeOH (19:1) as eluent to yield Intermediate 15. (Found: C, 51.65; H, 3.67; N, 6.88. C17H14C12N205 requires C, 51.40; H, 3.55; N, 7.05%); Vmax KBr disc/cm"1 3354 (OH) , 1737 (C02CH3) , 1522 and 1347 (N02) .
Example 1
1- (2 , 4-Dichlorophenyl) -2 - (4 ' -nitrophenyl) - 1-ethanol
Freshly ground sodium hydroxide (0.2 g) was added to a solution of 4-nitrotoluene (20.57 g; 0.15 mol.) and 2,4- dichlorobenzaldehyde (8.75 g; 0.05 mol.) in dry N, N- dimethylformamide (100 ml), and the reaction stirred under nitrogen at room temperature. The reaction mixture turned dark green within several minutes . After 2 hours the reaction mixture was acidified with concentrated hydrochloric acid (1 ml) , diluted with toluene and washed with water. After drying (MgS04) , both solvent and excess 4-nitrotoluene (90°C/0.25 mmHg) were removed in vacuo, to yield a red oil which solidified on standing to give a yellow solid. The solid was recrystallized (ethanol) to give the title compound of Example 1 (9.3 g; 59.6% yield) as colourless crystals, m.p. 154°C; Found: C, 53.91; H, 3.56;
N, 4.26, C14H1:LC12N03 requires C, 53.87; H, 3.55; N, 4.49%. nmax
(KBrJ/cm-1 3548 (OH) , 1514 and 1343 (N02) . dH (300MHz; DMSO- d6) 2.90 (1H, dd, Jω 13.5 Hz, J" XB = 8.1 Hz, CHAHBCH^H) , 3.06 (1H, dd, -JBA = 13.5 Hz, J^ = 3.8 Hz, C fβBCΗ.xOΗ.) , 5.15 (1H, ddd, " BX = 8.2 Hz, J" M = 3.8 Hz, J = 4.7 Hz, CHχOH) , 5.75 (1H, d, J" = 4.7, CHOH) , 7.46 (3H, m, Ar C(3)H, C(5)H and C(6)H) , 7.7 (2H, d, J = 8.7 Hz, Ar C(2')H and C(6' )H) , 8.2 (2H, d, J = 8.7 Hz, Ar C ( 3 ' ) H and C (5 ' ) H) .
Chiral chromatography: tr 9.32 min (49.4%), 10.73 min (49.8%) .
Column: Chiralpak AD (4.6 x 250 mm, Diacel Chemical Ltd) Mobile phase: propan-2-ol: hexane (50 : 50 v/v) . Flow rat 2 l/min. Detection: UN at 254 nm.
Example 2a
1- (2 , 4 -Dichlorophenyl) -2- (4' -nitrophenyl) -1, 2 -ethandione
The title compound of Example 2a was isolated as yellow crystals (ethanol) , following oxidation of the title compound of Example 1 when the reaction proceeded beyond 1.5 hours, m.p. 133-134°C. Found: C, 51.86; H, 2.09; Ν,
4.19. C14H7C12Ν04 requires C, 51.88; H, 2.18; N, 4.32%. nmax
(KBr) /cm"1 1681 (C = 0, a-diketone) , 1529 and 1347 (N02) . dH
(300 MHz; CDCl3) 7.43 (1H, dd, J = 1.7 Hz, J = 8.8 Hz, Ar
C(5)H) , 7.44 (1H, d, J" = 1.8Hz, Ar C(3)H) , 7.82 (1H, d, J = 8.8 Hz, Ar C(6)H), 8.17 (2H, d, J = 8.9 Hz, Ar C(2')H and C(6' )H) , 8.36 (2H, d, J = 8.9 Hz, Ar C(3' )H and C(5')H) .
Example 2b
1- (2 ,4 -Dichlorophenyl) -2- (4'nitrophenyl) -1, 2 -ethandione
Cone, nitric acid (30 ml, S.G. 1.42) was poured onto the title compound of Example 1 (5 g; 0.016 mol.) in a round- bottomed flask fitted with an air condenser. The reaction mixture was heated on a boiling water bath for 2.5 hours until the evolution of brown fumes of nitric oxide ceased, whereupon the solution was poured onto ice and stirred. The
resulting gum obtained after decantation, gave yellow crystals after crystallization (ethanol) , of the title compound of Example 2b (2.90 g, 55.9%), m.p. 132-134°C, with analytical data as shown in Example 2a and a mixed m.p. 132-134°C.
Example 3
2 , 2-Dibromo-l- (2 , 4 -dichlorophenyl) -2- ( 4 ' -nitrophenyl) -1- ethanone
Bromine (0.12 ml; 0.0025 mol.) was added to a solution of Intermediate 1 (0.75 g; 0.0025 mol.) and aluminium chloride (0.01 g) in diethyl ether (20 ml), with stirring in an ice- bath. After 30 minutes the colourless solution was extracted with water, and the organic phase dried (MgS04) and the solvent removed under vacuum to leave a yellow oil which solidified on standing. Crystallization (ethanol) gave bright yellow crystals of the title compound of Example 3 (0.89 g; 76.1%), m.p. 126-127°C. Found: C, 35.62; H, 1.70; N, 3.01. C14H7Br2Cl2N03 requires C, 35.94; H, 1.51; N, 2.99%. nmax (KBr) /cm"1 1681 (C = 0), 1529 and 1347 (N02) . dH (300MHz; CDCl3) 7.51 (2H, m, Ar C(3)H and C(5)H), 7.92 (1H, d, J = 8.8 Hz, Ar C(6)H) , 8.24 (2H, d, J" = 8.7 Hz, Ar C(2' )H and C(6')H, 8.42 (2H, d, J = 8.7 Hz, Ar C(3')H and C(5' )H) .
Example 4
1- (2 , 4-Dichlorophenyl) -1, l-ethylenedioxy-2- (4 ' -nitrophenyl) ethane
A mixture of ethylene glycol (10 ml) and p-toluene sulphonic acid (0.4 g) was refluxed in toluene (80 ml) with a Dean- Stark trap until evolution of water ceased (24hours) . Intermediate 1 (1.55 g; 0.005 mol.) was added to the reaction mixture and refluxing continued for a further 24hours. On cooling the reaction mixture was evaporated removing toulene, and the residue cooled in an ice-bath. The resulting precipitate was filtered to give, following crystallization (ethanol) , the title compound of Example 4 (0.46 g; 26.0%) as pale yellow crystals, m.p. 117-118°C. Found: C, 54.33; H, 3.78; N, 3.92. C16H13C12N04 requires C, 54.26; H, 3.70; N, 3.95%. nmax (KBr) /cm"1 1584 (C = C) , 1514 and 1342 (N02) . dH (300MHz; CDC13) 3.55 (2H, s, CH2) , 3.81
(2H, m, CH2 ketal) , 3.86 (2H, m, CH2 ketal) , 7.21 (1H, dd,
J = 8.4 Hz, J = 2.1 Hz, Ar C(5)H), 7.42 (2H, d, J" = 8.6 Hz,
Ar C(2')H and C(6')H), 7.43 (1H, d, J" = 8.4 Hz, Ar C(6)H, 7.49 (1H, d, J = 2.1 Hz, Ar C(3)H) , 8.13 (2H, d, J = 8.6 Hz, Ar C(3' )H and C(5' )H) .
Example 5
Di (1- (2, 4-dichlorophenyl) -2- {4 ' -nitrophenyl) ethyl) carbonate
A solution of the title compound of Example 1 (1.56 g; 0.005 mol.) and 1 , 1' -carbonyl diimidazole (3.24 g,- 0.01 mol.) in
anhydrous acetonitrile (50 ml) was stirred at room temperature for 6 hours, then concentrated to a small volume and the residue redissolved in dichloromethane. The organic phase was washed with brine, dried (MgS04) and evaporated to give, following recrystallization (ethanol), the title compound of Example 5 (3.01 g; 92.6%) as pale yellow crystals, m.p. 119°C. Found: C, 53.34; H, 3.36; N, 4.33 C29H20Cl4N2O7 requires C, 53.56; H, 3.10; N, 4.31%. nmax (KBr) /cm"1 1754 (C =0, carbonate), 1520 and 1344 (N02) . dH (300MHz; CDC13) 3.34 (4H, t, J = 7Hz, 2 xCH2CH) , 6.29 (2H, dd, J = 1 . 1 Hz, J = 5.3 Hz, 2 x CH2CH) , 7.37 (2H, dd, J" = 1.4 Hz, J" = 8.8 Hz, 2 x Ar C(5)H) , 7.42 (2H, d, J = 8.8 Hz, 2 x Ar C(6)H), 7.45 (4H, d, J = 8.5 Hz, 2 x Ar C(2')H and C(6')H_L, 7.52 (2H, d, J = 1.4 Hz, 2 x Ar C(3)H), 8.26 (4H, d, J" = 8.5 Hz, 2 x Ar C(3' )H and C(5' )H) .
Example 6
2- (2 ' . 4 ' -Dichlorophenyl-1- (4-nitrophenyl) -1-ethanol
Sodium borohydride (0.09 g; 0.0025 mol.) was added to a solution of Intermediate 5 (0.78 g; 0.0025 mol.) in tetrahydrofuran (20 ml) and a drop of water to solubilize the sodium borohydride. A dark red colour formed. The mixture was stirred at room temperature for 1 hour, during which time the solution turned pale yellow. Water (30 ml) was added and the solution concentrated to give a residue, which was redissolved in ethyl acetate. The organic solution was washed with brine, dried (MgS04) and evaporated
to an oil which gave, on recrystallization (ethanol), the title compound of Example 6 (0.72 g; 92.3%), as clusters of beige needles, m.p. 136°C. Found: C, 53.90; H, 3.58; N,
4.29,
requires C, 53.87; H, 3.55; N, 4.49%. nmax (KBr) /cm"1 3502 (OH), 1601 (C = C, Ar) , 1517 and 1343 (N02) . dH (300 MHz; DMSO-d6) 3.01 (2H, d, J = 6.7 Hz, CH2) , 4.95
(1H, q, J = 6.0 Hz, CHOH) , 5.77 (1H, d, J" = 4.8 Hz, CHOH) ,
7.33 (2H, m, Ar C(3')H and C(5')Hj_, 7.55 (H, d, J = 2.0 Hz,
Ar C(6')H), 7.57 (2H, d, J = 8.7 Hz, Ar C(2)H and C(6)H), 8.18 (2H, d, J" = 8.7 Hz, Ar C(3)H and C(5)H) .
Example 7
2- (2 ' , 4 ' -Dichlorophenyl) -1.1- ethylenedioxy- 1 - ( 4 - nitrophenyl) ethane
Intermediate 5 (0.78 g; 0.0025 mol.), was reacted with ethylene glycol (10 ml) in the presence of p-toluene sulphonic acid (0.2 g) in toluene (80 ml) under reflux with a Dean-Stark trap for 24 hours. The above work-up, yielded the title compound of Example 7 (0.29 g; 32.8%) as a white solid, m.p. 122°C. Found: C, 54.50; H, 3.63; N, 4.04.
C16H13C12N04 requires C, 54.26; H, 3.70; N, 3.95%. nraax
(KBrJ/cnr1 1584 (C = C) , 1519 and 1354 (N02) . dH (300 MHz;
CDC13) 3.29 (2H, s, CH2) , 3.71 (2H, m, CH2 ketal), 3.87 (2H, m, CH2 ketal), 7.12 (1H, dd, J" = 8.3 Hz, J = 2.1 Hz, Ar C(5')H), 7.24 (1H, d, " = 8.4 Hz, Ar C(6')H), 7.49 (1H, d, J = 2.3 Hz, Ar C(3')H), 7.52 (2H, d, J = 8.8 Hz, Ar C(2)H and C(6)-Hl, 8.12 (2H, d, J = 8.8 Hz, Ar C(3)H and C(5)H) .
Example 8
2 - ( 2 ' , 4 ' -Dichlorophenyl) - 1 - (4 - dimethylaminophenyl) - 2 - hydroxy-1-ethanone
Potassium cyanide (3 g) dissolved in water (60 ml) was added to a solution of 4-dimethylaminobenzaldehyde (14.9 g; 0.1 mol.) and 2 , 4-dichlorobenzaldehyde (17.6 g, 0.1 mol.) dissolved in 95% ethanol (80 ml) . After refluxing for 1 hour, the mixture was allowed to cool, when a crystalline material (9.6 g) separated. A further portion of potassium cyanide (1 g) was added to the filtrate and the mixture refluxed for 1 hour. After cooling a second crop of the title compound of Example 8 (2.1 g) was collected by filtration. The two crops of crystals were combined, washed twice with water and then with a small volume of ethanol, before crystallization (ethanol) to yield the title compound of Example 8 (10.9 g; 33.4%) as yellow crystals, m.p. 111°C. Found: C, 59.24; H, 4.80; N 4.38. C16H15C12N02 requires C, 59.27; H, 4.66; N, 4.32%. n^ (KBr) /cm"1 3419 (OH), 2920 (N-Me) , 1654 (C=0) . dH (300MHz; CDC13) 3.11 (6H, s, N(CH3)2), 4.93 (1H, d, J = 5.1 Hz, CHOH), 6.27 (1H, d, J = 4.6 Hz, CHOH) , 6.62 (2H, d, J" = 9.1 Hz, Ar ( (3)H and C(5)H) , 7.11 (1H, d, J = 8.4 Hz, Ar C(6')H), 7.18 (1H, dd, J" = 8.4 Hz, J = 1.9 Hz Ar C(5')H), 7.48 (1H, d, J" = 2.0 Hz, Ar C(3' )H) , 7.84 (2H, d, J = 9.1 Hz, Ar C(2)H and C(6)H) . m/e (APCI, low resolution) 148 and 149 ( (CH3) 2NC6H4CO+) 175 and 177 (C6H3C12CH0H+) .
Example 9
1- (2,4 -Dichlorophenyl ) -2 - (4 ' -dimethylaminophenyl) -1,2- ethandione
Freshly prepared Fehling's solution (50 ml) was added to a solution of the title compound of Example 8 (0.32 g; 0.01 mol.) in ethanol (30 ml), and the mixture heated for 30 minutes at 100°C. The blue solution quickly turned to a brown mixture with the precipitation of copper (I) oxide. After cooling, the copper (I) oxide was removed by filtration through celite, and the filtrate concentrated in vacuo . The concentrate was extracted with dichloromethane, washed with water, dried (MgS04) and the solvent removed by evaporation to give a red oil. Crystallization (ethanol) gave the title compound of Example 9 as fine orange needles, m.p. 155°C. Found: C, 59.39; H, 4.27; N 4.09. C16H13C12N02 requires C, 59.65; H, 4.07; N, 4.35%. nmax (KBrJ/cm-1 1683 (C=0) , 1601 (C=C) . dH (300 MHz; CDC13) 3.11 (6H, s, N(CH3)2), 6.76 (2H, d, J" = 9.1 Hz, Ar C(3')H and C(5')H), 7.44 (1H, dd, J = 8.4 Hz, J = 1.9 Hz, Ar C(5)H), 7.49 (1H, d, J" = 1.9, Ar C(3)H) , 7.87 (1H, d, J = 8.4 Hz, Ar C(6)H) , 7.96 (2H, d, J" = 9.0 Hz, Ar C(2' )H and C(6' ) H) .
Example 10
2- (4 ' -Aminophenyl) -1- (2 , 4-dichlorophenyl) -1, 2 -ethandione
Intermediate 7 ] (0.38 g; 0.001 mol.) was refluxed in cone. hydrochloric acid (20 ml) and methanol (10 ml) for 1 hour. On cooling the HCl salt precipitated from solution. The mixture was concentrated to half volume and the precipitate collected. The salt was redissolved in warm methanol (30 ml) and sodium hydroxide (2M; 10 ml) added to release the free amine . The solution was evaporated to dryness, and the residue dissolved in dichloromethane and washed with water. The organic phase was dried (MgS04) and evaporated to give a yellow oil. Trituration (ether) gave the title compound of Example 10 as yellow solid (0.24 g; 81.6%) m.p. 92-93°C. Found: C: 57.04; H, 2.97; N 4.51. C14H9C12N02 requires C, 57.17; H, 3.08; N, 4.76% nmax (KBr) /cm"1 3448 (NH) , 1675 (C=0, diketone) . dH (300 MHz; CDC13) 4.43 (2H, br, s, NH2) , 6.73 (2H, d, J = 8.7 Hz, Ar C(3)H and C(5)H) , 7.43 (1H, dd, J= 8.4 Hz, J" = 1.9 Hz, Ar C(5' )H) , 7.49 (1H, d, J= 1.9 Hz, Ar C(3')H), 7.87 (1H, d, J = 8.3 Hz, Ar C(6')H), 7.89 (2H, d, J" = 8.7 Hz, Ar C(2)H and C(6)H) .
Example 11
Methyl 2- (4-nitrophenyl) -4-oxo-4-phenylbutanoate
Anhydrous potassium carbonate (5.53 g, 40 mmol) in dry acetone (100 cm3) was stirred with Intermediate 8 (1.95 g, 9.9 mmol) for 30 minutes at reflux and Intermediate 9 (2.01
g, 10.1 mmol) was added dropwise over a period of 30 minutes. The solution was refluxed for a further 3 hours, after which the resulting dark brown mixture was filtered. The filtrate was concentrated under reduced pressure to leave a dark brown oil which crystallised when mixed with ether. The crystals were triturated with ether and filtered to give the title compound of Example 11 as pale green crystals (2.54 g, 72%) . M.P. 165.1-165.9°C . nmax KBr disc/ crrr 1 1728.1 (C02CH3) , 1681.4 (C=0) , 1519.0 and 1346.7 (N02) ; dH D3COCD3. 8.18 (2H, d, J=8.9 Hz, 3,5-PhH), 8.0 (2H, d, J=7.1 Hz, 2',6'-PhH) 7.67 (2H, d, J=8.8 Hz, 2,6-PhH), 7.59 (1H, t, J=7.2 Hz, 4-Ph-H_ _ 7.46 (2H, t, J=7.6 Hz3, 3,5-PhH), 4.40 (1H, dd, JAX=4.3,Hz JBX=10.1 Hz CH^ CHAHB) , 3.98 (1H, dd, JXB= 10.1 Hz, JM=18.3 Hz, O^CH^) , 3.61 (3H, s, CH3) , 3.48 (1H, dd, ^=4.3 Hz, JBA=18.2 Hz, C^CR^U^ ; dC 196.15 (C=0, C-4), 172.99 (C=0, Ac) , 147.80, 145.81, 135.13 and 132.48 (3 x Ph- C) , 132.48, 130.00, 129.387, 129.32, 124.54, and 122.673 (5 x CH, Ph-H), 53.21 (CH, C-2), 46.53 (CH3, Ac) and 42.51 (CH2, C-3) .
Example 12
Methyl 4- (4-bromophenyl) -2- (4-nitrophenyl) -4-oxobutanoate
The title compound of Example 12 was obtained from Intermediate 8 and 2-bromo-l- (4 -bromophenyl) -1-ethanone as a yellow solid (65%) M.P. 113.9-115.3°C. nmax KBr disc/cm"1 1725.6 (C02CH3) , 1672 (C=0) , 1516 and 1346 (N02) ; dH 8.23 (2H, d, J=7.9 Hz, 3,5-PhH), 7.85 (2H, d, J=7.7 Hz, 2',6'- PhH) , 7.65 (2h, d, J=7.8 Hz, 3'-5'-PhH), 7.57 (2H, d, J=8.2
Hz, 2,6-PhH) , 4.48 (IH, dd, JAX=4.6 Hz, JBX9.4 Hz, CHχCHAHB) , 3.95 (IH, dd, JXB=9.4 Hz, ^=18.0 Hz, CHXCHA H , 3.75 (3H, s, OCH3) , 3.34 (IH, dd, JXA=4.6 Hz, JBA= 18.0 Hz, CHXCHAHS) ; dC 196.15 (C=0, C-4) , 172.99 (C=0, Ac) , 160.98, 147.80, 145.81 and 135.13 (4 x Ph-C) , 132.48, 130.00, 129.39 and 124.54 , (4 x CH, Ph-H) , 53.21 (CH, C-2) , 46.53 (CH3, Ac) and 42.51 (CH2, C-3) .
Example 13
Methyl 4- (2 -chlorophenyl) -2- (4-nitrophenyl) -4-oxobutanoate
The title compound of Example 13 was obtained from Intermediates 8 and 10 as yellow crystals (22%) . M.P. 85.4- 86.2°C. nmax KBr disc/cm"1 1727.4 (C02CH3) , 1693.8 (C=0) , 1514.2 and 1343.8 (N02) ; dH 8.22 (2H, d, J=8.7 Hz, 3,5-PhH), 7.57 (IH, d, J=7.4 Hz, 6' -PhH), 7.55 (2H, d, J=8.8 Hz, 2,6- PhH), 7.45 (2H, d, J=3.7 Hz, 3', 5' -PhH), 7.33 (IH, m, 4'- PhH) , 4.48 (IH, dd, JM=4.9 Hz, JBX=9.5, Hz, CHXCHAHB) , 3.94 (IH, dd, JXB=9.5 Hz, JM= 18.1 Hz, O^CH^) , 3.75 (3H, s, CH3) , 3.40 (IH, dd, JXA= 4.9 Hz, JBA= 18.1 Hz, CH^H^CHB) ; dC 199.88 (C=0, C-4), 172.83 (C=0, Ac), 147.79, 145.61, 138.42 and 131.56 (4 x Ph-C), 132.78, 131.16, 129.83, 129.45, 127.50 and 124.50 (6 x CH, Ph-H), 53.20 (CH, C-2), 46.89 (CH3, Ac) and 46.47 (CH2, C-3).
Example 14
Methyl 4- (3 -chlorophenyl) -2- (4-nitrophenyl) -4 -oxobutanoate
The title compound of Example 14 was obtained from
Intermediates 8 and 10 as yellow crystals (41%) . M.P. 117.3- 118.2°C. nmax KBr disc/cm"1 1737.4 (C02CH3) , 1680.2 (C=0) , 1517.8 and 1350.8 (N02) ; dH 8.23 (2H, d, J=8.4 Hz, 3,5-PhH) , 7.94 (IH, bs, 2 '-PhH) , 7.85 (IH, d, J=7.4 Hz, 6 '-PhH) , 7.57 (3H, d, J=8.1 Hz, 2,6-and 4 '-PhH) , 7.43 (1Hz, t, J=7.7 Hz 5 '-PhH) , 4.44 (IH, dd, JM=4.5 Hz, JBX= 9.1 Hz, CHχCHAHB) , 3.97 (IH, dd, JXB= 9.4 Hz, JM 18.0Hz3, CHxHaHg) , 3.73 (3H, s, CH3) , 3.35 (IH, dd, XA=4.5 Hz, JBA=18.1 Hz, CHXCHAHB) . dC 195.95 (C=0, C-4) , 172.94 (C=0, Ac) , 147.78, 145.76, 137.90 and 135.45 (4 x Ph-C) , 133.95, 130.53, 129.34, 128.56 , ' 126.60 and 124.52 (6 x CH, Ph-H) , 53.12 (CH, C-2) , 46.45 (CH3, Ac) and 42.62 (CH2, C-3) .
Example 15
Methyl 4- (4 -chlorophenyl) -2- (4-nitrophenyl) -4 -oxobutanoate
The title compound of Example 15 was obtained from Intermediates 8 and 12 as yellow crystals (56%) . M.P. 107.5- 108.6°C. nraax KBr disc/cm"1 1726.1 (C02CH3) , 1673.3 (C=0) , 1517.2 and 1346.3 (N02) ; dH 8.22 (2H, d, J=8.6 Hz, 3,5-PhH) , 7.94 (2H, d, J=8.4 Hz, 2', 6' -PhH) , 7.57 (2H, d, J=8.7Hz, 2,6-PhH) , 7.46 (2H, d, J=8.4 Hz, 3', 5' PhH) , 4.45 (IH, dd, JM=4.6 Hz, JBX= 9.4 Hz, CHχCHAHB) , 3.95 (IH, dd, JXB=9.5 Hz, JM=18.0 Hz, CHXCHAHB) , 3.75 (3H, s, CH3) , 3.35 (IH, dd, JXA=4.8 Hz, JBA=18.0 Hz, CHXCHAHB) ; dC 195.94 (C=0, C-4) ,
173.00 (C=0, Ac) , 147.80, 145.84, 140.58 and 134.74 (4 x Ph- C) , 129.92, 129.48, 129.38 and 124.52 (4 x CH, Ph-H), 53.19 (CH, C-2), 46.58 (CH3, Ac) and 42.53 (CH2, C-3).
Example 16
Methyl 4 - (2,4 -dichlorophenyl ) - 2 - (4 -nitrophenyl) -4 - oxobutanoate
The title compound of Example 16 was obtained from
Intermediates 8 and 13 as pale yellow crystals (71%) . M.P. 118.3-118.8°C. nraax KBr disc/cm"1 1728.1 (C02CH3) , 1691.4
(C=0) , 1519.0 and 1346.7 (N02) ; d 8.2 (2H, d, J=8.7 Hz,
3,5-PhH) , 7.55 (IH, d, J=8.4 Hz, 6' -PhH) , 7.50 (2H, d, J=8.8
Hz, 2,6-PhH) , 7.45 (IH, d, J=1.9 Hz, 3' -PhH) 7.33 (IH, dd,
J=8.3 Hz, J=1.9 Hz, 5'-Phh) , 4.44 (IH, dd, JM=4.8 Hz, JBX=9.7 Hz, CHχCHAHB) , 3.86 (IH, dd, JXB=9.7 Hz, 0^18.1 Hz, CHXCHASB) , 3.70 (3H, s, CH3) , 3.32 (IH, dd, JXA=4.8 Hz, JBA=18.1 Hz, CHXCHAHB; dC 198.59 (C=0, C-4) , 172.78 (C=0, Ac) , 147.84, 145.43, 138.56, 136.53 and 132.79 (5 x Ph-C) , 131.13, 131.01, 129.41, 127.93 and 124.56 (5 x CH, Ph-H) , 53.25 (CH, C-2) , 46.92 (CH3,Ac) and 46.44 (CH2, C-3) .
Example 17
Methyl 4 - (3.4 -dichlorophenyl) -2 - (4 -nitrophenyl) -4- oxobutanoate
The title compound of Example 17 was obtained from Intermediates 8 and 14 as yellow crystals (47%) . M.P. 114.6-
115.7°C. nmax KBr disc/cm"1 1731.3 (C02CH3) , 1692.1 (C=0) , 1518.6 and 1346.6 (N02) ; dH 8.22 (2H, d, J=8.6 Hz, 3,5-PhH) , 8.06 (IH, d, J=1.8 Hz, 2 ' -PhH) , 7.82 (IH, dd, J=l .8 Hz, J=8.3 Hz, 6' -PhH) , 7.57 (IH, d, J=7.8 Hz, 5' -PhH) , 7.57 (2H, d, J=8.8 Hz, 2,6-PhH) , 4.45 (IH, dd, JM=4.6 Hz, JBX=9.5 Hz CHχCHAHB) 3.95 (IH, dd, JXB=9.6 Hz, JM=18.1 Hz CHXCHAHJ,) , 3.75 (3H, s, CH3) , 3.33 (IH, dd, 0^4.7 Hz, JBA= 18.1 Hz, CHXCHAHB) ; dC 195.06 (C=0, C-4) , 172.87 (C=0, Ac) , 147.80, 145.62, 138.62, 135.92 and 133.83 (5 x C, Ph-C) , 131.23, 130.48, 129.39, 127.53 and 124.54 (5 x CH, Ph-H) , 53.24 (CH, C-2) , 46.47 (CH3, Ac) and 42.51 (CH2, C-3) .
Example 18
Methyl 4- (4-nitrophenyl) -2- (4-nitrophenyl) -4 -oxobutanoate
The title compound was obtained from Intermediate 8 and 2- bromo- (4-nitrophenyl) -1-ethanone as yellow crystals (28%) .
M.P. 121.8-123.7°C. nmax KBr disc/cm"1 1730.2 (C02CH3) , 1693.2
(C=0) , 1530.1 and 1346.1 (N02) ; dH 8.32 (2H, d, J=8.8 Hz,
3', 5' -PhH), 8.22 (2H, d, J=8.8 Hz, 3,5-PhH), 8.16 (2H, d, J=8.8 Hz, 2' , 6' -PhH) , 7.60 (2H, d, J=8.8 Hz, 2,6-PhH) , 4.48 (IH, dd, JAX=4.5 HZ, JBX=9.6 HZ, C∑ CHAHB) , 4.05 (IH, dd, JXB= 9.6 Hz, JAB= 18.3 Hz, C^CH^) , 3.76 (3H, s, CH3) , 3.42 (IH, dd, 0^=4.5 Hz, JBA=18.3 Hz CHXCHAHB,- dC 195.88 (C=0, C-4) , 172.82 (C=0, Ac) , 150.94, 147.82, 145.50 and 140.79 (14 x Ph-C) , 129.62, 129.40, 124.58 and 124.37 (4 x CH, Ph-H) , 53.31 (CH, C-2) , 46.48 (CH3, Ac) and 43.04 (CH2, C-3) .
Example 19
3- (4-Nitrophenyl) -1-phenyl-l, 4-butanediol
To a solution of the title compound of Example 11 (1.01 g, 3.2 mmol) in diglyme (50 cm3) was added soldium borohydride (0.5 g, 13 mmol), and the mixture stirred overnight at room temperature. The purple solution was added to ice water (50 cm3) , ethyl acetate (50 cm3) and then acidified (2M HC1) . The organic layer was separated and washed with water (2 x 50 cm3) , saturated sodium bicarbonate (50 cm3) , water (50 cm3) , then dried (MgSO . The organic solvent was removed to leave a brown oil which crystallised when mixed with ether to give the title compound of Example 19 as yellow crystals (0.57 g, 62%). M.P. 142.9-143.9°C . (Found: C, 66.77; H, 5.99; N, 4.76. C16H17N04 requires C, 66.88; H, 5.96; N, 4.87%); n^ KBr disc/cm"1 3341.9 and 3268.8 (OH), 1516.8 and 1343.0 (N02) ; dH ds- DMSO 8.20 (2H, d, J=8.7 Hz, 3,5-PhH), 7.59 (2H, d, J=8.7 Hz, 2,6-PhH), 7.25 (5H, m, PhH), 5.27 (IH, d, J=4.5 Hz, CHOH), 4.78 (IH, t, J=5.4 Hz, CH2OH) , 4.18 (IH, m, CHOH) 3.6 (2H, m, CH2OH) , 3.25 (IH, dt , J=6.3 Hz, JXB = JYB = 10.5 Hz, CH2-CH3CHXHY) , 2.0 (IH, dt , Jcx=4.0 Hz, JBX= 10 Hz,
14 Hz, CHBCHχHγ-CHc-) , 1.85 (IH, dt , JCY= 2.6 Hz, JBY=10.8 Hz, J=13.5 Hz, -CHBCHχHy-CHc- ) . dC 152.93, 147.41 and 146.83 (3 X Ph-C), 130.49, 128.83, 127.48 126.34 and 124.03 (5 x CH, Ph-H), 70.69 (CH, C-4), 66.62 (CH2, C-l), 45.96 (CH, C-2) and 42.79 (CH2, C-3.
Example 20
1- (4 -bromophenyl) -3- (4-nitrophenyl) -1, 4-butanediol
The title compound of Example 20 was obtained from the title compound of Example 12. Column chromatography using ethyl acetate: petroleum ether (8:2 v:v) gave green crystals (79%) . M.P. 127.2-128.4°C (Found: C, 53.59; H, 3.44; N, 3.57. C16H17N04 requires C, 53.42; H, 3.42; N, 3.66%) ; n^. KBr disc/cm"1 3518.7 and 3395.1 (OH) , 1510.3 and 1352.8 (N02) ; dH dδ-DMSO 8.20 (2H, d, J=8.2 Hz, 3,5-PhH) , 7.56 (2H, d, J=8.4 Hz, 2,6-PhH) , 7.45 (2H, d, J=8.0 Hz, 2' ,6'-PhH) , 7.20 (2H, d, J=8.1 Hz, 3 ' ,5 '-PhH) , 5.36 (IH, d, J=4.5 Hz, CHOH) , 4.79 (IH, t, J=5.5 Hz, CH2OH) , 4.18 (IH, m, CH OH) , 3.59 (2H, m, CH2OH) , 3.2 (IH, dt, J=6.1 Hz, Jxg = Jra = 10 Hz, -CH2-CHBCHXHY- ) , 1.99 (IH, dt, Jcx=3.8 Hz, JBX = 10.2 Hz, Jγx = 14.3 Hz CHBCHχHγ-CHc-) , 1.85 (IH, dt , JCT=2.5 Hz,
Hz, -CHBCHχHγ-CHc) ; dC 152.47, 145.83, 145.03 and 119.73 (4 x Ph-C) , 130.75, 129.50, 127.70 and 123.10 (4 x CH, Ph-H) , 69.19 (CH, C-4) , 65.65 (CH2, C-l) , 44.94 (CH, C-2) and 41.59 (CH2, C-3) .
Example 21
1- (2-chlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol
The title compound of Example 21 was obtained from the title compound of Example 13. Column chromatography with ethyl acetate: petroleum ether (6:4 v:v) , pale yellow
(35%). m.p. 123.5 - 124.7°C. Vraax KBr disc/cm"1 3341.9 and 3268.8 (OH), 1516.8 and 1343.0 (N02) ; δ H d6 -DMSO 8.20
(2H, d, J=8.1 Hz, 3" -Ph-H), 7.61 (3H, d, J=7.8 Hz, 2"-Ph-
H, -Ph-H) , 7.35 (IH, t, J=7.3 Hz, Ph-H) . 7.30 (IH, d, J=7.6 Hz, -Ph-H) , 7.23 (IH, t, J=7.1Hz, Ph-H) , 5.44 (IH, d, J=4.6 Hz, CH-OH) , 4.79 (IH, t, J=5.1 Hz, CH2OH) , 4.48 (IH, m, CHcOH) , 3.59 (2H, t, J=5.8 Hz, CH2OH) , 3.32 (IH, m, CH2-CHBCHXHY) , 1.85 (2H, m, CHBCHχHγCHc) ; δC 152.29, 146.95, 144.81 and 130.97 (4 x C, Ph-C) , 130.62, 129.64, 129.06, 128.15, 128.04 and 123.88 (6 x CH, Ph-C) , 67.25 (CH, C-l) , 66.61 (CH2, C-4) , 45.95 (CH, C-3) and 41.11 (CH2, C-2) .
Example 22
1- (3 -chlorophenyl) -3- (4-nitrophenyl) -1, -butanediol
The title compound of Example 22 was obtained as crystals from the title compound of Example 14. (34%) . m.p. 114.4- 115.0°C. V^ KBr disc/cm"1 3341.9 and 3268.8 (OH) , 1516.8 and 1343.0 (N02) ; δH d6 -DMSO 8.17 (2H, d, J=8.4Hz, 3" -Phil) , 7.59 (2H, d, J=8.5 Hz, 2" -Ph-H) , 7.29 (4H, m, 2' , 4' , 5' and 6' -Ph-H) , 5.42 (IH, d, J=4.7Hz, CH-OH) , 4.78 (IH, t, J=5.2 Hz, CH2OH) , 4.18 (IH, m, CHcOH) , 3.59 (2H, m, CH2OH) , 3.23 (IH, m, CH2-CHBCHxHy) , 1.90 (2H, m, CHBCHχHγCHc) ; δC 152.62, 150.01, 146.85 and 133.67 (4 x C, Ph-C) , 130.73, 130.45, 127.37, 126.63, 125.06 and 124.02 (6 x CH, Ph-C) , 70.17 (CH, C-l) , 66.63 (CH2, C-4) , 45.90 (CH, C-3) and 42.42 (CH2, C-2) .
Example 23
1- (4 -chlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol
The title compound of Example 23 was obtained as a solid from the title compound of Example 15. (79%) . m.p. 124. - 125.3°C. Vmax KBr disc/cm"1 3525.9 and 3356.8 (OH) , 1506. and 1352.6 (N02) ; δH d6 - DMSO 8.17 (2H, d, J=8.3 Hz, 3" - Ph-H) , 7.55 (2H, d, J=8.3 Hz, 2" -Ph-H) , 7.33 (2H, d, J=8.7 Hz, 2' ,6' -Ph-H) , 7.26 (2H, d, J=8.0 Hz, 3' , 5' -Phil) , 5.37 (IH, d, J=3.4 Hz, CH-OH) , 4.79 (IH, t, J=4.5 Hz, CH2OH) , 4.19 (IH, m, CHcOH) , 3.59 (2H, brs , CH2OH) , 3.21
(IH, m, CH2-CHBCHXHY) , 2.00 (IH, m, CHBCHχHγCHc) , 1.83 (IH, m, CHBCHχHγCHc) ; δC 152.72, 146.83, 146.34 and 131.94 (4 x
C, Ph-C) , 130.43, 128.83, 128.23 and 124.02 (4 x CH, Ph-
C) , 70.08 (CH, C-l) 66.59 (CH2, C-4) , 45.88 (CH, C-3) and 42.56 (CH2, C-2) .
Example 24
1- (2.4 -dichlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol
The title compound of Example 24 was obtained as yellow crystals from the title compound of Example 16. (86%) . m.p. 126.8-128.5°C. (Found: C, 54.12; H, 4.23; N, 4.00) . C16H15C12N04 requires C, 54.08; H, 4.22; N, 3.94%) ; Vmax KBr disc/cm"1 3469 and 3364 (OH) , 1516 and 1347 (N02) ; δH dδ- DMSO 8.20 (2H, d, J=8.7 Hz, 3" -Ph-H) , 7.58 (2H, d, J=8.7 Hz, 2" -Ph-H) , 7.60 (IH, d, J=8.3 Hz, 6' -Ph-H) , 7.44 (IH, d, J=2.0 Hz, 3' -Ph-H) , 7.42 (IH, dd, J=2.0 J=8.4 Hz, 5'- Ph-H) , 5.51 (IH, d, J=4.7 Hz, CH-OH) , 4.78 (IH, t, J=5.4
Hz, CH2OH) , 4.42 (IH, m, CHcOH) , 3.57 (2H, t, J=5.9 Hz, CH2OH) , 3.3 (IH, CH2-CHBCHXHY) , 1.84 (2H, m, CHBCHχHγCHc) ; δC 150.00, 144.84, and 141,80, 130.5, 129.7 (5 x Ph-C) , 128.49, 127.52, 126.91, 126.17 and 121.78 (5 x CH, Ph-H) , 64.87 (CH, C-l) , 64.39 (CH2, C-4) , 43.74 (CH, C-3) and 38.78 (CH2, C-2) .
Example 25
1- (3, 4 -dichlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol
The title compound of Example 25 was obtained from the title compound of Example 17. (28%) . m.p. 126.2 - 126.9°C. Vmax KBr disc/cm'1 3341.9 and 3268.8 (OH) , 1516.8 and 1343.0 (N02) ; δH d6 -DMSO 8.15 (2H, d, J=8.3 Hz, 3" - Ph-H) , 7.55 (2H, d, J=8.4 Hz, 2" -Ph-H) , 7.50 (IH, d, J=8.1 Hz, 5' -Ph-H) , 7.46 (IH, d, J=1.3 Hz, 2 ' -Ph-H) , 7.23 (IH, dd, J=l.l, J=8.2 Hz, 6' -Ph-H) , 5.47 (IH, d, J=4.8 Hz, CH-OH) , 4.78 (IH, t, J=5.3 Hz, CH2OH) , 4.18 (IH, m, CHcOH) , 3.55 (2H, m, CH2OH) , 3.19 (IH, m, CH2-CHBCHXHY) , 1.93 (2H, m, CHBCHXHYCHC) ; δC 152.47, 148.52, 146.81, 131.6, 131.5 (5 x Ph-C) , 131.02, 130.46, 128.45, 126.78 and 123.98 (5 x CH, Ph-H), 69.69 (CH, C-l) 66.60 (CH2, C- 4) ,45.83 (CH, C-3) and 42.13 (CH2, C-2).
Example 26
1- (4-nitrophenyl) -3- (4-nitrophenyl) -1, 4-butanediol
The title compound of Example 26 was obtained from the title compound of Example 18. m.p. 121.8 - 123.7°C. (Found: C, 53.59; H, 3.44; N, 3.57. C16H16N206 requires C, 53.42; H, 3.42; N, 3.66%) ; Vmax KBr disc/cm"1 3518.7 and 3395.1 (OH) , 1510.3 and 1352.8 (N02) .
Example 27
3- (4-nitrophenyl) -5-phenyltetrahydro-2-furanone
The title compound of Example 11 (1.38g, 4.40mmol) in 70% ethanol/water (50 cm3) was stirred at room temperature with sodium borohydride (0.2g, 7.40mmol) for 8 hours. The resulting purple reaction mixture was added to ice water (50 cm3) and ethyl acetate (50 cm3) and then acidified (2M HC1) . The organic layer was separated and washed with water (2 x 50 cm3) , saturated sodium bicarbonate (50 cm3) , water (50 cm3) and then dried (MgSO . The volatile components were removed to leave a brown oil . The final product was purified by column chromatography with ethyl acetate:petroleum ether 3:7 to give a pale yellow solid (1.06g, 85%). m.p. 96.2 - 98.3°C. (Found: C, 67.56; H, 4.78; N, 4.90. C16H13N04 requires C, 67.83; H, 4.62; N, 4.94%); Vmax KBr disc/cirf1 1773 (C02CH-), 1518 and 1347 (N02) ; δH 8.24 (2H, d, J=8.8 Hz, 3" -Ph-H), 7.56 (2H, d, J=8.7 Hz, 2" -Ph-H), 7.45 (5H, m, Ph-H), 5.62 (IH, dd, JAX=5.45, JBX=10.7 Hz, CHχCHAHB) , 4.24 (IH, dd, JAY=8.3,
JBA=10.8 Hz, CHXCHAHBCHY) , 2.45 (IH, m, JXB=10.7, JYB=12.8, JM=12.8 Hz, CHXCHAHBCHY) ; δC 175.59 (Ac) , 147.79, 143.70 and 134.43 (3 x Ph-C) , 129.65, 129.38, 127.48, 126.02 and 124.55 (5 x CH, Ph-H) , 79.88 (CH, C-3) , 47.63 (CH, C-5) and 40.32 (CH2, C-4) .
Example 28
5- (4 -Bromophenyl) -3- (4-nitrophenyl) tetrahydro-2-f uranone
According to the procedure described in Example 27, the title compound of Example 28 was prepared as yellow crystals from the title compound of Example 12 (25%) . Vmax KBr disc/cm"1 1774 (-C02CH-) , 1519 and 1350 (N02) ; δH 8.16 (2H, d, J=8.6 Hz, 3" -Ph-H) , 7.49 (4H, t, J=8.7 Hz, 2" and 2',6' -Ph-H) , 7.24 (2H, d, J=8.4 Hz, 3' , 5' -Ph-H) , 5.46 (IH, dd, JM=5.46, JBX=10.7 Hz, CHχCHAHB) , 4.15 (IH, dd, JAY=8.3, JBY=12.8 Hz, CHAHBCHY) , 3.10 (IH, m, JXA=5.6,
Jra=12.8, JM=12.7 Hz CHXCHAHBCHY) ; δC 175.22 (Ac) , 147.84, 143.31, 137.44 and 123.36 (4 x Ph-C) , 132.54, 129.60,
127.66 and 124.46 (4 x CH, Ph-H) , 79.06 (CH, C-3) , 47.90 (CH, C-5) and 40.19 (CH2, C-4) .
Example 29
5- (2 , 4-dichlorophenyl) -3- (4-nitrophenyl) tetrahvdro-2- furanone
The title compound of Example 16 was employed according to the procedure described in Example 27, whereby a pale yellow oil was formed. Column chromatography with ethyl acetate : petroleum ether (3:7) gave pale yellow crystals of the title compound of Example 29 (48%). m.p. 148.7 - 153.9°C. (Found: C, 54.39; H, 3.32, N, 3.71. C^H^C^NG, requires C, 54.56; H, 3.15; N, 3.98%); Vmax KBr disc/cnr1
1780 (-C02CH-), 1519 and 1347 (N02) ; δH 8.28 (2H, d, J=8.7 Hz, 3" -Ph-H), 7.54 (IH, d, J=8.5 Hz, 6' -Ph-H), 7.53 (2H, d, J=8.7 Hz, 2" -Ph-H), 7.48 (IH, d, J=2.0 Hz, 3' -Ph-H), 7.40 (IH, dd, J=2.0, J=8.5 Hz, 5' -Ph-H), 5.62 (IH, dd, JM=5.6, JBX=10.3 Hz, CHχCHAHB) , 4.24 (IH, dd, JAY=8.6,
JBY=12.3 Hz, CHXCHAHBCHY) , 3.41 (IH, m, 0^=5.70, JYA=8.5, JBA=12.9 Hz, CHXCHAHBCHY) , 2.26 (IH, m, JXB=10.3, 0^=12.3, JM=12.9 Hz, CHXCHAHBCHY) ; δC 174.84 (Ac) , 147.96, 143.03, 135.53, 135.24 and 132.31 (5 x Ph-C) , 130.17, 129.50, 128.42, 127.43 and 124.67 (5 x CH, Ph-H) , 76.52 (CH, C-3) , 47.15 (CH, C-5) and 38.81 (CH2, C-4) .
Example 30
5- (2, 4-dichlorophenyl) -3- (4-aminophenyl) -2-pyrrolidinone
A mixture of Intermediate 15 (2.04g, 5.14mmol), acetic acid (30cm3) and water (2cm3) was stirred with a mechanical stirrer and Zinc dust (lOg) was added carefully. The
mixture was stirred and refluxed for 1 hour. Water (10cm3) was added and the solution was basified with NaOH (6M) . The organic components were extracted with ethyl acetate (3 x 50cm3) , dried (MgS04) and concentrated to yield the title compound of Example 30 as green crystals which were recrystallised from benzene (0.10g, 6%) . m.p. 215.0 - 218.0°C. (Found: C, 61.83; H, 4.66; N, 7.95. C1SH14C12N20 requires C, 59.82; H, 4.39; N, 8.72%); Vmax KBr disc/cm"1 3342 and 3220 (NH2) , 1695 (CH2CONH-); δH d6 -DMSO 7.62 (IH, d, J=1.8 Hz, 3' -Ph-H), 7.55 (IH, d, J=8.4 Hz, 6' -Ph-H), 7.50 (IH, dd, J=1.9, J=8.4 Hz, 5' -Ph-H), 6.85 (2H, d, J=8.4 Hz, 3" -Ph-H), 6.49 (2H, d, J=8.4 Hz, 2" - Ph-H), 4.97 (3H, m, CHχCHAHB and NH2) , 3.59 (IH, dd, JBY=9.1, JAY=10.4 Hz, CHAHBCHY) , 2.98 (IH, m, JXB=7.1, J^δ.7, ,7^=12.5 Hz, 01x0^0^) , 1.60 (IH, m, ^=8.7, JYA=10.7, JBA=12.4 Hz, CHXCHAHBCHY) .
Examples 31 and 32
Methyl 4- (2.4-dichlorophenylamino) -4-oxo-2- (4-nitrophenyl) butanoate and Methyl 3- (2 , 4-dichlorophenyloxoamino) -2- (4- nitrophenyl) propanoate
Intermediate 15 (2.67g, 6.72mmol) was stirred with phosphorus pentachloride (3g) in ether (20 cm3) for 3 hours. The volatile components were removed and water (25 cm3) added. The mixture was boiled for 10 minutes and the water was decanted to leave a yellow paste which was purified by column chromatography with ethyl
acetate :petroleum ether (3:70) to give two main fractions, namely the title compounds of Examples 31 and 32.
Example 31 (0.15g, 5.6%) . m.p. 124.3 - 125.7°C. Vraax KBr disc/cm"1 3291 (NH) , 1730 (C02CH3) , 1644 (C=0) , 1513 and 1349 (N02) ; δH 8.23 (2H, d, J=8.7 Hz, 3" -Ph-H) , 7.59 (IH, d, J=8.3 Hz, 6' -Ph-H) , 7.57 (2H, d, J=8.7 Hz, 2" - Ph-H) , 7.42 (IH, d, J=1.9 Hz, 3' -Ph-H) , 7.26 (IH, dd, J=1.9, J=8.3 Hz, 5' -Ph-H) , 4.27 (IH, dd, ^=5.8, JBX=8.7 Hz, CHχCHAHB) , 3.96 (2H, m, CHXCHAHB) , 3.70 (3H, s, OCH3) ; δC 172.64 (C=0, C-l) , 166.07 (C=0, C-4) , 148.00, 143.61, 137.55, 133.10 and 131.80 (5 x Ph-C) , 131.65, 130.52, 129.55, 128.04 and 124.57 (5 x CH, Ph-H) , 53.18 (OCH3) , 50.95 (CH, C-2) and 42.87 (CH2, C-3) .
Example 32 (1.04g, 39%) . m.p. 118.6 - 120.3°C. (Found: C, 51.29; H, 3.60; N, 7.11. C17H14C12N205 requires C, 51.40; H, 3.55; N, 7.05%) ; Vraax KBr disc/cm"1 3373 (NH) , 1726 (C02CH3) , 1697 (C=0) , 1516 and 1349 (N02) ; δH 8.18 (2H, d, J=7.0 Hz, 3" -Ph-H) , 7.68 (IH, brs, 6' -Ph-H) , 7.47 (2H, d, J=8.7 Hz, 2" -Ph-H) , 7.32 (IH, d, J=2.3 Hz, 3' -Ph-H) , 7.18 (IH, dd, J=2.3 , J=8.8 Hz, 5' -Ph-H) , 4.37 (IH, dd,
^=5.2, JBX=9.5 Hz, CHχCHAHB) , 3.68 (3H, s, OCH3) , 3.33 (IH, dd, JXB=9.5, JM=15.6 Hz, CHXCHAH , 2.78 (IH, dd, 0^=5.2, JBA=15.6 Hz, CHXCHAHB) ; δC 171.46 (C=0, C-l) , 167.05 (C=0, C-4) , 146.48, 143.84, 131.87, 128.47 and 122.36 (5 x Ph- C) , 127.90, 127.78, 126.87, 123.18 and 121.49 (5 x CH, Ph- H) , 51.92 (OCH3) , 45.97 (CH, C-2) and 39.51 (CH2, C-3) .
BIO OGICA METHODS
In Vitro Inhibition Studies
1. P450-RA
Sets of tubes, in triplicate, with a total volume of 400μl containing (11, 12-3H) retinoic acid lOnM (lOμl of 400 nM stock) , unlabelled retinoic acid in methanol (lOμl of 120μM stock to give 3μM) , inhibitor (8μl of 5mM ethanol stock to give lOOμM concentration in final assay volume) , phosphate buffer 50mM (pH=7.4, 312μl) , NADPH solution (50μl of 16mg/ml) were prepared, and the tubes vortexed and preheated in a water bath for 4 minutes .
The enzyme reaction was initiated by addition of rat liver microsomes (lOμl of lOmg/ml) and the mixture incubated at 37°C for 25 minutes. The enzyme action was arrested by addition of lOOμl of 1% formic acid and the tubes were placed in ice for 5 minutes. Then 3ml of ethyl acetate containing 0.02% butylated hydroxy anisole was added and the tubes vortexed for 10 seconds. The tubes were then left for another 5 minutes at room temperature and the organic layer (2ml) was removed from each tube and transferred to another set of tubes . The ethyl acetate extracts were evaporated using a univap centrifuge connected to a vacuum pump and a multitrap at -80°C.
After 60 minutes the tubes were removed and the residue was reconstituted in absolute ethanol (lOOμl) and 50μl was injected into a HPLC machine equipped with a lOμm C18
μBonda pack column (3.9x300mm, Millipore) using acetonitrile: water (containing 1% ammonium acetate) 75:25 as mobile phase and connected to a mixer (Reeve model 9702) and a radioactive detector (Reeve model 9701) . The results were analysed by an on line computer system. The scintillation fluid used was a mixture of 50:50 Hisafe 3 and methanol .
Percentage inhibition was calculated from the conversion rate of the samples containing inhibitors to that of control samples which contained absolute ethanol instead of inhibitor solution. Ketoconazole was used as a standard.
Due to the sensitivity of retinoic acid all the above assays were carried out in a dark room equipped with yellow light.
Claims
Claims ;
For use in therapy, a compound of the general
Formula (I]
(I)
where R1 and R2 together are =0 or
D c C
\ /
or R1 and R2 are independently selected from the group consisting of H, CH2OH, OH, halide and C02C1_4alkyl ;
R3 is H and R4 is OH or OT where T is
0 0
C - OR10 or C - R1
where R10 is C1-4alkyl, aryl (C1-4) alkyl ,
di -aryl (C1-4) alkyl or aryl; or
R3 and R4 together are =0:
(i) when R1 and R2 together are =0; or
(ii) when R1 and R2 are both halide; or
(iii) at least one of R1 and R2 is is C02C1_4alkyl ; or
each of R3 and R4 is H when R1 and R2 together are not =0; or
R1 and R3 together are
0 0
II II
- C - 0 or - C - NH
when n is 1, z is 0 and R2 and R4 are each H;
R5 and R6 are selected from the group consisting of H, halide, NH2, N (C1-4alkyl) 2 , NH (C1-4alkyl) and N02, with the proviso that R5 and Rs are not both H;
R7 is H, or R7 is halide when R5 is halide;
each of R8 and R9 is H or halide;
n is 0 or 1 ;
y and z are both 0, or one of y and z is 1 and the other of y and z is 0.
Use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, a compound of the general Formula (I) :
(I)
where R1 and R2 together are =0 or
or R1 and R2 are independently selected from the group consisting of H , CH20H, OH , halide and C02C1 -4alkyl ;
R3 is H and R4 is OH or OT where T is
O 0
- C - OR10 or - C - R10
where R10 is C1-4alkyl , aryl (C1-4) alkyl ,
di -aryl (C1-4) alkyl or aryl; or
R3 and R4 together are =0 :
(i) when R1 and R2 together are =0; or
(ii) when R1 and R2 are both halide; or
(iii) at least one of R1 and R2 is is C02C1_4alkyl ; or
each of R3 and R4 is H when R1 and R2 together are not =0 ; or
R1 and R3 together are
o o
II II
- C - 0 or - C - NH -
when n is i, z is O and R2 and R4 are each H;
R5 and R6 are selected from the group consisting of H, halide, NH2, N (C^alkyl) 2, NH (C1-4alkyl) and N02, with the proviso that R5 and R6 are not both H;
R7 is H, or R7 is halide when R5 is halide;
each of R8 and R9 is H or halide;
n is 0 or 1;
y and z are both 0, or one of y and z is 1 and the other of y and z is 0.
3. Use according to claim 1 or 2 , wherein
R1 and R2 are selected from the group consisting of H, OH, Br, C02Me and CH2OH; or
R1 and R2 together are =0 or
II II
- C - 0 or - C - NH -
when n is 1, z is 0 and R2 and R4 are each H.
4. Use according to claim 3, wherein R2 is H when R1 is selected from H, C02Me and CH2OH.
5. Use according to claim 4, wherein
R1 is C02Me, R2 is H and R3 and R4 together are =0; or
R1 is CH2OH, R2 is H, R3 is H and R4 is OH.
6. Use according to claim 1 or 2 , wherein R4 is OT, where T is
O II - C - OR10
where R10 is di-aryl (C1-4) alkyl
7. Use according to claim 6, wherein R10 is
di-aryl (C2_4) alkyl .
Use according to claim 7, wherein R10 is
di-phenyl (C2_4) alkyl
9. Use according to any of claims 1 to 8 , wherein R5 and R6 are selected from the group consisting of H, halide, NH2, N(C1-4alkyl) 2, NH (C^alkyl) and N02 , with the proviso that at least one of R5 and R6 is NH2, N(C1_4alkyl)2, NH (C1_4alkyl) and N02 and that both R5 and R6 are not N02 when R1 and R2 together are =0, R3 is H, R4 is OH, R7 is H, R8 is H, R9 is H, n is 1, y is 0 and z is 0.
10. Use according to claim 9, wherein R5 and R6 are selected from the group consisting of H, Br, Cl , NH2, N(Me)2 and N02, with the proviso that at least one of Rs and R6 is NH2, N(Me)2 and N02 and that both R5 and R6 are not N02 when R1 and R2 together are =0, R3 is H, R4 is OH, R7 is H, R8 is H, R9 is H, n is 1, y is 0 and z is 0.
1. For use in therapy, a compound of general Formula
(IA) or (IB) , or a pharmaceutically acceptable salt or prodrug thereof
(IA)
(IB)
where Alk represents C1-4 alkyl;
R2 is H, CH2OH, OH, halide or CO^ 4 alkyl;
R5 and R6 are selected from the group consisting of H, halide, NH2, N (C1_4alkyl) 2, NH (C1-4alkyl) and N02, with the proviso that R5 and R6 are not both H;
R7 is H, or halide when R5 is halide; and
each of R8 and R9 is H or halide.
12. Use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, a compound of general Formula (IA) or (IB) , or a pharmaceutically acceptable salt or prodrug thereof
(IA)
(IB)
where Alk represents C1-4 alkyl ;
R2 is H , CH2OH, OH, halide or C02C1-4 alkyl ;
R5 and R6 are selected from the group consisting of H, halide, NH2, N (C^alkyl) 2, NH (C^alkyl) and N02, with the proviso that R5 and R6 are not both H;
R7 is H, or halide when R5 is halide; and
each of R8 and R9 is H or halide.
13. For use in therapy, a compound of general Formula
(IC) or a pharmaceutically acceptable salt or prodrug thereof,
(IC)
where
Ra is selected from the group consisting of N02 , NH2, NH(C1-4alkyl) and N(C1-4alkyl) 2;
Rb is selected from the group consisting of H, halide and N02 and b is 1 or 2;
X can be selected from the group consisting of
-C(RC) (Rd)C(Re) (R£)-,
-C(RC) (Ra) (CH2)dC(Re) (Rf)-,
-C(RC) (Rd) (CH2)dC(Re) (Rf)N(Rg)- and
-C(RC) (Ra) (CH2)dN(Rg)C(Re) (Rf) - ;
wherein Rc and Rd can be independently selected from the group consisting of H, halide, OH, CH20H and
C02C1-4alkyl ; or
Rc and Rd together represent =0 or ethylenedioxy;
Re and Rf can be selected from the group consisting of H, OH and OC02Rh, where Rh represents (diaryl) alkyl ; or
Re and Rf together represent =0 or ethylenedioxy;
Rg is H or C1_4alkyl; and
d is an integer selected from 1 to 4; or
X can represent a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from
oxygen and nitrogen and which heterocyclic ring can be substituted by =0.
14. Use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, a compound of general Formula (IC) or a pharmaceutically acceptable salt or prodrug thereof,
(IC)
where
Ra is selected from the group consisting of N02, NH2, NH(C1-4alkyl) and N (C^alkyl) 2;
Rb is selected from the group consisting of H, halide and N02 and b is 1 or 2 ;
X can be selected from the group consisting of
-C(Rc) (Rd)C(Re) (Rf)-,
-C(RC) ( d) (CH2)dC(Re) (Rf)-,
-C(RC) (Rd) (CH2)dC(Re) (Rf)N(Rg) - and
-C(RC) (Rd) (CH2)dN(Rg)C(Re) (R£) - ;
wherein Rc and Rd can be independently selected from the group consisting of H, halide, OH, CH2OH and
C02C1_4alkyl ; or
Rc and Rd together represent =0 or ethylenedioxy;
Re and Rf can be selected from the group consisting of H, OH and 0C02Rh, where Rh represents (diaryl) alkyl ; or
Re and Rf together represent =0 or ethylenedioxy;
Rg is H or C1_4alkyl ; and
d is an integer selected from 1 to 4; or
X can represent a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =0.
15. Use according to claim 13 or 14, wherein said compound of general Formula (IC) is selected from the following:
(IC)
(IC) wherein
Ra, Rb and X are as defined in claim 13 or 14
16. Use according to any of claims 13 to 15, wherein Ra is selected from the group consisting of N02, NH2 and N(CH3)2.
17. Use according to any of claims 13 to 16, wherein Rb is selected from the group consisting of H, Br, Cl and N02.
18. Use according to any of claims 13 to 17, wherein X is selected from the group consisting of
-C(RC) (Rd)C(Re) (Rf) - ,
-C(RC) (Rd) (CH2)dC(Re) (Rf)- ,
-C(RC) (Rd) (CH2)dC(Re) (Rf)N(Rg)- and
-C(RC) (Rd) (CH2)dN(Rg)C(Re) (Rf) - , wherein
Rc, Rd, Re, Rf, Rg and d are as defined in claim 13 or 14.
19. Use according to claim 18, wherein X is selected from the group consisting of -CH2CH(OH)-, -C (=0) C (=0) - , C (halide) 2C(=0) -, -CH2C (ethylenedioxy) - , -CH2CH (0C02R - where Rh is as defined in claim 13 or 14, -CH(0H)CH2-, -C (ethylenedioxy) CH2- and -C (=0) CH (OH) - .
20. Use according to claim 19, wherein X is selected from the group consisting of -CH2CH(0H)-, -C(=0)C(=0)- C (Br) 2C (=0) - , -CH2C (ethylenedioxy) - ,
21. Use according to claim 18, wherein X is
-CH(C02C1_4alkyl) (CH2) dC (=0) - , wherein d is as defined in claim 13 or 14.
22. Use according to claim 21, wherein X is
-CH(C02Me)CH2C(=0) -.
23. Use according to claim 18, wherein X is
-CH(CH20H) (CH2)dCH(0H) -, wherein d is as defined in claim 13 or 14.
24. Use according to claim 23, wherein X is
•CH (CH20H) CH2CH (OH) - .
25. Use according to claim 18, wherein X is -CH(C02C1- 4alkyl) (CH2) dC (=0) NH- , wherein d is as defined in claim 13 or 14.
26. Use according to claim 25, wherein X is
-CH(C02Me)CH2C(=0)NH- .
27. Use according to claim 18, wherein X is
-CH(C02C1-4alkyl) (CH2)dNHC(=0) -, wherein d is as defined in claim 13 or 14.
28. Use according to claim 27, wherein X is
-CH (C02Me) CH2NHC (=0) - .
29. Use according to any of claims 13 to 17, wherein X represents a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =0.
30. Use according to claim 29, wherein X represents a 5 membered heterocyclic ring containing an oxygen or nitrogen heteroatom, which ring is substituted by =0 ,
31. Use according to claim 30, wherein the heterocyclic ring is either tetrahydrofuran or pyrrolidine.
32. Use according to any of claims 13 to 31, with the proviso that in the case of following Formula (IC)
(IC)
Ra and Rb do not both represent N02 when X represents -CH(OH)CH2C(=0) -.
33. Use according to any preceding claim, of at least one of the following compounds:
1- (2 , 4 -Dichlorophenyl) -2- (4-nitrophenyl) -1-ethanol ;
1- (2, 4 -Dichlorophenyl) -2- (4-nitrophenyl) -1,2- ethandione;
2 , 2-Dibromo-l- (2, 4-dichlorophenyl) -2- (4-nitrophenyl) - 1-ethanone;
1- (2 , 4 -Dichlorophenyl) -1, 1-ethylenedioxy-2 - (4- nitrophenyl) ethane;
Di (1- (2 , 4-dichlorophenyl) -2- (4-nitrophenyl) ethyl) carbonate;
2- (2 , 4 -Dichlorophenyl) -1- (4-nitrophenyl) -1-ethanol ;
2- (2 , 4 -Dichlorophenyl) -1, 1-ethylenedioxy-l- (4- nitrophenyl ) ethan ;
2- (2 , 4 -Dichlorophenyl) -1- (4-dimethylaminophenyl) -2- hydroxy- 1-ethanone ;
1- (2 , 4 -Dichlorophenyl) -2- (4-dimethylaminophenyl) -1,2- ethandione;
2- (4-Aminophenyl) -1- (2 , 4-dichlorophenyl) -1,2- ethandione;
Methyl 2- (4-nitrophenyl) -4-oxo-4-phenylbutanoate;
Methyl 4- (4 -bromophenyl) -2- (4-nitrophenyl) -4 - oxobutanoate ;
Methyl 4- (2 -chlorophenyl) -2- (4-nitrophenyl) -4- oxobutanoate ;
Methyl 4- (3 -chlorophenyl) -2- (4-nitrophenyl) -4- oxobutanoate;
Methyl 4- (4 -chlorophenyl) -2- (4-nitrophenyl) -4- oxobutanoate ;
Methyl 4- (2 , 4-dichlorophenyl) -2- (4-nitrophenyl) -4- oxobutanoate ;
Methyl 4- (3 , 4 -dichlorophenyl) -2- (4-nitrophenyl) -4- oxobutanoate ;
Methyl 4- (4-nitrophenyl) -2- (4-nitrophenyl) -4- oxobutanoate ;
3- (4 -Nitrophenyl) -1-phenyl-l, 4-butanediol;
1- (4 -bromophenyl) -3- (4-nitrophenyl) -1 , 4-butanediol ;
1- (2 -chlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol;
1- (3 -chlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol ;
1- (4 -chlorophenyl) -3- (4-nitrophenyl) -1, 4-butanediol ;
1- (2, 4 -dichlorophenyl) -3- (4-nitrophenyl) -1,4- butanediol ;
1- (3, 4-dichlorophenyl) -3- (4-nitrophenyl) -1,4- butanediol ;
1- (4-nitrophenyl) -3- (4-nitrophenyl) -1 , 4-butanediol ;
3- (4-nitrophenyl) -5-phenyltetrahydro-2-furanone ;
5- (4 -Bromophenyl) -3- (4-nitrophenyl) tetrahydro-2 - furanone ;
5- (2, 4-dichlorophenyl) -3- (4-nitrophenyl) tetrahydro-2- furanone ;
5- (2 , 4-dichlorophenyl) -3 - (4-aminophenyl) -2- pyrrolidinone ;
Methyl 4- (2 , 4-dichlorophenylamino) -4-oxo-2- (4- nitrophenyl) butanoate; or
Methyl 3 - (2,4 -dichlorophenyloxoamino) -2 - (4 - nitrophenyl) propanoate .
34. A method of treating a disease state ameliorated by the presence of retinoic acid, which method comprises administering to a patient suffering from or susceptible to such a disease state a therapeutically effective amount of a compound as defined in any of claims 1 to 33, or 35 to 62, or a pharmaceutically acceptable salt or prodrug thereof.
35. A compound of the general Formula (I) , or a pharmaceutically acceptable salt or prodrug thereof
(I)
where R1 and R2 together are =0 or
or R1 and R2 are independently selected from the group consisting of H, CH20H, OH, halide and C02C1_4alkyl ;
R3 is H and R4 is OH or OT where T is
O O
- C - OR10 or - C - R10
where R10 is C1-4alkyl , aryl (C1-4) alkyl ,
di-aryl (C1-4) alkyl or aryl; or
R3 and R4 together are =0:
(i) when R1 and R2 together are =0; or
(ii) when R1 and R2 are both halide; or
(iii) at least one of R1 and R2 is is C02C1-4alkyl ; or
each of R3 and R4 is H when R1 and R2 together are not =0 ; or
R1 and R3 together are
0 O
II II
- C - 0 or - C - NH
when n is i, z is O and R2 and R4 are each H;
R5 and R6 are selected from the group consisting of H, halide, NH2, N (C1-4alkyl) 2, NH (C1-4alkyl) and N02, with the proviso that at least one of R5 and R6 is NH2, N(C1_4alkyl)2, NH (C1-4alkyl) and N02 and that both R5 and R6 are not N02 when R1 and R2 together are =0, R3 is H, R4 is OH, R7 is H, R8 is H, R9 is H, n is 1, y is 0 and z is 0 ;
R7 is H, or R7 is halide when R5 is halide;
each of R8 and R9 is H or halide;
n is 0 or 1;
y and z are both 0, or one of y and z is 1 and the other of y and z is 0.
36. A compound according to claim 35, wherein
R1 and R2 are selected from the group consisting of H, OH, Br, C02Me and CH2OH; or
R1 and R2 together are =0 or
or R1 and R3 together are
0 0
II II - C - O or - C - NH
when n is 1, z is 0 and R2 and R4 are each H.
37. A compound according to claim 36, wherein R2 is H when R1 is selected from H, C02Me and CH2OH.
38. A compound according to claim 37, wherein
R1 is C02Me, R2 is H and R3 and R4 together are =0; or
R1 is CH2OH, R2 is H, R3 is H and R4 is OH.
39. A compound according to claim 35, wherein R4 is OT, where T is
O
OR1
where R10 is di-aryl (C1-4) alkyl
40. A compound according to claim 39, wherein R10 is
di-aryl (C2_4) alkyl .
41. A compound according to claim 40, wherein R10 is
di-phenyl (C2-4) alkyl .
42. A compound according to any of claims 35 to 41, wherein R5 and R6 are selected from the group consisting of H, Br, Cl, NH2, N(Me)2 and N02, with the proviso that at least one of R5 and R6 is NH2, N(Me)2 and N02 and that both R5 and R6 are not N02 when R1 and
R2 together are =0, R3 is H, R4 is OH, R7 is H, R8 is H, R9 is H, n is 1, y is 0 and z is 0.
43. A compound of general Formula (IA) or (IB) , or a pharmaceutically acceptable salt or prodrug thereof
(IA)
(IB)
where Alk represents C1-4 alkyl;
R2 is H, CH2OH, OH, halide or C02C1-4 alkyl;
R5 and R6 are selected from the group consisting of H, halide, NH2, N(C1.4al yl) 2, NH (C^alkyl) and N02, with the proviso that at least one of R5 and R6 is NH2 ,
N (C1-4alkyl) 2, NH (C1-4alkyl) and N02 and that compounds of Formula (IA) and (IB) do not include a compound of Formula (I) as defined in claim 1 where both R5 and R6 are N02 when R1 and R2 together are =0, R3 is H, R4 is OH, R7 is H, R8 is H, R9 is H, n is 1, y is 0 and z is 0;
R7 is H, or halide when R5 is halide; and
each of R8 and R9 is H or halide.
44. A compound of general Formula (IC) or a pharmaceutically acceptable salt or prodrug thereof,
(IC)
where
Ra is selected from the group consisting of N02 , NH2, NH(C1_4alkyl) and N(C1-4alkyl) 2;
Rb is selected from the group consisting of H, halide and N02 and b is 1 or 2 ;
X can be selected from the group consisting of
-C(RC) (Rd)C(Re) (Rf) -,
-C(Rc) (Rd) (CH2)dC(Re) (Rf) -,
-C(RC) (Rd) (CH2)dC(Re) (Rf)N(Rg) - and
-C(RC) (Rd) (CH2)dN(Rg)C(Re) (Rf)-;
wherein Rc and Rd can be independently selected from the group consisting of H, halide, OH, CH2OH and
C02C1-4alkyl ; or
Rc and Rd together represent =0 or ethylenedioxy;
Re and Rf can be selected from the group consisting of H, OH and 0C02Rh, where Rh represents (diaryl) alkyl ; or
Re and Rf together represent =0 or ethylenedioxy;
Rg is H or Chalky1 ; and
d is an integer selected from 1 to 4; or
X can represent a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =0, with the proviso that in the case of following Formula (IC)
(IC)
Ra and Rb do not both represent N02 when X represents -CH(OH)CH2C(=0) -.
45. A compound according to claim 44, wherein said compound of general Formula (IC) is selected from the following:
(IC)
(IC)
(IC) wherein
Ra, Rb and X are as defined in claim 44
46. A compound according to claim 44 or 45, wherein Ra is selected from the group consisting of N02, NH2 and N(CH3)2.
47. A compound according to any of claims 44 to 46, wherein Rb is selected from the group consisting of H, Br, Cl and N02.
48. A compound according to any of claims 44 to 47, wherein X is selected from the group consisting of
-C(RC) (Rd)C(Re) (Rf)- ,
-C(RC) (Rd) (CH2)dC(Re) (Rf) - ,
-C(RC) (Rd) (CH2)dC(Re) (Rf)N(Rg) - and
-C(Rc) (Rd) (CH2)dN(Rg)C(Re) (Rf) - , wherein
Rc, Rd, Re, Rf, Rg and d are as defined in claim 44.
49. A compound according to claim 48, wherein X is selected from the group consisting of
-CH2CH(OH)-, -C(=0)C(=0) -, C (halide) 2C (=0) -,
-CH2C (ethylenedioxy) -, -CH2CH (OC02Rh) - where Rh is as defined in claim 44, -CH(OH)CH2-, -
C (ethylenedioxy) CH2- and -C (=0) CH (OH) - .
50. A compound according to claim 49, wherein X is selected from the group consisting of -CH2CH(0H)-,
-C(=0)C(=0) -, -C(Br)2C(=0) -, -CH2C (ethylenedioxy) - ,
-CHjCH [OCOj-CHRiR-] - where Rx is 2 , 4-dichlorophenyl and R. is 4-nitrobenzyl, -CH(OH)CH2- , -C (ethylenedioxy) CH2- and -C(=0)CH(0H) -.
51. A compound according to claim 48, wherein X is
-CH(C02C1_4alkyl) (CH2) dC (=0) - , wherein d is as defined in claim 44.
52. A compound according to claim 51, wherein X is
-CH(C02Me)CH2C(=0) -.
53. A compound according to claim 48, wherein X is
-CH(CH2OH) (CH2)dCH(OH) -, wherein d is as defined in claim 44.
54. A compound according to claim 53, wherein X is
-CH (CH20H) CH2CH (OH) - .
55. A compound according to claim 48, wherein X is
-CH(C02C1_4alkyl) (CH2) dC (=0) NH- , wherein d is as defined in claim 44.
56. A compound according to claim 55, wherein X is
-CH(C02Me)CH2C(=0)NH- .
57. A compound according to claim 48, wherein X is
-CH(C02C1_4alkyl) (CH2) dNHC (=0) -, wherein d is as defined in claim 44.
A compound according to claim 57, wherein X is
-CH (C02Me) CH2NHC (=0) - .
59. A compound according to any of claims 44 to 47, wherein X represents a 5 or 6 membered heterocyclic ring containing at least one heteroatom selected from oxygen and nitrogen and which heterocyclic ring can be substituted by =0.
60. A compound according to claim 59, wherein X represents a 5 membered heterocyclic ring containing an oxygen or nitrogen heteroatom, which ring is substituted by =0.
61. A compound according to claim 60, wherein the heterocyclic ring is either tetrahydrofuran or pyrrolidine .
62. 1- (2, 4 -Dichlorophenyl) -2- (4-nitrophenyl) -1-ethanol,
1- (2 ,4 -Dichlorophenyl) -2- (4-nitrophenyl) -1,2- ethandione;
2 , 2-Dibromo-l- (2 , 4-dichlorophenyl) -2- (4-nitrophenyl) 1-ethanone;
1- (2, 4 -Dichlorophenyl) -1, 1 -ethylenedioxy-2 - (4- nitrophenyl) ethane;
Di (1- (2 , 4-dichlorophenyl) -2- (4-nitrophenyl) ethyl) carbonate;
2- (2, 4 -Dichlorophenyl) -1- (4-nitrophenyl) -1-ethanol;
2- (2, 4 -Dichlorophenyl) -1, 1-ethylenedioxy-1- (4- nitrophenyl) ethane ;
2- (2, 4 -Dichlorophenyl) -1- (4-dimethylaminophenyl) -2- hydroxy- 1-ethanone ;
1- (2, 4 -Dichlorophenyl) -2- (4-dimethylaminophenyl) -1,2- ethandione;
2- (4-Aminophenyl) -1- (2 , 4-dichlorophenyl) -1,2- ethandione ;
Methyl 2- (4-nitrophenyl) -4-oxo-4-phenylbutanoate;
Methyl 4- (4 -bromophenyl) -2- (4-nitrophenyl) -4- oxobutanoate;
Methyl 4- (2 -chlorophenyl) -2- (4-nitrophenyl) -4- oxobutanoate ;
Methyl 4- (3 -chlorophenyl) -2- (4-nitrophenyl) -4- oxobutanoate ;
Methyl 4- (4 -chlorophenyl) -2- (4-nitrophenyl) -4- oxobutanoate ;
Methyl 4- (2 , 4-dichlorophenyl) -2- (4-nitrophenyl) - - oxobutanoate ;
Methyl 4- (3 , 4-dichlorophenyl) -2- (4-nitrophenyl) -4- oxobutanoate ;
Methyl 4- (4-nitrophenyl) -2- (4-nitrophenyl) -4- oxobutanoate;
3- (4 -Nitrophenyl) -1-phenyl-l, 4-butanediol ;
1- (4 -bromophenyl) -3- (4-nitrophenyl) -1, 4-butanediol ;
1- (2 -chlorophenyl) -3- (4-nitrophenyl) -1 , 4-butanediol ;
1- (3 -chlorophenyl) -3- (4-nitrophenyl) -1 , 4-butanediol ;
1- (4 -chlorophenyl) -3- (4-nitrophenyl) -1 , 4-butanediol ;
1- (2 , 4-dichlorophenyl) -3- (4-nitrophenyl) -1,4- butanediol ;
1- (3 , 4-dichlorophenyl) -3- (4-nitrophenyl) -1,4- butanediol ;
1- (4-nitrophenyl) -3- (4-nitrophenyl) -1, 4-butanediol ;
3- (4-nitrophenyl) -5 -phenyltetrahydro-2-furanone;
5- (4 -Bromophenyl) -3- (4-nitrophenyl) tetrahydro-2- furanone ;
5- (2 , 4-dichlorophenyl) -3- (4-nitrophenyl) tetrahydro-2- furanone ;
5- (2 , 4-dichlorophenyl) -3- (4-aminophenyl) -2 - pyrrolidinone ;
Methyl 4- (2 , 4-dichlorophenylamino) -4-oxo-2- (4- nitrophenyl) butanoate; or
Methyl 3- (2 , 4-dichlorophenyloxoamino) -2- (4- nitrophenyl) propanoate.
63. A method of preparing a compound as defined in any of claims 35 to 43, with the proviso that said compound is defined by Formula (I) where each of n, y and z is 0, which method comprises reacting a substituted benzaldehyde derivative of Formula (II)
(II)
with any one of compounds of Formulae (Ilia) , (IV) or (V)
(ma)
(IV)
(V)
where Y in Formula (Ilia) is hydrogen or a group reactive with the aldehyde moiety of benzaldehyde derivatives of Formula (II) ;
in Formula (IV) Het is a heterocyclic moiety and X is a leaving group;
R1, R2, R5, R6, R7, R8 and R9 are as defined in claims 35 to 43; and
R5 represents R5 or a precursor thereof that can readily be converted to R5.
64. A method according to claim 63, wherein a compound of Formula (IV) is obtained by reaction of a heterocyclic group with a benzyl derivative of Formula (VI)
(VI)
where X is a leaving group.
65. A method of preparing a compound as defined in any of claims 35 to 43, with the proviso that said compound is defined by Formula (I) where n is 1 and each of y
and z is 0, which method comprises reacting a compound of Formula (II lb)
(Elb)
and a compound of Formula (VII)
(VII)
where in Formula (Illb) Y is hydrogen or a group reactive with the phenyl ring substituent
X-CH2-C(R3) (R4) - of a compound of Formula (VII)
in Formula (VII) X is a leaving group; and
R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in claims 35 to 43.
66. A method according to any of claims 63 to 65, wherein X is a halide.
67. A method according to claim 65, wherein a compound of Formula (VII) is obtained by halogenation of an
acetophenone derivative of Formula (VIII)
(VIII)
where R6, R8 and R9 are as defined in claims 35 to 43
68. A method according to claim 63 or 65, wherein a compound of Formula (Ilia) or (Illb) in which either
R1 or R2 represents -C02C1-4alkyl is prepared from a phenyl acetic acid derivative of Formula (IX)
(K)
where R2, R5 and R7 are as defined in claims 35 to 43
69. A method of preparing a compound according to claim 49 or 50, which method comprises reacting a substituted benzaldehyde derivative of Formula (X)
(X)
with any one of compounds of Formulae (XIa) , (Xlb) and (XIc)
(Xlb)
(XIc)
where Y in Formula (XIa) is hydrogen or a group reactive with the aldehyde moiety of benzaldehyde derivatives of Formula (X) ;
in Formula (Xlb) Het is a heterocyclic moiety and X is a leaving group;
Ra, Rb, Rc and Rd are as defined in claim 49 or 50; and
Ral represents Ra or a precursor thereof that can readily be converted to Ra.
0. A method of preparing a compound according to any of claims 51 to 54, which method comprises reacting a compound of Formula (XIa)
(XIa)
and a compound of Formula (XII)
X-(CH2)d-
(XII)
where in Formula (XIa) Y is hydrogen or a group reactive with the phenyl ring substituent
X-CH2-C (Re) (Rf) - of a compound of Formula (XII);
in Formula (XII) X is a leaving group; and
Ra, Rb, Rc, Rd, Re, Rf, b and d are as defined in any of claims 51 to 54.
71. A pharmaceutical Formulation comprising a compound according to any of claims 35 to 62, or a pharmaceutically acceptable salt or prodrug thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient therefor.
72. Use in the manufacture of a medicament capable of inhibiting retinoic acid metabolism, a compound according to any of claims 35 to 62.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2001233891A AU2001233891A1 (en) | 2000-02-17 | 2001-02-19 | Diphenyl compounds, formulations and uses thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0003671.5 | 2000-02-17 | ||
| GBGB0003671.5A GB0003671D0 (en) | 2000-02-17 | 2000-02-17 | Diphenyl-substituted lower alkanes |
Publications (2)
| Publication Number | Publication Date |
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| WO2001060781A2 true WO2001060781A2 (en) | 2001-08-23 |
| WO2001060781A3 WO2001060781A3 (en) | 2002-03-14 |
Family
ID=9885792
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2001/000686 WO2001060781A2 (en) | 2000-02-17 | 2001-02-19 | Diphenyl compounds, formulations and uses thereof |
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| Country | Link |
|---|---|
| AU (1) | AU2001233891A1 (en) |
| GB (1) | GB0003671D0 (en) |
| WO (1) | WO2001060781A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9428464B2 (en) | 2011-08-30 | 2016-08-30 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
| US9981918B2 (en) | 2011-08-30 | 2018-05-29 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
| US10258621B2 (en) | 2014-07-17 | 2019-04-16 | Chdi Foundation, Inc. | Methods and compositions for treating HIV-related disorders |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995005376A1 (en) * | 1993-08-19 | 1995-02-23 | Warner-Lambert Company | Substituted 2(5h)furanone, 2(5h)thiophenone and 2(5h)pyrrolone derivatives, their preparation and their use as endothelin antagonists |
| WO1999035129A1 (en) * | 1998-01-02 | 1999-07-15 | University College Cardiff Consultants Limited | Succinimide derivatives which inhibit retinoic acid metabolism |
-
2000
- 2000-02-17 GB GBGB0003671.5A patent/GB0003671D0/en not_active Ceased
-
2001
- 2001-02-19 WO PCT/GB2001/000686 patent/WO2001060781A2/en active Application Filing
- 2001-02-19 AU AU2001233891A patent/AU2001233891A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995005376A1 (en) * | 1993-08-19 | 1995-02-23 | Warner-Lambert Company | Substituted 2(5h)furanone, 2(5h)thiophenone and 2(5h)pyrrolone derivatives, their preparation and their use as endothelin antagonists |
| WO1999035129A1 (en) * | 1998-01-02 | 1999-07-15 | University College Cardiff Consultants Limited | Succinimide derivatives which inhibit retinoic acid metabolism |
Non-Patent Citations (3)
| Title |
|---|
| B.E. BETTS ET AL: "Chalcones and related compounds. Part VII. Catalysed exchange of hydrogen cyanide between acetone cyanohydrin and chalcones" JOURNAL OF THE CHEMICAL SOCIETY., 1958, pages 4193-4196, XP002180482 CHEMICAL SOCIETY. LETCHWORTH., GB * |
| CHEMICAL ABSTRACTS, vol. 127, no. 1, 7 July 1997 (1997-07-07) Columbus, Ohio, US; abstract no. 6132, YAO, ZUGUANG ET AL: "Synthesis of bis(1,2-diaryl-1,2-ethylenedithiolato)nick el complexes and their photostabilization action" XP002180484 -& DATABASE CAPLUS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; Database accession no. 127:6132 XP002180485 & HUAXUE YANJIU YU YINGYONG (1997), 9(2), 151-154 , * |
| CHEMICAL ABSTRACTS, vol. 29, no. 1, 1935 Columbus, Ohio, US; C.F.H. ALLEN ET AL: "Certain reactions of gamma-ketonic acids" column 135; XP002180483 & CAN. J. RESEARCH, vol. 11, 1934, pages 382-394, * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9428464B2 (en) | 2011-08-30 | 2016-08-30 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
| US9981918B2 (en) | 2011-08-30 | 2018-05-29 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
| US10258621B2 (en) | 2014-07-17 | 2019-04-16 | Chdi Foundation, Inc. | Methods and compositions for treating HIV-related disorders |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001060781A3 (en) | 2002-03-14 |
| GB0003671D0 (en) | 2000-04-05 |
| AU2001233891A1 (en) | 2001-08-27 |
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