WO2003000692A2 - Oxytocin agonists - Google Patents
Oxytocin agonists Download PDFInfo
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- WO2003000692A2 WO2003000692A2 PCT/GB2002/002872 GB0202872W WO03000692A2 WO 2003000692 A2 WO2003000692 A2 WO 2003000692A2 GB 0202872 W GB0202872 W GB 0202872W WO 03000692 A2 WO03000692 A2 WO 03000692A2
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- 0 *C(*)(CC1C(N)=C)C*1C(*Cc1c(*)cc(C(N)=O)c(*)c1*)=O Chemical compound *C(*)(CC1C(N)=C)C*1C(*Cc1c(*)cc(C(N)=O)c(*)c1*)=O 0.000 description 3
- VGLLTCFHMCXMCP-OUPQRBNQSA-N C/C=C\C=C/C(CNN)=C Chemical compound C/C=C\C=C/C(CNN)=C VGLLTCFHMCXMCP-OUPQRBNQSA-N 0.000 description 1
- NDOXTVBNTIUVNR-HJWRWDBZSA-N CC[O](C)/C=C(\C([O](C)CC)=O)/C#N Chemical compound CC[O](C)/C=C(\C([O](C)CC)=O)/C#N NDOXTVBNTIUVNR-HJWRWDBZSA-N 0.000 description 1
- LAYDFDMDUCVHBO-UHFFFAOYSA-N Cc(cc(cc1C)Br)c1C#N Chemical compound Cc(cc(cc1C)Br)c1C#N LAYDFDMDUCVHBO-UHFFFAOYSA-N 0.000 description 1
- QGLAYJCJLHNIGJ-UHFFFAOYSA-N Cc(cc(cc1C)Br)c1N Chemical compound Cc(cc(cc1C)Br)c1N QGLAYJCJLHNIGJ-UHFFFAOYSA-N 0.000 description 1
- DNOXFFNRMSJGBK-UHFFFAOYSA-N Cc(cc(cc1C)C(O)=O)c1C#N Chemical compound Cc(cc(cc1C)C(O)=O)c1C#N DNOXFFNRMSJGBK-UHFFFAOYSA-N 0.000 description 1
- VLXWEUASWRQBAY-UHFFFAOYSA-N Cc(cc1F)ccc1S Chemical compound Cc(cc1F)ccc1S VLXWEUASWRQBAY-UHFFFAOYSA-N 0.000 description 1
- ALFWHEYHCZRVLO-UHFFFAOYSA-N Cc1ccc(C(O)=O)c(F)c1 Chemical compound Cc1ccc(C(O)=O)c(F)c1 ALFWHEYHCZRVLO-UHFFFAOYSA-N 0.000 description 1
- LLOLLEPUQXDZSG-UHFFFAOYSA-N Cc1ccc(C(OC)=O)c(F)c1 Chemical compound Cc1ccc(C(OC)=O)c(F)c1 LLOLLEPUQXDZSG-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to a series of non-peptide oxytocin agonists and to pharmaceutical compositions comprising such compounds.
- the compositions are useful for the treatment of certain physiological disorders, such as erectile dysfunction.
- OT neurophyseal hormones oxytocin
- VP vasopressin
- Vasopressin differs from oxytocin in that it has phenylalanine at position 3 in place of isoleucine and arginine at position 8 in place of leucine. Both hormones are synthesised in vivo as larger precursors, neurophysins, which are subject to post-translational processing to release the mature peptides.
- OT and VP act through a family of heptahelical receptors. Only one OT receptor has so far been well characterised, while three VP receptors are known. These are designated the V 1a , V 1b and V 2 receptors.
- the first target organs to be identified for OT were the uterus, where it is implicated in the onset and progress of labour, and mammary glands, where it is involved in the regulation of milk expression.
- Other organs also express OT receptors, and it is clear that OT has a range of physiological roles that have not been fully elaborated yet.
- OT acting in the CNS is involved in the erectile response in males, and in the regulation of female sexual arousal.
- OT is erectogenic when administered i.c.v. to male rats. It also has erectogenic activity when given i.v., but the doses required are up to two orders of magnitude greater, which is consistent with a central mode of action.
- Vasopressin acts on the blood vessels, where it is a potent vasoconstrictor, and on the kidneys, where it promotes water reuptake leading to an antidiuretic effect.
- peptide analogues of OT are known in the literature. These include both agonists and antagonists. OT and its agonists are used, for example, to accelerate labour and to increase uterine muscle tone to control post-partum bleeding, and one antagonist, atosiban, has recently been registered as a treatment for pre-term labour.
- the peptidic nature of these compounds means that they are not likely to be bioavailable after oral dosing or to cross into the CNS.
- attention has increasingly turned to non-peptides.
- non-peptide OT antagonists in early-stage development. So far, however, there have been no reports of non-peptide OT agonists. This is not unexpected, as it is generally held that it is easier to find a receptor antagonist than an agonist.
- non-peptide OT receptor agonists should preferably be selective for the OT receptor over the VP receptors. They could be expected to show therapeutic utility in male and female sexual dysfunction, particularly male erectile dysfunction, in promoting labour, in controlling post-partum bleeding, in increasing milk let-down as well as a number of other indications.
- the present invention comprises novel compounds according to general formula 1 , and pharmaceutically acceptable salts thereof.
- G 1 is a group according to general formula 2 or 3.
- G 2 is a group according to general formula 4, 5, 6, 7, 8 or 9.
- a 1 is CH 2 , CH(OH), NH, N-alkyl, N-(CH 2 ) n -R 27 , O or S;
- a 4 and A 5 are each CH or N;
- a 6 is CH 2 , NH, N-alkyl or O;
- a 7 and A 11 are C or N;
- a 8 and A 9 are CH, N, NH, N(CH 2 ) m R 26 or S;
- a 12 and A 13 are N or C and A 14 ,
- a 15 and A 16 are NH, N-CH 3 , S, N or CH, provided that not more than one of A 8 , A 9 and A 10 is
- X 1 is O or NH;
- X 2 is NR 16 , CH-NR 17 R 18 , CH-CH 2 NR 17 R 18 , N + R 19 R 20 , CH-N + R R 22 R 23 or CH-CH 2 N + R 2 R 2 R 23 and Y is O or S.
- R ⁇ R 2 and R 3 are each H, alkyl, O-alkyl, F, Cl or Br;
- R 7 is H, alkyl or any group as defined above for R 3 ;
- R 8 , R 9 and R 10 are independently H or alkyl, or R 8 and R 9 together may be -(CH 2 ) g -;
- R 11 , R 2 , R 13 , R 14 and R 15 are all alkyl, or R 11 and R 12 together or R 14 and R 15 together may be -(CH 2 ) g -;
- R 16 , R 17 and R 18 are independently H or alkyl, or R 17 and R 18 together may be -(CH 2 ) ;
- R 19 , R 20 , R 21 , R 22 and R 23 are all alkyl, or R 19 and R 20 together or R 21 and R 22 together may be -(CH 2 ) ;
- R 24 and R 25 are independently alkyl, Ar or -(CH 2 ) k -Ar;
- R 26 is H, alkyl, optionally substituted phenyl, pyridyl
- Ar is thienyl or optionally substituted phenyl.
- the present invention comprises pharmaceutical compositions of these novel compounds, which compositions are useful for the treatment of, inter alia, male erectile dysfunction.
- the present invention comprises the use of such compositions in therapy and therapeutic methods using the compositions.
- the present invention comprises novel benzyl carbamates and ureas according to general formula 1.
- R 1 , R 2 and R 3 are independently selected from hydrogen (H), alkyl groups, alkoxy (O-alkyl) groups, and the halogens fluorine (F), chlorine (Cl) and bromine (Br).
- R 1 , R 2 and R 3 is H and at least one is not H. More preferably, one of R 1 , R 2 and R 3 is an alkyl group or a halogen and the others are H.
- R 1 is methyl or Cl and R 2 and R 3 are both H.
- both R 4 and R 5 are H or one is H and the other is O-alkyl. More preferably, both R 4 and R 5 are H or one is H and the other is methoxy. Furthermore, in embodiments where one of R 4 and R 5 is F, it is preferred that the other should also be F.
- the linking group X 1 is selected from oxygen (O) and unsubstituted nitrogen (NH).
- X 1 is NH.
- Y is selected from O and sulphur (S).
- a requirement of G 1 is the presence of at least one basic nitrogen atom or a quaternary salt derived from such a basic nitrogen atom within the group.
- the basic nitrogen atom may be present as a primary, secondary or tertiary amino group or a pyridyl nitrogen. When G 1 includes more than one such basic nitrogen atom then these may be the same or different. Accordingly, G 1 is selected from an acyclic group according to general formula 2 and a cyclic group according to general formula 3.
- R 6 and R 7 may be the same or different.
- R 6 is selected from a group according to one of general formulae 10 to 25.
- R 8 and R 9 together may be a polymethylene chain -(CH 2 ) g - where g is 4, 5 or 6, so as to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine or perhydroazepine ring.
- R 11 , R 12 , R 3 , R 14 and R 15 are all alkyl, or R 11 and R 12 together or R 4 and R 15 together may be -(CH 2 ) g - again allowing for pyrrolidine, piperidine and perhydroazepine rings.
- the attachment to the pyridine ring may be at the 2-, 3- or 4-position.
- R 7 may be any of the foregoing groups described for R 6 , or it may be a non-basic group selected from H and alkyl.
- h is 1 , 2 or 3 and i is 1 , 2, 3 or 4.
- X 2 is selected from the basic groups NR 16 , CH-NR 17 R 18 and CH-CH 2 NR 17 R 18 and the corresponding quaternary groups N + R 19 R 20 , CH-N + R 21 R 22 R 23 and CH-CH 2 N + R 21 R 22 R 23 .
- R 16 , R 17 and R 18 are independently selected from H and alkyl, or R 17 and R 18 together may be -(CH 2 )-, where j is 4, 5 or 6, such that R 17 , R 18 and the nitrogen atom to which they are attached may constitute a pyrrolidine, piperidine or perhydroazepine ring.
- R 19 , R 20 , R 21 , R 22 and R 23 are all alkyl, or R 19 and R 20 together or R 21 and R 22 together may be -(CH 2 )-.
- G 2 is selected from an acyclic group according to general formula 4, a fused bicyclic group according to general formulae 5, 7 and 8, and a fused tricyclic group according to general formulae 6 and 9.
- R 24 and R 25 are independently selected from alkyl, Ar and -(CH 2 ) k -Ar, where k is 1 , 2 or 3 and Ar is selected from thienyl and optionally substituted phenyl.
- Suitable substituents for the phenyl group are alkyl groups, OH, alkoxy groups, halogens, NH 2 , NH-alkyl and N(alkyl) 2 .
- the phenyl group may be substituted with up to three such substituents which may be the same or different.
- a 1 is selected from CH 2 , CH(OH), NH, N-alkyl, N-(CH 2 ) n -R 27 , O and S, where n is 2, 3 or 4 and R 27 is selected from OH, alkoxy groups, acyloxy (O-CO-alkyl) groups, NH 2 , NH-alkyl and N(alkyl) 2 .
- a 3 is S and A 4 and A 5 are both CH, so as to form a thiophene ring.
- Suitable substituents for the phenyl group are alkyl groups, OH, alkoxy groups, halogens, NH 2 , NH-alkyl and N(alkyl) 2 .
- the phenyl group may be substituted with up to three such substituents which may be the same or different.
- the ring constituted by A 7 , A 8 , A 9 , A 10 and A 11 is aromatic, and accordingly the groups must satisfy certain requirements.
- a "trigonal nitrogen” is a nitrogen atom linked covalently to three different atoms. Two of these atoms are the immediate neighbours to the nitrogen atom in the five-membered ring. The third is a hydrogen, carbon or other atom linked to the five-membered ring.
- a 8 , A 9 and A 10 may be NH, N-(CH 2 ) m -R 26 or S.
- a 7 and A 11 may not both simultaneously be N.
- a 6 is NH.
- a 8 is NH or N-(CH 2 ) m -R 26 .
- a 8 is NH or N-(CH 2 ) m -R 2e , A 9 is N and A 10 is CH.
- One of A 14 , A 15 and A 16 is NH, N-CH 3 or S or one of A 12 and A 13 is N.
- a 12 and A 13 may not both simultaneously be N.
- R 1A is methyl or Cl and R 4A is H or O-methyl.
- G 1 and G 2 are as previously defined.
- R , R , G and G are as previously defined.
- Another particularly preferred embodiment is a compound according to general formula 28.
- R , R , R , G and Y are as previously defined.
- R , R , R , A , G and Y are as previously defined.
- Acyclic secondary amines corresponding to HNR 24 R 25 are well known. Many are items of commerce. Those that are not may be prepared according to published methods or by simple modification of such methods. Some particularly useful methods are listed below. a) Alkylation
- the starting amide can itself be prepared using well known methods.
- Substituted benzoic acids corresponding to C 2 are not generally items of commerce, but they can be prepared using published methods or obvious variations of such methods.
- the main challenge is generally the elaboration of the -CH 2 X 1 H functionality at the 4- position.
- Proline and hydroxyproline derivatives are items of commerce.
- Other proline derivatives corresponding to C 3 can be prepared according to the methods set out in Dugave et al., Tet. Lett. 39, 1998, 1169; Petrillo et al., J. Med. Chem. 31 , 1988, 1148; and Smith et al., J. Med. Chem. 31 , 1988, 875.
- the quaternary ammonium salts can generally be prepared by treating a primary, secondary or tertiary amine with an excess of alkylating agent.
- the bond between C 1 and C 2 is a simple amide bond.
- the chemistry for making such bonds from a carboxylic acid and a secondary amine is well known in the art of organic synthesis, and particularly in the field of peptide synthesis.
- the carboxylic acid may be converted into a more reactive species such as an acid chloride (using, for example oxalyl chloride or thionyl chloride) or a mixed anhydride (using isobutyl chloroformate).
- the carboxylic acid and the secondary amine may be mixed in a suitable solvent as above, optionally in the presence of a base, and a condensing agent added.
- suitable condensing agents include carbodiimides, such as dicyclohexylcarbodiimide (DCC) and N-ethyl-N'-dimethylaminopropylcarbodiimide (EDC, also WSCDI for water- soluble carbodiimide), phosphorus reagents such as (benzotriazol-1-yloxy)- tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)- tripyrrolidinophosphonium hexafluorophosphate (PyBOP ® ) and bromothpyrrolidino- phosphonium hexafluorophosphate (PyBroP ® ), and ureas such as O-(benzotri
- the first step in the formation of this bond is generally to react the proline derivative with phosgene or a phosgene equivalent such as t chloromethyl chloroformate, bis(trichloromethyl)carbonate or carbonyldiimidazole. Again, an aprotic solvent and a tertiary amine base will generally be used.
- the intermediate formed in this step is usually not isolated.
- the reactive intermediate may be formed by the reaction of C 2 with the phosgene equivalent and the proline added in the second part of the synthesis.
- the bond between C 3 and C 2 is a simple amide bond, and it may be formed by the methods described above for the formation of the C 1 -C 2 bond.
- the bond is a thioamide. This is generally prepared by first making the simple amide and then treating this with Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1 ,3-dithia-2,4- diphosphetane-2,4-disulfide).
- a second aspect of the present invention is a pharmaceutical formulation that includes a compound as described above as an active ingredient.
- a third aspect of the present invention is the use of a compound according to the first aspect in the manufacture of such a composition.
- composition according to the present invention may be presented in any form that is known in the art.
- the formulation may be presented as a tablet, capsule, powder, suppository, cream, solution or suspension, or in a more complex form such as an adhesive patch.
- the formulation will generally include one or more excipients, such as diluents, bulking agents, binding agents, dispersants, solvents, preservatives, flavoring agents and the like.
- the excipients may optionally include one or more agents to control the release of the active species, such as a coating of a polymer that is insoluble at low pH but soluble at neutral or high pH.
- Such a coating prevents the release of the active agent in the stomach but allows its release in the intestines.
- the formulation may also include one or more additional pharmacologically active species. Preferably the formulation includes no such additional active agents.
- the composition is used to treat male or female sexual dysfunction, and more preferably erectile dysfunction.
- compositions of the present invention may be administered by any appropriate route that is known in the art.
- they may be administered by the oral, buccal, sublingual, rectal, intravaginal, nasal, pulmonary or transdermal routes.
- they may be given by injection, including intravenous, subcutaneous and intramuscular injection.
- the amount given will be determined by the attending physician taking into consideration all appropriate factors.
- a single dose will comprise between 0.1 mg and 1000mg, preferably between 1mg and 250mg, of active compound.
- the dose may be given on a single occasion or repeatedly. When given repeatedly, it may be given at regular intervals, such as once, twice or three times daily, or on demand, according to the condition being treated.
- Benzylhydrazine dihydrochloride (4.29g, 22mmol) was added to a solution of ethyl (ethoxymethylene)cyanoacetate (3.38g, 20mmol) and triethylamine (6.15ml, 44mmol, 2eq) in ethanol (40ml) and the mixture was heated at reflux for 18hr. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluant 60% pet. ether/40% ethyl acetate) to yield a pale yellow solid identified as ethyl 5- amino-1-benzylpyrazole-4-carboxylate (4.3g, 88%).
- Ethyl 1-benzyl-5-(2'-nitrophenylamino)pyrazole-4-carboxylate (2.5g, 6.8mmol) was dissolved in ethyl acetate/ethanol (1 :1 , 100ml) and hydrogenated over 10% Pd/C catalyst for 70 minutes. The mixture was filtered through Celite ® filter agent and the filtrate was concentrated in vacuo to give a white solid identified as ethyl 5-(2'-aminophenylamino)-1- benzylpyrazole-4-carboxylate (1.5g, 86%).
- LiAIH 4 (365mg, 10mmol) was added portionwise to a suspension of 1-benzyl-4,10- dihydropyrazolo[5,4-jb][1 ,5]benzodiazepin-4(5H)-one (780mg, 2.7mmol) in anhydrous THF (15ml) at 0°C over 10min. The resulting suspension was heated at reflux for 18hr, then allowed to cool to room temperature. A further portion of LiAIH 4 (90mg, 2.5mmol) was added and the mixture was heated at refluxed for 3hr. The mixture was cooled to 0°C, 35% ammonia solution (1 ml) was added dropwise over 10min and the mixture was stirred at RT for 1hr.
- Lawesson's reagent (6.79g, 16.8mmol) was added to a solution of 1-( ⁇ /-benzyl- oxycarbonyl-L-prolyl)-4-(tert-butyloxycarbonyl)perhydro-1 ,4-diazepine (12g, 28mmol) in toluene (200ml) and stirred at 90°C for 1 hr then 85°C for 18hr.
- lodomethane (13.9mg, 6.1 ⁇ l, 0.098mmol) was added to a solution of 4-methyl-1-( ⁇ /-(2- methyl-4-(1 -methyl-4, 10-dihydropyrazolo[5,4- ⁇ ][1 ,5]benzodiazepin-5-ylcarbonyl)benzyl- carbamoyl)-L-thioprolyl)perhydro-1 ,4-diazepine (30mg, 0.049mmol) in THF (10ml) and the mixture was stirred at RT for 4hr. The resulting solid was collected and dissolved in water (5ml).
- HOBt 14. ⁇ mg, 0.097mmol
- WSCD 22.6 ⁇ mg, 0.1 1 mmol
- 4-(pyrrolidinyl)piperidine (13.7mg, O.O ⁇ mmol) were added to an ice-cold solution of (4R)- ⁇ / ⁇ -(2-chloro-4-(5,6,7, ⁇ - tetrahydrothieno[3,2-j ]azepin-4-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline (40mg, O.O ⁇ l mmol) and triethylamine (1 ⁇ l, 0.12mmol) in dichloromethane (10ml).
- the compounds of the invention In the binding assay the compounds of the invention generally demonstrate significant inhibition of radioligand binding at concentrations of 50 ⁇ M or less. In the functional assay, the compounds of the invention cause significant cellular activation at concentrations of 30 ⁇ M or less. Preferred compounds cause significant activation at concentrations of 300nM or less and can induce the same maximal effect as OT. The compounds are either significantly less active or completely devoid of activity in assays for vasopressin-like activity.
- Representative compounds were tested for activity in the rat uterine contractility model, which is a recognised test for OT agonism.
- the compounds increased the strength and frequency of the uterine contractions at doses below 50mg/kg.
- Selected compounds were then given either i.e. v. or i.v. to male rats and the erectile response was determined.
- Tablets containing 100mg of the compound of Example 11 as the active agent are prepared from the following:
- the compounds according to the present invention act as agonists at the oxytocin receptor and accordingly they may find utility as pharmaceutical agents for the treatment of conditions such as sexual disorders including male erectile dysfunction and ejaculatory disorders, female sexual dysfunction, cancer of the prostate, breast, ovary and bones, osteoporosis, benign prostatic hyperplasia, post- partum bleeding, and depression.
- the compounds may also be used to induce labour or delivery of the placenta, to decrease arterial blood pressure, to decrease exaggerated responses to stress and to increase the nociceptive threshold.
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2003-7016688A KR20040010762A (en) | 2001-06-25 | 2002-06-24 | Oxytocin agonists |
JP2003507095A JP2005500317A (en) | 2001-06-25 | 2002-06-24 | Oxytocin agonist |
CA002450480A CA2450480A1 (en) | 2001-06-25 | 2002-06-24 | Oxytocin agonists |
MXPA03011980A MXPA03011980A (en) | 2001-06-25 | 2002-06-24 | Oxytocin agonists. |
IL15928902A IL159289A0 (en) | 2001-06-25 | 2002-06-24 | Oxytocin agonists |
NZ530035A NZ530035A (en) | 2001-06-25 | 2002-06-24 | Oxytocin agonists |
AT02732974T ATE291021T1 (en) | 2001-06-25 | 2002-06-24 | OXYTOCIN AGONISTS |
DE60203290T DE60203290T2 (en) | 2001-06-25 | 2002-06-24 | OXYTOCIN AGONISTS |
DK02732974T DK1399436T3 (en) | 2001-06-25 | 2002-06-24 | Oxytocin agonists |
US10/482,102 US20040235753A1 (en) | 2001-06-25 | 2002-06-24 | Oxytocin agonists |
EP02732974A EP1399436B1 (en) | 2001-06-25 | 2002-06-24 | Oxytocin agonists |
HU0400368A HUP0400368A3 (en) | 2001-06-25 | 2002-06-24 | Oxytocin agonists, pharmaceutical compositions containing them and their use in treatment of sexual dysfunctions |
NO20035772A NO20035772L (en) | 2001-06-25 | 2003-12-22 | oxytocin agonists |
HK04107317A HK1064666A1 (en) | 2001-06-25 | 2004-09-23 | Oxytocin agonists. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GBGB0115515.9A GB0115515D0 (en) | 2001-06-25 | 2001-06-25 | Oxytocin agonisys |
GB0115515.9 | 2001-06-25 |
Publications (2)
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WO2003000692A2 true WO2003000692A2 (en) | 2003-01-03 |
WO2003000692A3 WO2003000692A3 (en) | 2003-05-15 |
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US (1) | US20040235753A1 (en) |
EP (1) | EP1399436B1 (en) |
JP (1) | JP2005500317A (en) |
KR (1) | KR20040010762A (en) |
CN (1) | CN1606553A (en) |
AT (1) | ATE291021T1 (en) |
CA (1) | CA2450480A1 (en) |
CZ (1) | CZ20033414A3 (en) |
DE (1) | DE60203290T2 (en) |
DK (1) | DK1399436T3 (en) |
ES (1) | ES2239717T3 (en) |
GB (1) | GB0115515D0 (en) |
HK (1) | HK1064666A1 (en) |
HU (1) | HUP0400368A3 (en) |
IL (1) | IL159289A0 (en) |
MX (1) | MXPA03011980A (en) |
NO (1) | NO20035772L (en) |
NZ (1) | NZ530035A (en) |
PL (1) | PL367538A1 (en) |
PT (1) | PT1399436E (en) |
RU (1) | RU2309156C2 (en) |
WO (1) | WO2003000692A2 (en) |
ZA (1) | ZA200309626B (en) |
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EP1449844A1 (en) * | 2003-02-14 | 2004-08-25 | Ferring B.V. | benzamide derivatives as oxytocin agonists and vasopressin antagonists |
US7091314B2 (en) | 2002-02-27 | 2006-08-15 | Ferring Bv | Intermediates and methods for making heptapeptide oxytocin analogues |
JP2007504263A (en) * | 2003-09-05 | 2007-03-01 | フェリング ベスローテン フェンノートシャップ | Piperazines as oxytocin agonists |
WO2007050353A2 (en) * | 2005-10-24 | 2007-05-03 | Wyeth | Tricyclic compounds useful as oxytocin receptor agonists |
JP2008510684A (en) * | 2004-08-24 | 2008-04-10 | フェリング ベスローテン フェンノートシャップ | Vasopressin V1a antagonist |
WO2009033783A2 (en) * | 2007-09-11 | 2009-03-19 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
WO2009033820A2 (en) * | 2007-09-11 | 2009-03-19 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
WO2009033782A2 (en) * | 2007-09-11 | 2009-03-19 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
WO2009039981A2 (en) * | 2007-09-11 | 2009-04-02 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
WO2009043457A2 (en) * | 2007-09-11 | 2009-04-09 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
WO2011147889A1 (en) | 2010-05-25 | 2011-12-01 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for the treatment of a feeding disorder with early-onset in a patient |
WO2016089797A1 (en) | 2014-12-05 | 2016-06-09 | Merck Sharp & Dohme Corp. | Novel tricyclic compounds as inhibitors of mutant idh enzymes |
WO2017004674A1 (en) * | 2015-07-06 | 2017-01-12 | The University Of Sydney | Therapeutic compounds and compositions for treating social disorders and substance use disorders |
WO2018107216A1 (en) | 2016-12-12 | 2018-06-21 | The University Of Sydney | Non-peptide oxytocin receptor agonists |
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- 2002-06-24 WO PCT/GB2002/002872 patent/WO2003000692A2/en active IP Right Grant
- 2002-06-24 DK DK02732974T patent/DK1399436T3/en active
- 2002-06-24 NZ NZ530035A patent/NZ530035A/en unknown
- 2002-06-24 KR KR10-2003-7016688A patent/KR20040010762A/en not_active Application Discontinuation
- 2002-06-24 MX MXPA03011980A patent/MXPA03011980A/en active IP Right Grant
- 2002-06-24 CN CNA028125843A patent/CN1606553A/en active Pending
- 2002-06-24 EP EP02732974A patent/EP1399436B1/en not_active Expired - Lifetime
- 2002-06-24 HU HU0400368A patent/HUP0400368A3/en unknown
- 2002-06-24 CZ CZ20033414A patent/CZ20033414A3/en unknown
- 2002-06-24 ES ES02732974T patent/ES2239717T3/en not_active Expired - Lifetime
- 2002-06-24 US US10/482,102 patent/US20040235753A1/en not_active Abandoned
- 2002-06-24 DE DE60203290T patent/DE60203290T2/en not_active Expired - Fee Related
- 2002-06-24 IL IL15928902A patent/IL159289A0/en unknown
- 2002-06-24 RU RU2003136152/04A patent/RU2309156C2/en not_active IP Right Cessation
- 2002-06-24 CA CA002450480A patent/CA2450480A1/en not_active Abandoned
- 2002-06-24 AT AT02732974T patent/ATE291021T1/en not_active IP Right Cessation
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US7304181B2 (en) | 2002-02-27 | 2007-12-04 | Ferring Bv | Methods for making intermediates and oxytocin analogues |
US7816489B2 (en) | 2002-02-27 | 2010-10-19 | Ferring B.V. | Methods for making intermediates and oxytocin analogues |
US7091314B2 (en) | 2002-02-27 | 2006-08-15 | Ferring Bv | Intermediates and methods for making heptapeptide oxytocin analogues |
US7407949B2 (en) | 2003-02-14 | 2008-08-05 | Ferring B.V. | Benzamide derivatives as oxytocin agonists and vasopressin antagonists |
CN100349896C (en) * | 2003-02-14 | 2007-11-21 | 凡林有限公司 | Benzamide derivatives as oxytocin agonists and vasopressin antagonists |
EP1449844A1 (en) * | 2003-02-14 | 2004-08-25 | Ferring B.V. | benzamide derivatives as oxytocin agonists and vasopressin antagonists |
WO2004072083A1 (en) * | 2003-02-14 | 2004-08-26 | Ferring B.V. | Benzamide derivatives as oxytocin agonists and vasopressin antagonists |
JP2007504263A (en) * | 2003-09-05 | 2007-03-01 | フェリング ベスローテン フェンノートシャップ | Piperazines as oxytocin agonists |
JP2008510684A (en) * | 2004-08-24 | 2008-04-10 | フェリング ベスローテン フェンノートシャップ | Vasopressin V1a antagonist |
US8202858B2 (en) | 2004-08-24 | 2012-06-19 | Vantia Limited | Vasopressin V1a antagonists |
JP2010285442A (en) * | 2004-08-24 | 2010-12-24 | Vantia Ltd | VASOPRESSIN V1a ANTAGONIST |
WO2007050353A2 (en) * | 2005-10-24 | 2007-05-03 | Wyeth | Tricyclic compounds useful as oxytocin receptor agonists |
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WO2009033820A3 (en) * | 2007-09-11 | 2009-11-26 | Mondobiotech Laboratories Ag | Use of saralasin and carbetocin in combination to treat of eg aids or idiopathic pulmonary fibrosis |
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WO2009043457A3 (en) * | 2007-09-11 | 2009-11-26 | Mondobiotech Laboratories Ag | Use of human hemokinin-1 and optionally oxytocin to treat diseases involving excessive angiogenesis |
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WO2009043458A3 (en) * | 2007-09-11 | 2009-11-26 | Mondobiotech Laboratories Ag | Use of oxytocin to treat many diseases |
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Also Published As
Publication number | Publication date |
---|---|
RU2309156C2 (en) | 2007-10-27 |
PL367538A1 (en) | 2005-02-21 |
EP1399436A2 (en) | 2004-03-24 |
DE60203290T2 (en) | 2006-02-02 |
HUP0400368A2 (en) | 2004-08-30 |
ES2239717T3 (en) | 2005-10-01 |
KR20040010762A (en) | 2004-01-31 |
MXPA03011980A (en) | 2004-03-26 |
DE60203290D1 (en) | 2005-04-21 |
NZ530035A (en) | 2004-06-25 |
HK1064666A1 (en) | 2005-02-04 |
JP2005500317A (en) | 2005-01-06 |
CZ20033414A3 (en) | 2004-05-12 |
EP1399436B1 (en) | 2005-03-16 |
PT1399436E (en) | 2005-07-29 |
NO20035772L (en) | 2003-12-22 |
CA2450480A1 (en) | 2003-01-03 |
IL159289A0 (en) | 2004-06-01 |
WO2003000692A3 (en) | 2003-05-15 |
GB0115515D0 (en) | 2001-08-15 |
CN1606553A (en) | 2005-04-13 |
ZA200309626B (en) | 2004-05-12 |
HUP0400368A3 (en) | 2007-05-29 |
ATE291021T1 (en) | 2005-04-15 |
RU2003136152A (en) | 2005-05-20 |
DK1399436T3 (en) | 2005-05-30 |
US20040235753A1 (en) | 2004-11-25 |
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