EP.sub.4 receptor antagonists Number:7,417,068 from the United States Patent and Trademark Office (PTO) owispatent A compound of formula (I): ##STR00001## or a salt, solvate and chemically protected form thereof, wherein one of R.sup.2 and R.sup.5 is: (i) H or an optionally substituted C.sub.1-4 alkyl group; or (ii)an optionally substituted C.sub.5-7 aryl; and the other of R.sup.2 and R.sup.5 is the other group; m and n can be 0 or 1, and m+n=1 or 2 R.sup.N is H or optionally substituted C.sub.1-4 alkyl R.sup.3 is either: (i) carboxy; (ii) a group of formula (II): ##STR00002## (iii) a group of formula (III): ##STR00003## wherein R is optionally substituted C.sub.1-7 alkyl, C.sub.5-20 aryl, or NR.sup.N3R.sup.N4, where R.sup.N3 and R.sup.N4 are independently selected from optionally substituted C.sub.1-4 alkyl; or (iv) tetrazol-5-yl.<H antagonists, receptor, EP, sub, 4, recept, 7417068.html, Patent, pto, 7417068

Title: EP.sub.4 receptor antagonists

Abstract: A compound of formula (I): ##STR00001## or a salt, solvate and chemically protected form thereof, wherein one of R.sup.2 and R.sup.5 is: (i) H or an optionally substituted C.sub.1-4 alkyl group; or (ii)an optionally substituted C.sub.5-7 aryl; and the other of R.sup.2 and R.sup.5 is the other group; m and n can be 0 or 1, and m+n=1 or 2 R.sup.N is H or optionally substituted C.sub.1-4 alkyl R.sup.3 is either: (i) carboxy; (ii) a group of formula (II): ##STR00002## (iii) a group of formula (III): ##STR00003## wherein R is optionally substituted C.sub.1-7 alkyl, C.sub.5-20 aryl, or NR.sup.N3R.sup.N4, where R.sup.N3 and R.sup.N4 are independently selected from optionally substituted C.sub.1-4 alkyl; or (iv) tetrazol-5-yl.

Patent Number: 7,417,068 Issued on 08/26/2008 to Clark, et al.

Inventors: Clark; David Edward (Essex, GB), Harris; Neil Victor (Essex, GB), Fenton; Garry (Essex, GB), Hynd; George (Essex, GB), Stuttle; Keith Alfred James (Essex, GB), Sutton; Jonathan Mark (Essex, GB), Oxford; Alexander William (Hertfordshire, GB), Davis; Richard Jon (Hertfordshire, GB), Coleman; Robert Alexander (Hertfordshire, GB), Clark; Kenneth Lyle (Hertfordshire, GB)
Assignee: Asterand UK Limited (Hertfordshire, GB)

Appl. No.: 10/964,831

Filed: October 15, 2004

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
60512200	Oct., 2003

Foreign Application Priority Data


Oct 16, 2003 [GB]			0324269.0

Current U.S. Class: 514/461 ; 549/200; 549/429; 549/483; 549/487

Current International Class: A61K 31/341 (20060101); C07D 307/34 (20060101)

Field of Search: 549/200,429,483,487 514/461

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Primary Examiner: Shameem; Golam M
Attorney, Agent or Firm: Nixon & Vanderhye P.C.

Parent Case Text

The present application is based on and claims benefit of U.S. provisional application Ser. No. 60/512,200, filed 20 Oct. 2003, and GB 0324269.0, filed 16 Oct. 2003, the entire contents of each of which is hereby incorporated by reference.

Claims

The invention claimed is:

1. A compound of formula (I): ##STR00046## or a salt, solvate and chemically protected form thereof, wherein: either R.sup.2 is H or an optionally substituted C.sub.1-4 alkyl group and R.sup.5 is an optionally substituted C.sub.5-7 aryl; or R.sup.5 is H or an optionally substituted C.sub.1-4 alkyl group and R.sup.2 is an optionally substituted C.sub.5-7 aryl; m and n can be 0 or 1, and m+n=1 or 2 R.sup.N is H or optionally substituted C.sub.1-4 alkyl R.sup.3 is either: a group of formula (II): or ##STR00047## a group of formula (III): ##STR00048## wherein R is optionally substituted C.sub.1-7 alkyl, C.sub.5-20 aryl, or NR.sup.N3R.sup.N4, where R.sup.N3 and R.sup.N4 are independently selected from optionally substituted C.sub.1-4 alkyl.

2. A compound according to claim 1, wherein R.sup.5 is the optionally substituted C.sub.5-7 aryl group and R.sup.2 is H or the optionally substituted C.sub.1-4 alkyl group.

3. A compound according to claim 2, wherein R.sup.2 is selected from H or an optionally substituted C.sub.1-3 alkyl group.

4. A compound according to claim 3, wherein R.sup.2 is a methyl group.

5. A compound according to claim 2, wherein R.sup.5 is a C.sub.6 aryl group.

6. A compound according to claim 5, wherein R.sup.5 is phenyl.

7. A compound according to claim 1 wherein the C.sub.5-7 aryl group is substituted by substituents selected from C.sub.1-7 alkoxy groups.

8. A compound according to claim 1, wherein R is selected from an optionally substituted C.sub.5-20 aryl group, and an optionally substituted C.sub.5-20 aryl-C.sub.1-7 alkyl group.

9. A compound according to claim 1, wherein R is a C.sub.1-7 alkyl group.

10. A compound according to claim 1, wherein n+m=1.

11. A compound according to claim 10, wherein n is 0 and m is 1.

12. A compound according to claim 1, wherein R.sup.N is H or methyl.

13. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.

14. A method of treating a headache disorder comprising administering to a patient in need of treatment an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

15. A method according to claim 14, wherein the headache disorder is a migraine.

Description

This invention relates to EP.sub.4 receptor antagonists, pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions to treat various diseases.

BACKGROUND TO THE INVENTION

Prostanoids comprise prostaglandins (PGs) and thromboxanes (Txs) and their receptors fall into five different classes (DP, EP, FP, IP and TP) based on their sensitivity to the five naturally occurring prostanoids, PGD.sub.2, PGE.sub.2, PGF.sub.2.alpha., PGI.sub.2 and TxA.sub.2, respectively (Coleman, R. A., Prostanoid Receptors. IUPHAR compendium of receptor characterisation and classification, 2.sup.nd edition, 338-353, ISBN 0-9533510-3-3, 2000). EP receptors (for which the endogenous ligand is PGE.sub.2) have been subdivided into four types termed EP.sub.1, EP.sub.2, EP.sub.3 and EP.sub.4. These four types of EP receptors have been cloned and are distinct at both a molecular and pharmacological level (Coleman, R. A., 2000)

EP.sub.4 antagonists have been shown to be useful in the treatment of pain, and in particular, in the treatment of primary headache disorders, which include migraines, and secondary headache disorders, such as drug-induced headaches (WO 00/18405 and WO 01/72302). Dilation of the cerebral vasculature and the subsequent stimulation of pain stimulating, perivascular trigeminal sensory afferent nerves is recognised to play an important role in the pathophysiology of migraine. A sterile inflammatory response, associated with activation of cycloxygenase and the generation of PGE.sub.2, is also implicated in the pathophysiology of migraine. PGE.sub.2 levels have been shown to be raised during migraine attacks and PGE.sub.2 contributes to the pain of migraine by directly dilating cerebral arteries and by stimulating the release of vasoactive/pro-inflammatory peptides from the trigeminal nerves. These effects of PGE.sub.2 are mediated in whole or in part by EP.sub.4 receptors. Thus, by binding to and preventing the stimulation of EP.sub.4 receptors, EP.sub.4 antagonists may be used to treat the pain of migraine.

EP.sub.4 antagonists may also be useful in treating a number of other conditions and diseases. For example, they may be used in: the treatment of pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis; the treatment of musculoskeletal pain, lower back and neck pain, sprains and strains, neuropathic pain, sympathetically mediated pain, myositis, pain associated with cancer and fibromyalgia, pain associated with influenza or other viral infections, such as the common cold, rheumatic fever; pain associated with bowel disorders such as non-ulcer dyspepsia, irritable bowel syndrome; non-cardiac chest pain, pain associated with myocardial ischaemia, post-operative pain, headache, toothache and dysmenorrhea. 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; the treatment of inflammatory diseases including rheumatoid and osteoarthritis, psoriasis, dermatitis, retinitis, conjunctivitis, asthma, bronchitis, chronic obstructive pulmonary disease, inflammatory bowel disease, colitis, nephritis, gingivitis and hepatitis; the treatment of cancers including familial adenomatous polyposis, endometrial carcinoma, colorectal and cervical cancer; the treatment of bone disorders involving altered bone formation or resorption such as osteoporosis; women's health for the treatment of myometrial and endometrial disorders; the treatment of gastrointestinal disease including diarrhoea; the treatment of immunological disorders such as autoimmune disease, immunological deficiency diseases, organ transplantation and increasing the latency of HIV infection; the treatment of diseases of abnormal platelet function. (e.g. occlusive vascular diseases); the preparation of a drug with diuretic properties to treat or prevent various oedema, hypertension, premenstrual tension, urinary calculus, oliguria, hyperphosphaturia, mesangial proliferative glomerulonephritis, chronic renal failure or the like; the treatment of impotence or erectile dysfunction, and female sexual dysfunction; the treatment of hair growth disorders; the treatment of sleep disorders such as narcolepsy and insomnia; the treatment of cardiovascular diseases and shock states associated with hypotension (e.g. septic shock); the treatment of neurodegenerative diseases and for preventing neuronal damage following stroke, cardiac arrest, cardiopulmonary bypass, traumatic brain injury or spinal cord injury; the treatment of tinnitus; the treatment of dependence; and the treatment of complications of diabetes.

Although EP.sub.4 antagonists are known, it is desired to find novel EP.sub.4 antagonists, and in particular, EP.sub.4 antagonists which are selective against other EP receptors, i.e. EP.sub.1, EP.sub.2 and EP.sub.3.

SUMMARY OF THE INVENTION

A first aspect of the present invention provides a compound of formula (I):

##STR00004## or a salt, solvate and chemically protected form thereof, wherein: one of R.sup.2 and R.sup.5 is: (i) H or an optionally substituted C.sub.1-4 alkyl group; or (ii)an optionally substituted C.sub.5-7 aryl; and the other of R.sup.2 and R.sup.5 is the other group; m and n can be 0 or 1, and m+n=1 or 2 R.sup.N is H or optionally substituted C.sub.1-4 alkyl R.sup.3 is either: (i) carboxy; (ii) a group of formula (II):

##STR00005## (iii) a group of formula (III):

##STR00006## wherein R is optionally substituted C.sub.1-7 alkyl, C.sub.5-20 aryl, or NR.sup.N3R.sup.N4, where R.sup.N3 and R.sup.N4 are independently selected from optionally substituted C.sub.1-4 alkyl; or (iv) tetrazol-5-yl.

The compound is preferably not N-(5-phenyul-2-methyl-3-furoyl)-p-aminophenylacetic acid, i.e. R.sup.2=CH.sub.3, R.sup.5=phenyl, R.sup.N=H, n=0, m=1 and R.sup.3=carboxy.

A second aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of therapy.

A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined in the first aspect or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.

A further aspect of the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a condition alleviated by antagonism of an EP.sub.4 receptor.

Another aspect of the present invention provides a method of treating a condition which can be alleviated by antagonism of an EP.sub.4 receptor, which method comprises administering to a patient in need of treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Conditions which can be alleviated by antagonism of an EP.sub.4 receptor are discussed above, and particularly include primary headache disorders, most particularly migraines.

The present invention also provides methods of antagonizing EP.sub.4 receptors, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of formula (I).

In some embodiments, the compounds described above may be selective as against antagonism of the other three EP receptors, i.e. EP.sub.1, EP.sub.2 and EP.sub.3. This selectivity allows for targeting of the effect of the compounds of the invention, with possible benefits in the treatment of certain conditions.

Definitions

Monodentate Groups

(i.e groups with one point of covalent attachment)

Alkyl: The term "alkyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 7 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated or unsaturated. Thus, the term "alkyl" includes the sub-classes alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cylcoalkynyl, etc., discussed below.

In the context of alkyl groups, the prefixes (e.g. C.sub.1-4, C.sub.1-7) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term "C.sub.1-4 alkyl" as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of alkyl groups include C.sub.1-4 alkyl ("lower alkyl")and C.sub.1-7 alkyl. Note that the first prefix may vary according to other limitations; for example, for unsaturated alkyl groups, the first prefix must be at least 2; for cyclic alkyl groups, the first prefix must be at least 3; etc.

Examples of saturated alkyl groups include, but are not limited to, methyl (C.sub.1), ethyl (C.sub.2), propyl (C.sub.3), butyl (C.sub.4), pentyl (C.sub.5), hexyl (C.sub.6) and heptyl (C.sub.7).

Examples of saturated linear alkyl groups include, but are not limited to, methyl (C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), n-butyl (C.sub.4), n-pentyl (amyl) (C.sub.5), n-hexyl (C.sub.6), and n-heptyl (C.sub.7).

Examples of saturated branched alkyl groups include iso-propyl (C.sub.3), iso-butyl (C.sub.4), sec-butyl (C.sub.4), tert-butyl (C.sub.4), iso-pentyl (C.sub.5), and neo-pentyl (C.sub.5).

Alkenyl: The term "alkenyl" as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds. Examples of alkenyl groups include C.sub.2-4 alkenyl and C.sub.2-7 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl, --CH.dbd.CH.sub.2), 1-propenyl (--CH.dbd.CH--CH.sub.3), 2-propenyl (allyl, --CH--CH.dbd.CH.sub.2), isopropenyl (1-methylvinyl, --C(CH.sub.3).dbd.CH.sub.2), butenyl (C.sub.4), pentenyl (C.sub.5), and hexenyl (C.sub.6).

Alkynyl: The term "alkynyl" as used herein, pertains to an alkyl group having one or more carbon-carbon triple bonds. Examples of groups of alkynyl groups include C.sub.2-4 alkynyl and C.sub.2-7 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (ethinyl, --C.ident.CH) and 2-propynyl (propargyl, --CH.sub.2--C.ident.CH).

Cycloalkyl: The term "cycloalkyl" as used herein, pertains to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a carbocyclic ring of a carbocyclic compound, which carbocyclic ring may be saturated or unsaturated, which moiety has from 3 to 7 carbon atoms (unless otherwise specified), including from 3 to 7 ring atoms. Thus, the term "cycloalkyl" includes the sub-classes cycloalkenyl and cycloalkynyl. Preferably, each ring has from 3 to 7 ring atoms. Examples of groups of cycloalkyl groups include C.sub.3-7 cycloalkyl.

Examples of cycloalkyl groups include, but are not limited to, those derived from: saturated monocyclic hydrocarbon compounds: cyclopropane (C.sub.3), cyclobutane (C.sub.4), cyclopentane (C.sub.5), cyclohexane (C.sub.6), cycloheptane (C.sub.7), methylcyclopropane (C.sub.4), dimethylcyclopropane (C.sub.5), methylcyclobutane (C.sub.5), dimethylcyclobutane (C6), methylcyclopentane (C.sub.6), dimethylcyclopentane (C.sub.7), methylcyclohexane (C.sub.7); unsaturated monocyclic hydrocarbon compounds: cyclopropene (C.sub.3), cyclobutene (C.sub.4), cyclopentene (C.sub.5), cyclohexene (C.sub.6), methylcyclopropene (C.sub.4), dimethylcyclopropene (C.sub.5), methylcyclobutene (C.sub.5), dimethylcyclobutene (C.sub.6), methylcyclopentene (C.sub.6), dimethylcyclopentene (C.sub.7), methylcyclohexene (C.sub.7);

Heterocyclyl: The term "heterocyclyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.

In this context, the prefixes (e.g. C.sub.3-20, C.sub.3-7, C.sub.5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C.sub.5-6 heterocyclyl" as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms. Examples of groups of heterocyclyl groups include C.sub.3-20 heterocyclyl, C.sub.5-20 heterocyclyl, C.sub.3-15 heterocyclyl, C.sub.5-15 heterocyclyl, C.sub.3-12 heterocyclyl, C.sub.5-12 heterocyclyl, C.sub.3-10 heterocyclyl, C.sub.5-10 heterocyclyl, C.sub.3-7 heterocyclyl, C.sub.5-7 heterocyclyl, and C.sub.5-6 heterocyclyl.

Examples of monocyclic heterocyclyl groups include, but are not limited to, those derived from: N.sub.1: aziridine (C.sub.3), azetidine (C.sub.4), pyrrolidine (tetrahydropyrrole) (C.sub.5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C.sub.5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C.sub.5), piperidine (C.sub.6), dihydropyridine (C.sub.6), tetrahydropyridine (C.sub.6), azepine (C.sub.7); O.sub.1: oxirane (C.sub.3), oxetane (C.sub.4), oxolane (tetrahydrofuran) (C.sub.5), oxole (dihydrofuran) (C.sub.5), oxane (tetrahydropyran) (C.sub.6), dihydropyran (C.sub.6), pyran (C.sub.6), oxepin (C.sub.7); S.sub.1: thiirane (C.sub.3), thietane (C.sub.4), thiolane (tetrahydrothiophene) (C.sub.5), thiane (tetrahydrothiopyran) (C.sub.6), thiepane (C.sub.7); O.sub.2: dioxolane (C.sub.5), dioxane (C.sub.6), and dioxepane (C.sub.7); O.sub.3: trioxane (C.sub.6); N.sub.2: imidazolidine (C.sub.5), pyrazolidine (diazolidine) (C.sub.5), imidazoline (C.sub.5), pyrazoline (dihydropyrazole) (C.sub.5), piperazine (C.sub.6); N.sub.1O.sub.1: tetrahydrooxazole (C.sub.5), dihydrooxazole (C.sub.5), tetrahydroisoxazole (C.sub.5), dihydroisoxazole (C.sub.5), morpholine (C.sub.6), tetrahydrooxazine (C.sub.6), dihydrooxazine (C.sub.6), oxazine (C.sub.6); N.sub.1S.sub.1: thiazoline (C.sub.5), thiazolidine (C.sub.5), thiomorpholine (C.sub.6); N.sub.2O.sub.1: oxadiazine (C.sub.6); O.sub.1S.sub.1: oxathiole (C.sub.5) and oxathiane (thioxane) (C.sub.6); and, N.sub.1O.sub.1S.sub.1: oxathiazine (C.sub.6).

Aryl: The term "aryl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Preferably, each ring has from 5 to 7 ring atoms.

In this context, the prefixes (e.g. C.sub.3-20, C.sub.5-7, C.sub.5-6 etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C.sub.5-6 aryl" as used herein, pertains to an aryl group having 5 or 6 ring atoms. Examples of groups of aryl groups include C.sub.3-20 aryl, C.sub.5-20 aryl, C.sub.5-15 aryl, C.sub.5-12 aryl, C.sub.5-10 aryl, C.sub.5-7 aryl, C.sub.5-6 aryl, C.sub.5 aryl, and C.sub.6 aryl.

The ring atoms may be all carbon atoms, as in "carboaryl groups". Examples of carboaryl groups include C.sub.3-20 carboaryl, C.sub.5-20 carboaryl, C.sub.5-15 carboaryl, C.sub.5-12 carboaryl, C.sub.5-10 carboaryl, C.sub.5-7 carboaryl, C.sub.5-6 carboaryl, C.sub.5 carboaryl, and C.sub.6 carboaryl.

Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e. phenyl) (C.sub.6), naphthalene (C.sub.10), azulene (C.sub.10), anthracene (C.sub.14), phenanthrene (C.sub.14), naphthacene (C.sub.18), and pyrene (C.sub.16).

Examples of aryl groups which comprise fused rings, at least one of which is an aromatic ring, include, but are not limited to, groups derived from indane (e.g., 2,3-dihydro-1H-indene) (C.sub.9), indene (C.sub.9), isoindene (C.sub.9), tetraline (1,2,3,4-tetrahydronaphthalene (C.sub.10), acenaphthene (C.sub.12), fluorene (C.sub.13), phenalene (C.sub.13), acephenanthrene (C.sub.15), and aceanthrene (C.sub.16).

Alternatively, the ring atoms may include one or more heteroatoms, as in "heteroaryl groups". Examples of heteroaryl groups include C.sub.3-20 heteroaryl, C.sub.5-20 heteroaryl, C.sub.5-15 heteroaryl, C.sub.5-12 heteroaryl, C.sub.5-10 heteroaryl, C.sub.5-7 heteroaryl, C.sub.5-6 heteroaryl, C.sub.5 heteroaryl, and C.sub.6 heteroaryl.

Examples of monocyclic heteroaryl groups include, but are not limited to, those derived from: N.sub.1: pyrrole (azole) (C.sub.5), pyridine (azine) (C.sub.6); O.sub.1: furan (oxole) (C.sub.5); S.sub.1: thiophene (thiole) (C.sub.5); N.sub.1O.sub.1: oxazole (C.sub.5), isoxazole (C.sub.5), isoxazine (C.sub.6); N.sub.2O.sub.1: oxadiazole (furazan) (C.sub.5); N.sub.3O.sub.1: oxatriazole (C.sub.5); N.sub.1S.sub.1: thiazole (C.sub.5), isothiazole (C.sub.5); N.sub.2: imidazole (1,3-diazole) (C.sub.5), pyrazole (1,2-diazole) (C.sub.5), pyridazine (1,2-diazine) (C.sub.6), pyrimidine (1,3-diazine) (C.sub.6), pyrazine (1,4-diazine) (C.sub.6); N.sub.3: triazole (C.sub.5), triazine (C.sub.6); and, N.sub.4: tetrazole (C.sub.5).

Examples of heteroaryl groups which comprise fused rings, include, but are not limited to: C.sub.9 (with 2 fused rings) derived from benzofuran (O.sub.1), isobenzofuran (O1), indole (N.sub.1), isoindole (N.sub.1), indolizine (N.sub.1), indoline (N.sub.1), isoindoline (N.sub.1), purine (N.sub.4) (e.g., adenine, guanine), benzimidazole (N.sub.2), indazole (N.sub.2), benzoxazole (N.sub.1O.sub.1), benzisoxazole (N.sub.1O.sub.0), benzodioxole (O.sub.2), benzofurazan (N.sub.2O.sub.1), benzotriazole (N.sub.3), benzothiofuran (S.sub.1), benzothiazole (N.sub.1S.sub.1), benzothiadiazole (N.sub.2S); C.sub.10 (with 2 fused rings) derived from chromene (O.sub.1), isochromene (O.sub.1), chroman (O.sub.1), isochroman (O.sub.1), benzodioxan (O.sub.2), quinoline (N.sub.1), isoquinoline (N.sub.1), quinolizine (N.sub.1), benzoxazine (N.sub.1O.sub.1), benzodiazine (N.sub.2), pyridopyridine (N.sub.2), quinoxaline (N.sub.2), quinazoline (N.sub.2), cinnoline (N.sub.2), phthalazine (N.sub.2), naphthyridine (N.sub.2), pteridine (N.sub.4); C.sub.11 (with 2 fused rings) derived from benzodiazepine (N.sub.2); C.sub.13 (with 3 fused rings) derived from carbazole (N.sub.1), dibenzofuran (O.sub.1), dibenzothiophene (S.sub.1), carboline (N.sub.2), perimidine (N.sub.2), pyridoindole (N.sub.2); and, C.sub.14 (with 3 fused rings) derived from acridine (N.sub.1), xanthene (O.sub.1), thioxanthene (S.sub.1), oxanthrene (O.sub.2), phenoxathiin (O.sub.1S.sub.1), phenazine (N.sub.2), phenoxazine (N.sub.1O.sub.1), phenothiazine (N.sub.1S.sub.1), thianthrene (S.sub.2), phenanthridine (N.sub.1), phenanthroline (N.sub.2), phenazine (N.sub.2).

If a heteroaryl or heterocyclyl group contains a nitrogen ring atom, this ring atom, where possible, may be in a oxidised state, as an N-oxide.

The above groups, whether alone or part of another substituent, may themselves optionally be substituted with one or more groups selected from themselves, the additional monodentate substituents listed below and alkoxylene.

Halo: --F, --Cl, --Br, and --I.

Hydroxy: --OH.

Ether: --OR, wherein R is an ether substituent, for example, a C.sub.1-7 alkyl group (also referred to as a C.sub.1-7 alkoxy group, discussed below), a C.sub.3-20 heterocyclyl group (also referred to as a C.sub.3-20 heterocyclyloxy group), or a C.sub.5-20 aryl group (also referred to as a C.sub.5-20 aryloxy group), preferably a C.sub.1-7 alkyl group.

C.sub.1-7 alkoxy: --OR, wherein R is a C.sub.1-7 alkyl group. Examples of C.sub.1-7 alkoxy groups include, but are not limited to, --OMe (methoxy), --OEt (ethoxy), --O(nPr) (n-propoxy), --O(iPr) (isopropoxy), --O(nBu) (n-butoxy), --O(sBu) (sec-butoxy), --O(iBu) (isobutoxy), and --O(tBu) (tert-butoxy).

Oxo (keto, -one): .dbd.O.

Thione (thioketone): .dbd.S.

Imino (imine): .dbd.NR, wherein R is an imino substituent, for example, hydrogen, C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably hydrogen or a C.sub.1-7 alkyl group. Examples of imino groups include, but are not limited to, .dbd.NH, .dbd.NMe, .dbd.NEt, and .dbd.NPh.

Formyl (carbaldehyde, carboxaldehyde): --C(.dbd.O)H.

Acyl (keto): --C(.dbd.O)R, wherein R is an acyl substituent, for example, a C.sub.1-7 alkyl group (also referred to as C.sub.1-7 alkylacyl or C.sub.1-7 alkanoyl), a C.sub.3-20 heterocyclyl group (also referred to as C.sub.3-20 heterocyclylacyl), or a C.sub.5-20 aryl group (also referred to as C.sub.5-20 arylacyl), preferably a C.sub.1-7 alkyl group. Examples of acyl groups include, but are not limited to, --C (.dbd.O) CH.sub.3 (acetyl), --C(.dbd.O)CH.sub.2CH.sub.3 (propionyl), --C(.dbd.O)C(CH.sub.3).sub.3 (t-butyryl), and --C(.dbd.O)Ph (benzoyl, phenone).

Carboxy (carboxylic acid): --C(.dbd.O)OH.

Thiocarboxy (thiocarboxylic acid): --C(.dbd.S)SH.

Thiolocarboxy (thiolocarboxylic acid): --C(.dbd.O)SH.

Thionocarboxy (thionocarboxylic acid): --C(.dbd.S)OH.

Imidic acid: --C(.dbd.NH)OH.

Hydroxamic acid: --C(.dbd.NOH)OH.

Ester (carboxylate, carboxylic acid ester, oxycarbonyl): --C(.dbd.O)OR, wherein R is an ester substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group. Examples of ester groups include, but are not limited to, --C(.dbd.O)OCH.sub.3, --C(.dbd.O)OCH.sub.2CH.sub.3, --C(.dbd.O)OC(CH.sub.3).sub.3, and --C(.dbd.O)OPh.

Acyloxy (reverse ester): --OC(.dbd.O)R, wherein R is an acyloxy substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group. Examples of acyloxy groups include, but are not limited to, --OC(.dbd.O)CH.sub.3 (acetoxy), --OC(.dbd.O)CH.sub.2CH.sub.3, --OC(.dbd.O)C(CH.sub.3).sub.3, --OC(.dbd.O)Ph, and --OC(.dbd.O)CH.sub.2Ph.

Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): --C(.dbd.O)NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are independently amino substituents, as defined for amino groups. Examples of amido groups include, but are not limited to, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3, --C(.dbd.O)N(CH.sub.3).sub.2, --C(.dbd.O)NHCH.sub.2CH.sub.3, and --C(.dbd.O)N(CH.sub.2CH.sub.3).sub.2, as well as amido groups in which R.sup.1 and R.sup.2 together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.

Acylamino: --NR.sup.1C(.dbd.O)R.sup.2, wherein R.sup.1 is an amide substituent, for example, hydrogen, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably hydrogen or a C.sub.1-7 alkyl group, and R.sup.2 is an acyl substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably hydrogen or a C.sub.1-7 alkyl group. Examples of acylamide groups include, but are not limited to, --NHC(.dbd.O)CH.sub.3, --NHC(.dbd.O)CH.sub.2CH.sub.3, and --NHC(.dbd.O)Ph. R.sup.1 and R.sup.2 may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl:

##STR00007##

Thioamido (thiocarbamyl): --C(.dbd.S)NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are independently amino substituents, as defined for amino groups. Examples of thioamido groups include, but are not limited to, --C(.dbd.S)NH.sub.2, --C(.dbd.S)NHCH.sub.3, --C(.dbd.S)N(CH.sub.3).sub.2, and --C(.dbd.S)NHCH.sub.2CH.sub.3.

Ureido: --N(R.sup.1)CONR.sup.2R.sup.3wherein R.sup.2 and R.sup.3 are independently amino substituents, as defined for amino groups, and R.sup.1 is a ureido substituent, for example, hydrogen, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably hydrogen or a C.sub.1-7 alkyl group. Examples of ureido groups include, but are not limited to, --NHCONH.sub.2, --NHCONHMe, --NHCONHEt, --NHCONMe.sub.2, --NHCONEt.sub.2, --NMeCONH.sub.2, --NMeCONHMe, --NMeCONHEt, --NMeCONMe.sub.2, and --NMeCONEt.sub.2.

Guanidino: --NH--C(.dbd.NH)NH.sub.2.

Tetrazolyl: a five membered aromatic ring having four nitrogen atoms and one carbon atom,

##STR00008##

Amino: --NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are independently amino substituents, for example, hydrogen, a C.sub.1-7 alkyl group (also referred to as C.sub.1-7 alkylamino or di-C.sub.1-7 alkylamino), a C.sub.3-20 heterocyclyl group, or a C.sub.5-20aryl group, preferably H or a C.sub.1-7 alkyl group, or, in the case of a "cyclic" amino group, R.sup.1 and R.sup.2, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms. Amino groups may be primary (--NH.sub.2), secondary (--NHR.sup.1), or tertiary (--NHR.sup.1R.sup.2), and in cationic form, may be quaternary (--.sup.+NR.sup.1R.sup.2R.sup.3). Examples of amino groups include, but are not limited to, --NH.sub.2, --NHCH.sub.3, --NHC(CH.sub.3).sub.2, --N(CH.sub.3).sub.2, --N(CH.sub.2CH.sub.3).sub.2, and --NHPh. Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.

Amidine (amidino): --C(.dbd.NR)NR.sub.2, wherein each R is an amidine substituent, for example, hydrogen, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably H or a C.sub.1-7 alkyl group. Examples of amidine groups include, but are not limited to, --C(.dbd.NH)NH.sub.2, --C(.dbd.NH)NMe.sub.2, and --C(.dbd.NMe)NMe.sub.2.

Nitro: --NO.sub.2.

Nitroso: --NO.

Cyano (nitrile, carbonitrile): --CN.

Sulfhydryl (thiol, mercapto): --SH.

Thioether (sulfide): --SR, wherein R is a thioether substituent, for example, a C.sub.1-7 alkyl group (also referred to as a C.sub.1-7 alkylthio group), a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group. Examples of C.sub.1-7 alkylthio groups include, but are not limited to, --SCH.sub.3 and --SCH.sub.2CH.sub.3.

Disulfide: --SS--R, wherein R is a disulfide substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group (also referred to herein as C.sub.1-7 alkyl disulfide). Examples of C.sub.1-7 alkyl disulfide groups include, but are not limited to, --SSCH.sub.3 and --SSCH.sub.2CH.sub.3.

Sulfine (sulfinyl, sulfoxide): --S(.dbd.O) R, wherein R is a sulfine substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group. Examples of sulfine groups include, but are not limited to, --S(.dbd.O)CH.sub.3 and --S(.dbd.O)CH.sub.2CH.sub.3.

Sulfone (sulfonyl): --S (.dbd.O).sub.2R, wherein R is a sulfone substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group, including, for example, a fluorinated or perfluorinated C.sub.1-7 alkyl group. Examples of sulfone groups include, but are not limited to, --S(.dbd.O).sub.2CH.sub.3 (methanesulfonyl, mesyl), --S(.dbd.O).sub.2CF.sub.3 (triflyl), --S(.dbd.O).sub.2CH.sub.2CH.sub.3 (esyl), --S(.dbd.O).sub.2C.sub.4F.sub.9 (nonaflyl), --S(.dbd.O).sub.2CH.sub.2CF.sub.3 (tresyl), --S(.dbd.O).sub.2CH.sub.2CH.sub.2NH.sub.2 (tauryl), --S(.dbd.O).sub.2Ph (phenylsulfonyl, besyl), 4-methylphenylsulfonyl (tosyl), 4-chlorophenylsulfonyl (closyl), 4-bromophenylsulfonyl (brosyl), 4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsyl), and 5-dimethylamino-naphthalen-1-ylsulfonate (dansyl).

Sulfinic acid (sulfino): --S(.dbd.O)OH, --SO.sub.2H.

Sulfonic acid (sulfo): --S(.dbd.O).sub.2OH, --SO.sub.3H.

Sulfinate (sulfinic acid ester): --S(.dbd.O)OR; wherein R is a sulfinate substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group. Examples of sulfinate groups include, but are not limited to, --S(.dbd.O)OCH.sub.3 (methoxysulfinyl; methyl sulfinate) and --S(.dbd.O)OCH.sub.2CH.sub.3 (ethoxysulfinyl; ethyl sulfinate).

Sulfinyloxy: --OS(.dbd.O)R, wherein R is a sulfinyloxy substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group. Examples of sulfinyloxy groups include, but are not limited to, --OS(.dbd.O)CH.sub.3 and --OS(.dbd.O)CH.sub.2CH.sub.3.

Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide): --S(.dbd.O)NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are independently amino substituents, as defined for amino groups. Examples of sulfamyl groups include, but are not limited to, --S(.dbd.O)NH.sub.2, --S(.dbd.O)NH(CH.sub.3), --S(.dbd.O)N(CH.sub.3).sub.2, --S(.dbd.O)NH(CH.sub.2CH.sub.3), --S(.dbd.O)N(CH.sub.2CH.sub.3).sub.2, and --S(.dbd.O) NHPh.

Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide): --S(.dbd.O).sub.2NR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are independently amino substituents, as defined for amino groups. Examples of sulfonamido groups include, but are not limited to, --S(.dbd.O).sub.2NH.sub.2, --S(.dbd.O).sub.2NH(CH.sub.3), --S(.dbd.O).sub.2N(CH.sub.3).sub.2, --S(.dbd.O).sub.2NH (CH.sub.2CH.sub.3), --S(.dbd.O).sub.2N (CH.sub.2CH.sub.3).sub.2, and --S(.dbd.O).sub.2NHPh.

Sulfonamino: --NR.sup.1S(.dbd.O).sub.2R, wherein R.sup.1 is an amino substituent, as defined for amino groups, and R is a sulfonamino substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group. Examples of sulfonamino groups include, but are not limited to, --NHS(.dbd.O).sub.2CH.sub.3 and --N(CH.sub.3)S(.dbd.O).sub.2C.sub.6H.sub.5.

Sulfinamino: --NR.sup.1S(.dbd.O)R, wherein R.sup.1 is an amino substituent, as defined for amino groups, and R is a sulfinamino substituent, for example, a C.sub.1-7 alkyl group, a C.sub.3-20 heterocyclyl group, or a C.sub.5-20 aryl group, preferably a C.sub.1-7 alkyl group. Examples of sulfinamino groups include, but are not limited to, --NHS(.dbd.O)CH.sub.3 and --N(CH.sub.3)S(.dbd.O)C.sub.6H.sub.5.

As already mentioned, the above described groups may be substituted, and particular examples include, but are not limited to, C.sub.3-20 aryl-C.sub.1-7 alkyl groups, which include benzyl (phenylmethyl, PhCH.sub.2--), benzhydryl (Ph.sub.2CH--), trityl (triphenylmethyl, Ph.sub.3C--), phenethyl (phenylethyl, Ph--CH.sub.2CH.sub.2--), styryl (Ph--CH.dbd.CH--) and cinnamyl (Ph--CH.dbd.CH--CH.sub.2--).

Bidentate Groups

(i.e. groups with two points of covalent attachment; linking groups)

Alkylene: The term "C.sub.1-3 alkylene", as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms from each of two different carbon atoms, of a linear hydrocarbon compound having from 1 to 3 carbon atoms, which may be saturated or unsaturated. Thus, the term "alkylene" includes the sub-classes alkenylene and alkynylene.

In this context, the prefix C.sub.1-3 denotes the number of carbon atoms, or range of number of carbon atoms.

Examples of saturated C.sub.1-3 alkylene groups include --CH.sub.2-- (methylene), --CH.sub.2CH.sub.2-- (ethylene) and --CH.sub.2CH.sub.2CH.sub.2-- (propylene).

Examples of unsaturated C.sub.1-3 alkylene groups (which may be termed "C.sub.2-3 alkenylene" or "C.sub.2-3 alkynylene", as appropriate) include --CH.dbd.CH-- (vinylene), --CH.dbd.CH.dbd.CH.sub.2--, --CH.sub.2--CH.dbd.CH--, --C.ident.C--, --C.ident.C.dbd.CH.sub.2-- and --CH.sub.2--C.ident.C--.

The C.sub.1-3 alkylene group may be substituted by any monodentate substituent described above.

Alkoxylene: The term "alkoxylene," as used herein, pertains to a bidentate group of formula --O(CH.sub.2).sub.nO--, where n is 1 or 2.

Includes other Forms

Unless otherwise specified, included in the above are the well known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid (--COOH) also includes the anionic (carboxylate) form (--COO.sup.-), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (--N.sup.+HR.sup.1R.sup.2), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (--O.sup.-), a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group.

Isomers, Salts, Solvates and Protected Forms

Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- and exo-forms; R-, S-, and