WO2007017264A2 - Pyrrolopyridinederivatives as modulators of the cannabinoid receptor for the treatment of immune and inflammatory disorders - Google Patents
Pyrrolopyridinederivatives as modulators of the cannabinoid receptor for the treatment of immune and inflammatory disorders Download PDFInfo
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- WO2007017264A2 WO2007017264A2 PCT/EP2006/007875 EP2006007875W WO2007017264A2 WO 2007017264 A2 WO2007017264 A2 WO 2007017264A2 EP 2006007875 W EP2006007875 W EP 2006007875W WO 2007017264 A2 WO2007017264 A2 WO 2007017264A2
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- 0 C**c1c(C(*)=O)c(*)nc(**)c1C Chemical compound C**c1c(C(*)=O)c(*)nc(**)c1C 0.000 description 1
- KXEKHYJVGLGJQB-UHFFFAOYSA-N CC(C)(C)OC([n](cc(C)c1c(cn2)I)c1c2Cl)=O Chemical compound CC(C)(C)OC([n](cc(C)c1c(cn2)I)c1c2Cl)=O KXEKHYJVGLGJQB-UHFFFAOYSA-N 0.000 description 1
- NRAOZGQJRXAKCL-UHFFFAOYSA-N C[n](ccc1c(NC(c2cc(Cl)ccc2)=O)nc2)c1c2C(N1CCOCC1)=O Chemical compound C[n](ccc1c(NC(c2cc(Cl)ccc2)=O)nc2)c1c2C(N1CCOCC1)=O NRAOZGQJRXAKCL-UHFFFAOYSA-N 0.000 description 1
- CPNNLEYFDUMSDQ-UHFFFAOYSA-N Cc(c1c(cn2)C(N3CCOCC3)=O)c[nH]c1c2Sc1cccc(Cl)c1 Chemical compound Cc(c1c(cn2)C(N3CCOCC3)=O)c[nH]c1c2Sc1cccc(Cl)c1 CPNNLEYFDUMSDQ-UHFFFAOYSA-N 0.000 description 1
- ANZVAGURXBBUTM-UHFFFAOYSA-N Cc(c1c(cn2)I)c[nH]c1c2Cl Chemical compound Cc(c1c(cn2)I)c[nH]c1c2Cl ANZVAGURXBBUTM-UHFFFAOYSA-N 0.000 description 1
- IDDAOAADMYBDCF-UHFFFAOYSA-N Cc1c(C)[nH]c2c1c(C(O)=O)cnc2Cl Chemical compound Cc1c(C)[nH]c2c1c(C(O)=O)cnc2Cl IDDAOAADMYBDCF-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Definitions
- the present invention relates to novel pyrrolopyridme derivatives, pharmaceutical compositions containing these compounds and their use in the treatment of diseases, particularly pain, which diseases are caused directly or indirectly by an increase or decrease in activity of the cannabinoid receptor.
- Cannabinoids are a specific class of psychoactive compounds present m Indian cannabis ⁇ Cannabis sativa), including about sixty different molecules, the most representative being cannabmol, cannabidiol and several isomers of tetrahydrocannabinol.
- Knowledge of the therapeutic activity of cannabis dates back to the ancient dynasties of China, where, 5,000 years ago, cannabis was used for the treatment of asthma, migraine and some gynaecological disorders. These uses later became so established that, around 1850, cannabis extracts were included in the US Pharmacopaeia and remained there until 1947.
- Cannabinoids are known to cause different effects on various systems and/or organs, the most important being on the central nervous system and on the cardiovascular system. These effects include alterations in memory and cognition, eupho ⁇ a, and sedation. Cannabinoids also increase heart rate and vary systemic arterial pressure. Peripheral effects related to bronchial constriction, immunomodulation, and inflammation have also been observed. The capability of cannabinoids to reduce intraocular pressure and to affect respiratory and endoc ⁇ ne systems is also well documented. See e.g. L.E. Holhster, Health Aspects of Cannabis, Pharmacological Reviews, Vol. 38, pp. 1-20, (1986). More recently, it was found that cannabinoids suppress the cellular and humoral immune responses and exhibit antiinflammatory properties. Wirth et al., Antiinflammatory Properties of Cannabichrome, Life Science, Vol. 26, pp. 1991-1995, (1980).
- the first cannabinoid receptor was found to be mainly located in the brain, in neural cell lines, and, only to a lesser extent, at the peripheral level. In view of its location, it was called the central receptor ("CBl"). See Matsuda et al., "Structure of a Cannabinoid Receptor and Functional Expression of the Cloned cDNA," Nature, Vol. 346, pp. 561-564 (1990). The second cannabinoid receptor (“CB2”) was identified in the spleen, and was assumed to modulate the non psychoactive effects of the cannabinoids. See Munro et el., "Molecular Characte ⁇ zation of a Peripheral Receptor for Cannabinoids," Nature. Vol. 365, pp. 61-65 (1993).
- the total size of the patient population suffe ⁇ ng from pain is vast (almost 300 million), dominated by those suffering from back pain, osteo-arth ⁇ tic pain and post-operative pain.
- Neuropathic pain associated with neuronal lesions such as those induced by diabetes, HIV, herpes infection, or stroke) occurs with lower, but still substantial prevalence, as does cancer pain.
- the pathogenic mechanisms that give rise to pain symptoms can be grouped into two mam catego ⁇ es: - those that are components of inflammatory tissue responses (Inflammatory Pain);
- Chronic inflammatory pam consists predominantly of osteoarthritis, chronic low back pam and rheumatoid arthritis. The pam results from acute and on-going injury and/or inflammation. There may be both spontaneous and provoked pain. There is an underlying pathological hypersensitivity as a result of physiological hyperexcitabihty and the release of inflammatory mediators which further potentiate this hyperexcitability.
- CB2 receptors are expressed on inflammatory cells (T cells, B cells, macrophages, mast cells) and mediate immune suppression through inhibition of cellular interaction/ inflammatory mediator release. CB2 receptors may also be expressed on sensory nerve terminals and therefore directly inhibit hyperalgesia.
- CB2 modulators are believed to offer an unique approach toward the pharmacotherapy of immune disorders, inflammation, osteoporosis, renal ischemia and other pathophysiological conditions.
- the present invention provides novel pyrrolopyridme derivatives of formula (I) and pharmaceutically acceptable de ⁇ vatives thereof, pharmaceutical compositions containing these compounds or de ⁇ vatives, and their use as CB2 receptor modulators, which are useful in the treatment of a variety of disorders.
- the present invention further comprises a method for treating disease mediated by CB2 receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
- cannabmoids act on receptors capable of modulating different functional effects, and in view of the low homology between CB2 and CB 1 , a class of drugs selective for the specific receptor sub-type is desirable.
- the natural or synthetic cannabmoids currently available do not fulfil this function because they are active on both receptors.
- the present invention includes compounds which are capable of selectively modulating the receptors for cannabinoids and therefore the pathologies associated with such receptors.
- the invention provides compounds of formula (I):
- R 1 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl and halosubshtutedC 1-6 alkyl;
- R 2 is hydrogen or (CH 2 ) m R 3 where m is 0 or 1 ; or R 1 and R 2 together with N to which they are attached form an optionally substituted 4- to 8- membered non-aromatic heterocyclyl ring;
- R 3 is a 4- to 8- membered non-aromatic heterocyclyl group, a C 3 g cycloalkyl group, a straight or branched Ci -10 alkyl, a C 2 . 10 alkenyl, a C 3 . 8 cycloalkenyl, a C 2 . 10 alkynyl, a C 3 8 cycloalkynyl or phenyl group, any of which can be unsubstituted or substituted, or R 5 ;
- p is 0, 1 or 2
- X is CH 2 O, S, or SO 2 ;
- R 6 is phenyl, C 3 6 cycloalkyl, a straight or branched C 1-6 alkyl group, -CH 2 -C 3 . 6 cycloalkyl, -CH 2 -phenyl, 4- to 8- membered non-aromatic heterocyclyl group, or a bicyclic group any of which can be unsubstituted or substituted, however when X 4 is a bond R 6 is substituted phenyl; R 7 is OH, C 1 6 alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 or SOqR 9 ;
- R 8a is H or C 1-6 alkyl
- R 8b is H or C 1-6 alkyl
- R 9 is Ci -6 alkyl
- R 10 is hydrogen, substituted or unsubstituted (C 1 . 6 )alkyl or chloro;
- R 1 ' is hydrogen or C,. 6 alkyl;
- R 12 is hydrogen or C 1-6 alkyl
- R 13 is hydrogen or C 1-6 alkyl; q is 0, 1 or 2; and pharmaceutically acceptable derivatives thereof.
- compounds of formula (I) are compounds of fomula (Ia) or (Ib):
- R 1 is hydrogen or methyl. In one embodiment R 13 is hydrogen or methyl. In one embodiment R 2 is (CH 2 ) m R 3 where m is 0 or 1.
- R 3 or R 6 are independently selected from a non-aromatic heterocyclyl group
- the ring may contain 1, 2, 3, or 4 hetero atoms.
- the hetero atoms are selected from oxygen, nitrogen or sulphur.
- 4- membered groups are 2- or 3- azetidmyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide and thioxetanyl-s,s-dioxide.
- Examples of 5- membered heterocyclyl groups in this instance include dioxolanyl, pyrrohdinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-s,s-dioxide, and tetrahydrothiophenyl-s-oxide.
- 6-membered heterocyclyl groups are morphohnyl, pipe ⁇ dinyl, piperazmyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl-s,s-dioxide, thiomorpholmyl, thiomorphohnyl-s,s-dioxide, tetrahydropyridmyl, dioxanyl, tetrahydrothiopyran- 1,1 -dioxide, and tetrahydrothiopyran-1 -oxide.
- 7- membered heterocyclyl groups are azapine and oxapine.
- 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl, azathiacyclooctanyl, oxacylcooctanyl, thiacyclooctanyl, azathiacyclooctanyl-s-oxide, azathiacyclooctanyl-s,s-dioxide, thiacyclooctanyl-s,s-dioxide and thiacyclooctanyl-s-oxide.
- R 3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, or an unsubstituted or substituted C 3 . 8 cycloalkyl group
- R 3 is an unsubstituted or substituted 4- to 8- membered non- aromatic heterocyclyl group, said group is tetrahydropyranyl.
- R 3 is tetrahydropyranyl or cyclobutyl.
- R 4 is hydrogen.
- R 1 is hydrogen.
- R 13 is hydrogen.
- R 12 is hydrogen or methyl.
- the ring may optionally contain 1, 2, 3 or 4 further hetero atoms.
- the ring may be saturated or unsaturated.
- the further hetero atoms are selected from oxygen, nitrogen or sulphur.
- An example of a 4- membered heterocyclyl ring is azetidinyl.
- Examples of a 5- membered heterocyclyl ring are pyrrohdinyl and pyrazohdinyl.
- 6-membered heterocyclyl nngs are morphohnyl, p ⁇ erazinyl, pipe ⁇ dinyl, tetrahydropy ⁇ dinyl, thiomorphohne-s,s-dioxide, thiomorphohnyl and thiomorpholmyl-s-oxide.
- Examples of a 7- membered heterocyclyl ring are azapine or oxapme.
- Examples of 8-membered heterocyclyl nngs are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
- R 1 and R 2 together with the nitrogen to which they are attached form a morpholinyl, thiomorphohnyl-s,s-dioxide, pyrrohdinyl or pipe ⁇ dmyl ring.
- R 6 is a bicyclic group it can be selected from a 7 to 10 membered aromatic group for example napthyl, 7 to 10 membered heteroaromatic for example indolyl, isoindolyl, benzofuranyl, benzothiophenyl, quinohnyl and lsoqumohnyl or a 7 to 10 membered heteroaromatic group for example dihydrobenzofuranyl, mdolinyl and dihydrothiophenyl.
- a 7 to 10 membered aromatic group for example napthyl
- 7 to 10 membered heteroaromatic for example indolyl, isoindolyl, benzofuranyl, benzothiophenyl, quinohnyl and lsoqumohnyl
- a 7 to 10 membered heteroaromatic group for example dihydrobenzofuranyl, mdolinyl and dihydrothiophenyl.
- R 6 When R 6 is a bicyclic group it can be an indolyl, benzofuranyl, or napthyl group
- R 6 is phenyl, C 3 . 6 cycloalkyl, straight or branched C 1-6 alkyl or -CH 2 C 3 . 6 cycloalkyl, tetrahyrdofuranyl any of which can be unsubstituted or substituted.
- R 6 is a substituted phenyl.
- R 4 and R 6 together with the nitrogen to which they are attached form a morphohnyl, pyrrohdinyl or pipe ⁇ dmyl ring.
- R 7 is OH.
- R 10 is hydrogen.
- R 11 is methyl or hydrogen.
- R 13 is methyl or hydrogen. In one embodiment X is CH 2 .
- R 6 When R 6 is substituted, it may be substituted by 1 , 2 or 3 substituents, the substituent or substituents may be selected from: C 1-6 alkyl, halosubstitutedC]. 6 alkyl e.g. t ⁇ fluoromethyl, C 1-6 alkoxy, a hydroxy group, a cyano group, halo, a C 1-6 alkyl sulfonyl group, -CONH 2 ,-NHCOCH 3 , -
- R 6 is substituted by 1 or 2 substituents.
- R 6 is substituted by halo, cyano, methyl, t ⁇ fluoromethyl, ethyl, propyl, isopropyl, methoxy, tnfluoromethoxy or -SO 2 CH 3 .
- R 1 and R 2 or R 4 and R 6 together with N to which they are attached form a 4- to 8- membered non-aromatic heterocyclyl ⁇ ng which is substituted, or when R 3 is substituted
- the substituent or substituents may be selected from: C 1-6 alkyl, C 1 6 alkoxy, a hydroxy group, halosubstituted C 1 . 6 alkyl e.g. t ⁇ fluoromethyl, halosubstituted C ⁇ alkoxy e.g.
- R 1 and R 2 or R 4 and R 6 together with N to which they are attached form a 4- to 8- membered non-aromatic heterocyclyl ⁇ ng which is substituted, or when R 3 is substituted there can be 1, 2 or 3 substituents.
- R 10 When R 10 is substituted, the substituents may be selected from fluoro, chloro or bromo.
- the invention is compounds of formula (Ic) or (Id);
- X 4 is O, S, SO 2 , or bond, or X 4 is -NHCO or -NHCH 2 such that R 6 X 4 is R 6 CONH or R 6 CH 2 NH;
- R 1 is hydrogen
- R 2 is (CH 2 ) H1 R 3 where m is O or 1; or R 1 and R 2 together with N to which they are attached form a morpholinyl, pyrrohdinyl, prpe ⁇ dmyl, thiomorpholme-s,s-dioxide ⁇ ng any of which may be unsubstituted or substituted; R 3 is a selected from tetrahydrfuranyl, a C 3 . 6 cycloalkyl group;
- R 6 is an phenyl, C 3 . 6 cycloalkyl, straight or branched C 1-6 alkyl or -CH 2 C 3 6 cycloalkyl - CH 2 phenyl any of which can be unsubstituted or substituted.
- R 11 is hydrogen or methyl;
- R 12 is hydrogen or methyl; and pharmaceutically acceptable derivatives thereof.
- R 6 is substituted phenyl. In one embodiment X 4 is O
- compounds of formula (I) show selectivity for CB2 over CB 1.
- compounds of formula (I) have an EC50 value at the cloned human cannabmoid CB2 receptor of at least 50 times the EC50 values at the cloned human cannabinoid CBl receptor and/or have less than 10% efficacy at the CBl receptor.
- Compounds of formula (I) may be more potent and/or more soluble and/or more bioavailable and/or produce a more linear increase in exposure when the compounds are orally administered to a mammal than earlier published compounds which are agonists of CB2.
- pharmaceutically acceptable derivative means any pharmaceutically acceptable salt, ester, salt of such ester or solvate of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
- pharmaceutically acceptable de ⁇ vative is a salt or solvate of compound of formula (I).
- salts referred to above will be physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiological acceptable salts thereof.
- Pharmaceutically acceptable salts include those desc ⁇ bed by Berge, Bighley and Monkhouse , J. Pharm. Sci., 1977, 66, 1-19.
- pharmaceutically acceptable salts includes salts prepared from pharmaceutically acceptable nontoxic bases including inorganic bases and organic bases.
- Salts de ⁇ ved from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
- Salts de ⁇ ved from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resms, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpipe ⁇ dine, glucamine, glucosamine, hishdine, hydrabamine, lsopropylamine, lysine, methylglucamine, morphohne, piperazine
- salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids include acetic, benzenesulfonic, benzoic, camphorsulfomc, citric, ethanesulfonic, fuma ⁇ c, gluconic, glutamic, hydrobromic, hydrochloric, lsethionic, lactic, maleic, malic, mandehc, methanesulfomc, mucic, nitric, pamoic, pantothenic, phospho ⁇ c, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
- Examples of pharmaceutically acceptable salts include the ammonium, calcium, magnesium, potassium, and sodium salts, and those formed from maleic, fuma ⁇ c, benzoic, ascorbic, pamoic, succinic, hydrochlo ⁇ c, sulfu ⁇ c, bismethylenesahcylic, methanesulfomc, ethanedisulfonic, propionic, tarta ⁇ c, salicylic, cit ⁇ c, gluconic, aspartic, stea ⁇ c, palmitic, ltaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phospho ⁇ c and nit ⁇ c acids.
- 'halogen or halo' are used to represent fluorine, chlorine, bromine or iodine.
- 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i- butyl, pentyl, hexyl, 1,1-dimethylethyl, heptyl, octyl, nonyl, decyl or combinations thereof.
- 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, l-propoxy, n-butoxy, s-butoxy, t-butoxy group, i-butoxy, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
- 'cycloalkyF means a closed saturated ⁇ ng, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
- alkenyl' means as a group or part of a group means a straight or branched chain carbon chain or combinations thereof containing 1 or more double bonds, for example butenyl, pentenyl, hexenyl or heptenyl, or octenyl.
- 'cycloalkenyF means a closed non-aromatic carbon ⁇ ng containing 1 or more double bonds, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, or cyclooctenyl.
- 'alkynyl' as a group or part of a group means a straight or branched chain carbon chain or combinations containing 1 or more triple carbon bonds for example ethynyl, propynyl, butynyl, pentynyl, hexynyl or combinations thereof.
- 'cycloalkynyl' means a closed non-aromatic carbon ring containing 1 or more triple carbon bonds for example cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl or combinations thereof.
- 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the ⁇ ngs is aromatic, for example naphthyl.
- R 1 , R 2 , R 6 , R 10 , R 11 , R 12 and R 13 are as defined for compounds of formula (I) and LG is a leaving group for example halo, e.g chloro, and PG is a protecting group for example Ci- 6 alkyl ester e.g. methyl ester.
- R 1 , R 2 , R 6 , R 10 , R 11 , R 13 are as defined for compounds of formula (I), LG 1 is a leaving group for example halo, e.g chloro, LG 2 is a leaving group for example halo, e.g iodo and PG 1 is a protecting group for example COOt-butyl.
- X 4 is S or SO 2 can be prepared as described in Scheme 3 and 4.
- R 1 , R 2 , R 6 , R 10 , R 11 , R 12 and R 13 are as defined for compounds of formula (I) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example C 1 6 alkyl ester e.g. methyl ester or ethyl ester.
- R 1 , R 2 , R 6 , R 10 , R 11 , R 13 are as defined for compounds of formula (I) and LG 1 is a leaving group for example halo, e.g chloro, LG 2 is a leaving group for example halo e.g iodo, PG 1 is a protecting group for example CO 2 -?-butyl.
- LG 1 is a leaving group for example halo, e.g chloro
- LG 2 is a leaving group for example halo e.g iodo
- PG 1 is a protecting group for example CO 2 -?-butyl.
- R 1 , R 2 , R 6 , R 10 , R 11 , R 12 and R 13 are as defined for compounds of formula (I) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example Ci_ 6 alkyl ester e.g. methyl ester or ethyl ester.
- X 4 is NHCO such that R 6 X 4 is R 6 CONH can be prepared as desc ⁇ bed m Scheme 6.
- R 1 , R 2 , R 6 , R 10 , R 1 1 , R 12 and R 13 are as defined for compounds of formula (I) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example C ⁇ alkyl ester e.g. methyl ester or ethyl ester.
- LG is a leaving group for example halo, e.g chloro
- PG is a protecting group for example C ⁇ alkyl ester e.g. methyl ester or ethyl ester.
- R 1 , R 2 , R 6 , R 10 , R u , R 12 , R 13 are as defined for compounds of formula (I) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example Ci. 6 alkyl ester e.g. methyl ester or ethyl ester.
- X 4 is a bond can be prepared as desc ⁇ bed in Scheme 8.
- R 1 , R 2 , R 6 , R 10 , R 11 , R 13 are as defined for compounds of formula (I) and LG 1 is a leaving group for example halo, e.g chloro, LG 2 is a leaving group for example halo, e g. iodo, PG 1 is a protecting group for example -CO 2 -rt>utyl.
- the present invention encompasses all isomers of compounds of formula (I) and their pharmaceutically acceptable de ⁇ vatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in compounds of formula (I), the present invention includes withm its scope all possible diastereoismers, including mixtures thereof The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
- the subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlo ⁇ ne, such as 3 H, 11 C, 14 C, 18 F, 123 I and 125 I.
- Isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. T ⁇ tiated, i.e., 3 H, and carbon-14, i.e., ' 4 C, isotopes are particularly preferred for their ease of preparation and detectabihty.
- 11 C and 8 F isotopes are particularly useful in PET (positron emission tomography), and 125 I isotopes are particularly useful m SPECT (single photon emission computerized tomography), all useful in brain imaging.
- substitution with heavier isotopes such as deute ⁇ um, i.e., 2 H, can 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.
- Isotopically labeled compounds of formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
- Compounds of formula (I) may be prepared in crystalline or non-crystallme form, and, if crystalline, may optionally be hydrated or solvated. This invention includes withm its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.
- compounds of the invention will be useful in the treatment of the disorders that follow.
- compounds of formula (I) may be useful as analgesics.
- they may be useful in the treatment of chronic inflammatory pam (e.g.
- pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis including the property of disease modification and joint structure preservation; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pam; sympathetically maintained pam; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine, pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
- Compounds of the invention may also have disease modification or joint structure preservation properties in multiple sclerosis, rheumatoid arthritis, osteo-arthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.
- Compounds of the invention may be particularly useful m the treatment of neuropathic pam.
- Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed.
- Neuronal injury may occur in the pe ⁇ pheral nerves, dorsal roots, spinal cord or certain regions in the brain.
- Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them.
- Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV -related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often desc ⁇ bed as spontaneous shooting and lancinating pain, or ongoing, burning pam.
- Compounds of formula (I) may also be useful in the treatment of fever.
- Compounds of formula (I) may also be useful in the treatment of inflammation, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD); gastrointestinal tract disorders (e.g.
- an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia
- Compounds of formula (I) may also be useful in the treatment of bladder hyperrelexia following bladder inflammation.
- Compounds of formula (I) may also be useful in the treatment of immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation.
- the compounds of formula (I) may also be effective in increasing the latency of HIV infection.
- Compounds of formula (I) may also be useful in the treatment of diseases of abnormal platelet function (e.g. occlusive vascular diseases).
- diseases of abnormal platelet function e.g. occlusive vascular diseases.
- Compounds of formula (I) may also be useful in the treatment of neuritis, heart burn, dysphagia, pelvic hypersensitivity, urinary incontinence, cystitis or pru ⁇ tis.
- Compounds of formula (I) may also be useful for the preparation of a drug with diuretic action. Compounds of formula (I) may also be useful in the treatment of impotence or erectile dysfunction.
- Compounds of formula (I) may also be useful for attenuating the hemodynamic side effects of non-steroidal anti-inflammatory drugs (NSAID's) and cyclooxygenase-2 (COX-2) inhibitors.
- Compounds of formula (I) may also be useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt- Jakob disease, motor neuron disease); vascular dementia (including multi-mfarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease ; metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
- the compounds may also be useful for the treatment of amyotrophic lateral sclerosis (ALS) and neuroinflamation.
- ALS amy
- Compounds of formula (I) may also be useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic bram injury, spinal cord injury or the like.
- Compounds of formula (I) may also be useful in the treatment of tinnitus.
- Compounds of formula (I) may also be useful in the treatment of psychiatric disease for example schizophrenia, depression (which term is used herein to include bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia for example of the Alzheimer's type, schizoaffective disorder or the depressed type, and depressive disorders resulting from general medical conditions including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc), anxiety disorders (including generalised anxiety disorder and social anxiety disorder), panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder, memory disorders, including dementia, amnesic
- Compounds of formula (I) may also be useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependence - inducing agent.
- dependence inducing agents include opioids (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine.
- opioids e.g. morphine
- CNS depressants e.g. ethanol
- psychostimulants e.g. cocaine
- nicotine nicotine
- Compounds of the invention may bind selectively to the CB2 receptor; such compounds may be particularly useful in treating CB2 receptor mediated diseases.
- treatment includes the treatment of established disorders and also includes the prophylaxis thereof.
- prophylaxis is used herein to mean preventing symptoms in an already afflicted subject or preventing recurrance of symptoms in an afflicted subject and is not limited to complete prevention of an afflication.
- a compound of formula (I) or a pharmaceutically acceptable de ⁇ vative thereof for use in the treatment of a condition which is mediated by the activity of cannabmoid 2 receptors.
- a method of treating a mammal for example a human suffering from a condition which is mediated by the activity of cannabmoid 2 receptors which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable de ⁇ vative thereof.
- a mammal for example a human suffe ⁇ ng from an immune disorder, an inflammatory disorder, pain, rheumatoid arthritis, multiple sclerosis, osteoarthritis or osteoporosis which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable de ⁇ vative thereof.
- the pain is selected from inflammatory pain, viseral pain, cancer pam, neuropathic pain, lower back pain, muscular sceletal, post operative pam, acute pam and migraine.
- the inflammatory pam is pam associated with rheumatoid arthritis or osteoarthritis.
- a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a therapeutic agent for the treatment or prevention of a condition such as an immune disorder, an inflammatory disorder, pam, rheumatoid arthritis, multiple sclerosis, osteoarth ⁇ tis or osteoporosis.
- a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine.
- modulator means both antagonist, partial or full agonist and inverse agonist.
- the present modulators are agonists.
- Compounds of formula (I) and their pharmaceutically acceptable de ⁇ vatives may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parentarally, sub-lmgually, dermally, lntranasally, transdermally, rectally, via inhalation or via buccal administration.
- Compounds of formula (I) and their pharmaceutically acceptable de ⁇ vatives which are active when given orally can be formulated as liquids, tablets, capsules and lozenges.
- a liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, olive oil, glyce ⁇ ne, glucose (syrup) or water with a flavouring, suspending, or colou ⁇ ng agent.
- any pharmaceutical carrier routinely used for preparing solid formulations may be used.
- examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
- any routine encapsulation is suitable, for example using the aforementioned carriers or a semi solid e.g. mono di-glyce ⁇ des of capric acid, GelucireTM and LabrasolTM, or a hard capsule shell e.g gelatin.
- a soft shell capsule e.g.
- any pharmaceutical carrier routinely used for prepa ⁇ ng dispersions or suspensions may be considered, for example aqueous gums or oils, and are incorporated in a soft capsule shell.
- Typical parenteral compositions consist of a solution or suspension of a compound or derivative in a ste ⁇ le aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
- compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or t ⁇ chlorofluoromethane.
- a typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable de ⁇ vative thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
- a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
- Typical dermal and transdermal formulations comprise a conventional aqueous or nonaqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
- the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
- Each dosage unit for oral administration contains suitably from 0.001 mg to 500 mg, for example 0.01 mg to 500 mg such as from 0.01 mg to 100 mg, and each dosage unit for parenteral administration contains suitably from 0.001 mg to 100 mg, of a compound of formula (I) or a pharmaceutically acceptable de ⁇ vative thereof calculated as the free acid.
- Each dosage unit for suppository administration contains suitably from 0.001 mg to 500 mg, for example 0.01 mg to 500 mg such as from 0.01 mg to 100 mg.
- Each dosage unit for intranasal administration contains suitably 1-400 mg and suitably 10 to 200 mg per person.
- a topical formulation contains suitably 0.01 to 5.0% of a compound of formula (I).
- the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 1000 mg/Kg, of a compound of formula(I) or a pharmaceutically acceptable de ⁇ vative thereof calculated as the free acid.
- the daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 200 mg/Kg, of a compound of formula (I) or a pharmaceutically acceptable de ⁇ vative thereof calculated as the free acid.
- the daily dosage regimen for suppository administration is suitably about 0.01 mg/Kg to 1000 mg/Kg, of a compound of formula(I) or a pharmaceutically acceptable de ⁇ vative thereof calculated as the free acid.
- the daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person.
- the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity. It may be advantageous to prepare the compounds of the present invention as nanoparticles. This may improve the oral bioavailability of the compounds.
- nanoparticulate is defined as solid particles with 50% of the particles having a particle size of less than l ⁇ m, for example less than 0.75 ⁇ m
- the particle size of the solid particles of compound (I) may be determined by laser diffraction.
- a suitable machine for determining particle size by laser diffraction is a Lecotrac laser particle size analyser, using an HELOS optical bench fitted with a QUIXEL dispersion unit.
- Numerous processes for the synthesis of solid particles in nanoparticulate form are known. Typically these processes involve a milling process, for example a wet milling process in the presence of a surface modifying agent that inhibits aggregation and/or crystal growth of the nanoparticles once created. Alternatively these processes may involve a precipitation process, for example, a process of precipitation in an aqueous medium from a solution of the drug in a nonaqueous solvent.
- the present invention provides a process for preparing compound (I) in nanoparticulate form as hereinbefore defined, which process comprises milling or precipitation.
- Such processes may be readily adapted for the preparation of compound (I) in nanoparticulate form. Such processes form a further aspect of the invention.
- the process of the present invention may use a wet milling step carried out in a mill such as a dispersion mill in order to produce a nanoparticulate form of the compound.
- the present invention may be put into practice using a conventional wet milling technique, such as that described in Lachman et al., The Theory and Practice of Industrial Pharmacy, Chapter 2, "Milling” p.45 (1986).
- WO02/00196 SmithKline Beecham pic
- the present invention provides a process for preparing compounds of the invention in nanoparticulate form comprising wet milling a suspension of compound in a mill having at least one chamber and agitation means, said chamber(s) and/or said agitation means comprising a lub ⁇ cated nylon, as described in WO02/00196.
- the suspension of a compound of the invention for use in the wet milling is typically a liquid suspension of the coarse compound in a liquid medium.
- suspension is meant that the compound is essentially insoluble in the liquid medium.
- Representative liquid media include an aqueous medium.
- the average particle size of coarse compound of the invention may be up to lmm in diameter. This advantageously avoids the need to pre-process the compound.
- the aqueous medium to be subjected to the milling comp ⁇ ses compound (I) present in from about 1% to about 40% w/w, suitably from about 10% to about 30% w/w, for example about 20% w/w.
- the aqueous medium may further comp ⁇ se one or more pharmaceutically acceptable water- soluble earners which are suitable for ste ⁇ c stabilisation and the subsequent processing of compound (I) after milling to a pharmaceutical composition, e.g. by spray drying.
- Pharmaceutically acceptable excipients most suitable for ste ⁇ c stabilisation and spray-drying are surfactants such as poloxamers, sodium lauryl sulphate and polysorbates etc; stabilisers such as celluloses e.g. hydroxypropylmethyl cellulose; and earners such as carbohydrates e.g. manmtol.
- the aqueous medium to be subjected to the milling may further compnse hydroxypropylmethyl cellulose (HPMC) present from about 0.1 to about 10% w/w.
- HPMC hydroxypropylmethyl cellulose
- the process of the present invention may comp ⁇ se the subsequent step of drying compound of the invention to yield a powder.
- the present invention provides a process for preparing a pharmaceutical composition contain a compound of the present invention which process comprises producing compound of formula (I) in nanoparticulate form optionally followed by drying to yield a powder.
- a further aspect of the invention is a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable de ⁇ viate thereof in which the compound of formula (I) or a pharmaceutically acceptable de ⁇ viate thereof is present in solid particles in nanoparticulate form, in admixture with one or more pharmaceutically acceptable earners or excipients.
- drying is meant the removal of any water or other liquid vehicle used dunng the process to keep compound of formula (I) in liquid suspension or solution.
- This drying step may be any process for drying known in the art, including freeze drying, spray granulation or spray drying. Of these methods spray drying is particularly preferred. All of these techniques are well known in the art. Spray drying/fluid bed granulation of milled compositions is earned out most suitably using a spray dryer such as a Mobile Minor Spray Dryer [Niro, Denmark], or a fluid bed d ⁇ er, such as those manufactured by Glatt, Germany.
- the invention provides a pharmaceutical composition as hereinbefore defined, in the form of a dried powder, obtainable by wet milling solid particles of compound of formaula (I) followed by spray-drying the resultant suspension.
- the pharmaceutical composition as hereinbefore defined further comprises HPMC present in less than 15% w/w, for example, in the range 0.1 to 10% w/w.
- the CB2 receptor compounds for use in the instant invention may be used in combination with other therapeutic agents, for example COX-2 inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib or COX-189; 5 -lipoxygenase inhibitors; NSAID's, such as aspirin, diclofenac, lndomethacm, nabumetone or lbuprofen; leukot ⁇ ene receptor antagonists; DMARD's such as methotrexate; adenosine Al receptor agonists; sodium channel blockers, such as lamot ⁇ gme; NMDA receptor modulators, such as glycine receptor antagonists; gabapentm and related compounds; tricyclic antidepressants such as ami trip tylme; neurone stabilising antiepileptic drugs; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics
- COX-2 inhibitors are disclosed in US Patent Nos. 5,474,995 US5,633,272; US5,466,823, US6,310,099 and US6.291.523; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691, WO99/12930, WO00/26216, WO00/52008, WO00/38311, WO01/58881 and WO02/18374.
- Suitable 5HT6 compounds for a combination suitable for the treatment of e.g Alzhemiers disease or cognative enhancement may be selected from SGS518 (Saegis), BGC20 761 (BTG disclosed in WO00/34242), WAY466 (Wyeth), PO4368554 (Hoffman Ia Roche), BVT5182 (Biovitron) and LY483518 (Lily), SB742457 (GSK) and/or compounds disclosed as Example 1 to 50 in WO03/080580.
- the compound of the present invention may be administered in combination with other active substances such as 5HT3 antagonists, NK-I antagonists, serotonin agonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants and/or dopaminergic antidepressants.
- active substances such as 5HT3 antagonists, NK-I antagonists, serotonin agonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants and/or dopaminergic antidepressants.
- Suitable 5HT3 antagonists which may be used in combination of the compound of the inventions include for example ondansetron, granisetron, metoclopramide.
- Suitable serotonin agonists which may be used in combination with the compound of the invention include sumatriptan, rauwolscme, yohimbine, metoclopramide.
- Suitable SSRIs which may be used in combination with the compound of the invention include fluoxetine, citalopram, femoxetme, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
- Suitable SNRIs which may be used m combination with the compound of the invention include venlafaxine and reboxetine.
- Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include lmrpramine, amit ⁇ ptihne, chlomipramine and nortnptilme.
- Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and ammeptine.
- Compounds of the present invention may used in combination with PDE4 inhibitors.
- PDE4 inhibitor useful in this invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act in as PDE4 inhibitor, and which is only or essentially only a PDE4 inhibitor, not compounds which inhibit to a degree of exhibiting a therapeutic effect other members of the PDE family as well as PDE4.
- a PDE4 antagonist which has an IC 50 ratio of about 0.1 or greater as regards the IC 50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC 50 for the form which binds rolipram with a low affinity.
- Compounds of the present invention or combinations with PDE4 can be used in treating inflammation and as bronchodilators.
- hPDE 4 human monocyte recombinant PDE 4
- the preferred PDE4 inhibitors of for use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity.
- the preferred compounds will have an IC 50 ratio of about 0.1 or greater as regards the IC 50 for the PDE 4 catalytic form which binds rolipram with a high affinity divided by the IC 50 for the form which binds rolipram with a low affinity.
- U.S. patent 5,998,428, which desc ⁇ bes these methods in more detail.
- the PDE4 inhibitors are those PDE4 inhibitors which have an IC 50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0.
- a further aspect of the invention is an CB2 modulator in combination with a PDE4 inhibitor and pharmaceutical compositions comprising said combination.
- a further aspect of the invention is a method of treating lung disorders for example asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD) and cough or a disorder which can be treated with a broncodilator which comprises administering to a mammal including man, an effective amount of a CB modulator or a pharmaceutically acceptable derivative therefore and an effective amount of a PDE4 inhibitor or a pharmaceutically acceptable derivative thereof.
- COPD chronic obstructive pulmonary disease
- An additional aspect of the invention is the use of an effective amount of a CB2 modulator or a pharmaceutically acceptable de ⁇ vative therefore and an effective amount of a PDE4 inhibitor or a pharmaceutically acceptable de ⁇ vative thereof in the manufacture of a medicament in the treatment of lung disorders for example asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD) and cough or for the manufacture of a brocodilator.
- cough can have a number of forms and includes productive, nonproductive, hyper-reactive, asthma and COPD associated
- a further aspect of the invention is a patient pack comprsing an effective amount of a CB 2 modulator or a pharmaceutically acceptable de ⁇ vative therefore and an effective amount of a PDE4 inhibitor or a pharmaceutically acceptable derivative
- Possible PDE4 compounds are as [cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-carboxylate] also known as cilomilast or A ⁇ flo®, 2-carbomethoxy- 4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-one, and cis [4-cyano- 4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol]. They can be made by the processed desc ⁇ bed in US patents 5,449,686 and 5,552,438.
- PDE4 inhibitors specific inhibitors, which can be used in this invention are AWD- 12-281 from ASTA MEDICA (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98); a 9- benzyladenine de ⁇ vative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Sche ⁇ ng-Plough; a benzodiazepine PDE4 inhibitor identified as CI-IOl 8 (PD-168787; Parke- Davis/Warner-Lambert); a benzodioxole de ⁇ vative Kyowa Hakko disclosed in WO 9916766, V- 11294A from Napp (Landells, LJ.
- arofyllme arofyllme, atizoram, BAY-19-8004, benafent ⁇ ne, BYK-33043, CC-3052, CDP-840, cipamfylline, CP-220629, CP-293121, D-22888, D-4396, denbufylhne, f ⁇ laminast, GW-3600, lbudilast, KF- 17625, KS-506-G, laprafylhne, NA-0226A, NA-23063A, ORG-20241, ORG-30029, PDB-093, pentoxifylline, piclamilast, rolipram, RPR-117658, RPR-122818, RPR-132294, RPR- 132703, RS-17597, RS-25344-000, SB-207499, SB210667, SB211572, SB-211600, SB212066, SB212179, SDZ-ISQ-844, SDZ-MNS-949, SK
- the PDE4 inhibitor is selected from cilomilast, AWD-12-281 , NCS-613, D- 4418, CI-IOl 8, V-11294A, roflumilast or T-440.
- Compounds of the present invention may also be of use in treating atherosclerosis in combination with an anti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-angmal, anti- hypertension agent or an agent for lowering Lp(a).
- examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists.
- agents for lowe ⁇ ng Lp(a) include the aminophosphonates described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar SA and SmithKline Beecham)
- antihyerpertension agents are angiotensin-convertmg enzyme inhibitors, angiotensm-II receptor antagonists, ACE / NEP inhibitors, -blockers, calcium channel blockers, PDE inhibitors, aldosterone blockers
- a preferred combination therapy will be the use of a compound of the present invention and a statin.
- the statins are a well known class of cholesterol lowe ⁇ ng agents and include atorvastatin, simvarstatin, pravastatin, ce ⁇ vastatm, fluvastatin, lovastatin and ZD 4522 (also referred to as S-4522, Astra Zeneca).
- the two agents may be administered at substantially the same time or at different times, according to the discretion of the physician.
- a further preferred combination therapy will be the use of a compound of the present invention and an anti-diabetic agent or an insulin sensitiser.
- preferred compounds for use with a compound of the present invention include the PPARgamma activators, for instance G 1262570 (Glaxo Wellcome) and also the ghtazone class of compounds such as rosightazone (Avandia, SmithKlme Beecham), troghtazone and pioghtazone.
- PPARgamma activators for instance G 1262570 (Glaxo Wellcome)
- ghtazone class of compounds such as rosightazone (Avandia, SmithKlme Beecham), troghtazone and pioghtazone.
- the compounds of any of the above combinations or compositions may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
- the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents.
- compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
- the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
- dose of each compound may differ from that when the compound is used alone. Approp ⁇ ate doses will be readily appreciated by those skilled in the art.
- Yeast (Saccharomyces cerevisiae) cells expressing the human cannabinoid CBl receptor were generated by integration of an expression cassette into the ura 3 chromosomal locus of yeast strain MMY23.
- This cassette consisted of DNA sequence encoding the human CBl receptor flanked by the yeast GPD promoter to the 5' end of CBl and a yeast transcriptional terminator sequence to the 3' end of CBl.
- MMY23 expresses a yeast/mammalian chimeric G-protein alpha subunit in which the C-terminal 5 amino acids of Gpal are replaced with the C-termmal 5 ammo acids of human G ⁇ il/2 (as described in Brown et al. (2000), Yeast 16: 11-22).
- Agonists were prepared as 10 mM stocks in DMSO. EC 50 values (the concentration required to produce 50% maximal response) were estimated using 4 fold dilutions (BiomekFX, Beckman) into DMSO. Agonist solutions in DMSO (1% final assay volume) were transferred into black microtitre plates from Greiner (384-well) Cells were suspended at a density of 0.2 OD 60 o/ml in SC media lacking histidine, uracil, tryptophan, adenine and leucine and supplemented with 1OmM 3-aminot ⁇ azole, 0.1M sodium phosphate pH 7.0, and lO ⁇ M fluorescein di- ⁇ -D- glucopyranoside (FDGIu).
- FDGIu lO ⁇ M fluorescein di- ⁇ -D- glucopyranoside
- Emax MaX[ C ompound X] " Min [compound x] / MaX [H U210] - Min [HU2 io] X 100%
- MaX [Compound X] and Min [Compouild X] are the fitted maximum and minimum respectively from the concentration effect curve for compound X
- Max [H u 2 io ] and Min [HU2 io ] are the fitted maximum and minimum respectively from the concentration effect curve for (6aR,10aR)-3-(l,l'- Dimethylheptyl)-6a,7, 10,1 Oa-tetrahydro-1 -hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9- methanol (HU210; available from Toc ⁇ s).
- Equieffective molar ratio (EMR) values were calculated from the equation
- EMR EC 50 [compound X] / EC 50 [HU210]
- EC 50 [com p ound x ] is the EC 50 of compound X and EC 50 [ H U2 IO] IS the EC 50 Of HU210.
- Yeast (Saccharomyces cerevisiae) cells expressing the human cannabinoid CB2 receptor were generated by integration of an expression cassette into the ura3 chromosomal locus of yeast strain MMY23.
- This cassette consisted of DNA sequence encoding the human CB2 receptor flanked by the yeast GPD promoter to the 5' end of CB2 and a yeast transcriptional terminator sequence to the 3' end of CB2.
- MMY23 expresses a yeast/mammalian chimeric G-protem alpha subunit in which the C-termmal 5 ammo acids of Gpal are replaced with the C-terminal 5 ammo acids of human G ⁇ il/2 (as described in Brown et al.
- Agonists were prepared as 10 mM solutions in DMSO. EC 50 values (the concentration required to produce 50% maximal response) were estimated using 4 fold dilutions (BiomekFX, Beckman) into DMSO. Agonist solutions in DMSO (1% final assay volume) were transferred into black microtitre plates from Greiner (384-well). Cells were suspended at a density of 0.2 OD 60 o/ml in SC media lacking histidme, uracil, tryptophan, adenine and leucine and supplemented with 1OmM 3-ammot ⁇ azole, 0.1M sodium phosphate pH 7.0, and lO ⁇ M fluorescein di- ⁇ -D- glucopyranoside (FDGIu).
- FDGIu lO ⁇ M fluorescein di- ⁇ -D- glucopyranoside
- Em 3x Max [compound x] - Min [compound X] / Max [HU 21 o] - Mm [HU 21 o] x 100% where Max [compound X] and Min [compound X] are the fitted maximum and minimum respectively from the concentration effect curve for compound X, and Max [H u 2 io ] and Min [H u 2 io ] are the fitted maximum and minimum respectively from the concentration effect curve for (6aR,10aR)-3-(l,l'- Dimethylheptyl)-6a,7, 10,1 Oa-tetrahydro- 1 -hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9- methanol (HU210; available from Toc ⁇ s).
- Equieffective molar ratio (EMR) values were calculated from the equation
- EC 50 [ compound x] is the EC 50 of compound X and EC 50 [HU2io ] IS the EC 50 Of HU210.
- the compounds of Examples 1 to 34, 37, 38, 40, 42 to 57 and 60 to 62 tested according to this method had an EC 50 values of ⁇ 300nM and efficacy value of >50% at the cloned human cannabinoid CB2 receptor.
- Example 35, 41 and 58 tested according to this method had an EC 50 values between 30OnM and 100OnM and efficacy value of >50% at the cloned human cannabinoid CB2 receptor.
- the compounds of Examples 39, 59 and 63 to 70 tested according to this method had an EC 50 values >1000nM and/or efficacy value ⁇ 50% at the cloned human cannabinoid CB2 receptor.
- the compound of Example 36 was not tested. The results given are averages of a number of expe ⁇ ments.
- CB2 agonist effects may be determined using a reporter gene assay. These studies are performed using a CHO-Kl cell line expressing human recombinant CB2 receptors (CHO-Kl CB2 CRE-LUC cells). These cells additionally express a "CRE-LUC" reporter gene construct comprising the gene for luciferase under the control of multiple cAMP response element binding protein promoters. In these cells, increases in intracellular cAMP levels leads to transcription of the luciferase gene and the subsequent production of luciferase. The expression of luciferase is measured by addition to the cells of a proprietary mixture containing luciferm, the substrate for luciferase (Luchte, Perkm Elmer, Cat No 6016919).
- CHO-Kl CB2 CRE-LUC cells are grown in DMEM/F12 plus glutamax I medium (Gibco Cat. No. 31331-028), supplemented with 9% FBS (Gibco, Cat. No. 16000-040) and 0.5mg.mr' G418 (Gibco, Cat. No. 10131-027) and 0.5mg.ml ' Hygromycin (Invitrogen, Cat. No. 10687-010).
- Cells are grown as a monolayer culture in 162cm 2 vented Nunclon flasks (NUNC, Cat. No. 178883) in 27.5ml of media in a humidified 95% air and 5% CO 2 atmosphere at 37 0 C.
- the growth media When confluent, the growth media is replaced with DMEM/F12 medium (Gibco, Cat. No. 31331-028) containing 10OnM of the CB2 inverse agonist, SR144528, and the cells are incubated at 37 0 C for 30-60mms. Flasks are rinsed twice with 25ml Dulbecco's phosphate buffered saline (PBS, Gibco Cat. No. 14190-094) and then harvested by incubation for lOmms in 10ml of Versene (Gibco, Cat. No. 15040-033).
- PBS Dulbecco's phosphate buffered saline
- Cells are detached by a sharp blow to the flask and the cell suspension made up to 50ml with PBS and centrifuged at 250xg for 5mms.
- the cell pellet is re-suspended in 24mls of phenol-red free DMEM/F12 assay buffer (Gibco, Cat. No. 11039-021) and 50 ⁇ l of cell suspension (approximately 50,000 cells) is added to 96 well plates (Costar, Cat. No. 3904 - clear bottomed black well plates) containing 50 ⁇ l of test agonist in 2 ⁇ M forskohn (final assay concentration of l ⁇ M FSK).
- Test agonists are prepared as 1OmM solutions in DMSO and diluted into phenol-red free DMEM/F12 assay buffer containing 2 ⁇ M forskohn to produce a 20 ⁇ M solution of test agonist. Subsequent se ⁇ al dilutions of test agonist are prepared in the assay buffer containing forskohn and each test agonist is routinely examined over a final assay concentration range of lO ⁇ M to 1OnM (or lower if required).
- the plates are mixed on a plate shaker for 5mms (800-1000 rpm) and then centrifuged briefly (5-1Os) at 250xg, placed in a Bioplate without their lids, and incubated for 4-5hr in a humidified 95% air and 5% CO 2 atmosphere at 37 0 C.
- the 96 well plates are removed from the incubator and placed at RT for 10-15mms before addition of 25 ⁇ l of Luchte solution, prepared according to the manufacturer's instructions.
- the plates are sealed with Topseal A (Perkin Elmer, Cat. No. 6005185), mixed on a plate shaker for 5mins (800-1000 rpm) and then cent ⁇ fuged briefly (5-1Os) at 250xg. Finally, luminescence is measured using a Packard TopCount scintillation counter.
- the columns used are Waters Atlantis, the dimensions of which are 19mm x 100mm (small scale) and 30mm x 100mm (large scale).
- the stationary phase particle size is 5 ⁇ m.
- Agilent 1100 Gradient Pump, Agilent 1100 Autosampler, Agilent 1100 DAD Dectector, Agilent
- Agilent 1100 Gradient Pump Agilent 1100 DAD Dectector, Agilent 1100 Degasser, Agilent 1100 Oven, Agilent 1100 Controller, Waters ZMD Mass Spectrometer, Gilson 402 Syringe Pump
- the column used is a Waters Atlantis, the dimensions of which are 4.6mm x 50mm.
- the stationary phase particle size is 3 ⁇ m.
- the gene ⁇ c method used has a 4 minute runtime, which comprises of a 3-mmute gradient (0-100%
- the above method has a flow rate of 1.5ml/mins
- Methyl l-methyl-2-[2-(methyloxy)-2-oxoethyl]-lH-pyrrole-3-carboxylate (1Og) in dry tetrahydrofuran (200ml) was stirred at room temperature under argon.
- Sodium hydride (60% dispersion in mineral oil, 8g) was added portionwise followed by methyl formate (4.5ml) and the mixture was left to stir overnight.
- the reaction mixture was cooled in an ice bath and quenched by the addition of the minimum amount of methanol.
- the solution was re-cooled and acidified to pHl with aqueous 5N hydrochloric acid.
- Examples in Table 1 were prepared in a manner similar to Example 1 from 4-chloro-l-methyl-7-(4- mo ⁇ holinylcarbonyl)-lH-pyrrolo[3,2-c]pyridine and the approp ⁇ ate commercially available phenol or alcohol. The reactions were monitored by LCMS and reaction times were between two and ten hours. For Examples 7 to 16, the dimethylformamide was not evaporated prior to purification by MDAP.
- Examples in Table 2 were prepared in a manner similar to Example 1 from either 4-chloro-l- methyl-7-(l-pyrrohdinylcarbonyl)-lH-pyrrolo[3,2-c]pyridine or 4-chloro-7-[(l,l-dioxido-4- thiomorpholinyl)carbonyl]-l-methyl-lH-pyrrolo[3,2-c]pyridine and the approp ⁇ ate commercially available phenol, alcohol or benzyl alcohol. The mixtures were heated under microwave conditions at 180 0 C for two hours.
- Example 36 4-[(3-Chlorophenyl)thio]-l-methyl-7-(l-piperidinylcarbonyl)-lH-pyrrolo[3,2- c] pyridine
- Example 37 4-[(3-ChIorophenyl)sulfonyI]-l-methyl-7-(l-piperidinylcarbonyl)-lH- pyr rolo [3,2-c] pyridine
- Example 40 l-Methyl-7-(4-morpholinylcarbonyI)-4- ⁇ 3-[(trifluoromethyl)oxy]phenyl ⁇ -lH- pyrrolo [3,2-c] pyridine hydrochloride
- Examples in Table 3 were prepared in a manner similar to Example 50 from 1 , 1 -dimethylethyl 7- chloro-4- ⁇ [(cyclobutylmethyl)ammo]carbonyl ⁇ -3-methyl-lH-pyrrolo[2,3-c]pyridme-l -carboxylate and the appropriate commercially available phenol. Microwave reaction times were either six, ten or twelve hours. Examples 51, 52, 54 and 55 were pu ⁇ fied by Biotage chromatography over silica gel eluting with 50% ethyl acetate/hexane. Example 55 was not dissolved in ethyl acetate and treated with IM hydrochlo ⁇ c acid in diethyl ether.
- Example 60 7-[(3-Chlorophenyl)thio]-3-methyl-4-(4-morpholinylcarbonyl)-lH-pyrrolo[2,3- c] pyridine
- Example 63 was heated in the microwave for ten minutes and purified eluting with 50% ethyl acetate/hexane.
- Examples 64, 65, 67, 68, 69, and 70 were purified eluting with ethyl acetate and
- Example 66 was purified elutmg with 30% ethyl acetate/hexane.
- Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in va ⁇ ous forms and with numerous excipients. Examples of such formulations are given below.
- a compound of formula (I) or a pharmaceutically acceptable de ⁇ vative thereof, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
- Active ingredient 40 mg Compound of formula (I) or pharmaceutically acceptable derivative
- Procedure for tablet formulation Ingredients 1, 2, 3 and 4 are blended m a suitable mixer/blender. Sufficient water is added portion- wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules. The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. The wet granules are then dried in an oven at 14O 0 F (60 0 C) until dry. The dry granules are lubricated with ingredient No. 5, and the lub ⁇ cated granules are compressed on a suitable tablet press.
- a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula (I) in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers.
Abstract
The present invention relates to novel pyrrolopyridine derivatives of formula (I), pharmaceutical compositions containing these compounds and their use in the treatment of diseases, particularly pain, which diseases are caused directly or indirectly by an increase or decrease-in activity of the cannabinoid receptor, wherein: X1 is NH and X2 and X3 together form a -CR13=CR11-group or X3 is NR12 and X2 and X1 together form a -CR13=CR11- group; X4 is O, SO2, S, or a bond, or X4 is -NHCO or -NHCH2 such that R6X4 is R6CONH or R6CH2NH; R1 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl and halosubstituted C1-6 alkyl; R2 is hydrogen or (CH2)mR3 where m is 0 or 1; or R1 and R2 together with N to which they are attached form an optionally substituted 4- to 8- membered non-aromatic heterocyclyl ring; R3 is a 4- to8- membered non-aromatic heterocyclyl group, a C3-8 cycloalkyl group, a straight or branched C1-10 alkyl, a C2-10 alkenyl, a C3-8 cycloalkenyl, a C2-10 alkynyl, a C3-8 cycloalkynyl or phenyl group, any of which can be unsubstituted or substituted, or R5; wherein p is 0, 1 or 2, and X is CH2. O, S, or SO2; R6 is phenyl, C3-6 cycloalkyl, a straight or branched C1-6 alkyl group, -CH2-C3-6 cycloalkyl, -CH2-phenyl, 4- to 8- membered non-aromatic heterocyclyl group, or a bicyclic group any of which can be unsubstituted or substituted, however when X4 is a bond R6 is substituted phenyl; R7 is OH, C1-6 alkoxy, NR8aR8b, NHCOR9, NHSO2R9 or SOqR9; R8a is H or C1-6 alkyl; R8b is Hor C1-6 alkyl; R9 is C1-6 alkyl; R10 is hydrogen, substituted or unsubstituted (C1-6)alkyl or chloro; R11 is hydrogen or C1-6 alkyl; R12 is hydrogen or C1-6 alkyl; R13 is hydrogen or C1-6 alkyl; q is 0, 1 or 2.
Description
Compounds
The present invention relates to novel pyrrolopyridme derivatives, pharmaceutical compositions containing these compounds and their use in the treatment of diseases, particularly pain, which diseases are caused directly or indirectly by an increase or decrease in activity of the cannabinoid receptor.
Cannabinoids are a specific class of psychoactive compounds present m Indian cannabis {Cannabis sativa), including about sixty different molecules, the most representative being cannabmol, cannabidiol and several isomers of tetrahydrocannabinol. Knowledge of the therapeutic activity of cannabis dates back to the ancient dynasties of China, where, 5,000 years ago, cannabis was used for the treatment of asthma, migraine and some gynaecological disorders. These uses later became so established that, around 1850, cannabis extracts were included in the US Pharmacopaeia and remained there until 1947.
Cannabinoids are known to cause different effects on various systems and/or organs, the most important being on the central nervous system and on the cardiovascular system. These effects include alterations in memory and cognition, euphoπa, and sedation. Cannabinoids also increase heart rate and vary systemic arterial pressure. Peripheral effects related to bronchial constriction, immunomodulation, and inflammation have also been observed. The capability of cannabinoids to reduce intraocular pressure and to affect respiratory and endocπne systems is also well documented. See e.g. L.E. Holhster, Health Aspects of Cannabis, Pharmacological Reviews, Vol. 38, pp. 1-20, (1986). More recently, it was found that cannabinoids suppress the cellular and humoral immune responses and exhibit antiinflammatory properties. Wirth et al., Antiinflammatory Properties of Cannabichrome, Life Science, Vol. 26, pp. 1991-1995, (1980).
In spite of the foregoing benefits, the therapeutic use of cannabis is controversial, both due to its relevant psychoactive effects (causing dependence and addiction), and due to manifold side effects that have not yet been completely clarified. Although work in this field has been ongoing since the 1940's, evidence indicating that the peripheral effects of cannabinoids are directly mediated, and not secondary to a CNS effect, has been limited by the lack of receptor characteπzation, the lack of information concerning an endogenous cannabinoid hgand and, until recently, the lack of receptor subtype selective compounds.
The first cannabinoid receptor was found to be mainly located in the brain, in neural cell lines, and, only to a lesser extent, at the peripheral level. In view of its location, it was called the central receptor ("CBl"). See Matsuda et al., "Structure of a Cannabinoid Receptor and Functional Expression of the Cloned cDNA," Nature, Vol. 346, pp. 561-564 (1990). The second cannabinoid receptor ("CB2") was identified in the spleen, and was assumed to modulate the non psychoactive effects of the cannabinoids. See Munro et el., "Molecular Characteπzation of a Peripheral Receptor for Cannabinoids," Nature. Vol. 365, pp. 61-65 (1993).
The foregoing indications and the preferential localization of the CB2 receptor in the immune system confirms a specific role of CB2 in modulating the immune and antiinflammatory response to stimuli of different sources.
The total size of the patient population suffeπng from pain is vast (almost 300 million), dominated by those suffering from back pain, osteo-arthπtic pain and post-operative pain.
Neuropathic pain (associated with neuronal lesions such as those induced by diabetes, HIV, herpes infection, or stroke) occurs with lower, but still substantial prevalence, as does cancer pain.
The pathogenic mechanisms that give rise to pain symptoms can be grouped into two mam categoπes: - those that are components of inflammatory tissue responses (Inflammatory Pain);
- those that result from a neuronal lesion of some form (Neuropathic Pam). Chronic inflammatory pam consists predominantly of osteoarthritis, chronic low back pam and rheumatoid arthritis. The pam results from acute and on-going injury and/or inflammation. There may be both spontaneous and provoked pain. There is an underlying pathological hypersensitivity as a result of physiological hyperexcitabihty and the release of inflammatory mediators which further potentiate this hyperexcitability. CB2 receptors are expressed on inflammatory cells (T cells, B cells, macrophages, mast cells) and mediate immune suppression through inhibition of cellular interaction/ inflammatory mediator release. CB2 receptors may also be expressed on sensory nerve terminals and therefore directly inhibit hyperalgesia.
More recently, data suggests a role for CB2 receptor activation in the CNS. Until recently the CB2 receptor was thought to be restricted to the periphery, however emerging data suggests inflammatory pain-mediated induction of CB2 receptor expression in rat spmal cord which coincides with the appearance of activated microglia (Zhang et. al., 2003). Furthermore CB2 receptor agonists have been shown to reduce mechanically evoked responses and wind-up of wide dynamic range neurones in spmal cord dorsal horn in animal models of inflammatory pain (Zhang et. al., 2003, Eur J. Neurosci. 17: 2750-2754, Nackley et. al., 2004, J. Neurophys. 92: 3562-3574, Elmes et. al., 2004, Eur. J. Neurosci. 20: 2311-2320.)
The role of CB2 in immunomodulation, inflammation, osteoporosis, cardiovascular, renal and other disease conditions is now being examined.
Based on the foregoing, there is a need for compounds which have activity against the CB2 receptor. Thus, CB2 modulators are believed to offer an unique approach toward the pharmacotherapy of immune disorders, inflammation, osteoporosis, renal ischemia and other pathophysiological conditions. The present invention provides novel pyrrolopyridme derivatives of formula (I) and pharmaceutically acceptable deπvatives thereof, pharmaceutical compositions containing these compounds or deπvatives, and their use as CB2 receptor modulators, which are useful in the treatment of a variety of disorders.
The present invention further comprises a method for treating disease mediated by CB2 receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
In light of the fact that cannabmoids act on receptors capable of modulating different functional effects, and in view of the low homology between CB2 and CB 1 , a class of drugs selective for the specific receptor sub-type is desirable. The natural or synthetic cannabmoids currently available do not fulfil this function because they are active on both receptors.
In one embodiment of the present invention includes compounds which are capable of selectively modulating the receptors for cannabinoids and therefore the pathologies associated with such receptors.
The invention provides compounds of formula (I):
X1 is NH and X2 and X3 together form a -CR13=CRπ- group or X3 is NR12 and X2 and X1 together form a -CR13=CRU- group; X4 is O, SO2, S, or a bond, or X4 is -NHCO or -NHCH2 such that R6X4 is R6CONH or
R6CH2NH,
R1 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl and halosubshtutedC1-6 alkyl;
R2 is hydrogen or (CH2)mR3 where m is 0 or 1 ; or R1 and R2 together with N to which they are attached form an optionally substituted 4- to 8- membered non-aromatic heterocyclyl ring;
R3 is a 4- to 8- membered non-aromatic heterocyclyl group, a C3 g cycloalkyl group, a straight or branched Ci-10 alkyl, a C2.10alkenyl, a C3.8cycloalkenyl, a C2.10alkynyl, a C3 8cycloalkynyl or phenyl group, any of which can be unsubstituted or substituted, or R5;
R5 is
R6 is phenyl, C3 6cycloalkyl, a straight or branched C1-6 alkyl group, -CH2-C3.6cycloalkyl, -CH2-phenyl, 4- to 8- membered non-aromatic heterocyclyl group, or a bicyclic group any of which can be unsubstituted or substituted, however when X4 is a bond R6 is substituted phenyl; R7 is OH, C1 6alkoxy, NR8aR8b, NHCOR9, NHSO2R9 or SOqR9;
R8a is H or C1-6alkyl;
R8b is H or C1-6alkyl;
R9 is Ci-6alkyl;
R10 is hydrogen, substituted or unsubstituted (C1.6)alkyl or chloro; R1 ' is hydrogen or C,.6alkyl;
R12 is hydrogen or C1-6alkyl
R13 is hydrogen or C1-6alkyl; q is 0, 1 or 2; and pharmaceutically acceptable derivatives thereof.
In one embodiment compounds of formula (I) are compounds of fomula (Ia) or (Ib):
(Ia) (Ib)
wherein X4, R1, R2 R6 ; R11, R12, and R13 are as defined for compounds of formula (I).
In one embodiment R1 is hydrogen or methyl. In one embodiment R13 is hydrogen or methyl. In one embodiment R2 is (CH2)mR3 where m is 0 or 1.
When R3 or R6 are independently selected from a non-aromatic heterocyclyl group, the ring may contain 1, 2, 3, or 4 hetero atoms. In one embodiment the hetero atoms are selected from oxygen, nitrogen or sulphur. Examples of 4- membered groups are 2- or 3- azetidmyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide and thioxetanyl-s,s-dioxide. Examples of 5- membered heterocyclyl groups in this instance include dioxolanyl, pyrrohdinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-s,s-dioxide, and tetrahydrothiophenyl-s-oxide. Examples of 6-membered heterocyclyl groups are morphohnyl, pipeπdinyl, piperazmyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl-s,s-dioxide, thiomorpholmyl, thiomorphohnyl-s,s-dioxide, tetrahydropyridmyl, dioxanyl, tetrahydrothiopyran- 1,1 -dioxide, and tetrahydrothiopyran-1 -oxide. Examples of 7- membered heterocyclyl groups are azapine and oxapine. Examples of 8- membered groups are azacyclooctanyl, azaoxacyclooctanyl, azathiacyclooctanyl, oxacylcooctanyl, thiacyclooctanyl, azathiacyclooctanyl-s-oxide, azathiacyclooctanyl-s,s-dioxide, thiacyclooctanyl-s,s-dioxide and thiacyclooctanyl-s-oxide.
In one embodiment R3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, or an unsubstituted or substituted C3.8 cycloalkyl group
In one embodiment when R3 is an unsubstituted or substituted 4- to 8- membered non- aromatic heterocyclyl group, said group is tetrahydropyranyl.
In one embodiment R3 is tetrahydropyranyl or cyclobutyl. In one embodiment R4 is hydrogen. In one embodiment R1 is hydrogen. In one embodiment R13 is hydrogen. In one embodiment R12 is hydrogen or methyl.
When R1 and R2 taken together with the N to which they are attached form an optionally substituted non-aromatic heterocyclyl group, or when R4 and R6 taken together with the N to which they are attached form an optionally substituted non-aromatic heterocyclyl group the ring may optionally contain 1, 2, 3 or 4 further hetero atoms. The ring may be saturated or unsaturated. In one embodiment the further hetero atoms are selected from oxygen, nitrogen or sulphur. An example of a 4- membered heterocyclyl ring is azetidinyl. Examples of a 5- membered
heterocyclyl ring are pyrrohdinyl and pyrazohdinyl. Examples of 6-membered heterocyclyl nngs are morphohnyl, pφerazinyl, pipeπdinyl, tetrahydropyπdinyl, thiomorphohne-s,s-dioxide, thiomorphohnyl and thiomorpholmyl-s-oxide. Examples of a 7- membered heterocyclyl ring are azapine or oxapme. Examples of 8-membered heterocyclyl nngs are azacyclooctanyl, azaoxacyclooctanyl or azathiacyclooctanyl.
In one embodiment R1 and R2 together with the nitrogen to which they are attached form a morpholinyl, thiomorphohnyl-s,s-dioxide, pyrrohdinyl or pipeπdmyl ring.
When R6 is a bicyclic group it can be selected from a 7 to 10 membered aromatic group for example napthyl, 7 to 10 membered heteroaromatic for example indolyl, isoindolyl, benzofuranyl, benzothiophenyl, quinohnyl and lsoqumohnyl or a 7 to 10 membered heteroaromatic group for example dihydrobenzofuranyl, mdolinyl and dihydrothiophenyl.
When R6 is a bicyclic group it can be an indolyl, benzofuranyl, or napthyl group In one embodiment R6 is phenyl, C3.6cycloalkyl, straight or branched C1-6 alkyl or -CH2C3. 6cycloalkyl, tetrahyrdofuranyl any of which can be unsubstituted or substituted. In one embodiment R6 is a substituted phenyl.
In one embodiment when R4 and R6 together with the nitrogen to which they are attached form a morphohnyl, pyrrohdinyl or pipeπdmyl ring. In one embodiment R7 is OH. In one embodiment R10 is hydrogen. In one embodiment R11 is methyl or hydrogen.
In one embodiment R13 is methyl or hydrogen. In one embodiment X is CH2.
When R6 is substituted, it may be substituted by 1 , 2 or 3 substituents, the substituent or substituents may be selected from: C1-6 alkyl, halosubstitutedC].6 alkyl e.g. tπfluoromethyl, C1-6 alkoxy, a hydroxy group, a cyano group, halo, a C1-6alkyl sulfonyl group, -CONH2,-NHCOCH3, -
COOH, halosubstituted C1-6 alkoxy e.g. tπfluoromethyoxy, NR8aR8b and SO2NR8aR8b wherein R8a and R8b are as defined above.
In one embodiment R6 is substituted by 1 or 2 substituents.
In one embodiment R6 is substituted by halo, cyano, methyl, tπfluoromethyl, ethyl, propyl, isopropyl, methoxy, tnfluoromethoxy or -SO2CH3.
When R1 and R2 or R4 and R6 together with N to which they are attached form a 4- to 8- membered non-aromatic heterocyclyl πng which is substituted, or when R3 is substituted, the substituent or substituents may be selected from: C1-6 alkyl, C1 6 alkoxy, a hydroxy group, halosubstituted C1.6alkyl e.g. tπfluoromethyl, halosubstituted C^alkoxy e.g. tπfluoromethyoxy, a cyano group, halo or a sulfonyl group, methylsulfonyl, NR8a R8b, CONH2, NHCOCH3, (=O), COOH, CONHCH3 , CON(CH3) 2 and NHSO2CH3 wherein R8a and R8b are as described above.
When R1 and R2 or R4 and R6 together with N to which they are attached form a 4- to 8- membered non-aromatic heterocyclyl πng which is substituted, or when R3 is substituted there can be 1, 2 or 3 substituents. When R10 is substituted, the substituents may be selected from fluoro, chloro or bromo.
(Ic) (Id)
wherein
X4 is O, S, SO2, or bond, or X4 is -NHCO or -NHCH2 such that R6X4 is R6CONH or R6CH2NH;
R1 is hydrogen;
R2 is (CH2)H1R3 where m is O or 1; or R1 and R2 together with N to which they are attached form a morpholinyl, pyrrohdinyl, prpeπdmyl, thiomorpholme-s,s-dioxide πng any of which may be unsubstituted or substituted; R3 is a selected from tetrahydrfuranyl, a C3.6 cycloalkyl group;
R6 is an phenyl, C3.6cycloalkyl, straight or branched C1-6 alkyl or -CH2C3 6cycloalkyl - CH2phenyl any of which can be unsubstituted or substituted. R11 is hydrogen or methyl; R12 is hydrogen or methyl; and pharmaceutically acceptable derivatives thereof.
In one embodiment R6 is substituted phenyl. In one embodiment X4 is O
In certain embodiments compounds of formula (I) show selectivity for CB2 over CB 1.
In one embodiment compounds of formula (I) have an EC50 value at the cloned human cannabmoid CB2 receptor of at least 50 times the EC50 values at the cloned human cannabinoid CBl receptor and/or have less than 10% efficacy at the CBl receptor.
Compounds of formula (I) may be more potent and/or more soluble and/or more bioavailable and/or produce a more linear increase in exposure when the compounds are orally administered to a mammal than earlier published compounds which are agonists of CB2.
The invention is described using the following definitions unless otherwise indicated. The term "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, ester, salt of such ester or solvate of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof. In one embodiment the pharmaceutically acceptable deπvative is a salt or solvate of compound of formula (I).
It will be appreciated by those skilled in the art that compounds of formula (I) may be modified to provide pharmaceutically acceptable deπvatives thereof at any of the functional groups in the compounds, and that the compounds of formula (I) may be deπvatised at more than one position.
It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiological acceptable salts thereof. Pharmaceutically acceptable salts include those descπbed by Berge, Bighley and Monkhouse , J. Pharm. Sci., 1977, 66, 1-19. The term "pharmaceutically acceptable salts" includes salts prepared from pharmaceutically acceptable nontoxic bases including inorganic bases and organic bases. Salts deπved from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Salts deπved from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resms, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpipeπdine, glucamine, glucosamine, hishdine, hydrabamine, lsopropylamine, lysine, methylglucamine, morphohne, piperazine, pipeπdme, polyamine resins, procaine, purines, theobromine, tπethylamine, tπmethylamine, tπshydroxylmethyl ammo methane, tπpropyl amine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfomc, citric, ethanesulfonic, fumaπc, gluconic, glutamic, hydrobromic, hydrochloric, lsethionic, lactic, maleic, malic, mandehc, methanesulfomc, mucic, nitric, pamoic, pantothenic, phosphoπc, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
Examples of pharmaceutically acceptable salts include the ammonium, calcium, magnesium, potassium, and sodium salts, and those formed from maleic, fumaπc, benzoic, ascorbic, pamoic, succinic, hydrochloπc, sulfuπc, bismethylenesahcylic, methanesulfomc, ethanedisulfonic, propionic, tartaπc, salicylic, citπc, gluconic, aspartic, steaπc, palmitic, ltaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoπc and nitπc acids.
The terms 'halogen or halo' are used to represent fluorine, chlorine, bromine or iodine. The term 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i- butyl, pentyl, hexyl, 1,1-dimethylethyl, heptyl, octyl, nonyl, decyl or combinations thereof. The term 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, l-propoxy, n-butoxy, s-butoxy, t-butoxy group, i-butoxy, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group.
The term 'cycloalkyF means a closed saturated πng, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or cyclooctyl.
The term 'alkenyl' means as a group or part of a group means a straight or branched chain carbon chain or combinations thereof containing 1 or more double bonds, for example butenyl, pentenyl, hexenyl or heptenyl, or octenyl.
The term 'cycloalkenyF means a closed non-aromatic carbon πng containing 1 or more double bonds, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, or cyclooctenyl.
The term 'alkynyl' as a group or part of a group means a straight or branched chain carbon chain or combinations containing 1 or more triple carbon bonds for example ethynyl, propynyl, butynyl, pentynyl, hexynyl or combinations thereof.
The term 'cycloalkynyl' means a closed non-aromatic carbon ring containing 1 or more triple carbon bonds for example cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl or combinations thereof.
The term 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the πngs is aromatic, for example naphthyl.
Compounds where X4 is O can be prepared as described in Schemes 1 or 2:
Scheme 1 :
wherein R1, R2, R6, R10, R11, R12 and R13 are as defined for compounds of formula (I) and LG is a leaving group for example halo, e.g chloro, and PG is a protecting group for example Ci- 6alkyl ester e.g. methyl ester.
R6OH
wherein R1, R2, R6, R10, R11, R13 are as defined for compounds of formula (I), LG1 is a leaving group for example halo, e.g chloro, LG2 is a leaving group for example halo, e.g iodo and PG1 is a protecting group for example COOt-butyl.
Compounds wherein X4 is S or SO2 can be prepared as described in Scheme 3 and 4.
Scheme 3.
HSR6
wherein R1, R2, R6, R10, R11, R12 and R13 are as defined for compounds of formula (I) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example C1 6alkyl ester e.g. methyl ester or ethyl ester.
Scheme 4
R6SH Deprotect
oxidation
wherein R1, R2, R6, R10, R11, R13 are as defined for compounds of formula (I) and LG1 is a leaving group for example halo, e.g chloro, LG2 is a leaving group for example halo e.g iodo, PG1 is a protecting group for example CO2-?-butyl.
Compounds wherein X4 is NHCH2 such that R6X4 is R6CH2NH be prepared as described in Scheme 5.
Scheme 5:
wherein R1, R2, R6, R10, R11, R12 and R13 are as defined for compounds of formula (I) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example Ci_6alkyl ester e.g. methyl ester or ethyl ester.
Compounds where X4 is NHCO such that R6X4 is R6CONH can be prepared as descπbed m Scheme 6.
Scheme 6.
wherein R1, R2, R6, R10, R1 1, R12 and R13 are as defined for compounds of formula (I) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example C^alkyl ester e.g. methyl ester or ethyl ester.
Compounds where X4 is a bond can be prepared as described in Scheme 7.
Scheme 7.
R6boronιc acid
wherein R1, R2, R6, R10, Ru, R12, R13 are as defined for compounds of formula (I) and LG is a leaving group for example halo, e.g chloro, PG is a protecting group for example Ci.6alkyl ester e.g. methyl ester or ethyl ester.
Compounds where X4 is a bond can be prepared as descπbed in Scheme 8. Scheme 8
R6boronιc aαd
wherein R1, R2, R6, R10, R11, R13 are as defined for compounds of formula (I) and LG1 is a leaving group for example halo, e.g chloro, LG2 is a leaving group for example halo, e g. iodo, PG1 is a protecting group for example -CO2-rt>utyl.
It is to be understood that the present invention encompasses all isomers of compounds of formula (I) and their pharmaceutically acceptable deπvatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are
present in compounds of formula (I), the present invention includes withm its scope all possible diastereoismers, including mixtures thereof The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. The subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chloπne, such as 3H, 11C, 14C, 18F, 123I and 125I.
Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tπtiated, i.e., 3H, and carbon-14, i.e., '4C, isotopes are particularly preferred for their ease of preparation and detectabihty. 11C and 8F isotopes are particularly useful in PET (positron emission tomography), and 125I isotopes are particularly useful m SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuteπum, i.e., 2H, can 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. Isotopically labeled compounds of formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Compounds of formula (I) may be prepared in crystalline or non-crystallme form, and, if crystalline, may optionally be hydrated or solvated. This invention includes withm its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.
In view of their ability to bind to the CB2 receptor, it is believed that compounds of the invention will be useful in the treatment of the disorders that follow. Thus, compounds of formula (I) may be useful as analgesics. For example they may be useful in the treatment of chronic inflammatory pam (e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) including the property of disease modification and joint structure preservation; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pam; sympathetically maintained pam; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine, pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea. Compounds of the invention may also have disease modification or joint structure preservation properties in multiple sclerosis, rheumatoid arthritis, osteo-arthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.
Compounds of the invention may be particularly useful m the treatment of neuropathic pam. Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peπpheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV -related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often descπbed as spontaneous shooting and lancinating pain, or ongoing, burning pam. In addition, there is pam associated with normally non- painful sensations such as "pms and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pam sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
Compounds of formula (I) may also be useful in the treatment of fever.
Compounds of formula (I) may also be useful in the treatment of inflammation, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD); gastrointestinal tract disorders (e.g. aphthous ulcer, Crohn's disease, atopic gastritis, gastritis vaπaloforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastroesophageal reflux disease); organ transplantation; other conditions with an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin's disease, sclerodoma, myaesthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, myocardial ischemia, pyrexia, systemic lupus erythematosus, tendinitis, bursitis, and Sjogren's syndrome.
Compounds of formula (I) may also be useful in the treatment of bladder hyperrelexia following bladder inflammation.
Compounds of formula (I) may also be useful in the treatment of immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation. The compounds of formula (I) may also be effective in increasing the latency of HIV infection.
Compounds of formula (I) may also be useful in the treatment of diseases of abnormal platelet function (e.g. occlusive vascular diseases).
Compounds of formula (I) may also be useful in the treatment of neuritis, heart burn, dysphagia, pelvic hypersensitivity, urinary incontinence, cystitis or pruπtis.
Compounds of formula (I) may also be useful for the preparation of a drug with diuretic action.
Compounds of formula (I) may also be useful in the treatment of impotence or erectile dysfunction.
Compounds of formula (I) may also be useful for attenuating the hemodynamic side effects of non-steroidal anti-inflammatory drugs (NSAID's) and cyclooxygenase-2 (COX-2) inhibitors. Compounds of formula (I) may also be useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt- Jakob disease, motor neuron disease); vascular dementia (including multi-mfarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease ; metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment. The compounds may also be useful for the treatment of amyotrophic lateral sclerosis (ALS) and neuroinflamation.
Compounds of formula (I) may also be useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic bram injury, spinal cord injury or the like.
Compounds of formula (I) may also be useful in the treatment of tinnitus. Compounds of formula (I) may also be useful in the treatment of psychiatric disease for example schizophrenia, depression (which term is used herein to include bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia for example of the Alzheimer's type, schizoaffective disorder or the depressed type, and depressive disorders resulting from general medical conditions including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc), anxiety disorders (including generalised anxiety disorder and social anxiety disorder), panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder, memory disorders, including dementia, amnesic disorders and age-associated memory impairment, disorders of eatmg behaviours, including anorexia nervosa and bulimia nervosa, sexual dysfunction, sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawal from abuse of drugs such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine (phencychdme-like compounds), opiates (e.g. cannabis, herom, morphine), amphetamine or amphetamine-related drugs (e.g. dextroamphetamine, methylamphetamine) or a combination thereof.
Compounds of formula (I) may also be useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependence - inducing agent. Examples of dependence inducing agents include opioids (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine. Compounds of formula (I) may also be useful in the treatment of kidney dysfunction
(nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome), liver dysfunction (hepatitis, cirrhosis), gastrointestinal dysfunction (diarrhoea) and colon cancer.
Compounds of the invention may bind selectively to the CB2 receptor; such compounds may be particularly useful in treating CB2 receptor mediated diseases.
The term "treatment" or "treating" as used herein includes the treatment of established disorders and also includes the prophylaxis thereof. The term " prophylaxis" is used herein to mean preventing symptoms in an already afflicted subject or preventing recurrance of symptoms in an afflicted subject and is not limited to complete prevention of an afflication.
According to a further aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable deπvative thereof for use in human or veterinary medicine.
According to another aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable deπvative thereof for use in the treatment of a condition which is mediated by the activity of cannabmoid 2 receptors.
According to a further aspect of the invention, we provide a method of treating a mammal, for example a human suffering from a condition which is mediated by the activity of cannabmoid 2 receptors which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable deπvative thereof.
According to a further aspect of the invention we provide a method of treating a mammal, for example a human suffeπng from an immune disorder, an inflammatory disorder, pain, rheumatoid arthritis, multiple sclerosis, osteoarthritis or osteoporosis which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable deπvative thereof.
In one embodiment the pain is selected from inflammatory pain, viseral pain, cancer pam, neuropathic pain, lower back pain, muscular sceletal, post operative pam, acute pam and migraine. For example, the inflammatory pam is pam associated with rheumatoid arthritis or osteoarthritis.
According to another aspect of the invention is provided the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a therapeutic agent for the treatment or prevention of a condition such as an immune disorder, an inflammatory disorder, pam, rheumatoid arthritis, multiple sclerosis, osteoarthπtis or osteoporosis.
In order to use a compound of formula (I) or a pharmaceutically acceptable deπvative thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect of the invention is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine.
As used herein, "modulator" means both antagonist, partial or full agonist and inverse agonist. In one embodiment the present modulators are agonists.
Compounds of formula (I) and their pharmaceutically acceptable deπvatives may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parentarally, sub-lmgually, dermally, lntranasally, transdermally, rectally, via inhalation or via buccal administration. Compounds of formula (I) and their pharmaceutically acceptable deπvatives which are active when given orally can be formulated as liquids, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, olive oil, glyceπne, glucose (syrup) or water with a flavouring,
suspending, or colouπng agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers or a semi solid e.g. mono di-glyceπdes of capric acid, Gelucire™ and Labrasol™, or a hard capsule shell e.g gelatin. Where the composition is in the form of a soft shell capsule e.g. gelatin, any pharmaceutical carrier routinely used for prepaπng dispersions or suspensions may be considered, for example aqueous gums or oils, and are incorporated in a soft capsule shell. Typical parenteral compositions consist of a solution or suspension of a compound or derivative in a steπle aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or tπchlorofluoromethane.
A typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable deπvative thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
Typical dermal and transdermal formulations comprise a conventional aqueous or nonaqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
In one embodiment the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
Each dosage unit for oral administration contains suitably from 0.001 mg to 500 mg, for example 0.01 mg to 500 mg such as from 0.01 mg to 100 mg, and each dosage unit for parenteral administration contains suitably from 0.001 mg to 100 mg, of a compound of formula (I) or a pharmaceutically acceptable deπvative thereof calculated as the free acid. Each dosage unit for suppository administration contains suitably from 0.001 mg to 500 mg, for example 0.01 mg to 500 mg such as from 0.01 mg to 100 mg. Each dosage unit for intranasal administration contains suitably 1-400 mg and suitably 10 to 200 mg per person. A topical formulation contains suitably 0.01 to 5.0% of a compound of formula (I).
The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 1000 mg/Kg, of a compound of formula(I) or a pharmaceutically acceptable deπvative thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 200 mg/Kg, of a compound of formula (I) or a pharmaceutically acceptable deπvative thereof calculated as the free acid. The daily dosage regimen for suppository administration is suitably about 0.01 mg/Kg to 1000 mg/Kg, of a compound of formula(I) or a pharmaceutically acceptable deπvative thereof calculated as the free acid. The daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
It may be advantageous to prepare the compounds of the present invention as nanoparticles. This may improve the oral bioavailability of the compounds. For the purposes of the present invention "nanoparticulate" is defined as solid particles with 50% of the particles having a particle size of less than l μm, for example less than 0.75μm The particle size of the solid particles of compound (I) may be determined by laser diffraction. A suitable machine for determining particle size by laser diffraction is a Lecotrac laser particle size analyser, using an HELOS optical bench fitted with a QUIXEL dispersion unit.
Numerous processes for the synthesis of solid particles in nanoparticulate form are known. Typically these processes involve a milling process, for example a wet milling process in the presence of a surface modifying agent that inhibits aggregation and/or crystal growth of the nanoparticles once created. Alternatively these processes may involve a precipitation process, for example, a process of precipitation in an aqueous medium from a solution of the drug in a nonaqueous solvent.
Accordingly, in a further aspect, the present invention provides a process for preparing compound (I) in nanoparticulate form as hereinbefore defined, which process comprises milling or precipitation.
Representative processes for the preparation of solid particles in nanoparticulate form are described in the patents and publications listed below. U.S. Patent No. 4,826,689 to Violanto & Fischer, U. S. Patent No. 5,145,684 to Liversidge et al U.S Patent No. 5,298,262 to Na & Rajagopalan, U.S. Patent No. 5,302,401 Liversidge et al
U.S. Patent No. 5,336,507 to Na & Rajagopalan, U.S. Patent No. 5,340,564 to Illig & Sarpotdar U.S. Patent No. 5,346,702 to Na Rajagopalan, U.S. Patent No. 5,352,459 to Hollister et al U.S. Patent No. 5,354,560 to Lovrecich, U.S. Patent No. 5,384,124 to Courteille et al, U.S. Patent No. 5,429,824 to June, U.S. Patent No. 5,503,723 to Ruddy et al, U.S. Patent No. 5,510 118 to Bosch et al, U.S. Patent No. 5,518 to Bruno et al, U.S. Patent No. 5,518,738 to Eickhoff et al, U.S. Patent No. 5,534,270 to De Castro, U.S. Patent No. 5,536,508 to Canal et al, U.S. Patent No. 5,552,160 to Liversidge et al, U.S. Patent No. 5,560,931 to Eickhoff et al, U.S. Patent No. 5,560,932 to Bagchi et al, U.S. Patent No. 5,565,188 to Wong et al, U.S. Patent No. 5,571,536 to Eickhoff et al, U.S. Patent No. 5,573,783 to Desieno & Stetsko, U.S Patent No. 5,580,579 to Ruddy et al, U.S. Patent No 5,585,108 to Ruddy et al, U.S. Patent No. 5,587,143 to Wong, U.S. Patent No. 5,591456 to Franson et al, U.S. Patent No. 5,622,938 to Wong, U.S. Patent No 5,662,883 to Bagchi et al, U.S. Patent No. 5,665,331 to Bagchi et al, U.S Patent No. 5,718,919 to Ruddy et al, U.S. Patent No. 5,747,001 to Wiedmann et al, WO93/25190, WO96/24336, WO 97/14407, WO 98/35666, WO 99/65469, WO 00/18374, WO 00/27369, WO 00/30615 and WO 01/41760.
Such processes may be readily adapted for the preparation of compound (I) in nanoparticulate form. Such processes form a further aspect of the invention.
The process of the present invention may use a wet milling step carried out in a mill such as a dispersion mill in order to produce a nanoparticulate form of the compound. The present invention may be put into practice using a conventional wet milling technique, such as that described in Lachman et al., The Theory and Practice of Industrial Pharmacy, Chapter 2, "Milling" p.45 (1986).
In a further refinement, WO02/00196 (SmithKline Beecham pic) descπbes a wet milling procedure using a mill in which at least some of the surfaces are made of nylon (polyamide) comprising one or more internal lubricants, for use in the preparation of solid particles of a drug substance in nanoparticulate form. In another aspect the present invention provides a process for preparing compounds of the invention in nanoparticulate form comprising wet milling a suspension of compound in a mill having at least one chamber and agitation means, said chamber(s) and/or said agitation means comprising a lubπcated nylon, as described in WO02/00196.
The suspension of a compound of the invention for use in the wet milling is typically a liquid suspension of the coarse compound in a liquid medium. By "suspension" is meant that the compound is essentially insoluble in the liquid medium. Representative liquid media include an aqueous medium. Using the process of the present invention the average particle size of coarse compound of the invention may be up to lmm in diameter. This advantageously avoids the need to pre-process the compound. In a further aspect of the invention the aqueous medium to be subjected to the milling compπses compound (I) present in from about 1% to about 40% w/w, suitably from about 10% to about 30% w/w, for example about 20% w/w.
The aqueous medium may further compπse one or more pharmaceutically acceptable water- soluble earners which are suitable for steπc stabilisation and the subsequent processing of compound (I) after milling to a pharmaceutical composition, e.g. by spray drying. Pharmaceutically acceptable excipients most suitable for steπc stabilisation and spray-drying are surfactants such as poloxamers, sodium lauryl sulphate and polysorbates etc; stabilisers such as celluloses e.g. hydroxypropylmethyl cellulose; and earners such as carbohydrates e.g. manmtol.
In a further aspect of the invention the aqueous medium to be subjected to the milling may further compnse hydroxypropylmethyl cellulose (HPMC) present from about 0.1 to about 10% w/w.
The process of the present invention may compπse the subsequent step of drying compound of the invention to yield a powder.
Accordingly, in a further aspect, the present invention provides a process for preparing a pharmaceutical composition contain a compound of the present invention which process comprises producing compound of formula (I) in nanoparticulate form optionally followed by drying to yield a powder.
A further aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable deπviate thereof in which the compound of formula (I) or a pharmaceutically acceptable deπviate thereof is present in solid particles in nanoparticulate form, in admixture with one or more pharmaceutically acceptable earners or excipients.
By "drying" is meant the removal of any water or other liquid vehicle used dunng the process to keep compound of formula (I) in liquid suspension or solution. This drying step may be any process for drying known in the art, including freeze drying, spray granulation or spray drying. Of these methods spray drying is particularly preferred. All of these techniques are well known in the art. Spray drying/fluid bed granulation of milled compositions is earned out most suitably using a spray dryer such as a Mobile Minor Spray Dryer [Niro, Denmark], or a fluid bed dπer, such as those manufactured by Glatt, Germany.
In a further aspect the invention provides a pharmaceutical composition as hereinbefore defined, in the form of a dried powder, obtainable by wet milling solid particles of compound of formaula (I) followed by spray-drying the resultant suspension.
In one embodiment, the pharmaceutical composition as hereinbefore defined, further comprises HPMC present in less than 15% w/w, for example, in the range 0.1 to 10% w/w.
The CB2 receptor compounds for use in the instant invention may be used in combination with other therapeutic agents, for example COX-2 inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib or COX-189; 5 -lipoxygenase inhibitors; NSAID's, such as aspirin, diclofenac, lndomethacm, nabumetone or lbuprofen; leukotπene receptor antagonists; DMARD's such as methotrexate; adenosine Al receptor agonists; sodium channel blockers, such as lamotπgme; NMDA receptor modulators, such as glycine receptor antagonists; gabapentm and related compounds; tricyclic antidepressants such as ami trip tylme; neurone stabilising antiepileptic drugs; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; 5HTi agonists, such as tπptans, for example sumatriptan, naratriptan, zolmitπptan, eletπptan, frovatriptan, almotπptan or rizatriptan; EP1 receptor hgands, EP4 receptor hgands; EP2 receptor hgands; EP3 receptor hgands; EP4 antagonists; EP2 antagonists and EP3 antagonists; bradykinm receptor hgands and vanilloid receptor ligand, antirheumatoid arthritis drugs, for example anti TNF drugs e.g. enbrel, remicade, anti-IL-1 drugs, DMARDS e.g. leflunamide or 5HT6 compounds. When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
Additional COX-2 inhibitors are disclosed in US Patent Nos. 5,474,995 US5,633,272; US5,466,823, US6,310,099 and US6.291.523; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691, WO99/12930, WO00/26216, WO00/52008, WO00/38311, WO01/58881 and WO02/18374. Suitable 5HT6 compounds for a combination suitable for the treatment of e.g Alzhemiers disease or cognative enhancement, may be selected from SGS518 (Saegis), BGC20 761 (BTG disclosed in WO00/34242), WAY466 (Wyeth), PO4368554 (Hoffman Ia Roche), BVT5182 (Biovitron) and LY483518 (Lily), SB742457 (GSK) and/or compounds disclosed as Example 1 to 50 in WO03/080580. The compound of the present invention may be administered in combination with other active substances such as 5HT3 antagonists, NK-I antagonists, serotonin agonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants and/or dopaminergic antidepressants.
Suitable 5HT3 antagonists which may be used in combination of the compound of the inventions include for example ondansetron, granisetron, metoclopramide.
Suitable serotonin agonists which may be used in combination with the compound of the invention include sumatriptan, rauwolscme, yohimbine, metoclopramide.
Suitable SSRIs which may be used in combination with the compound of the invention include fluoxetine, citalopram, femoxetme, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
Suitable SNRIs which may be used m combination with the compound of the invention include venlafaxine and reboxetine.
Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include lmrpramine, amitπptihne, chlomipramine and nortnptilme.
Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and ammeptine. Compounds of the present invention may used in combination with PDE4 inhibitors. The
PDE4 inhibitor useful in this invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act in as PDE4 inhibitor, and which is only or essentially only a PDE4 inhibitor, not compounds which inhibit to a degree of exhibiting a therapeutic effect other members of the PDE family as well as PDE4. Generally it is preferred to use a PDE4 antagonist which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity. Compounds of the present invention or combinations with PDE4 can be used in treating inflammation and as bronchodilators.
There are at least two binding forms on human monocyte recombinant PDE 4 (hPDE 4) at which inhibitors bind. One explanation for these observations is that hPDE 4 exists in two distinct forms. One binds the likes of rolipram and denbufylhne with a high affinity while the other binds these compounds with a low affinity. The preferred PDE4 inhibitors of for use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. Another way to state this is that the preferred compounds will have an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE 4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity. Reference is made to U.S. patent 5,998,428, which descπbes these methods in more detail.
It is incorporated herein in full as though set forth herein
Suitably the PDE4 inhibitors are those PDE4 inhibitors which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0.
A further aspect of the invention is an CB2 modulator in combination with a PDE4 inhibitor and pharmaceutical compositions comprising said combination.
A further aspect of the invention is a method of treating lung disorders for example asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD) and cough or a disorder which can be treated with a broncodilator which comprises administering to a mammal including man, an effective amount of a CB modulator or a pharmaceutically acceptable derivative therefore and an effective amount of a PDE4 inhibitor or a pharmaceutically acceptable derivative thereof.
An additional aspect of the invention is the use of an effective amount of a CB2 modulator or a pharmaceutically acceptable deπvative therefore and an effective amount of a PDE4 inhibitor or a pharmaceutically acceptable deπvative thereof in the manufacture of a medicament in the treatment of lung disorders for example asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD) and cough or for the manufacture of a brocodilator.
When used herein cough can have a number of forms and includes productive, nonproductive, hyper-reactive, asthma and COPD associated
A further aspect of the invention is a patient pack comprsing an effective amount of a CB 2 modulator or a pharmaceutically acceptable deπvative therefore and an effective amount of a PDE4 inhibitor or a pharmaceutically acceptable derivative
Possible PDE4 compounds are as [cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-carboxylate] also known as cilomilast or Aπflo®, 2-carbomethoxy- 4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-one, and cis [4-cyano- 4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol]. They can be made by the processed descπbed in US patents 5,449,686 and 5,552,438. Other PDE4 inhibitors, specific inhibitors, which can be used in this invention are AWD- 12-281 from ASTA MEDICA (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98); a 9- benzyladenine deπvative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Scheπng-Plough; a benzodiazepine PDE4 inhibitor identified as CI-IOl 8 (PD-168787; Parke- Davis/Warner-Lambert); a benzodioxole deπvative Kyowa Hakko disclosed in WO 9916766, V- 11294A from Napp (Landells, LJ. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12(Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazmone (WO 99/47505) from Byk-Gulden (now Altana); or a compound identified as T- 440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 162). Additional PDE4 inhibitors are disclosed on pages 2 to 15 of WO01/13953. Specifically selected are arofyllme, atizoram, BAY-19-8004, benafentπne, BYK-33043, CC-3052, CDP-840, cipamfylline, CP-220629, CP-293121, D-22888, D-4396, denbufylhne, fϊlaminast, GW-3600, lbudilast, KF- 17625, KS-506-G, laprafylhne, NA-0226A, NA-23063A, ORG-20241, ORG-30029, PDB-093, pentoxifylline, piclamilast, rolipram, RPR-117658, RPR-122818, RPR-132294, RPR- 132703, RS-17597, RS-25344-000, SB-207499, SB210667, SB211572, SB-211600, SB212066, SB212179, SDZ-ISQ-844, SDZ-MNS-949, SKF-107806, SQ-20006, T-2585, tibenelast, tolafentπne, UCB-29646, V-11294A, YM-58997, YM-976 and zardaveπne. In one embodiment the PDE4 inhibitor is selected from cilomilast, AWD-12-281 , NCS-613, D- 4418, CI-IOl 8, V-11294A, roflumilast or T-440. Compounds of the present invention may also be of use in treating atherosclerosis in combination with an anti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-angmal, anti- hypertension agent or an agent for lowering Lp(a). Examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists. Examples of agents for loweπng Lp(a) include the aminophosphonates described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar SA and SmithKline Beecham) Examples of antihyerpertension agents are angiotensin-convertmg enzyme inhibitors, angiotensm-II receptor antagonists, ACE / NEP inhibitors, -blockers, calcium channel blockers, PDE inhibitors, aldosterone blockers
A preferred combination therapy will be the use of a compound of the present invention and a statin. The statins are a well known class of cholesterol loweπng agents and include atorvastatin, simvarstatin, pravastatin, ceπvastatm, fluvastatin, lovastatin and ZD 4522 (also referred to as S-4522, Astra Zeneca). The two agents may be administered at substantially the same time or at different times, according to the discretion of the physician.
A further preferred combination therapy will be the use of a compound of the present invention and an anti-diabetic agent or an insulin sensitiser. Withm this class, preferred compounds for use with a compound of the present invention include the PPARgamma activators, for instance G 1262570 (Glaxo Wellcome) and also the ghtazone class of compounds such as rosightazone (Avandia, SmithKlme Beecham), troghtazone and pioghtazone.
It will be appreciated that the compounds of any of the above combinations or compositions may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropπate doses will be readily appreciated by those skilled in the art.
Determination of cannabinoid CBl Receptor Agonist Activity
The cannabinoid CB 1 receptor agonist activity of compounds of formula (I) was determined in accordance with the following expeπmental method.
Experimental Method
Yeast (Saccharomyces cerevisiae) cells expressing the human cannabinoid CBl receptor were generated by integration of an expression cassette into the ura 3 chromosomal locus of yeast strain MMY23. This cassette consisted of DNA sequence encoding the human CBl receptor flanked by the yeast GPD promoter to the 5' end of CBl and a yeast transcriptional terminator sequence to the 3' end of CBl. MMY23 expresses a yeast/mammalian chimeric G-protein alpha subunit in which the C-terminal 5 amino acids of Gpal are replaced with the C-termmal 5 ammo acids of human Gαil/2 (as described in Brown et al. (2000), Yeast 16: 11-22). Cells were grown at 300C in liquid Synthetic Complete (SC) yeast media (Guthrie and Fink (1991), Methods in Enzymology, Vol. 194) lacking uracil, tryptophan, adenine and leucine to late logarithmic phase (approximately 6 OD600/ml).
Agonists were prepared as 10 mM stocks in DMSO. EC50 values (the concentration required to produce 50% maximal response) were estimated using 4 fold dilutions (BiomekFX, Beckman) into DMSO. Agonist solutions in DMSO (1% final assay volume) were transferred into black microtitre plates from Greiner (384-well) Cells were suspended at a density of 0.2 OD60o/ml
in SC media lacking histidine, uracil, tryptophan, adenine and leucine and supplemented with 1OmM 3-aminotπazole, 0.1M sodium phosphate pH 7.0, and lOμM fluorescein di-β-D- glucopyranoside (FDGIu). This mixture (50ul per well) was added to agonist in the assay plates (Multidrop 384, Labsystems). After incubation at 300C for 24 hours, fluorescence resulting from degradation of FDGIu to fluorescein due to exoglucanase, an endogenous yeast enzyme produced during agonist-stimulated cell growth, was determined using a fluorescence microtitre plate reader (Tecan Spectrofluor or LJL analyst excitation wavelength: 485nm; emission wavelength: 535nm). Fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter fit to generate a concentration effect value. Efficacy (Em3x) was calculated from the equation
Emax = MaX[Compound X] " Min[compound x] / MaX[HU210] - Min[HU2io] X 100% where MaX[Compound X] and Min[Compouild X] are the fitted maximum and minimum respectively from the concentration effect curve for compound X, and Max[Hu2io] and Min[HU2io] are the fitted maximum and minimum respectively from the concentration effect curve for (6aR,10aR)-3-(l,l'- Dimethylheptyl)-6a,7, 10,1 Oa-tetrahydro-1 -hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9- methanol (HU210; available from Tocπs). Equieffective molar ratio (EMR) values were calculated from the equation
EMR = EC50 [compound X] / EC50 [HU210]
Where EC50 [compound x] is the EC50 of compound X and EC50 [HU2IO] IS the EC50 Of HU210.
Compounds of the Examples tested according to this method had EC50 values >l,000nM and/or an efficacy of <30% at the cloned human cannabinoid CBl receptor, except Example 24 which had activity of between 300 to 100OnM and efficacy of 77%. The results given are averages of a number of expeπments.
Determination of cannabinoid CB2 Receptor Agonist Activity
The cannabinoid CB2 receptor agonist activity of compounds of formula (I) was determined in accordance with the following experimental method.
Experimental Method
Yeast (Saccharomyces cerevisiae) cells expressing the human cannabinoid CB2 receptor were generated by integration of an expression cassette into the ura3 chromosomal locus of yeast strain MMY23. This cassette consisted of DNA sequence encoding the human CB2 receptor flanked by the yeast GPD promoter to the 5' end of CB2 and a yeast transcriptional terminator sequence to the 3' end of CB2. MMY23 expresses a yeast/mammalian chimeric G-protem alpha
subunit in which the C-termmal 5 ammo acids of Gpal are replaced with the C-terminal 5 ammo acids of human Gαil/2 (as described in Brown et al. (2000), Yeast 16: 1 1-22). Cells were grown at 300C in liquid Synthetic Complete (SC) yeast media (Guthrie and Fmk (1991), Methods in Enzymology, Vol. 194) lacking uracil, tryptophan, adenine and leucine to late logarithmic phase (approximately 6 OD60o/ml).
Agonists were prepared as 10 mM solutions in DMSO. EC50 values (the concentration required to produce 50% maximal response) were estimated using 4 fold dilutions (BiomekFX, Beckman) into DMSO. Agonist solutions in DMSO (1% final assay volume) were transferred into black microtitre plates from Greiner (384-well). Cells were suspended at a density of 0.2 OD60o/ml in SC media lacking histidme, uracil, tryptophan, adenine and leucine and supplemented with 1OmM 3-ammotπazole, 0.1M sodium phosphate pH 7.0, and lOμM fluorescein di-β-D- glucopyranoside (FDGIu). This mixture (50ul per well) was added to agonist in the assay plates (Multidrop 384, Labsystems). After incubation at 300C for 24 hours, fluorescence resulting from degradation of FDGIu to fluorescein due to exoglucanase, an endogenous yeast enzyme produced during agonist-stimulated cell growth, was determined using a fluorescence microtitre plate reader (Tecan Spectrofluor or LJL Analyst excitation wavelength: 485nm; emission wavelength: 535nm). Fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter fit to generate a concentration effect value. Efficacy (Em3x) was calculated from the equation Em3x = Max[compound x] - Min[compound X] / Max[HU21 o] - Mm[HU21 o] x 100% where Max[compound X] and Min[compound X] are the fitted maximum and minimum respectively from the concentration effect curve for compound X, and Max[Hu2io] and Min[Hu2io] are the fitted maximum and minimum respectively from the concentration effect curve for (6aR,10aR)-3-(l,l'- Dimethylheptyl)-6a,7, 10,1 Oa-tetrahydro- 1 -hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9- methanol (HU210; available from Tocπs). Equieffective molar ratio (EMR) values were calculated from the equation
EMR = EC50 [compound X] / EC50 [HU210]
Where EC50 [compound x] is the EC50 of compound X and EC50 [HU2io] IS the EC50Of HU210.
The compounds of Examples 1 to 34, 37, 38, 40, 42 to 57 and 60 to 62 tested according to this method had an EC50 values of <300nM and efficacy value of >50% at the cloned human cannabinoid CB2 receptor.
The compounds of Example 35, 41 and 58 tested according to this method had an EC50 values between 30OnM and 100OnM and efficacy value of >50% at the cloned human cannabinoid CB2 receptor.
The compounds of Examples 39, 59 and 63 to 70 tested according to this method had an EC50 values >1000nM and/or efficacy value <50% at the cloned human cannabinoid CB2 receptor.
The compound of Example 36 was not tested. The results given are averages of a number of expeπments.
Experimental Method Measurement of CB2 agonist effects in a reporter gene assay
CB2 agonist effects may be determined using a reporter gene assay. These studies are performed using a CHO-Kl cell line expressing human recombinant CB2 receptors (CHO-Kl CB2 CRE-LUC cells). These cells additionally express a "CRE-LUC" reporter gene construct comprising the gene for luciferase under the control of multiple cAMP response element binding protein promoters. In these cells, increases in intracellular cAMP levels leads to transcription of the luciferase gene and the subsequent production of luciferase. The expression of luciferase is measured by addition to the cells of a proprietary mixture containing luciferm, the substrate for luciferase (Luchte, Perkm Elmer, Cat No 6016919). The resultant reaction leads to the generation of light which is measured in a TopCount scintillation counter. In the CHO-Kl CB2 CRE-LUC cells, forskohn produces a marked increase in luciferase expression and CB2 agonists inhibit this response. The CHO-Kl CB2 CRE-LUC cells routinely express a high level of constitutive CB2 receptor activity. This was overcome in these experiments by pre-treatmg the cells with the inverse agonist, SR144528, for 30-60mms before use. This treatment has been shown to eliminate constitutive CB2 receptor activity (Bouaboula et al., 1999).
Methods
CHO-Kl CB2 CRE-LUC cells are grown in DMEM/F12 plus glutamax I medium (Gibco Cat. No. 31331-028), supplemented with 9% FBS (Gibco, Cat. No. 16000-040) and 0.5mg.mr' G418 (Gibco, Cat. No. 10131-027) and 0.5mg.ml ' Hygromycin (Invitrogen, Cat. No. 10687-010). Cells are grown as a monolayer culture in 162cm2 vented Nunclon flasks (NUNC, Cat. No. 178883) in 27.5ml of media in a humidified 95% air and 5% CO2 atmosphere at 370C. When confluent, the growth media is replaced with DMEM/F12 medium (Gibco, Cat. No. 31331-028) containing 10OnM of the CB2 inverse agonist, SR144528, and the cells are incubated at 370C for 30-60mms. Flasks are rinsed twice with 25ml Dulbecco's phosphate buffered saline (PBS, Gibco Cat. No. 14190-094) and then harvested by incubation for lOmms in 10ml of Versene (Gibco, Cat. No. 15040-033). Cells are detached by a sharp blow to the flask and the cell suspension made up to 50ml with PBS and centrifuged at 250xg for 5mms. The cell pellet is re-suspended in 24mls of phenol-red free DMEM/F12 assay buffer (Gibco, Cat. No. 11039-021) and 50μl of cell suspension (approximately 50,000 cells) is added to 96 well plates (Costar, Cat. No. 3904 - clear bottomed black well plates) containing 50μl of test agonist in 2μM forskohn (final assay concentration of lμM FSK). Test agonists are prepared as 1OmM solutions in DMSO and diluted into phenol-red free DMEM/F12 assay buffer containing 2μM forskohn to produce a 20μM solution of test agonist. Subsequent seπal dilutions of test agonist are prepared in the assay buffer containing forskohn and each test agonist is routinely examined over a final assay concentration range of lOμM to 1OnM (or lower if required). The plates are mixed on a plate shaker for 5mms (800-1000 rpm) and then centrifuged briefly (5-1Os) at 250xg, placed in a Bioplate without their lids, and incubated for 4-5hr in a humidified 95% air and 5% CO2 atmosphere at 370C. The 96 well plates are removed from the incubator and placed at RT for 10-15mms before addition of 25μl of Luchte solution, prepared
according to the manufacturer's instructions. The plates are sealed with Topseal A (Perkin Elmer, Cat. No. 6005185), mixed on a plate shaker for 5mins (800-1000 rpm) and then centπfuged briefly (5-1Os) at 250xg. Finally, luminescence is measured using a Packard TopCount scintillation counter.
Data Analysis
For each compound maximal inhibition of the forskhn response and the EC50 for this effect is determined. In each expeπment the reference agonist FTU210 is included and the maximal effect of each test agonist is expressed relative to the maximal effect produced by HU210 to provide an estimate of intrinsic activity. In addition the EC50 of each compound is divided by the EC50 for HU210 to calculate the equipotent molar ratio (EMR) for the test compound.
Reference
Bouaboula M. Dussossoy D. Casellas P. Regulation of peπpheral cannabmoid receptor CB2 phosphorylation by the inverse agonist SR 144528. Implications for receptor biological responses. Journal of Biological Chemistry. 274(29) -20397-405, 1999
The following examples are illustrative, but not limiting of the embodiments of the present invention. Abbreviations:
AcOH (acetic acid), Bn (benzyl), Bu, Pr, Me, Et (butyl, propyl, methyl ethyl), DMSO (dimethyl sulfoxide), DCM (dichloromethane), DME (1,2-dimethoxyethane), DMF (N5N- dimethylformamide), EDC (l-(3-dimethylaminopropyl)-3-ethylcarbodnmide), EtOAc (ethyl acetate), EtOH (ethanol), HPLC (High pressure liquid chromatography), LC/MS (Liquid chromatography/Mass spectroscopy), MDAP (Mass Directed AutoPuπfication), MeCN (acetomtrile), MeOH (methanol), NMR (Nuclear Magnetic Resonance (spectrum)), NMP (N- methyl pyrrohdone), SPE (Solid Phase Extraction), TFA (Tπfluoroacetic acid), THF (tetrahydrofuran), s, d, t, q, m, br (singlet, doublet, triplet, quartet, multiplet, broad.)
Conditions, Hardware and software used for Mass Directed Auto-Purification Systems used in Examples.
Hardware
Waters 2525 Binary Gradient Module, Waters 515 Makeup Pump, Waters Pump Control Module Waters 2767 Inject Collect, Waters Column Fluidics Manager, Waters 2996 Photodiode Array
Dectector, Waters ZQ Mass Spectrometer, Gilson 202 fraction collector, Gilson Aspec waste collector
Software
Waters Masslynx version 4 Column
The columns used are Waters Atlantis, the dimensions of which are 19mm x 100mm (small scale) and 30mm x 100mm (large scale). The stationary phase particle size is 5μm.
Solvents
A : Aqueous solvent = Water + 0 1% Formic Acid
B : Organic solvent = Acetonitrile + 0.1% Formic Acid
Make up solvent = Methanol : Water 80:20
Needle πnse solvent = Methanol Methods
There are four methods used depending on the analytical retention time of the compound of interest. They all have a 13.5-mmute runtime, which comprises of a 10-minute gradient followed by a 13.5 mmute column flush and re-equilibration step.
Large/Small Scale 1.0-1.6 = 0-20% B Large/Small Scale 1.5-2.1 = 15-55% B
Large/Small Scale 2.0-2.7 = 30-85% B
Large/Small Scale 2.6-4.0 = 50-99% B
Flow rate
All of the above methods have a flow rate of either 20mls/mm (Small Scale) or 40mls/mm (Large Scale)
LCMS for the Examples were run on one of the following systems, MS3-2, MS3-1, MS2-2,
MS2-1, MS1-3, MS1-2 or MSl-I.
Hardware MS3-2
Agilent 1100 Gradient Pump, Agilent 1100 Autosampler, Agilent 1100 DAD Dectector, Agilent
1100 Degasser, Agilent 1100 Oven, Agilent 1100 Controller, Agilent 1100 ALSTherm, Waters ZQ
Mass Spectrometer, Sedere Sedex 85
MS3-1 Waters Alliance 2795, Waters 2996 Photodiode Array Detector, Waters ZQ Mass Spectrometer
Sedere Sedex 75
MS2-2
Agilent 1100 Gradient Pump, Agilent 1100 DAD Dectector, Agilent 1100 Degasser, Agilent 1100
Oven, Agilent 1100 Controller, Waters ZQ Mass Spectrometer, Waters 2777 Sample Manager Sedere Sedex 75
MS2-1
Agilent 1100 Gradient Pump, Agilent 1100 DAD Dectector, Agilent 1100 Degasser, Agilent 1100
Oven, Agilent 1100 Controller, Waters ZMD Mass Spectrometer, Gilson 402 Syringe Pump,
Gilson 233XL Sample Rack, Sedere Sedex 75 MS1-3
Waters Alliance 2795, Waters 996 Photodiode Array Detector, Waters ZQ Mass Spectrometer
Sedere Sedex 75
MS1-2
Agilent 1100 Gradient Pump, Agilent 1100 DAD Dectector, Agilent 1100 Degasser, Agilent 1100 Oven, Agilent 1100 Controller, Waters ZMD Mass Spectrometer, Gilson 402 Syringe Pump
Gilson 233XL Sample Rack, Sedere Sedex 75
MSl-I
Waters Alliance 2795, Waters 996 Photodiode Array Detector, Waters ZQ Mass Spectrometer
Sedere Sedex 75
The software, column and solvent system used on the above systems were the same and was recorded below.
Software Waters Masslynx versions 4.0
Column
The column used is a Waters Atlantis, the dimensions of which are 4.6mm x 50mm. The stationary phase particle size is 3μm.
Solvents A : Aqueous solvent = Water + 0.05% Formic Acid
B : Organic solvent = Acetonitrile + 0.05% Formic Acid
Method
The geneπc method used has a 4 minute runtime, which comprises of a 3-mmute gradient (0-100%
B) followed by a 1 mmute column flush. Flow rate
The above method has a flow rate of 1.5ml/mins
Intermediate 1: 2-(Carboxymethyl)-l-methyl-lH-pyrrole-3-carboxylic acid
Methylamme (40% in water, 110ml) and water (44ml) were cooled to 1O0C and 1,3 -acetone dicarboxyhc acid (20.4g) was added portionwise keeping the temperature below 200C. Once the reaction mixture had cooled back to ~10°C, chloroacetaldehyde (50% in water, 30.1ml) was added dropwise keeping the temperature below 15°C. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was cooled in an ice bath and acidified to pHl with 5N hydrochloric acid, whereby a precipitate formed. The precipitate was filtered off and dissolved m boiling acetic acid which upon cooling precipitated. The solid was filtered off and dried to afford the title compound as an off-white solid (17.57g). LC/MS [M+Na] 206 consistent with molecular formula C8H9NO4
Intermediate 2: Methyl l-methyl-2-[2-(methyloxy)-2-oxoethyl]-lH-pyrrole-3-carboxylate
2-(Carboxymethyl)-l -methyl- lH-pyrrole-3-carboxylic acid (17.2g), p-toluenesulfonic acid (1 Ig) and methanol (250ml) were refluxed under argon for twenty three hours. The solvent was evaporated and the residue washed with ethanol to afford the title compound as a white solid (16g). LC/MS [MH ] 210 consistent with molecular formula Ci0H13NO4
Intermediate 3: Methyl 2-{2-hydroxy-l-[(methyloxy)carbonyl]ethenyl}-l-methyl-lH-pyrrole- 3-carboxylate
Methyl l-methyl-2-[2-(methyloxy)-2-oxoethyl]-lH-pyrrole-3-carboxylate (1Og) in dry tetrahydrofuran (200ml) was stirred at room temperature under argon. Sodium hydride (60% dispersion in mineral oil, 8g) was added portionwise followed by methyl formate (4.5ml) and the mixture was left to stir overnight. The reaction mixture was cooled in an ice bath and quenched by the addition of the minimum amount of methanol. The solution was re-cooled and acidified to pHl with aqueous 5N hydrochloric acid. The reaction mixture was diluted with ethyl acetate and water, the aqueous separated and extracted three times with ethyl acetate. The combined organic layers were then washed with brme, dπed (MgSO4) and filtered The solvent was evaporated to afford an oil consisting of two layers. The top layer was discarded and the lower layer solidified on standing to afford the crude title compound as a brown solid (12.76g). LC/MS [M+Na] 262 consistent with isomers of molecular formula C1 !H13NO5
Intermediate 4: Methyl 2-{2-ammo-l-[(methyloxy)carbonyl]ethenyl}-l-methyl-lH-pyrrole-3- carboxylate
(12.76g), ammonium acetate (2Og) and methanol (100ml) were refluxed under argon for two hours. After cooling the solvent was evaporated and the residue dissolved in ethyl acetate and washed with water, the aqueous was separated and extracted three times with ethyl acetate. The combined orgamcs were washed with saturated brme solution and the organic layer was dπed (MgSO4) and evaporated. The residue was dissolved in the minimum amount of ethyl acetate and a precipitate formed which was filtered off to afford the title compound as an off-white solid (6g). The filtrate was evaporated and the residue obtained was purified by chromatography on a silica column using the Flashmaster II eluting with an ethyl acetate/hexane gradient (30% to 100% ethyl acetate) to afford the title compound as a white solid (6g). The solids were combined and used in the next reaction without further purification.
LC/MS [M+Na] 261 consistent with isomers of molecular formula C11H14N2O4
A mixture of methyl 2-{2-amino-l-[(methyloxy)carbonyl]ethenyl}-l-methyl-lH-pyrrole-3- carboxylate (8g), sodium ter/-butoxide (0.64g) and dimethylformamide (80ml) was divided equally between 8x1 OmI sealed vessels and heated under microwave conditions at 1600C for five minutes. The cooled solutions were combined and added slowly to iced water and stirred for ten minutes. A precipitate formed which was filtered off and dπed to afford the title compound as a white solid (2.4g). The aqueous filtrate was extracted three times with ethyl acetate and the combined organic layers washed with saturated brine solution. The dried (Na2SO4) organic layer was evaporated to afford a yellow oil which was triturated with warm isopropyl alcohol to afford the title compound as a white solid (2.Ig). The combined weight of the title compound was (4.5g). LC/MS [MH"] 207 consistent with molecular formula Ci0H10N2O3.
Intermediate 6: Methyl 4-chloro-l-methyl-lH-pyrrolo[3,2-c]pyridine-7-carboxylate
Methyl l-methyl-4-oxo-4,5-dihydro-lH-pyrrolo[3,2-c]pyπdine-7-carboxylate (4.5g) and phenyl dichlorophosphate (10ml) were heated at 1800C under argon for thirty minutes. The reaction mixture was allowed to cool, carefully poured onto iced water (200ml), and extracted with ethyl acetate (4 x 250ml). The ethyl acetate layers were combined, dπed (MgSO4) and evaporated to a yellow solid. The solid was purified by chromatography on a silica column using the Flashmaster II eluting with an ethyl acetate/hexane gradient (0% to 70% ethyl acetate) to afford the title compound as an off white solid (2.9g). LC/MS [MH+] 225 consistent with molecular formula Ci0H9 35ClN2O2.
Intermediate 7: 4-Chloro-l-methyl-lH-pyrrolo[3,2-c]pyridine-7-carboxylic acid
To a solution of methyl 4-chloro-l-methyl-lH-pyrrolo[3,2-c]pyridine-7-carboxylate (0.5g), in methanol (20ml) was added aqueous 2M sodium hydroxide solution (2ml) and the mixture was heated to reflux for four hours. The methanol was evaporated and the residue was dissolved m water (50ml) and acidified to pΗ 1 using aqueous 2M hydrochloπc acid. Solid sodium chloride was added to saturate the aqueous phase, which was extracted with tetrahydrofuran (2 x 50ml). The tetrahydrofuran layers were combined and evaporated to afford the title compound (460mg). 1HNMR (MeOD) δ 3.95 (3H, s), 6.69 (IH, d), 7.62 (IH, d), 8.37 (IH, s), 13.60 (IH, bs)
Intermediate 8: 4-Chloro-l-methyl-7-(4-morpholinylcarbonyl)-lH-pyrrolo[3,2-c]pyridine
To a solution of 4-chloro-l -methyl- lH-pyrrolo[3,2-c]pyridine-7-carboxyhc acid (460mg) in dimethylformamide (10ml) was added l-[3-(dimethylamino)propyl]-3-ethylcarbodnmide (512mg), 1 -hydroxybenzotriazole (387mg), N-ethylmorpholme (2ml) and morpholme (0.39ml). The solution was stirred at room temperature overnight. The reaction mixture was diluted with water (50ml) and extracted three times with ethyl acetate (50ml). The ethyl acetate layers were combined, dried
(MgSO4) then evaporated. The residue was purified by chromatography on a silica column using the Flashmaster II eluting with an ethyl acetate/hexane gradient (10% to 80% ethyl acetate) over twenty minutes to afford the title compound (502mg).
LC/MS [MH+] 280 consistent with molecular formula C13Hi4 35ClN3O2
Intermediate 9: 4-Chloro-7-[(l,l-dioxido-4-thiomorpholinyl)carbonyl]-l-methyl-lH- pyrrolo [3,2-c] pyridine
Prepared in a manner similar to Intermediate 8 from 4-chloro-l-methyl-lH-pyrrolo[3,2-c]pyridme-
7-carboxylic acid (2.28g) and thiomorphohne 1,1 -dioxide (2.45g). The reaction mixture was evaporated, diluted with water (50ml) and extracted three times with ethyl acetate (50ml). The ethyl acetate layers were combined, washed with saturated sodium bicarbonate solution then dried (MgSO4) and evaporated to afford the title compound (3.32g).
Intermediate 10: 4-Chloro-l-methyl-7-(l-pyrrolidinylcarbonyl)-lH-pyrrolo[3,2-c]pyridine
Prepared in a manner similar to Intermediate 8 from 4-chloro-l -methyl-lH-pyrrolo[3,2-c]pyπdine- 7-carboxylic acid (0.77g) and pyrrolidine (0.39g). The reaction mixture was evaporated, diluted with water (50ml) and extracted three times with ethyl acetate (50ml). The ethyl acetate layers were combined, washed with saturated sodium bicarbonate solution then dried (MgSO4) and evaporated to afford the title compound (1.09g).
LC/MS [MH+] 264 consistent with molecular formula C13H14 35ClN3O.
Intermediate 11: l-Methyl-4-oxo-4,5-dihydro-lH-pyrrolo[3,2-c]pyridine-7-carboxylic acid
To a solution of methyl l-methyl-4-oxo-4,5-dihydro-lH-pyrrolo[3,2-c]pyridine-7-carboxylate (0.95Og) in methanol (10ml), was added aqueous 2M sodium hydroxide solution (2ml). The mixture was heated under microwave conditions at 12O0C for twenty minutes. The methanol was evaporated, the residue dissolved in water (10ml) and acidified to pH 1 using aqueous 2M hydrochloric acid. The precipitate formed was filtered off and washed with water (5ml) and dried to afford the title compound (852mg). LC/MS [MH+] 193 consistent with molecular formula C9 H8 N2 O3
Intermediate 12: 1 -Methyl-7-(4-morpholinylcarbonyl)-l ,5-dihydro-4H-pyrrolo [3,2-c] pyridin- 4-one
To a solution of l-methyl-4-oxo-4,5-dihydro-lH-pyrrolo[3,2-c]pyridme-7-carboxylic acid (852mg) in dimethylformamide (10ml) was added l-[3-(dimethylammo)propyl]-3-ethylcarbodπmide (760mg) , 1 -hydroxybenzotriazole (560mg), N-ethylmorpholme (2ml) and morpholme (577mg). The solution was stirred at room temperature overnight and the dimethylformamide was evaporated. The residue was purified by chromatography over a silica column using the Flashmaster II eluting with a dichloromethane/methanol gradient (95% to 5%) over twenty minutes to afford the title compound (1.09g). LC/MS [MH+] 262 consistent with molecular formula Ci3H]5N3O3
Intermediate 13: 4-Chloro-l-methyl-7-(l-piperidinylcarbonyl)-lH-pyrrolo[3,2-c]pyridine
A solution of oxalyl chloride (3.43ml) in dichloromethane (40ml) was cooled to O0C and 4-chloro- l-methyl-lH-pyrrolo[3,2-c]pyridme-7-carboxylic acid (3.75g) was added portionwise followed by the addition of dimethylformamide (4 drops). The reaction mixture was stirred at 00C for ninety minutes, dichloromethane (5ml) was added and stirring continued for a further thirty minutes. The reaction mixture was evaporated and the residue dissolved in dichloromethane (20ml) and dimethylformamide (10ml). N-Ethylmorpholine (9.09ml) followed by pipeπdine (3.53ml) were added and the mixture stirred at O0C for forty five minutes. The reaction mixture was evaporated and the residue dissolved in ethyl acetate (150ml). The organic layer was washed with water
(100ml), sodium bicarbonate (3 x 100ml) and bπne (30ml) then dried (MgSO4) and evaporated to afford a yellow oil. The oil was triturated with diethyl ether to afford a solid, which was filtered and dπed at 6O0C under vacuum, to afford the title compound (3.95g). LC/MS [MH+] 278 consistent with molecular formula C14H16 35ClN3O.
To a solution of 4-chloro-l-methyl-7-(4-moφhohnylcarbonyl)-lH-pyrrolo[3,2-c]pyridine (lOOmg) in tetrahydrofuran (ImI) was added tπs(dibenzylideneacetone)dipalladium(0) (2mg), 2- (dicyclohexylphosphmo) biphenyl (2mg) and lithium hexamethyldisilazane (0.428ml) and the mixture sealed and heated at 65°C for seventeen hours. On cooling, the mixture was treated with IM tetrabutylammonium fluoride in tetrahydrofuran (ImI) and evaporated. The mixture was purified by MDAP to afford the title compound (48mg). LC/MS [MH+] 261 consistent with molecular formula CnH16N4O2
Intermediate 15: 5-Iodo-3-nitro-2(lH)-pyridinone
O"
A suspension of 3-nitro-2(lH)-pyridinone (can be purchased from Aldnch) (51.4g) in acetic acid (230ml), water (50ml), concentrated sulphuric acid (7ml) and peπodic acid (17.6g) was stirred at 9O0C for fifteen minutes whereby a solution was obtained Iodme crystals (38.25g) were added portionwise and after twenty minutes a dense yellow precipitate had formed. The mixture was cooled and saturated sodium thiosulphate (250ml) added. The solid was filtered and washed with saturated sodium thiosulphate (250ml) followed by water. The solid was sucked dry then dπed over sodium hydroxide at 5O0C under vacuum to afford the title compound (91.4g).
LC/MS [MH+] 267 consistent with molecular formula C5H3 127IN2O3
Intermediate 16: 2-Chloro-5-iodo-3-nitro-pyridine
9"
A suspension of 5-iodo-3-nitro-2(lH)-pyπdmone (4Og) in phenyl dichlorophosphate (80ml) was heated at 18O0C for thirty minutes whereby a brown solution was obtained. The solution was allowed to cool then poured onto ice/water and neutralised by a portionwise addition of solid sodium bicarbonate. The aqueous was extracted with ethyl acetate (300ml) which was then washed with 5% sodium bicarbonate solution (2 x 250ml). The organic layer was dried (MgSO4), and evaporated to give a pale brown solid. The solid was stirred in iso-hexane for 2h, filtered off, washed with iso-hexane and dried at 5O0C under vacuum to afford the title compound (34.Ig). LC/MS [M-I"] 158 consistent with molecular formula C5H2 35Cl127IN2O2
To a solution of 1 -propenylmagnesium bromide (0.5M solution in tetrahydrofuran, 240ml) at O0C was added a solution of 2-chloro-5-iodo-3-nitro-pyridine (1 Ig) in dry tetrahydrofuran, dropwise over thirty minutes. After ten minutes at O0C the reaction was quenched with saturated ammonium chloride (300ml). The mixture was then extracted with ethyl acetate (300ml) which was dπed
(MgSO4) and evaporated to give a red oily solid. The residue was triturated with dichloromethane and refrigerated overnight. The solid was then filtered off, sucked dry then dried at 6O0C under vacuum to afford the title compound (3.67g). The filtrate was evaporated, dissolved in the minimum of dichloromethane and seeded with the above to afford a further crop (200mg). LC/MS [MH+] 293 consistent with molecular formula C8H6 35ClIN2
Intermediate 18: 1,1-Dimethylethyl 7-chloro-4-iodo-3-methyl-lH-pyrrolo[2,3-c]pyridine-l- carboxylate
To a solution of 7-chloro-4-iodo-3-methyl-lH-pyrrolo[2,3-c]pyridme (5g) in dry tetrahydrofuran (250ml) at O0C under an atmosphere of nitrogen was added portionwise sodium hydride (60% dispersion in mineral oil, 1.5g). After addition, the solution was stirred at room temperature for thirty minutes. The solution was then re -cooled to O0C and a solution of di-tert-butyl dicarbonate (5.6g) in dry tetrahydrofuran (60ml) was added dropwise. The solution was stirred for ninety minutes warming to room temperature and then partitioned between ethyl acetate and water and washed with water until the pH of the aqueous was neutral. The organic layer was dried (MgSO4) and evaporated to afford a brown oil which solidified. The solid was purified by Biotage chromatography over silica gel (10Og), eluting with iso-hexane followed by 5% ethyl acetate/iso hexane to afford the title compound as a pale yellow solid. (5.5g). LC/MS [M-1Bu] 337 consistent with molecular formula C13H14 35ClIN2O2
Intermediate 19: 7-Chloro-l-{[(l,l-dimethylethyI)oxy]carbonyl}-3-methyl-lH-pyrrolo[2,3- c]pyridine-4-carboxylic acid
To a solution of 1 , 1 -dimethylethyl 7-chloro-4-iodo-3-methyl-lΗ-pyrrolo[2,3-c]pyridme-l- carboxylate (4g) in dry tetrahydrofuran (80ml) at room temperature under an atmosphere of nitrogen, was added 4A molecular sieves. The solution was cooled to -400C and a solution of isopropylmagnesium chloride (2M in tetrahydrofuran, 10.8ml) was added dropwise and the
solution stirred at -4O0C for five minutes. The solution was saturated with a stream of carbon dioxide gas passed through a column of Drieπte and then diluted with ethyl acetate (100ml). The organic layer was extracted with IN sodium hydroxide solution (2 x 200ml) and the combined aqueous was then acidified to pHl with concentrated hydrochloric acid. The aqueous layers were combined and extracted with ethyl acetate (2 x 200ml). The organic layers were combined and washed with water (3 x 250ml), dried (MgSO4) and evaporated to afford a solid. The solid was triturated with iso-hexane, filtered off and washed with iso-hexane. The solid was then sucked dry and dned at 5O0C to afford the title compound (2.55g). LC/MS [M-1Bu] 255 consistent with molecular formula C14H15 35ClN2O4
Intermediate 20: 1,1-Dimethylethyl 7-chloro-3-methyl-4-(4-morpholinylcarbonyl)-lH- pyrrolo[2,3-c]pyridine-l-carboxylate
To a solution of 7-chloro-l-{[(l,l-dimethylethyl)oxy]carbonyl}-3-methyl-lH-pyrrolo[2,3- c]pyπdme-4-carboxylic acid (300mg) in dimethylformamide (4ml) was added 4-ethylmorpholine (0.492ml), morphohne (0.172ml), 1 -hydroxybenzotriazole hydrate (204mg) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (223mg) and the solution stirred at room temperature overnight. The solution was diluted with ethyl acetate (50ml) and washed with 5% sodium bicarbonate solution (2 x 10ml) and water (2 x 20ml). The organic layer was dried (MgSO4) and evaporated to afford the title compound as a white foam which was used without further purification. LC/MS [MH+] 380 consistent with molecular formula C18H19 35ClN3O4
Intermediate 21: 1,1-Dimethylethyl 7-chloro-3-methyl-4-{[methyl(tetrahydro-2H-pyran-4- ylmethyl)amino]carbonyl}-lH-pyrrolo[2,3-c]pyridine-l-carboxylate
To a solution of 7-chloro-l-{[(l,l-dimethylethyl)oxy]carbonyl}-3-methyl-lH-pyrrolo[2,3- c]pyridme-4-carboxylic acid (350mg) in dimethylformamide (4ml) was added 4-ethylmorpholine (0.574ml), N-methyl-l-(tetrahydro-2H-pyran-4-yl)methanamme hydrochloπde (280mg), 1- hydroxybenzotriazole hydrate (238mg) and l-(3-dimethylammopropyl)-3-ethylcarbodπmide hydrochloride (260mg) and the solution stirred at room temperature overnight. The solution was diluted with ethyl acetate (50ml) and washed with 5% sodium bicarbonate solution (3 x 20ml) and water (2 x 20ml). The organic layer was dned (MgSO4) and evaporated to afford the title compound as a yellow oil (540mg) which was used without further purification. LC/MS [M-'Bu] 366 consistent with molecular formula C21H28 35ClN3O4
Intermediate 22: 1,1-Dimethylethyl 7-chloro-4-{[(cyclobutylmethyl)amino]carbonyl}-3- methyl-1 H-pyrrolo [2,3-c] pyridine-1 -carboxylate
To a solution of 7-chloro-l-{[(l,l-dimethylethyl)oxy]carbonyl}-3-methyl-lH-pyrrolo[2,3- c]pyridine-4-carboxyhc acid (Ig) in dimethylformamide (15ml) was added 4-ethylmorphohne (1.6ml), (cyclobutylmethyl)amine hydrochloride (586mg), 1 -hydroxybenzotπazole hydrate (682mg) and l-(3-dirnethylaminopropyl)-3-ethylcarbodnmide hydrochloride (743mg) and the solution stirred at room temperature overnight. The solution was diluted with ethyl acetate (50ml) and washed with 5% sodium bicarbonate solution (3 x 20ml) and water (2 x 20ml). The organic layer was dπed (MgSO4) and evaporated to afford the title compound which was used without further purification. LC/MS [MH+] 378 consistent with molecular formula C19H24 35ClN3O3
Intermediate 23 : 7-Chloro-4-iodo-2,3-dimethyl-l H-pyrrolo [2,3-c] pyridine
To a solution of 1 -methyl- 1 -propenylmagnesium bromide (0.5M solution in tetrahydrofuran) (142ml) at O0C was added a solution of 2-chloro-5-iodo-3-mtro-pyridme (6.53g) in dry tetrahydrofuran (140ml), dropwise over ten minutes. After ten minutes at 00C the reaction mixture was quenched with saturated ammonium chloride (200ml). The mixture was extracted with ethyl acetate (200ml) which was washed with water (3 x 200ml), then dried (MgSO4) and evaporated to a brown oil. The residue was purified by Biotage chromatography elutmg with 10% ethyl acetate/hexane to afford the title compound as a yellow solid (928mg). LC/MS [MH+] 307 consistent with molecular formula C9H8 35ClIN2
Intermediate 24: 7-Chloro-2,3-dimethyl-lH-pyrrolo [2,3-c] pyridine-4-carboxylic acid
To a solution of 7-chloro-4-iodo-2,3-dimethyl-lH-pyrrolo[2,3-c]pyridine (490mg) in dry tetrahydrofuran (15ml) at room temperature under an atmosphere of argon, was added 4A molecular sieves. The solution was cooled to O0C and a solution of isopropylmagnesium chloride (2M in tetrahydrofuran, 2.4ml) was added dropwise keeping the internal temperature below 1O0C. The mixture was stirred at 50C for thirty minutes, saturated with a stream of carbon dioxide gas passed through a column of Dπerite and then diluted with ethyl acetate. The organic layer was
extracted with saturated ammonium chloπde which was then acidified to pHl with concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the organic layer washed twice with water, dried (MgSO4) and evaporated to afford the title compound (200mg) as a pale yellow solid. LC/MS [MH+] 225 consistent with molecular formula C10H9 35ClN2O2
Intermediate 25: 7-Chloro-2,3-dimethyl-4-(l-morpholin-4-yl-methanoyl)-pyrrolo[2,3- c] pyridine
To a solution of 7-chloro-2,3-dimethyl-lH-pyrrolo[2,3-c]pyπdme-4-carboxylic acid (99mg) in dimethylformamide (2ml) was added 4-ethylmorpholme (0.225ml), morphohne (0.077ml), 1- hydroxybenzotriazole hydrate (93mg) and l-(3-dimethylammopropyl)-3-ethylcarbodiimide hydrochloride (102mg) and the solution stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50ml) and washed with saturated sodium bicarbonate solution (10ml) and water (10ml). The organic layer was dπed (MgSO4) and evaporated to afford a yellow oil (146mg) which was used without further purification. LC/MS [MH+] 294 consistent with molecular formula Ci4H16 35ClN3O2
Intermediate 26: 7-Chloro-N-(cyclobutylmethyl)-2,3-dimethyl-lH-pyrrolo [2,3-c] pyridine-4- carboxamide
Prepared in a similar manner to Intermediate 25 from 7-chloro-2,3-dimethyl-lH-pyrrolo[2,3- c]pyridine-4-carboxyhc acid and (cyclobutylmethyl)amine hydrochloride. LC/MS [MH+] 292 consistent with molecular formula C15H18 35ClN3O
Intermedate 27: 1,1-Dimethylethyl 7-chloro-3-methyl-4-{[(tetrahydro-2H-pyran-4- ylmethyl)amino] carbonyl} - 1 H-pyr rolo [2 ,3-c] pyridine- 1 -carboxylate
To a solution of 7-chloro-l-{[(l,l-dimethylethyl)oxy]carbonyl}-3-methyl-lH-pyrrolo[2,3- c]pyπdine-4-carboxylic acid (300mg) m dimethylformamide (4ml) was added 4-ethylmorpholme (0.492ml), (tetrahydro-2H-pyran-4-ylmethyl)amine hydrochloπde (222mg), 1-
hydroxybenzotriazole hydrate (204mg) and l-(3-dimethylammopropyl)-3-ethylcarbodiimide hydrochloride (223mg) and the solution stirred at room temperature overnight. The solution was diluted with ethyl acetate (50ml) and washed with 5% sodium bicarbonate solution (2 x 10ml) and water (2 x 20ml). The organic layer was dπed (MgSO4) and evaporated to afford the title compound as an off-white foam which was used without further purification. LC/MS [MH+] 408 consistent with molecular formula C20H26 35ClN3O4
Example 1: 4-[(3-Chlorophenyl)oxy]-l-methyl-7-(4-morpholinylcarbonyl)-lH-pyrrolo[3,2- c] pyridine hydrochloride
To a solution of 3-chlorophenol (0.055ml) in dimethylformamide (ImI) in a microwave vial was added portionwise sodium hydride (60% dispersed in mineral oil, 20mg). The mixture was stirred at room temperature for twenty minutes then 4-chloro-l-methyl-7-(4-morphohnylcarbonyl)-lH- pyrrolo[3,2-c]pyridine (lOOmg) in dimethylformamide (ImI) was added. The mixture was heated under microwave conditions at 1800C for four hours. The dimethylformamide was evaporated, the residue puπfied by MDAP, treated with 4M hydrochloric acid in 1,4-dioxan, and then freeze dried to afford the title compound (24mg).
LC/MS [MH+] 372 consistent with molecular formula Ci9H18 35ClN3O3
Examples in Table 1 were prepared in a manner similar to Example 1 from 4-chloro-l-methyl-7-(4- moφholinylcarbonyl)-lH-pyrrolo[3,2-c]pyridine and the appropπate commercially available phenol or alcohol. The reactions were monitored by LCMS and reaction times were between two and ten hours. For Examples 7 to 16, the dimethylformamide was not evaporated prior to purification by MDAP.
Table 1
Examples in Table 2 were prepared in a manner similar to Example 1 from either 4-chloro-l- methyl-7-(l-pyrrohdinylcarbonyl)-lH-pyrrolo[3,2-c]pyridine or 4-chloro-7-[(l,l-dioxido-4- thiomorpholinyl)carbonyl]-l-methyl-lH-pyrrolo[3,2-c]pyridine and the appropπate commercially available phenol, alcohol or benzyl alcohol. The mixtures were heated under microwave conditions at 1800C for two hours.
Table 2.
Example 36: 4-[(3-Chlorophenyl)thio]-l-methyl-7-(l-piperidinylcarbonyl)-lH-pyrrolo[3,2- c] pyridine
To a solution of 3-chlorobenzenethiol (0.335ml) in dimethylformamide (2ml) in a microwave vial was added portionwise sodium hydride (60% dispersed in mineral oil, 115mg). The mixture was stirred at room temperature for twenty minutes then 4-chloro-l-methyl-7-(l-pipeπdmylcarbonyl)- lH-pyrrolo[3,2-c]pyridine (200mg) in dimethylformamide (2ml) was added. The reaction mixture was heated under microwave conditions at 1800C for two hours. The reaction mixture was diluted with ethyl acetate (50ml) and washed with water (2 x 20ml) then dπed (MgSO4) and evaporated to an oil. The oil was purified by column chromatography on a Biotage silica column elutmg with 1 : 1 ethyl acetate/hexane to afford the title compound (274mg).
LC/MS [MH+] 386 consistent with molecular formula C20H20 ClN3OS
Example 37 : 4-[(3-ChIorophenyl)sulfonyI]-l-methyl-7-(l-piperidinylcarbonyl)-lH- pyr rolo [3,2-c] pyridine
To a solution of 4-[(3-chlorophenyl)thio]-l-methyl-7-(l-pipeπdmylcarbonyl)-lH-pyrrolo[3,2- cjpyridme (270mg) in dichloromethane (9ml) at 00C was added 3-chloroperoxybenzoic acid (394mg) and the solution stirred for two hours. The reaction mixture was diluted with dichloromethane and washed with sodium thiosulphate, saturated sodium bicarbonate solution and water. The organic layer was dπed (MgSO4) and evaporated to an off white foam. Purification by MDAP afforded the title compound as a white foam (185mg). LC/MS [MH+] 418 consistent with molecular formula C20H20 35ClN3O3S
Example 38 : Λf-[(3-Chlorophenyl)methyl]-l-methyl-7-(4-morpholinylcarbonyl)-lH- pyrrolo [3,2-c] pyridin-4-amine hydrochloride
A mixture of4-chloro-l-methyl-7-(4-moφhohnylcarbonyl)-lΗ-pyrrolo[3,2-c]pyridine (170mg), 3- chlorobenzylamine (0.11ml) and methanesulfonic acid (0.060ml) in 1,4-dioxan (1.5ml) was heated under microwave conditions at 1800C for thirty minutes. The 1,4-dioxan was evaporated, and the residue partitioned between dichloromethane and water. The organic layer was washed with water, dried (Na2SO4) and evaporated to a brown oil. The oil was purified by MDAP, dissolved in ethyl acetate (2ml), treated with IM hydrochloπc acid in diethyl ether, and then evaporated to afford the title compound as a white solid (38mg). LC/MS [MH+] 385 consistent with molecular formula C20H21 35ClN4O2
Example 39: 3-Chloro-N-[l-methyl-7-(4-morpholinylcarbonyl)-lH-pyrrolo[3,2-c]pyridin-4- yl]benzamide hydrochloride
To a solution of l-methyl-7-(4-moφholinylcarbonyl)-lH-pyrrolo[3,2-c]pyridin-4-amine (50mg) in dimethylformamide (2ml) was added l-[3-(dimethylammo)propyl]-3-ethylcarbodπmide (44mg) ,
1-hydroxybenzotπazole (31mg), N-ethylmorpholme (88mg) and 3-chlorobenzoic acid (60mg). The solution was stirred at room temperature overnight and the dimethylformamide was evaporated. The residue was puπfied by MDAP, dissolved in methanol, treated with IM hydrochloric acid in diethyl ether then evaporated and freeze dried to afford the title compound (24mg). LC/MS [MH+] 399 consistent with molecular formula C20H19 35ClN4O3
Example 40: l-Methyl-7-(4-morpholinylcarbonyI)-4-{3-[(trifluoromethyl)oxy]phenyl}-lH- pyrrolo [3,2-c] pyridine hydrochloride
To a solution of 4-chloro-l-methyl-7-(4-morpholmylcarbonyl)-lH-pyrrolo[3,2-c]pyridine (lOOmg) in 1, 2 -dimethoxy ethane (2ml) was added 2M sodium carbonate solution (ImI) and after degassing was added 3-(tπfluoromethoxy)phenylboronic acid (139mg) and tetrakistπphenylphosphme palladium (21mg). The mixture was heated at 800C for ninety minutes, stood overnight at room temperature then heated at 800C for thirty minutes. The reaction mixture was diluted with ethyl acetate and washed twice with water followed by bπne then dried (MgSO4) and evaporated to a yellow oil. The oil was puπfied by MDAP, dissolved in methanol (2ml), treated with IM hydrochloric acid in diethyl ether, evaporated, triturated with diethyl ether and filtered off to afford the title compound as a yellow solid (98mg). LC/MS [MH+] 406 consistent with molecular formula C20H18F3N3O3
Example 41: 4-(3-Chlorophenyl)-l-methyl-7-(4-morpholinylcarbonyl)-lH-pyrrolo[3,2- c] pyridine hydrochloride
To a solution of 4-chloro-l-methyl-7-(4-morphohnylcarbonyl)-lH-pyrrolo[3,2-c]pyridine (lOOmg) in 1 ,2-dimethoxyethane (2ml) was added 2M sodium carbonate solution (ImI) and after degassing was added 3-chlorophenylboronic acid (11 lmg) and tetrakistriphenylphosphme palladium (21mg). The mixture was heated at 800C for ninety minutes and stood overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed twice with water followed by bπne then dried (MgSO4) and evaporated to a yellow oil. The oil was puπfied by MDAP, dissolved in methanol (2ml), treated with IM hydrochloric acid in diethyl ether, evaporated, tπturated with diethyl ether and filtered off to afford the title compound as a yellow solid (83mg).
LC/MS [MH+] 356 consistent with molecular formula C19H18 ClN3O2
Example 42 : 7-[(3-Chlorophenyl)oxy]-3-methyl-4-(4-morpholinylcarbonyI)-lH-pyrrolo[2,3- c] pyridine
To a solution of 3-chlorophenol (0.176ml) in dry 1,4-dioxan (ImI) m a microwave vial was added portionwise sodium hydride (60% dispersed in mineral oil, 67mg) at room temperature. After effervescence had ceased a solution of 1,1-dimethylethyl 7 -chloro-3 -methyl -4-(4- morpholmylcarbonyl)-lH-pyrrolo[2,3-c]pyridine-l-carboxylate (160mg) in dry 1,4-dioxan (1.5ml) was added and the solution heated under microwave conditions at 18O0C for three hours. The 1,4- dioxan was evaporated, the residue dissolved in ethyl acetate (50ml), washed with water (2 x 25ml) then dried (MgSO4) and evaporated. The residue was purified by MDAP followed by triturating with diethyl ether to afford a white solid which was dried at 400C under vacuum to afford the title compound (55mg). LC/MS [MH+] 372 consistent with molecular formula C19H18 35ClN3O3
Example 43: 7-[(3-Chlorophenyl)oxy]-N,3-dimethyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-lH- pyrrolo [2,3-c] pyridine-4-carboxamide
Prepared in a similar manner to Example 42 from 1,1-dimethylethyl 7-chloro-3-methyl-4- {[methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}-lH-pyrrolo[2,3-c]pyridme-l- carboxylate (120mg) except that it was heated for six hours, methanol was used to transfer the reaction mixture to a round bottomed flask before evaporation, included a saturated sodium bicarbonate wash m the work up, and was puπfied by Biotage chromatography over silica gel eluting with 50% ethyl acetate/hexane and then with 100% ethyl acetate. The residue was dissolved in ethyl acetate and treated with IM hydrochloric acid in diethyl ether. After dilution with diethyl ether, a white solid was filtered off and dried to afford the title compound (34mg).
LC/MS [MH ] 414 consistent with molecular formula C22H24 ClN3O3
Example 44 : 7-[(3-Bromophenyl)oxy]-N,3-dimethyl-N-(tetrahydro-2H-pyran-4-ylmethyl)- lH-pyrrolo[2,3-c]pyridine-4-carboxamide
Prepared in a similar manner to Example 42 from 1 , 1 -dimethylethyl 7-chloro-3 -methyl -4- {[methyl(tetrahydro-2H-pyran-4-ylmethyl)ammo]carbonyl}-lH-pyrrolo[2,3-c]pyridme-l- carboxylate (120mg) and 3-bromophenol (197mg) except that it was heated for six hours, methanol was used to transfer the reaction mixture to a round bottomed flask before evaporation, included a saturated sodium bicarbonate wash in the work up, and was puπfied by Biotage chromatography over silica gel eluting with hexane, 50% ethyl acetate/hexane and then with 100% ethyl acetate. The residue was dissolved in ethyl acetate and treated with IM hydrochloric acid in diethyl ether. On dilution with diethyl ether, a white solid was filtered off and dπed to give the title compound (40mg). LC/MS [MH+] 460 consistent with molecular formula C22H24 81BrN3O3
Example 45 : 7-[(3-Bromophenyl)oxy]-3-methyl-4-(4-morpholinylcarbonyl)-lH-pyrrolo[2,3- c] pyridine
Prepared in a similar manner to Example 42 from 1 , 1 -dimethylethyl 7-chloro-3 -methyl -4-(4- morphohnylcarbonyl)-lΗ-pyrrolo[2,3-c]pyridme-l-carboxylate (150mg) and 3-bromophenol (273mg) except that it was heated for six hours, included a 2N sodium hydroxide wash in the work up, and was purified by MDAP to afford the title compound (96mg). LC/MS [MH+] 418 consistent with molecular formula Cj9H18 81BrN3O3
Example 46: 7-[(2,4-Dichlorophenyl)oxy]-3-methyl-4-(4-morpholinylcarbonyl)-lH- pyrrolo [2,3-c] pyridine
Prepared in a similar manner to Example 42 from 1 , 1 -dimethylethyl 7-chloro-3-methyl-4-(4- morpholmylcarbony^-lH-pyrrolop^-cJpyridme-l-carboxylate (lOOmg) and 2,4-dichlorophenol (171mg) except that it was heated for twelve hours. Methanol was used to transfer the reaction mixture to a round bottomed flask before evaporation, dichloromethane was used instead of ethyl acetate and included a saturated sodium bicarbonate wash in the work up, and was purified by Biotage chromatography over silica gel eluting with 50% ethyl acetate/hexane. The residue was dissolved in methanol and treated with IM hydrochloric acid in diethyl ether. Evaporation and triturating with diethyl ether afforded a white solid which was filtered off and dπed to afford the title compound (23mg).
LC/MS [MH+] 406 consistent with molecular formula C19H17 35Cl2N3O3
Example 47: 3-Methyl-7-{[3-(methyloxy)phenyl]oxy}-4-(4-morpholinylcarbonyl)-lH- pyrrolo [2,3-c] pyridine
Prepared in a similar manner to Example 42 from 1,1 -dimethyl ethyl 7 -chl oro-3 -methyl -4-(4- morpholmylcarbonyl)-lH-pyrrolo[2,3-c]pyridine-l-carboxylate (lOOmg) and 3-methoxyphenol (0.115ml) except that it was heated for ten hours. Methanol was used to transfer the reaction mixture to a round bottomed flask before evaporation, included a saturated sodium bicarbonate wash in the work up, and was purified by Biotage chromatography over silica gel eluting with 80% ethyl acetate/hexane to afford the title compound (38mg). LC/MS [MH+] 368 consistent with molecular formula C2OH21N3O4
Example 48 : 3-Methyl-4-(4-morpholinylcarbonyl)-7-(phenyloxy)-lH-pyrrolo[2,3-c]pyridine
Prepared in a similar manner to Example 42 from 1 , 1 -dimethylethyl 7 -chl oro-3 -methyl -4-(4- moφholinylcarbonyl)-lH-pyrrolo[2,3-c]pyridme-l-carboxylate (lOOmg) and phenol (99mg) except that it was heated for ten hours. Methanol was used to transfer the reaction mixture to a round bottomed flask before evaporation, included a saturated sodium bicarbonate wash in the work up, and was purified by Biotage chromatography over silica gel eluting with 70% ethyl acetate/hexane to afford the title compound (57mg). LC/MS [MH+] 338 consistent with molecular formula C19H19N3O3
Example 49 : 7-(Cyclohexyloxy)-3-methyl-4-(4-morpholinylcarbonyl)-lH-pyrrolo[2,3- c] pyridine
Prepared in a similar manner to Example 42 from 1 , 1 -dimethylethyl 7-chl oro-3 -methyl -4-(4- morpholmylcarbonyO-lH-pyrroloP^-cJpyridme-l-carboxylate (lOOmg) and cyclohexanol (0.11 ImI) except that it was heated for two hours. Methanol was used to transfer the reaction mixture to a round bottomed flask before evaporation, included a saturated sodium bicarbonate wash in the work up, and was purified by Biotage chromatography over silica gel eluting with 50% ethyl acetate/hexane to afford the title compound (52mg). LC/MS [MH+] 344 consistent with molecular formula C19H25N3O3
Example 50: 7-[(3-Bromophenyl)oxy]-N-(cyclobutylmethyl)-3-methyl-lH-pyrrolo[2,3- c] py ridine-4-carboxamide
{[(cyclobutylmethyl)ammo]carbonyl} -3 -methyl- lH-pyrrolo[2,3-c]pyri dine- 1 -carboxylate ( 120mg) and 3-bromophenol (183mg) except that it was heated for six hours, methanol was used to transfer the reaction mixture to a round bottomed flask before evaporation, included a saturated sodium bicarbonate wash in the work up, and was purified by Biotage chromatography over silica gel elutmg with 25% ethyl acetate/hexane. The residue was dissolved in ethyl acetate and treated with IM hydrochloπc acid in diethyl ether to afford a white solid which was filtered off and dπed to afford the title compound (32mg). LC/MS [MH+] 416 consistent with molecular formula C20H20 81BrN3O2
Examples in Table 3 were prepared in a manner similar to Example 50 from 1 , 1 -dimethylethyl 7- chloro-4-{[(cyclobutylmethyl)ammo]carbonyl}-3-methyl-lH-pyrrolo[2,3-c]pyridme-l -carboxylate and the appropriate commercially available phenol. Microwave reaction times were either six, ten or twelve hours. Examples 51, 52, 54 and 55 were puπfied by Biotage chromatography over silica gel eluting with 50% ethyl acetate/hexane. Example 55 was not dissolved in ethyl acetate and treated with IM hydrochloπc acid in diethyl ether.
Table 3.
Example 56 : 7-[(3-Chlorophenyl)oxy]-2,3-dimethyl-4-(4-morpholinylcarbonyl)-lH- pyrrolo [2,3-c] pyridine
To a solution of 3-chlorophenol (0.092ml) in dry 1,4-dioxan (ImI) in a microwave vial was added portionwise sodium hydride (60% dispersed in mineral oil, 35mg) at room temperature. After effervescence had ceased a solution of 7-chloro-2,3-dimethyl-4-(l-moφholm-4-yl-methanoyl)- pyrrolo[2,3-c]pyridine (160mg) in dry 1,4-dioxan (1.5ml) was added and the solution heated under microwave conditions at 18O0C for thirteen hours. The 1 ,4-dioxan was evaporated and the residue dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and water then dried (MgSO4) and evaporated. The residue was purified by Biotage chromatography eluting with 20% ethyl acetate/hexane to afford the title compound as an off white foam (34mg). LC/MS [MH+] 386 consistent with molecular formula C20H20 35ClN3O3
Example 57 : 7-[(3-Chlorophenyl)oxy]-N-(cyclobutylmethyl)-2,3-dimethyl-lH-pyrrolo[2,3- c] pyridine-4-carboxamide
Prepared in a similar manner to Example 56 except that the reaction time was twenty one hours. LC/MS [MH+] 384 consistent with molecular formula C21H22 35ClN3O2
Example 58: 7-[(3-Chlorophenyl)oxy]-3-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-lH- pyrrolo [2,3-c] pyridine-4-carboxamide
Prepared in a similar manner to Example 42 from 1 , 1 -dimethyl ethyl 7-chloro-3 -methyl -4- {[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}-lH-pyrrolo[2,3-c]pyridine-l-carboxylate (165mg) except that it was heated for five hours, included a saturated sodium bicarbonate wash in the work up, and was puπfied by Biotage chromatography over silica gel eluting with dichloromethane and then with 2-4% methanol/dichloromethane. The residue was dissolved in ethyl acetate and treated with IM hydrochloπc acid in diethyl ether. After dilution with diethyl ether a white solid was filtered off and dried to afford the title compound (58mg). LC/MS [MH]+ 400 consistent with molecular formula C21H22 35ClN1O,
Example 59: 3-Methyl-4-(4-morpholinylcarbonyl)-7-(tetrahydro-2H-pyran-4-yloxy)-lH- pyrrolo [2,3-c] pyridine
Prepared in a similar manner to Example 42 from 1 , 1 -dimethylethyl 7-chloro-3-methyl-4-(4- moφhohnylcarbonyl)-lH-pyrrolo[2,3-c]pyridme-l-carboxylate (lOOmg) and tetrahydro-4H-pyran- 4-ol (0.1ml) except that the solvent was dimethylformamide and it was heated for three and a half hours. The reaction mixture was diluted with ethyl acetate and washed three times with water then dried (MgSO4) and evaporated to a brown oil. The oil was punfied by Biotage chromatography over silica gel eluting with 50% ethyl acetate/hexane then ethyl acetate to afford the title compound as an off white solid (7mg). LC/MS [MH+] 346 consistent with molecular formula C18H23N3O4
Example 60: 7-[(3-Chlorophenyl)thio]-3-methyl-4-(4-morpholinylcarbonyl)-lH-pyrrolo[2,3- c] pyridine
To a solution of 3-chlorobenzenethiol (0.307ml) in dry 1,4-dioxan (3ml) in a microwave vial was added portionwise sodium hydride (60% dispersed in mineral oil, 105mg). The mixture was stirred at room temperature until effervescence had ceased and then 1 , 1 -dimethylethyl 7-chloro-3-methyl- 4-(4-moφholmylcarbonyl)-lH-pyrrolo[2,3-c]pyπdine-l-carboxylate (250mg) in dimethylformamide (2ml) was added. The mixture was heated under microwave conditions at
1800C for 2 hours. The reaction mixture was diluted with ethyl acetate (100ml) and washed with water (3 x 25ml) then dried (MgSO4) and evaporated to a brown gum. The gum was purified by column chromatography on a Biotage silica column eluting with 50% ethyl acetate/hexane followed by ethyl acetate to afford the title compound (212mg) as a white foam. LC/MS [MH+] 388 consistent with molecular formula C19H18 35ClN3O2S
Example 61 : 7-[(3-Chlorophenyl)sulfonyl]-3-methyl-4-(4-morpholinylcarbonyI)-lH- pyrrolo [2,3-c] pyridine
To a solution of 7-[(3-chlorophenyl)thio]-3-methyl-4-(4-moφhohnylcarbonyl)-lH-pyrrolo[2,3- c]pyridme (93mg) in dichloromethane (3ml) at 00C was added 3-chloroperoxybenzoic acid (135mg) and the solution stirred for two hours. The reaction mixture was diluted with dichloromethane and washed with sodium thiosulphate, saturated sodium bicarbonate solution and water. The organic layer was dried (MgSO4) and evaporated to a white solid. Purification by column chromatography on a Biotage silica column elutmg with 25% ethyl acetate/hexane followed by 40% ethyl acetate/hexane followed by 50% ethyl acetate/hexane afforded the title compound as a white foam (46mg).
LC/MS [MH+] 420 consistent with molecular formula C19H18 35ClN3O4S
Example 62 : 3-Methyl-4-(4-morpholinylcarbonyl)-7-{3-[(trifluoromethyl)oxy]phenyl}-lH- pyrrolo [2,3-c] pyridine
To a solution of 1 , 1 -dimethylethyl 7-chloro-3-methyl-4-(4-morpholinylcarbonyl)-lH-pyrrolo[2,3- c]pyridine-l-carboxylate (lOOmg) in 1 ,2-dimethoxyethane (2ml) was added 2M sodium carbonate solution (ImI) and after degassing 3-(tπfluoromethoxy)phenylboronic acid (85mg) and tetrakistπphenylphosphme palladium (15mg) was added. The mixture was heated at 800C for ninety minutes then diluted with ethyl acetate (50ml), washed with water (2 x 20ml) dried (MgSO4) and evaporated. The residue was dissolved in 1 ,4-dioxan and heated under microwave conditions at 18O0C for 25 minutes to remove the BOC group then evaporated. The residue was purified by Biotage chromatography over silica gel loading with dichloromethane and eluting with 50-75% ethyl acetate/hexane to afford the title compound as a white foam (5 lmg). LC/MS [MH+] 406 consistent with molecular formula C20H18F3N3O3
Examples in the following table were prepared in a manner similar to Example 62. Example 63 was heated in the microwave for ten minutes and purified eluting with 50% ethyl acetate/hexane. Examples 64, 65, 67, 68, 69, and 70 were purified eluting with ethyl acetate and Example 66 was purified elutmg with 30% ethyl acetate/hexane.
Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in vaπous forms and with numerous excipients. Examples of such formulations are given below.
Example 71: Inhalant Formulation
A compound of formula (I) or a pharmaceutically acceptable deπvative thereof, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
Example 72: Tablet Formulation
Tablets/Ingredients Per Tablet
1. Active ingredient 40 mg (Compound of formula (I) or pharmaceutically acceptable derivative)
2. Corn Starch 20 mg 3. Alginic acid 20 mg
4. Sodium Alginate 20 mg
5. Mg stearate 1.3 mg
Procedure for tablet formulation: Ingredients 1, 2, 3 and 4 are blended m a suitable mixer/blender. Sufficient water is added portion- wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules. The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. The wet granules are then dried in an oven at 14O0F (600C) until dry. The dry granules are lubricated with ingredient No. 5, and the lubπcated granules are compressed on a suitable tablet press.
Example 73: Parenteral Formulation
A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula (I) in polyethylene glycol with heating. This
solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers.
Claims
A compound of formula (I):
X, is NH and X2 and X3 together form a -CR1 J=CR' ' - group or X3 is NR12 and X2 and X1 together form a -CR13=CRπ- group;
X4 is O, SO2, S, or a bond, or X4 is -NHCO or -NHCH2 such that R6X4 is R6CONH or R6CH2NH;
R1 is selected from hydrogen, C1 6 alkyl, C3-6 cycloalkyl and halosubstitutedC] 6 alkyl;
R2 is hydrogen or (CH2)H1R3 where m is 0 or 1 ; or R1 and R2 together with N to which they are attached form an optionally substituted 4- to 8- membered non-aromatic heterocyclyl ring;
R3 is a 4- to 8- membered non-aromatic heterocyclyl group, a C3-8 cycloalkyl group, a straight or branched C1 10 alkyl, a C2.10alkenyl, a C3.8cycloalkenyl, a C2.10alkynyl, a C3_8cycloalkynyl or phenyl group, any of which can be unsubstituted or substituted, or R5;
R6 is phenyl, C3 6cycloalkyl, a straight or branched C1-6 alkyl group, -CH2-C3 6cycloalkyl, -CH2-phenyl, 4- to 8- membered non-aromatic heterocyclyl group, or a bicyclic group any of which can be unsubstituted or substituted, however when X4 is a bond R6 is substituted phenyl;
R7 is OH, C^alkoxy, NR8aR8b, NHCOR9, NHSO2R9 or SOqR9;
RSa is H or Chalky.;
R8b is H or Cβalkyl;
R9 is Cβalkyl;
R10 is hydrogen, substituted or unsubstituted (C].6)alkyl or chloro;
R11 is hydrogen or d^alkyl;
R12 is hydrogen or C^alkyl
R13 is hydrogen or C1-6alkyl; q is 0, 1 or 2; or a pharmaceutically acceptable deπvative thereof.
2. A compound as claimed in claim 1 wherein the compound is of fomula (Ia) or (Ib):
(Ia) (Ib)
3. A compound as claimed in claim 1 or 2 wherein R1 is hydrogen or methyl.
4. A compound as claimed in any preceedmg claim wherein R2 is (CH2)mR3 where m is 0 or 1.
5. A compound as claimed in any preceedmg claim wherein R3 is an unsubstituted or substituted 4- to 8- membered non-aromatic heterocyclyl group, or an unsubstituted or substituted C3-8 cycloalkyl group
6. A compound as claimed in any preceedmg claim wherein R3 is tetrahydropyranyl or cyclobutyl.
7. A compound as claimed claim 1 or 2 claim wherein R1 and R2 together with the nitrogen to which they are attached form a morphohnyl, thiomorpholmyl-s,s-dioxide, pyrrolidinyl or pipeπdmyl πng.
8. A compound as claimed in any preceedmg claim wherein R13 is hydrogen or methyl.
9. A compound as claimed in any preceedmg claim wherein R6 is a substituted phenyl.
(Ic) (Id)
wherein
X4 is O, S, SO2, or bond, or X4 is -NHCO or -NHCH2 such that R6X4 is R6CONH or R6CH2NH;
R1 is hydrogen;
R2 is (CH2)H1R3 where m is 0 or 1; or R1 and R2 together with N to which they are attached form a morpholinyl, pyrrohdmyl, pipeπdmyl, thiomorpholme-s,s-dioxide ring any of which may be unsubstituted or substituted;
R3 is a selected from tetrahydrfuranyl, a C3-6 cycloalkyl group;
R6 is an phenyl, C3 6cycloalkyl, straight or branched C1 6 alkyl or -CH2C3.6cycloalkyl - CH2phenyl any of which can be unsubstituted or substituted.
R11 is hydrogen or methyl;
R12 is hydrogen or methyl; or a pharmaceutically acceptable deπvatives thereof.
11. A pharmaceutical composition comprising a compound as claimed in any preceding claim or a pharmaceutically acceptable deπvative thereof.
12. A pharmaceutical composition as claimed in claim 11 further comprising a pharmaceutical carrier or diluent thereof.
13. A pharmaceutical composition as claimed in claim 11 or 12 further comprising a second theraputic agent.
14. A compound of formula (I) as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable deπvative thereof for use in human or veterinary medicine.
15. A compound of formula (I) as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by the activity of cannabmoid 2 receptors.
16. The use of a compound of formula (I) as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable derivative thereof for the manufacture of a therapeutic agent for the treatment of a condition which is mediated by the activity of cannabmoid 2 receptors.
17. A method of treating mammal for example a human suffering from a condition which is mediated by the activity of cannabinoid 2 receptor which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable derivative thereof.
18. The compound as claimed in claim 15 or the use as claimed in claim 16 or the method of treatment as claimed in claim 17 wherein the condition which is mediated by the activity of cannabinoid 2 receptor is an immune disorder, an inflammatory disorder, pam, rheumatoid arthritis, multiple sclerosis, osteoarthritis or osteoporosis.
19. The compound, use or method as claimed in claim 18, wherein the pam is selected from inflammatory pain, viseral pain, cancer pain, neuropathic pam, lower back pain, muscular sceletal, post operative pam. acute pam and migraine.
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2009076454A2 (en) * | 2007-12-12 | 2009-06-18 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2010027875A3 (en) * | 2008-08-27 | 2010-06-10 | Calcimedica Inc. | Compounds that modulate intracellular calcium |
WO2010113834A1 (en) | 2009-03-30 | 2010-10-07 | アステラス製薬株式会社 | Pyrimidine compound |
US8263641B2 (en) | 2007-09-10 | 2012-09-11 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US8524763B2 (en) | 2008-09-22 | 2013-09-03 | Calcimedica, Inc. | Inhibitors of store operated calcium release |
US8618307B2 (en) | 2009-09-16 | 2013-12-31 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2014084330A1 (en) * | 2012-11-30 | 2014-06-05 | 協和発酵キリン株式会社 | Nitrogen-containing heterocyclic compound |
US8791106B2 (en) | 2010-07-29 | 2014-07-29 | Astellas Pharma Inc. | Fused ring pyridine compound |
EP2963031A2 (en) | 2007-11-30 | 2016-01-06 | Zynerba Pharmaceuticals, Inc. | Prodrugs of tetrahydrocannabinol, compositions comprising prodrugs of tetrahydrocannabinol and methods of using the same |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110627846B (en) * | 2019-10-30 | 2022-11-29 | 河南师范大学 | Galactoside-tetrastyrene compound, preparation method thereof and application thereof as drug carrier |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001058869A2 (en) * | 2000-02-11 | 2001-08-16 | Bristol-Myers Squibb Company | Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators in treating respiratory and non-respiratory diseases |
US20020022624A1 (en) * | 2000-07-13 | 2002-02-21 | Kevin Dinnell | Azaindole derivatives and their use as therapeutic agents |
WO2005066126A1 (en) * | 2003-12-23 | 2005-07-21 | Eli Lilly And Company | Cb1 modulator compounds |
WO2005121140A1 (en) * | 2004-06-09 | 2005-12-22 | Glaxo Group Limited | Pyrrolopyridine derivatives |
-
2005
- 2005-08-09 GB GBGB0516379.5A patent/GB0516379D0/en not_active Ceased
-
2006
- 2006-08-07 WO PCT/EP2006/007875 patent/WO2007017264A2/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001058869A2 (en) * | 2000-02-11 | 2001-08-16 | Bristol-Myers Squibb Company | Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators in treating respiratory and non-respiratory diseases |
US20020022624A1 (en) * | 2000-07-13 | 2002-02-21 | Kevin Dinnell | Azaindole derivatives and their use as therapeutic agents |
WO2005066126A1 (en) * | 2003-12-23 | 2005-07-21 | Eli Lilly And Company | Cb1 modulator compounds |
WO2005121140A1 (en) * | 2004-06-09 | 2005-12-22 | Glaxo Group Limited | Pyrrolopyridine derivatives |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8524765B2 (en) | 2007-09-10 | 2013-09-03 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US8263641B2 (en) | 2007-09-10 | 2012-09-11 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
EP2963031A2 (en) | 2007-11-30 | 2016-01-06 | Zynerba Pharmaceuticals, Inc. | Prodrugs of tetrahydrocannabinol, compositions comprising prodrugs of tetrahydrocannabinol and methods of using the same |
US8389567B2 (en) | 2007-12-12 | 2013-03-05 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2009076454A3 (en) * | 2007-12-12 | 2009-09-24 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2009076454A2 (en) * | 2007-12-12 | 2009-06-18 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US8394848B2 (en) | 2008-08-27 | 2013-03-12 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US8383670B2 (en) | 2008-08-27 | 2013-02-26 | Calcimedica, Inc. | Trisubstituted thiophenes that modulate intracellular calcium |
US7906553B2 (en) | 2008-08-27 | 2011-03-15 | Calcimedica, Inc. | Substituted thiophene modulators of intracellular calcium |
WO2010027875A3 (en) * | 2008-08-27 | 2010-06-10 | Calcimedica Inc. | Compounds that modulate intracellular calcium |
US8524763B2 (en) | 2008-09-22 | 2013-09-03 | Calcimedica, Inc. | Inhibitors of store operated calcium release |
US8524727B2 (en) | 2009-03-30 | 2013-09-03 | Astellas Pharma Inc. | Pyrimidine compound |
WO2010113834A1 (en) | 2009-03-30 | 2010-10-07 | アステラス製薬株式会社 | Pyrimidine compound |
US8618307B2 (en) | 2009-09-16 | 2013-12-31 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US8791106B2 (en) | 2010-07-29 | 2014-07-29 | Astellas Pharma Inc. | Fused ring pyridine compound |
WO2014084330A1 (en) * | 2012-11-30 | 2014-06-05 | 協和発酵キリン株式会社 | Nitrogen-containing heterocyclic compound |
CN104995173A (en) * | 2012-11-30 | 2015-10-21 | 协和发酵麒麟株式会社 | Nitrogen-containing heterocyclic compound |
JPWO2014084330A1 (en) * | 2012-11-30 | 2017-01-05 | 協和発酵キリン株式会社 | Nitrogen-containing heterocyclic compounds |
US9701689B2 (en) | 2012-11-30 | 2017-07-11 | Kyowa Hakko Kirin Co., Ltd. | Substituted pyridines and pyridazines as CCR10 receptor inhibitors |
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