Bicyclic vasopressin agonists

Details Bicyclic vasopressin agonists Bicyclic vasopressin agonists

2002-06-10

2003-12-16

Seaman, D. Margaret (Department: 1675)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S211100, C514S212010, C514S215000, C514S217010, C514S221000, C540S491000, C540S492000, C540S521000, C540S523000

Reexamination Certificate

active

06664249

ABSTRACT:

FIELD OF INVENTION
This application is a 371 of PCT/GB00/04055, filed Oct. 20, 2000. The present invention relates to a class of novel chemical entities which act as agonists of the peptide hormone vasopressin. They reduce urine output from the kidneys and so are useful in the treatment of certain human diseases characterised by polyuria. They are also useful in the control of urinary incontinence and bleeding disorders.
BACKGROUND TO THE INVENTION
Vasopressin is a peptide hormone secreted by the posterior pituitary gland. It acts on the kidney to increase water retention and so reduce urine output. For this reason, vasopressin is alternatively known as “antidiuretic hormone”. It also acts on the vasculature, where it produces a hypertensive effect. The cellular receptors that mediate these two actions have been characterised and shown to be different. The antidiuretic action is mediated by the type-2 vasopressin receptor, commonly called the V
2
receptor. Agents that can interact with the V
2
receptor and activate it in the same way as vasopressin are called V
2
receptor agonists (or simply V
2
agonists). Such agents will have an antidiuretic action. If these agents interact selectively with the V
2
receptor and not the other vasopressin receptor subtypes, then they will not have the hypertensive effect of vasopressin. This would be an important safety consideration and make such agents attractive for the treatment of human disease conditions characterised by polyuria (which is herein taken to mean excessive urine production).
In fact, such an agent is already in use in human therapy. Desmopressin (otherwise [1-desamino, D-Arg
8
]vasopressin, Minirin™, DDAVP™) is a peptide analogue of vasopressin which is selectively an agonist at the V
2
receptor. It is used in the treatment of central diabetes insipidus, which is a condition that results from defective secretion of vasopressin. It is also employed in the control of nocturnal enuresis and may also be of use in the control of nocturia. However, desmopressin is not an ideal agent in all respects. Even the best current syntheses of the agent are lengthy, and desmopressin is not amenable to the most convenient of purification techniques such as crystallisation. Consequently, desmopressin is relatively expensive. It has a very low oral bioavailability, and there is some variability in this parameter.
Overall then, there exists a need for a selective vasopressin V
2
receptor agonist that is easy to prepare and purify, and that has a high and predictable oral bioavailability. Such properties are most likely to be obtained with a non-peptide compound. These considerations have led other groups to investigate non-peptide vasopressin V
2
agonists, and their results are disclosed in, for example, International Patent Applications WO97/22591, WO99/06403, WO99/06409, WO00/46224, WO00/46225, WO00/46227 and WO00/46228. The compounds disclosed in these documents are, however, less than ideal. In particular, they have poor oral bioavailability, probably due in part to their low aqueous solubility. The present invention provides compounds with improved solubility and bioavailability.
Besides its antidiuretic actions, desmopressin is used to increase the concentration in the blood of the coagulation proteins known as Factor VIII and von Willebrand factor. In the clinical context, this makes desmopressin useful in the treatment of haemophilia A and von Willebrand's disease. Similar applications would be open to the non-peptide agonists of the present invention.
SUMMARY OF THE INVENTION
As disclosed herein, the present invention relates to a series of compounds that are non-peptide agonists of vasopressin and which are selective for the V
2
receptor subtype. The compounds are described by general formula 1
wherein:
V is a covalent bond or NH,
X is selected from CH
2
, O and N-alkyl,
Z is either S or —CH═CH—,
R
1
and R
2
are independently selected from H, F, Cl, Br and alkyl,
R
3
is selected from OH, O-alkyl and NR
4
R
5
,
R
4
and R
5
are each independently H or alkyl, or together are —(CH
2
)
q
—,
p is 0, 1, 2, 3 or 4, and
q is 4 or 5.
The invention further comprises pharmaceutical compositions incorporating these vasopressin agonists, which compositions are particularly useful in the treatment of central diabetes insipidus, nocturnal enuresis and nocturia.
DESCRIPTION OF THE INVENTION
The present invention comprises N-acyl tetrahydroazepine derivatives defined by general formula 1.
In this formula, V represents an NH group or a covalent bond. X represents a methylene group (—CH
2
—), an oxygen atom (O) or N-alkyl. Z represents a sulphur atom (S) or a group —CH═CH—.
R
1
and R
2
are each independently selected from H, F, Cl, Br and alkyl groups.
R
3
is selected from OH, O-alkyl and NR
4
R
5
.
R
4
and R
5
are each independently selected from H and alkyl groups. Alternatively, they may together be —(CH
2
)
q
—, where q is 4 or 5, such that together with the nitrogen atom to which they are attached they form a pyrrolidine or piperidine ring.
The integer p may take the values 0, 1, 2, 3 and 4. When p is 0, a covalent bond exists between V and the COR
3
group. When p is 0 and V is a covalent bond then a single covalent bond exists between the two carbonyl groups.
As used herein, “alkyl” includes saturated hydrocarbon residues, linear or branched, with up to six carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, neopentyl and n-hexyl.
Certain compounds of general formula 1 are capable of forming salts with acids or bases. For example, compounds containing a basic nitrogen atom can form addition salts with mineral and organic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulphonic acid, citric acid and benzoic acid. Compounds containing acidic groups can form salts with bases. Examples of such salts include the sodium, potassium, calcium, triethylammonium and tetraethylammonium salts. Furthermore, compounds that have both acidic and basic groups can form internal salts (zwitterions). Insofar as these salts are pharmaceutically acceptable, they are included within the scope of the invention.
In a preferred embodiment of the invention, the group Z is —CH═CH—.
In another preferred embodiment of the invention, Z is S.
In another preferred embodiment of the invention, X is a methylene group CH
2
.
In another preferred embodiment of the invention, R
1
is a hydrogen atom and R
2
is a methyl group or a chlorine atom.
In another preferred embodiment of the invention, R
1
is a methyl group or a chlorine atom and R
2
is a hydrogen atom.
In another preferred embodiment of the invention, R
3
is O-alkyl.
Particularly preferred compounds within the invention combine the features of these preferred embodiments.
Individual preferred compounds within the invention include (but are not limited to) the following:
1-(4-[N-(4-methoxy-4-oxobutanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-methoxy-2-oxoethanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-hydroxy-2-oxoethanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(5-methoxy-5-oxopentanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-ethoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-hydroxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(3-methyl-4-[N-(2-methylamino-2-oxoethylcarbamoyl)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-dimethylamino-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-methoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,
1-(4-[N-(2-amino-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-t

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