Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
• • 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
• • 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
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • 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
  • A61P17/08—Antiseborrheics
• • 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
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/008—Preparations for oily skin
• • 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
  • C07D401/12—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 chain containing hetero atoms as chain links
• • 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
  • C07D403/12—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 chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to methods of modulating the activity of the melanocortin-5 receptor.
• the present invention relates to the use of a family of 1 ,4-diazepan-2-ones and derivatives thereof to modulate the activity of the melanocortin-5 receptor.
• the invention also relates to methods and uses of the compounds in the treatment of conditions in which antagonism of the melanocortin-5 receptor is beneficial.
• the melanocortin-5 receptor (MC5R) is a G-protein coupled receptor (GPCR) belonging to the family of melanocortin receptors. There are five melanocortin receptors that have been isolated and cloned to date: MC1 R, MC2R, MC3R, MC4R and MC5R.
• GPCR G-protein coupled receptor
• the melanocortin receptors participate in a variety of physiologic functions, providing a number of opportunities for therapeutic intervention in physiologic processes through alteration (i.e., a statistically significant increase or decrease) or modulation (e.g., up-regulation or down- regulation) of melanocortin receptor signalling activity.
• the melanocortin receptor family members are regulated by natural peptide agonists such as ACTH and the melanocyte-stimulating hormones ( ⁇ -, ⁇ -, ⁇ -MSH) derived from pro-opiomelanocortin (POMC) and by peptide antagonists such as Agouti signal protein (ASP) and Agouti-related peptide (AGRP).
• ACTH the melanocyte-stimulating hormones
• ⁇ -, ⁇ -, ⁇ -MSH melanocyte-stimulating hormones
• POMC pro-opiomelanocortin
• ASP Agouti signal protein
• AGRP Agouti-related peptide
• the MC2R differs from the other melanocortin receptors in that it binds only ACTH but not MSH ligands. It is highly expressed in the adenal gland and controls corticosteroid synthesis.
• the MC3R is found in the brain, but also elsewhere in the body, and appears to play a role in the regulation of energy homeostasis, and possibly sexual dysfunction.
• the MC4R is found almost exclusively in the brain, with some reports of its presence elsewhere. It has been strongly associated with feeding control, and also implicated with sexual desire.
• the MC5R is widely expressed in peripheral tissues, particularly in the exocrine glands, with some receptor also expressed in the brain.
• the MC5R has been cloned and expressed from multiple species, including humans in 1993 (though called MC2 in this paper) (Chhajlani 1993), rat in 1994 (Griffon 1994) mice in 1994 (Gantz 1994; Labbe 1994) and in 1995 (Fathi 1995), canine (Houseknecht 2003), rhesus monkey (Huang 2000), sheep (Barrett 1994), zebrafish (Ringholm 2002), goldfish (Cerda-Reverter 2003), spiny dogfish (Klovins 2004), rainbow trout (Haitina 2004), and chicken (Ling 2004), with the MC5R gene also identified in pig (Kim 2000). Patents covering the MC5R sequence in humans (Wikberg 2002), mice (Yamada 1997),
• mice lacking MC5R have reduced sebum production, as evidenced by a marked inability to shed water from their fur, and a reduced quantity of sebum isolated from their hair. Significantly, these mice were otherwise generally healthy, with no readily visible abnormalities (appearance, behaviour, growth, muscle mass, adipose mass, reproduction, basal and stress-induced corticosterone, glucose and insulin levels) (Chen 1997). Further studies have identified reductions in pheromones, causing alterations in aggressive behaviours between mice (Caldwell 2002; Morgan 2004a; Morgan 2004b; Morgan 2006).
• mice in which the POMC-derived peptide native ligands of MC5R have been knocked out show a similar phenotype (Yaswen 1999).
• a synergistic effect between ⁇ -MSH and testosterone was observed in rats, with testosterone increasing sebaceous gland and cell volumes (presumably via increased proliferation), ⁇ -MSH increasing dermal lipogenesis, and the combination increasing sebum secretion (Thody 1975a; Thody 1975b).
• human sebocytes have been shown to express MC5R, via detection of MC5R transcripts in micro-dissected sebaceous glands (Thiboutot 2000), detection of MC5R in human facial sebaceous glands by immunostaining (Hatta 2001 ), detection of MC5R mRNA and MC5R in human sebaceous glands, cultured human sebocytes and rat preputial cells (Thiboutot 2000) and detection of MC5R as punctate particles within sebaceous glands by staining with polyclonal antibodies, seen in differentiated but not undifferentiated sebocytes (Zhang 2006).
• MC5R mRNA was also detected in sebaceous glands from the skin of wild-type mice, but not in skin sections of the MC5R-knockout mice (Chen 1997).
• Treatment of human sebocytes with cholera toxin (ChT), bovine pituitary extract (BPE), ⁇ - MSH or NDP-MSH increases lipid droplet formation, squalene synthesis, and MC5R expression (Zhang 2003; Zhang 2006), While both MC1 R and MC5R have been detected in sebaceous cells, treatment of primary human sebocyte cell culture with NDP-MSH or BPE caused a substantial increase in human MC5R expression compared to serum-free conditions, correlating with sebocyte differentiation.
• a family of 1 ,2,4-thiadiazole derivatives with MC5R antagonist activity (138-320 nM) were found to reduce sebum formation both in human sebocyte cell cultures and when applied topically to human skin grafted onto immunodeficient mice (Eisinger 2003a-d; 2006a,b).
• Sebaceous secretion is a common affliction. Sebaceous glands occur over most of the body, with dense concentrations of large glands on the face, scalp and upper trunk (Simpson and Cunliffe p43.1 ). Sebaceous secretion is dependent in part on androgenic hormones, possibly partly mediated by 5 ⁇ -reductase processing of testosterone to 5 ⁇ -DHT (dihydrotestosterone). Sebum consists of a species-specific mixture of lipids.
• Sebum is the main nutrient of P. acnes, thus reduction of sebum will reduce the subsequent bacterial infection and inflammation response.
• Androgenic sex hormones appear to play a role in the development of acne, with strong correlations with sebum production (Makrantonaki 2007).
• Two oral contraceptive pills are approved by the FDA for the treatment of acne vulgaris (Harper 2005), and these compounds appear to act by reducing androgen mediated sebum formation. Diet (Cordain 2005; Smith 2007b), stress (Zouboulis 2004) and genetic factors (Goulden 1999; Bataille 2006) also may play a role in acne, again potentially via increased sebum production.
• acnes (Simpson and Cunliffe p43.37, 43.46; Williams 2006). Both topical retinoids and benzoyl peroxide cause skin irritation, and retinoids can cause photosensitivity (Williams 2006).
• Oral therapies include isotretinoin, antibiotics, hormones, and steroids. In females, antiandrogens have been shown to reduce sebum production (by approximately 40-80%, though with no placebo control group) and improve acne (Simpson and Cunliffe p43.44; Burke 1984; Goodfellow 1984).
• Laser and UV-based therapies are gaining acceptance, and are believed to act through heating of the sebaceous gland followed by reduction in sebum formation; with reductions in both sebum formation and acne lesions measured (Jih 2006; Bhardwaj 2005).
• oral isotretinoin and hormonal therapies act by regulating the sebaceous gland to reduce sebum secretion (Clarke 2007).
• oral isotretinoin 13-cis-retinoic acid, Roaccutane, Accutane was introduced in 1983 and still remains the most clinically effective anti-acne therapy.
• Seborrhoea or excessive skin oil production, is often associated with severe acne.
• Seborrheic dermatitis SD is a skin disease associated with sebum-rich areas of the scalp, face and trunk with scaly, flaky, itchy red skin affecting 3-5% of the population; dandruff represents a mild form of this dermatitis affecting 15-20% of the population.
• Seborrhoea and SD appear more common in patients with Parkinson's disease or mood disorders (facial paralysis, supraorbital injury, poliomyelitis, syringomyelia, quadriplegia, unilateral injury to the ganglion Gasser and those with HIV/AIDS) (Plewig 1999). Studies have shown that seborrheic dermatitis is also associated with chronic alcoholic pancreatitis, hepatitis C virus and various cancers. It is also common in patients with genetic disorders, such as Down's syndrome, Hailey-Hailey disease and cardio-facio cutaneous syndrome (Gupta 2004). MC5R antagonists may be useful for treating these indications.
• Muir-Torre syndrome consists of sebaceous gland adenomas associated with an internal adenocarcinoma (usually colon, breast, ovary or prostate). Preventing sebaceous cell differentiation may provide an effective treatment for arresting tumour growth. Oral isotretinoin has been used for this purpose (Graefe 2000). Sebaceous hyperplasia is a benign hyperplasia of the sebaceous glands, generating yellowish small papules on the skin surface, usually the face.
• the disease is associated with excessive undifferentiated sebocyte proliferation, but not excessive sebum formation.
• Ectopic sebaceous glands are similar yellow papules found in the mouth or on the penile shaft. Both respond to oral isotreinoin. A compound that reduced sebocyte proliferation could be an effective treatment.
• ⁇ -MSH shows immunosuppressive effects in humans, suppressing a variety of inflammation responses, and the MC5R has been implicated in these immunomodulating activities.
• MC5R mRNA was found to be expressed at high levels in human CD4+ T helper (Th) cells and in moderate levels in other human peripheral blood leukocytes (Andersen 2005).
• Th human CD4+ T helper
• MC5R was detected in the lymphoid organs (Labbe, 1994), and MC5R was found on the surface of mouse pro-B-lymphocyte cells where it appears to mediate ⁇ -MSH activation of the JAK2 signalling pathway, enhancing cellular proliferation (Buggy 1998).
• Induction of CD25+ CD4+ regulatory T-cells by ⁇ -MSH also appears to be through MC5R (Taylor 2001 ).
• Therapeutic regulation of biological signal transduction includes modulation of MC5R-mediated cellular events including, inter alia, inhibition or potentiation of interactions among MC5R-binding and activating or deactivating molecules, or of other agents that regulate MC5R activities.
• An increased ability to so regulate MC5R may facilitate the development of methods for modulating sebum secretion or other biological processes, and for treating conditions associated with such pathways such as acne as described above.
• the present invention provides a method of down-regulating the activity of MC5R or a fragment, analogue or functional equivalent thereof comprising exposing the MC5R or a fragment or analogue or functional equivalent thereof to a compound of the formula (I):
• Y is a group of formula -(CR a R ⁇ u ) n -;
• R is an amino acid side chain group
• R 1 is selected from the group consisting of H, optionally substituted d-C ⁇ alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted CrC 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 - C 18 heteroaryl;
• R 2 and R 3 are each independently selected from the group consisting of H, optionally substituted Ci-Ci 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 - Ci 2 alkynyl, optionally substituted Ci-Ci 2 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted Ci-Ci 8 heteroaryl;
• each R 5a and R 5b are independently selected from the group consisting of H, halogen,
• R 6 , R 7 and R 8 are each independently selected from the group consisting of H, halogen, hydroxy, optionally substituted CrC 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 1 -C 12 heteroalkyl, optionally substituted C 1 -C 10 heteroalkenyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 - C 18 heteroaryl, optionally substituted amino, optionally substituted carboxy, CrC 12 alkyloxy, and optionally substituted thio, or
• R 6 , R 7 and R 8 when taken together with the carbon atom to which they are attached two or more of R 6 , R 7 and R 8 form a moiety selected from the group consisting of optionally substituted C 2 - C 12 alkenyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 2 - C 12 heterocycloalkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 - C 18 heteroaryl, or
• R 6 , R 7 and R 8 when taken together with one or more of R 5a and R 5b and the atoms to which they are attached form a moiety selected from the group consisting of an optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted CrC 18 heteroaryl;
• each R 9 and R 10 is independently selected from the group consisting of H, optionally substituted CrC 12 alkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 - C 18 heteroaryl;
• each R 11 and R 12 is independently selected from the group consisting of H, and optionally substituted CrC 12 alkyl;
• n is an integer selected from the group consisting of 1 , 2, 3 and 4;
• r is an integer selected from the group consisting of 1 , 2, 3, and 4;
• s is an integer selected from the group consisting of 1 , 2, 3, and 4; or a pharmaceutically acceptable salt or prodrug thereof.
• the MC5R or fragment or analogue or functional equivalent thereof is in a cell and the method comprises exposing the cell to a compound of formula (I).
• the invention provides a method of down-regulating the activity of MC5R or fragment or analogue or functional equivalent thereof in a mammal comprising administering a MC5R-modulating amount of a compound of the invention to the mammal.
• the invention provides the use of a compound of the formula (I) in down-regulating the activity of MC5R or a fragment, analogue or functional equivalent thereof.
• the invention provides the use of a compound of formula (I) in the preparation of a medicament for down-regulating the activity of MC5R or fragment or analogue or functional equivalent thereof in a mammal.
• the invention provides a method of treating, preventing, or controlling a condition associated with the activity of MC5R or a fragment, analogue or functional equivalent thereof in a mammal the method comprising administering a therapeutically effective amount of a compound of formula (I).
• the compound may be administered in any way known in the art although in one aspect the compound is administered topically. In another aspect the compound is administered orally. In another aspect the compound is administered parenterally.
• the condition is selected from the group consisting of acne, seborrhoea, and seborrheic dermatitis. In one embodiment the condition is acne vulgaris.
• the compound of formula (I) is administered in combination with a second active agent. In one embodiment the second active agent is selected from the group consisting of antibiotics, retinoids, anti-androgens, and steroids.
• the invention provides the use of a compound of formula (I) in the preparation of a medicament for treating, preventing, or controlling a condition associated with the activity of MC5R or a fragment, analogue or functional equivalent thereof in a mammal.
• the medicament is adapted to be administered topically.
• the medicament is adapted to be administered orally.
• the compound is administered parenterally.
• the condition is selected from the group consisting of acne, seborrhoea, and seborrheic dermatitis.
• the condition is acne vulgaris.
• the invention provides a method of reducing sebum secretion by a mammal the method comprising administering a therapeutically effective amount of a compound of formula (I) to the mammal.
• the compound of the invention may be administered in any way known in the art although in one aspect the compound is administered topically. In another aspect the compound is administered orally. In another aspect the compound is administered parenterally.
• the medicament in the preparation of a medicament for reducing sebum secretion in a mammal.
• the medicament is adapted to be administered topically.
• the medicament is adapted to be administered orally.
• the compound is administered parenterally.
• the term "optionally substituted” as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more non-hydrogen substituent groups.
• R a , R b , R c and R d are each independently selected from the group consisting of H, C1-C12 alkyl, C1-C12 haloalkyl, C 2 -Ci 2 alkenyl, C 2 -Ci 2 alkynyl, C1-C10 heteroalkyl, C 3 -Ci 2 cycloalkyl, C 3 -Ci 2 cycloalkenyl, C r Ci 2 heterocycloalkyl, C r Ci 2 heterocycloalkenyl, C 6 -Ci 8 aryl,
• Ci-Ci 8 heteroaryl and acyl, or any two or more of R a , R b , R c and R d , when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
• Examples of particularly suitable optional substituents include F, Cl, Br, I, CH 3 , CH 2 CH 3 , OH, OCH 3 , CF 3 , OCF 3 , NO 2 , NH 2 , and CN.
• amino acid side chain group represents a natural or unnatural side chain group present in a protein.
• the term includes side chain moieties present in naturally occurring proteins including the naturally occurring amino acid side chain moieties identified in table 1 below.
• the term also includes derivatives or analogs thereof.
• derivative or analogue of an amino acid side chain group includes modifications and variations to naturally occurring side chain groups. With reference to the table above most of the naturally occurring amino acid side chain groups may be classified as alkyl, aryl, arylalkyl or heteroalkyl moieties. As such derivatives of amino acid side chain groups include straight or branched, cyclic or non-cyclic alkyl, aryl, heteroaryl, heteroarylalkyl, arylalkyl or heteroalkyl moieties.
• Amino acid side chain groups as discussed above also include optionally substituted derivatives of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heteroalkyl moieties.
• the optional substituents may be selected from the group defined above.
• the optional substituents may be selected from but are not limited to OH, Cl, Br, F, COOH, C00R z , CONH 2 , NH 2 , NHR Z , NR Z R Z , SH, SR Z , SO 2 R 2 , SO 2 H and SOR Z wherein R z is an alkyl, aryl or arylalkyl moiety.
• the group may be a terminal group or a bridging group. This is intended to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety.
• alkyl alkyl
• alkylene alkylene
• the modifier indicating the number of carbon atoms present in the moiety indicates that the alkyl moiety has from 1 to 6 carbon atoms.
• the modifier "C 1 -C- I s" in front of the term “heteroaryl” indicates that the heteroaromatic ring may have from 1 to 18 carbon atoms as part of the total number of atoms in the ring system.
• examples of acyl include acetyl and benzoyl.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
• Alkenyl as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms, most preferably 2- 6 carbon atoms, in the normal chain.
• the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z.
• Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
• the group may be a terminal group or a bridging group.
• alkenyloxy refers to an alkenyl-O- group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C 1 -C 6 alkenyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
• Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C 1 -C 14 alkyl, more preferably a C 1 -C 1 0 alkyl, most preferably CrC 6 unless otherwise noted.
• suitable straight and branched CrC 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.
• the group may be a terminal group or a bridging group.
• Alkylamino includes both mono-alkylamino and dialkylamino, unless specified.
• “Mono-alkylamino” means a Alkyl-NH- group, in which alkyl is as defined herein.
• “Dialkylamino” means a (alkyl) 2 N- group, in which each alkyl may be the same or different and are each as defined herein for alkyl.
• the alkyl group is preferably a CrC 6 alkyl group.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
• Alkyloxy refers to an alkyl-O- group in which alkyl is as defined herein.
• the alkyloxy is a Ci-C 6 alkyloxy. Examples include, but are not limited to, methoxy and ethoxy.
• the group may be a terminal group or a bridging group.
• Alkyloxyalkyl refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
• Alkyloxyary refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group.
• the alkyl group is preferably a C 1 -C 6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
• Alkyloxycycloalkyl refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the cycloalkyl group.
• Alkyloxyheteroary refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroaryl group.
• Alkyloxyheterocycloalkyl refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heterocycloalkyl group.
• the alkyl group is preferably a C 1 -C 6 alkyl group.
• Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
• the alkyl group is preferably a CrC 6 alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
• Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-14 carbon atoms, more preferably 2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.
• Exemplary structures include, but are not limited to, ethynyl and propynyl.
• the group may be a terminal group or a bridging group.
• Alkynyloxy refers to an alkynyl-O- group in which alkynyl is as defined herein. Preferred alkynyloxy groups are C 1 -C 6 alkynyloxy groups.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
• Aminoalkyl means an NH 2 -alkyl- group in which the alkyl group is as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
• Aryl as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring.
• aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C 5-7 cycloalkyl or C 5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
• the group may be a terminal group or a bridging group.
• an aryl group is a C 6 -C 18 aryl group.
• Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein.
• exemplary arylalkenyl groups include phenylallyl.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
• Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a Ci -5 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl, 1-naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
• Arylalkyloxy refers to an aryl-alkyl-O- group in which the alkyl and aryl are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
• Arylamino includes both mono-arylamino and di-arylamino unless specified.
• Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein.
• di-arylamino means a group of formula (aryl) 2 N- where each aryl may be the same or different and are each as defined herein for aryl.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
• Arylheteroalkyl means an aryl-heteroalkyl- group in which the aryl and heteroalkyl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
• Aryloxy refers to an aryl-O- group in which the aryl is as defined herein.
• the aryloxy is a C 6 -Ci 8 aryloxy, more preferably a C 6 -Ci 0 aryloxy.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
• a “bond” is a linkage between atoms in a compound or molecule.
• the bond may be a single bond, a double bond, or a triple bond.
• Cyclic group refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system.
• Examples of cyclic groups include cycloalkyl, cycloalkenyl and aryl.
• Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
• Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
• the cycloalkenyl group may be substituted by one or more substituent groups.
• the group may be a terminal group or a bridging group.
• Cycloalkyl refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group.
• Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as defined herein.
• Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
• Cycloalkylalkenyl means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
• Cycloalkylheteroalkyl means a cycloalkyl-heteroalkyl- group in which the cycloalkyl and heteroalkyl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
• Cycloalkyloxy refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein.
• the cycloalkyloxy is a C-rC 6 cycloalkyloxy.
• examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy.
• the group may be a terminal group or a bridging group.
• the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
• Cycloalkenyloxy refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein.
• the cycloalkenyloxy is a CrC ⁇ cycloalkenyloxy.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
• Haloalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
• a haloalkyl group typically has the formula C n H (2n +i- m ) Xm wherein each X is independently selected from the group consisting of F, Cl, Br and I .
• n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
• m is typically 1 to 6, more preferably 1 to 3.
• Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.
• Haloalkenyl refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I.
• Haloalkynyl refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I. "Halogen” represents chlorine, fluorine, bromine or iodine.
• Heteroalkyl refers to a straight- or branched-chain alkyl group preferably having from
• heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.
• the group may be a terminal group or a bridging group.
• Heteroaryl either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.
• heteroaryl examples include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, pheno
• Heteroarylalkyl means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moiety.
• heteroarylalkyl groups include pyridylmethyl.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
• Heteroarylalkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
• Heteroarylheteroalkyl means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
• Heteroaryloxy refers to a heteroaryl-O- group in which the heteroaryl is as defined herein. Preferably the heteroaryloxy is a Ci-Ci 2 heteroaryloxy.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
• Heterocyclic refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom.
• heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.
• Heterocycloalkenyl refers to a heterocycloalkyl as defined herein but containing at least one double bond.
• the group may be a terminal group or a bridging group.
• Heterocycloalkyl refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
• heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4-oxazepane, and 1 ,4-oxathiapane.
• the group may be a terminal group or a bridging group.
• Heterocycloalkylalkyl refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as defined herein.
• exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
• Heterocycloalkylalkenyl refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and alkenyl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
• Heterocycloalkylheteroalkyl means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl and heteroalkyl moieties are as defined herein.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
• Heterocycloalkyloxy refers to a heterocycloalkyl-O- group in which the heterocycloalkyl is as defined herein.
• the heterocycloalkyloxy is a Cr C 6 heterocycloalkyloxy.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
• Heterocycloalkenyloxy refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein.
• the heterocycloalkenyloxy is a CrC 6 heterocycloalkenyloxy.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
• Hydroalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an OH group.
• a hydroxyalkyl group typically has the formula C n Hp n+I-X) (OH) x
• n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
• x is typically 1 to 6, more preferably 1 to 3.
• “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
• the group may be a terminal group or a bridging group.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
• the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
• Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
• the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) wherein one or more atoms have the same atomic number as, but an atomic mass or mass number different from, the atomic mass or mass number usually found in nature.
• isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
• isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
• substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• Substitution with positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
• PET Positron Emission Topography
• Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically- labeled reagents in place of the non-labeled reagent previously employed.
• Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
• each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
• pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts.
• Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
• organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing
• agents that are solids it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
• Prodrug means a compound that undergoes conversion to a compound of formula (I) within a biological system, usually by metabolic means (e.g. by hydrolysis, reduction or oxidation).
• metabolic means e.g. by hydrolysis, reduction or oxidation.
• an ester prodrug of a compound of formula (I) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule.
• Suitable esters of compounds of formula (I) containing a hydroxyl group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
• an ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
• ester prodrugs are those described by FJ. Leinweber, Drug Metab. Res., 18:379, 1987.
• an acyl prodrug of a compound of formula (I) containing an amino group may be convertible by hydrolysis in vivo to the parent molecule.
• prodrugs for these and other functional groups, including amines are described in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V. Stella, R. Borchardt, M. Hageman, R.Oliyai, H. Maag and J Tilley; Springer, 2007).
• terapéuticaally effective amount or “effective amount” is an amount sufficient to effect beneficial or desired clinical results.
• An effective amount can be administered in one or more administrations.
• An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
• the term "functional equivalent” is intended to include variants of the specific receptor described herein. It will be understood that receptors may have isoforms, such that while the primary, secondary, tertiary or quaternary structure of a given receptor isoform is different to the prototypical receptor; the molecule maintains biological activity as a receptor. Isoforms may arise from normal allelic variation within a population and include mutations such as amino acid substitution, deletion, addition, truncation, or duplication. Also included within the term “functional equivalent” are variants generated at the level of transcription.
• the preferred stereochemistry at the 3 and 5 positions of the ring of the compounds of formula (I) is the 3S, 5S diastereomer. Accordingly, in one embodiment of the methods and uses of the invention the compound of formula (I) used is a compound of formula (Ia):
• R 1 , R 2 , R 3 , R 5a , R 5b , R 6 , R 7 , R 8 , X, Y and r are as defined above,
• Z is a group of formula -(CR 13 R 14 ) q -;
• R 4a and R 4b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic moiety, or
• R 4a and R 4b when taken together with any R 13 or R 14 and the atoms to which they are attached forms an optionally substituted heterocyclic moiety
• R 13 and R 14 are each independently selected from the group consisting of H, halogen, OH, Ci-Ci 2 alkyl, C 6 -C 18 aryl, d-C 12 hydroxyalkyl, d-C 12 haloalkyl, d-C 12 alkyloxy and C 1 - d 2 haloalkyloxy, or
• R 13 and R 14 when taken together with the carbon to which they are attached R 13 and R 14 form an optionally substituted C 3 -d 2 cycloalkyl, or an optionally substituted d-d 2 heterocycloalkyl group, or
• R 13 and R 14 when taken together with one of R 4a , and R 4b and the atoms to which they are attached form an optionally substituted heterocyclic moiety, or
• R 13 and R 14 when taken together with one of R 15 , R 16 , R 17 , R 18 , R 19 or R 20 and the atoms to which they are attached form an optionally substituted cyclic moiety;
• each R 15 , R 15a , R 16 , R 16a , R 17 , R 17a , R 18 , R 19 and R 20 is independently selected from the group consisting of H, optionally substituted d-d 2 alkyl, optionally substituted C 1 - C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted d-dsheteroaryl, or
• R 15 , R 15a , R 16 , R 16a , R 17 , R 17a , R 18 , R 19 and R 20 when taken together with the atoms to which they are attached form an optionally substituted cyclic group, or
• R 15 , R 16 , R 17 , R 18 , R 19 and R 20 when taken together with one of R 13 and R 14 and the atoms to which they are attached form an optionally substituted cyclic moiety;
• q is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5; or a pharmaceutically acceptable salt or prodrug thereof.
• n is 1 and Y is -CR 9 R 10 -. In another embodiment of the suitable compounds n is 2 and Y is -CR 9 R 10 CR 9 R 10 -.
• each R 9 and R 10 is independently selected from H and CH 3 . In one specific embodiment R 9 and R 10 are both H. Accordingly in one embodiment of the compounds suitable for use in the invention Y is -CH 2 -. In another embodiment of compounds suitable for use in the invention Y is - CH 2 CH 2 -. In yet an even further embodiment of compounds suitable for use in the invention Y is -C(CHa) 2 -.
• R 2 is H or CrC 6 alkyl. In a specific embodiment R 2 is H.
• R 3 is H or CrC 6 alkyl. In a specific embodiment R 3 is H.
• R 2 H
• R 1 , R 4 , R 5a , R 5b , R 6 , R 7 , R 8 and r are as defined above.
• R 4 is optionally substituted Ci-Ci 8 heteroaryl. In another embodiment R 4 is optionally substituted C 3 -Ci 2 cycloalkyl. In another embodiment R 4 is Cr Ci 2 alkyl
• R 15 and R 16 when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidin-1-yl, pyrrolidin-1 -yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1 -yl and 1-azepanyl.
• R 16 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2, CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3, CH 2 CH(CH 3 ) 2, C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
• R 17 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2, CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3, CH 2 CH(CH 3 ) 2, C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
• R 1 , R 4a , R 4b , R 5a , R 5b , R 6 , R 7 , R 8 , Z and r are as defined for formula (I).
• r is selected from the group consisting of 1 , 2, 3, and 4. In one specific embodiment r is 1. In another specific embodiment r is 2. In yet a further specific embodiment r is 3. In an even further specific embodiment r is 4.
• R 1 , R 4 , R 6 , R 7 , R 8 and Z are as defined for formula (I).
• This provides compounds of formula (Ha).
• R 1 , R 4a , R 4b , R 6 , R 7 , R 8 , and Z are as defined for formula (I).
• Z is a group of formula
• R 13 and R 14 are independently selected from H and CrC 6 alkyl.
• R and R are each independently selected from H and CH 3 .
• R 13 and R 14 are both H.
• at least one of R 13 and R 14 when taken together with at least one of R 4a and R 4b and the atoms to which they are attached form an optionally substituted heterocycloalkyl group.
• Z is - (CH 2 ) q -
• q is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5. In one specific embodiment q is 1. In another specific embodiment q is 2, in yet an even further specific embodiment q is 3, and in yet an even further specific embodiment q is 4.
• R 1 , R 4a , R 4b , R 6 , and R 8 are as defined for formula (I).
• R 1 , R 4a , R 4b , R 6 , and R 8 are as defined for formula (I).
• R 4b is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2, CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3, CH 2 CH(CH 3 ) 2, C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
• R 4a and R 4b when taken together with the nitrogen atom to which they are attached form an optionally substituted C 2 -Ci 2 heterocycloalkyl group, an optionally substituted C 2 -Ci 2 heterocycloalkenyl group or an optionally substituted Ci-Ci 8 heteroaryl group.
• R 4a and R 4b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, piperazin-1-yl, morpholin-4-yl and azepan-1-yl.
• the compound of formula (I) is one in which one of R 4a and R 4b when taken together with the nitrogen atom to which it is attached and one of R 13 and R 14 and the carbon atom to which it is attached form an optionally substituted C 2 -Ci 2 heterocycloalkyl group.
• one of R 4a and R 4b when taken together with the nitrogen atom to which it is attached and one of R 13 and R 14 and the carbon atom to which it is attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl, and azepanyl.
• NR 4a R 4b in the compounds which are useful in the methods and uses of the invention include:
• R 7 is H.
• R 6 and R 8 are each independently selected from the group consisting of H, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 6 -Ci 8 aryl and optionally substituted Ci-Ci 8 heteroaryl.
• R 6 is selected from the group consisting of H, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2-methylbutyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionally substituted phenyl and optionally substituted CrC 5 heteroaryl
• R 6 is optionally substituted phenyl or optionally substituted Ci-Ci ⁇ heteroaryl.
• R 8 is selected from the group consisting of H, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2-methyl-butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, optionally substituted phenyl and optionally substituted C 1 -C5 heteroaryl.
• R 8 is methyl, ethyl, phenyl or optionally substituted CrC 5 heteroaryl.
• R 6 , R 7 and R 8 when taken together with the carbon to which they are attached form a moiety selected from the group consisting of optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted Ci-Ci 8 heteroaryl.
• R 6 , R 7 and R 8 when taken together with the carbon to which they are attached form an optionally substituted C 6 -Ci 8 aryl group.
• R 6 , R 7 and R 8 when taken together with the carbon atom to which they are attached form a disubstituted phenyl group.
• the disubstituted phenyl group is a 2,4-disubstituted phen-1-yl group or a 3,5-disubstituted phen-1-yl group.
• substituents may be present on the disubstituted phenyl group as defined above.
• substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2- trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3- dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl,
• the disubstituted phenyl group is a 3,5- dichlorophen-1-yl group.
• R 1 is selected from the group consisting of optionally substituted C 2 -C 12 alkenyl, optionally substituted C 6 -Ci 8 aryl and optionally substituted Ci-Ci 8 heteroaryl.
• R 1 is optionally substituted C 6 -Ci 8 aryl.
• the C 6 -Ci 8 aryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C 6 -Ci 8 aryl is a monocyclic moiety. In certain embodiments the C 6 -Ci 8 aryl is a bicyclic moiety.
• R 1 is an optionally substituted C 6 -Ci 8 aryl selected from the group consisting of optionally substituted phenyl, biphenyl, and optionally substituted naphthyl.
• the moieties may be unsubstituted or may be substituted with one or more optional substituents.
• a wide variety of optional substituents may be used as defined above.
• Such optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3- dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent- 4-enyl, hexyl, heptyl, octyl, phenyl, NH 2 , cyano, phenoxy, hydroxy, methoxy, ethoxy, pyrrol-1- yl, and 3,5-dimethyl-pyrazol-1-yl.
• substituents may be located at any substitutable position around the aryl ring available for substitution as would be clear to a skilled addressee.
• suitable optionally substituted phenyl compounds include, but are not limited to, 2-methoxy-phenyl, 3- methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4- trifluoromethyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 2- fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl- phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-difluoro-phenyl, 2- chloro-6-
• R 1 is optionally substituted biphenyl
• the point of attachment of R 1 to the remainder of the molecule may be at the 2-, 3- or 4- position relative to the point of attachment of the second phenyl ring.
• the biphenyl may be an optionally substituted biphen-2-yl, or an optionally substituted biphen-3-yl, or an optionally substituted biphen-4-yl.
• the optionally substituted biphenyl is an optionally substituted biphen-4-yl.
• the optionally substituted biphenyl may be substituted in any suitable position.
• R 1 is optionally substituted naphthyl
• the point of attachment of R 1 to the remainder of the molecule may be at the 1 or 2 position.
• the naphthyl may be an optionally substituted naphth-1-yl, or an optionally substituted naphth-2-yl.
• the optionally substituted naphthyl is an optionally substituted naphth-2-yl.
• the optionally substituted naphthyl may be substituted in any suitable position.
• Suitable optionally substituted naphth-2-yls include, but are not limited to, 6-fluoro-naphth-2-yl, 6- bromo-naphth-2-yl, 6-chloro-naphth-2-yl, 1-methoxy-naphth-2-yl, 3-methoxy-naphth-2-yl, 6- methoxy-naphth-2-yl, 1-hydroxy-naphth-2-yl, and 6-amino-naphth-2-yl.
• R 1 is optionally substituted Ci-Ci 8 heteroaryl.
• the Ci-Ci 8 heteroaryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the Ci-Ci 8 heteroaryl is a monocyclic moiety. In certain embodiments the Ci-C-i ⁇ heteroaryl is a bicyclic moiety.
• heteroaryl moieties include, but are not limited to, indol-2-yl, indol-3-yl quinolin-2-yl quinolin-3- yl, isoquinolin-3-yl, quinoxaline-2-yl, benzo[b]furan-2-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-5-yl, thiazole-4-yl, benzimidazole-5-yl, benzotriazol-5-yl, furan-2-yl, benzo[d]thiazole-6-yl, pyrazole-1-yl, pyrazole-4-yl and thiophen-2-yl. These may also be optionally substituted as discussed above.
• R 1 is an optionally substituted C 2 -Ci 2 alkenyl.
• the optionally substituted alkenyl may contain one or more double bonds with each of the double bonds being independently in the E or Z configuration.
• the alkenyl contains a single double bond which is in the E configuration.
• R 1 is an optionally substituted C 2 -Ci 2 alkenyl of the formula:
• R 1a is selected from the group consisting of H, halogen and optionally substituted Cr Ci 2 alkyl;
• R 1b and R 1c are each independently selected from the group consisting of H, halogen, optionally substituted Ci-Ci 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted
• C 2 -Ci 2 alkynyl optionally substituted Ci-Ci 2 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted CrCisheteroaryl.
• R 1a is H. In one form of this embodiment R 1b is H.
• R 1 is of the formula:
• R 1c is optionally substituted Ce-
• Ci 8 aryl The C 6 -Ci 8 aryl may be monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C ⁇ -Cisaryl is a monocyclic moiety. In certain embodiments the C ⁇ -Cisaryl is a bicyclic moiety.
• R 1c is an optionally substituted C 6 -Ci 8 aryl selected from the group consisting of optionally substituted phenyl and optionally substituted naphthyl.
• the moieties may be unsubstituted or may be substituted with one or more optional substituents.
• a wide variety of optional substituents may be used as defined above.
• Such optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH 2 , cyano, phenoxy, hydroxy, methoxy, ethoxy, methylenedioxy, pyrrol- 1-yl, and 3,5-dimethyl-pyrazol-1-yl.
• substituents may be located at any substitutable position around the aryl ring available for substitution as would be clear to a skilled addressee.
• suitable optionally substituted phenyl compounds include, but are not limited to, 2-methoxy-phenyl, 3- methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4- trifluoromethyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 2- fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl- phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-difluoro-phenyl, 2- chloro-6-
• the compounds of formula (I) are antagonists of the MC5R and therefore may be used to modulate the activity of MC5R or a fragment or analogue or functional equivalent thereof by exposing MC5R or a fragment or analogue or functional equivalent thereof to a compound of the invention.
• This can occur in vitro in assays where the downregulation of MC5R activity is desirable, however it is typically more beneficial when utilised in downregulation of MC5R activity in a patient.
• the amount of downregulation provided by the compounds of the invention will vary from compound to compound and will also be affected by the amount of compound administered. In one embodiment the amount of downregulation is at least 10%. In another embodiment the amount of downregulation is at least 20%. In an even further embodiment the amount of downregulation is at least 50%.
• the methods of the present invention may be used in the treatment of any condition in which modulation of the activity of MC5R or a fragment or analogue or functional equivalent thereof would lead to a beneficial effect on that condition.
• the compounds suitable for use in the present invention may be used in methods of treating, preventing, or controlling a condition associated either directly or indirectly with the activity of MC5R or a fragment or analogue or functional equivalent thereof in a mammal wherein an MC5R modulating amount of the compound of the invention is administered to the mammal.
• One condition associated with MC5R activity is excess sebum secretion and conditions related thereto.
• the condition is selected from the group consisting of acne, seborrhoea, and seborrheic dermatitis.
• the acne is selected from the group consisting of acne vulgaris, acne, acne conglobata and acne fulminans.
• the condition is acne vulgaris.
• downregulation of MC5R leads to a reduction of sebum secretion and can thus be used in the treatment or prophylaxis of a number of conditions in which excess sebum secretion is observed such as acne, seborrhoea and seborrheic dermatitis.
• the methods of the invention may also be useful in the treatment, prevention or control of a number of conditions that relate to biological processes controlled by MC5R, such as diseases related to inflammation.
• the compounds of formula (I) may also be useful for the treatment or prevention of cancers, such as Muir-Torre syndrome or other cancers of the sebaceous gland. Due to their impact on sebum secretion the compounds of formula (I) may also find application in treatments where reduced sebum secretion is desirable such as in cosmetic treatments.
• the compounds may thus be used in methods of reducing sebum secretion by a mammal, the method comprising administering an effective amount of a compound of formula
• the compounds of formula (I) may be used in the treatment of conditions in any species in which MC5R is present, most typically mammals.
• species in which MC5R is found and hence species in which the compounds may be used include humans, rats, mice, dogs, rhesus monkey, sheep, zebrafish, goldfish, spiny dogfish, rainbow trout and chickens.
• the mammal is a human.
• Administration of compounds within Formula (I) to a patient such as humans can be by topical administration, by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion.
• the active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose.
• the compounds of formula (I) can be administered in any form or mode which makes the compound bioavailable.
• One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19 th edition, Mack Publishing Co. (1995) for further information.
• the compounds of formula (I) can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient.
• a pharmaceutically acceptable carrier diluent or excipient.
• the compounds of formula (I), while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.
• the compounds are, however, typically used in the form of pharmaceutical compositions which are formulated depending on the desired mode of administration.
• the compositions are prepared in manners well known in the art.
• a compound of formula (I) is typically combined with the carrier to produce a dosage form suitable for the particular patient being treated and the particular mode of administration.
• a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of the compound of the invention, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99.95 percent of the total composition.
• Representative dosage forms will generally contain between from about 1 mg to about 500 mg of a compound of the invention, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
• Compounds of the present invention may also be formulated for topical delivery in formulations such as solutions, ointments, lotions, gels, creams, microemulsions or transdermal patches.
• these topical formulations may contain from 0.005 to 5% (wt/wt or wt/vol) of a compound of the invention.
• the compounds of formula (I) may be used or administered in combination with one or more additional drug (s).
• the compounds of the present invention may be used in combination with one or more other pharmaceutically-active compounds, such as other antiacne treatments.
• the other pharmaceutically active agent is selected from the group consisting of antibiotics, retinoids, anti-androgens, and steroids.
• examples of other pharmaceutically active compounds that may be combined with a compound of formula (I) and administered in concurrent or sequential combination therewith may include, by way of non-limiting example, other anti-acne agents such as oral retinoids (e.g. isotretinoin), topical retinoids (e.g.
• antibiotics e.g. clindamycin, erythromycin, minocycline, tetracycline, benzoyl peroxide
• hormonal therapies e.g. drospirenone, norgestimate - ethinyl estradiol, cyproterone acetate.
• these components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug(s).
• compositions suitable for use in the invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
• suitable aqueous and non aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.
• the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
• Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• Examples of embedding compositions which can be used include polymeric substances and waxes.
• the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
• the active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifier
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
• suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
• compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• the active agent may be in the form of an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.
• the composition may be delivered via a liposome, nanosome, rivosome, or nutri-diffuser vehicle.
• a formulation may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents.
• a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents.
• the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Methods for producing formulations for topical administration are known in the art.
• compositions used for topical administration typically contain a pharmaceutically acceptable carrier which may be any vehicle that is toxicologically and pharmaceutically acceptable.
• Typical pharmaceutically acceptable carriers that can be used in compositions of the present invention include water, ethanol, acetone, isopropyl alcohol, stearyl alcohol, freons, polyvinyl pyrrolidone, propylene glycol, polyethlyene glycol, fragrances, gel-producing materials, mineral oil, stearic acid, spermaceti, sorbitan, monoleate, polysorbates, "Tweens," sorbitol, methyl cellulose, petrolatum, a mineral oil (vaseline oil), which may be any petroleum based product; modified or unmodified vegetable oils such as peanut oil, wheatgerm oil, linseed oil, jojoba oil, apricot kernel oil, walnut oil, palm oil, pistachio oil, sesame oil, colza oil, cade oil, corn germ oil, peach kernel oil, poppy
• compositions for topical administration may be formulated in numerous forms. However, the composition may often take the form of an aqueous or oily solution or dispersion or emulsion or a gel or a cream.
• An emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.
• the oil phase of water-in-oil or oil-in-water emulsions may comprise for example: a) hydrocarbon oils such as paraffin or mineral oils; b) waxes such as beeswax or paraffin wax; c) natural oils such as sunflower oil, apricot kernel oil, shea butter or jojoba oil; d) silicone oils such as dimethicone, cyclomethicone or cetyldimethicone; e) fatty acid esters such as isopropyl palmitate, isopropyl myristate, dioctylmaleate, glyceryl oleate and cetostearyl isononanoate; f) fatty alcohols such as cetyl alcohol or stearyl alcohol and mixtures thereof (eg cetearyl alcohol); g) polypropylene glycol or polyethylene glycol ethers, eg PPG-14 butyl ether; or h) mixtures thereof.
• hydrocarbon oils such as paraffin or
• Emulsifiers used may be any emulsifiers known in the art for use in water-in-oil or oil- in-water emulsions.
• Known cosmetically acceptable emulsifiers include: a) sesquioleates such as sorbitan sesquioleate, available commercially for example under the trade name Arlacel 83 (ICI), or polyglyceryl-2-sesquioleate; b) ethoxylated esters of derivatives of natural oils such as the polyethoxylated ester of hydrogenated castor oil available commercially for example under the trade name Arlacel 989 (ICI); c) silicone emulsifiers such as silicone polyols available commercially for example under the trade name ABIL WS08 (Th.
• emulsifiers such as fatty acid soaps e.g. potassium stearate and fatty acid sulphates e.g. sodium cetostearyl sulphate available commercially under the trade name Dehydag (Henkel); e) ethoxylated fatty alcohols, for example the emulsifiers available commercially under the trade name Brij (ICI); f) sorbitan esters, for example the emulsifiers available commercially under the trade name Span (ICI); g) ethoxylated sorbitan esters, for example the emulsifiers available commercially under the trade name Tween (ICI); h) ethoxylated fatty acid esters such as ethoxylated stearates, for example the emulsifiers available commercially under the trade name Myrj (ICI); i) ethoxylated mono-, di-, and triglycerides, for example the
• Gels for topical administration may be aqueous or non-aqueous. Aqueous gels are preferred.
• the gel will contain a thickening agent or gelling agent in order to give sufficient viscosity to the gel.
• a variety of thickening agents may be used according to the nature of the liquid carrier and the viscosity required and these are recited hereinafter.
• a particularly suitable thickener is a copolymer of acryloyl dimethyl tauric acid (or a salt thereof), preferably a copolymer of that monomer with another vinylic monomer.
• the thickening agent is a copolymer of a salt of acryloyl dimethyl tauric acid with another vinylic monomer.
• the salt may be a salt of a Group I alkali metal, but is more preferably an ammonium salt.
• suitable copolymer thickening agents are: i) Ammonium acryloyl dimethyl taurate I vinyl pyrrolidone copolymer, ie a copolymer of ammonium acryloyl dimethyl taurate and vinyl pyrrolidone (1-vinyl-2-pyrrolidone).
• composition may additionally comprise other skincare active agents which are well known in the art which may be effective to aid the normal functioning of the skin.
• One group of preferred compositions comprise hydrolysed milk protein to regulate sebum production.
• composition may additionally comprise other components which will be well known to those skilled in the art such as emollients, humectants, emulsion stabilising salts, preservatives, chelating agents or sequestering agents (sequestrants), abrasives, antioxidants, stabilisers, pH adjusters, surfactants, thickeners, diluents, perfumes and colourings.
• the topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas.
• dermal penetration enhancers include dimethylsulfoxide and related analogues.
• the amount of compound administered will preferably treat and reduce or alleviate the condition.
• a therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, sex, diet, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.
• a preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day.
• a more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day.
• a suitable dose can be administered in multiple sub-doses per day.
• the resulting secondary amine is acylated under standard peptide coupling conditions with the protected amino acid, P 2 -NHCH(U)- CO 2 H, where U represents either the final R side chain, a protected final side chain R-P 3 , or a precursor that requires chemical modification to form the final R side chain.
• V R 1 X
• Preparative scale HPLC was carried out on a Waters Delta Prep 3000 HPLC system with peak detection by UV (Waters model 486 tunable absorbance detector), using Phenomenex Luna 10 ⁇ C5 100A, 250 x 21.20 mm (20 mg scale), Phenomenex Luna 15 ⁇ C8(2) 100A, 250 x 30.00 mm (50 mg scale), or Phenomenex Luna 15 ⁇ C8(2) 100A, 250 x 50.00 mm (100 mg scale) HPLC columns.
• the solvent system employed various gradients of 0.05% TFA in water (Solvent A) and 0.05% TFA in 90:10 acetonitrile:water (Solvent B).
• the organic phase is then washed with 1 N HCI (3 x 100 ml_), H 2 O (3 x 100 ml_), saturated NaHCO 3 aqueous solution (3 x 100 ml.) and brine (1 x 10 ml_).
• the organic phase is then dried (MgSO 4 ) and the EtOAc removed to give the Weinreb amide (2) as a white solid or an oil.
• Vv ⁇ ⁇ H3 MgBrCH CH 2 V ⁇ ,.Y
• the ⁇ , ⁇ - unsaturated ketone (3) may be isolated by rotary evaporation or it may be used in solution without further purification. If the intention is to use the ⁇ , ⁇ -unsaturated ketone (3) in solution the volume is reduced to 100 ml. by rotary evaporation and stored for later use.
• the DIC may be replaced with HATU (15 mmol) and DIPEA (15 mmol).
• the reaction is stirred at room temperature overnight.
• the DCM is removed by rotary evaporation and the residue is taken up in EtOAc (100 ml_).
• the organic layer is washed with saturated sodium bicarbonate solution (2 x 100 ml_), saturated ammonium chloride solution (2 x 100 ml.) and brine (2 x 100 ml_).
• the organic phase is dried and the solvent removed under reduced pressure.
• the residue is subjected to column chromatography on silica gel using petroleum ethe ⁇ EtOAc to give 5.
• the procedure adopted for the removal of the P2 protecting group will vary depending upon the exact nature of the protecting group. As will be appreciated by a skilled addressee a large number of possible protecting groups may be used and a skilled worker in the art will readily be able to determine an appropriate procedure for the removal of any particular protecting group from procedures known in the art. Nevertheless in order to assist the reader general procedures for the removal of the more common protecting groups are provided.
• P 2 Fmoc: To compound 5 (2 mmol) in DCM (3 ml.) is added diethylamine (20 mmol). The reaction is stirred at room temperature for 1 hr. The DCM and diethylamine is then removed by rotary evaporation. DCM (5 mL) and sodium triacetoxyborohydride (3 mmol) are then added, and the reaction stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 mL), dried (MgSO 4 ) and the DCM removed to give the cyclised product A. This may be purified by flash chromatography on silica gel or used without purification.
• P 2 Cbz: A mixture of crude 5 (1 mmol) and 5% Pd/C (200 mg) in 2-propanol (15 mL) is shaken at room temperature under hydrogen (30 psi) for 24 hrs. The mixture is then filtered through a pad of Celite and the filtrate concentrated under reduced pressure to give a crude product. Purification by flash chromatography on silica gel (100% EtOAc) may be used to give A.
• the residue may be purified by preparative HPLC to give the piperidinyl product.
• the purified product is isolated as the TFA salt, but is readily converted into the free base via neutralisation with aqueous NaHCO 3 and extraction into an organic solvent, or further converted into the HCI salt by acidification with 1 N HCI.
• the amino ketone 12 (44 mg, 0.053 mmol) in DCM (2 mL) was cyclized by addition of NaBH(OAc) 3 (40mg, 0.18 mmol) in one portion at room temperature. The resulting mixture was stirred for 3 hrs, followed by addition of saturated NaHCO 3 aqueous solution (3 mL). The aqueous layer was extracted with DCM (3 x 3 mL) and the combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was filtered through a short plug of silica gel eluting with DCM followed by EtOAc then EtOAc/IPA (9:1 ) to give the desired product 13 as a white solid. It was used in the next step without further purification. MS (ESI) 807 (M+1 ); HPLC f R 7.75 min.
• 6-chloro-2-naphthoic acid A suspension of 6-bromo-2-naphthoic acid (3.0 g, 11.47 mmol), CuCI (1 1.7 g, 114.64 mmol) and CuI (2.19 g, 1 1.50 mmol) in degassed DMF (45 mL) was heated to reflux under argon in dark for 4 hrs. After cooling to room temperature, the solution was decanted into H 2 O (200 mL) and the resulting mixture was extracted with EtOAc (2 x 500 mL).
• the organic phase was washed with H 2 O (3x 100 mL), saturated sodium bicarbonate solution (3x 50 mL), H 2 O (3x 50 mL), 1 M HCI (3x 50 mL), brine (3x 50 mL).
• the organic phase was dried (MgSO 4 ) and the EtOAc removed to give the Weinreb amide 44 as a white solid (0.43 g, 23%).
• te/t-butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate 16 (Boc-Gly Weinreb amide, 1.4 g, 6.4 mmol) in DCM (5 mL) and TFA (3 mL) were stirred at room temperature 1 hr. The solvent was removed under reduced pressure, followed by addition of DCM (20 mL) and then DIPEA until basic. The solution was cooled to 0° C and allyl chloroformate added (1.4 mL, 13.2 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was neutralised with 1 M HCI and extracted with EtOAc.
• Example 46 Synthesis of Compound 47 (3S,5S)-3-(2-tert-butoxycarbonylaminoethyl)- 5-(allyloxycarbonylaminomethyl)-1-(3,5-dichlorobenzyll)-1 ,4-diazepan-2-one
• the reaction was evacuated and stirred and room temperature for 1 hr.
• the DCM was removed under reduced pressure to give the crude product 48 (0.15 g. 75%) which was used in the next reaction without purification.

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