Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-11
2003-02-04
Bernhardt, Emily (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253090, C514S254020, C514S254030, C514S254050, C544S295000, C544S364000, C544S366000, C544S367000, C544S369000, C544S371000
Reexamination Certificate
active
06514975
ABSTRACT:
This invention relates to tetrazole derivatives which have utility as ligands for opioid receptors.
More particularly, this invention relates to tetrazoles, their preparation and their use as selective agonists for the delta receptor.
At least three subtypes of opioid receptors (mu, delta and kappa) are described and documented in the scientific literature. All three receptors are to be present in the central and peripheral nervous systems of many species including man. Activation of delta receptors is known to produce antinociception in rodents and can induce analgesia in man, in addition to influencing motility of the gastrointestinal tract [see Burks, T. F. (1995) in “The pharmacology of opioid peptides”, Tseng L. F. ed. Harwood Academic Publishers].
We have discovered a novel class of tetrazole derivatives which are potent and selective delta opioid agonists which are useful for preventing or treating inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, disorders of respiratory function, gastrointestinal disorders such as functional bowel disease, functional GI disorders such as irritable bowel syndrome, functional diarrhoea, functional distension, functional pain, non-ulcerogenic dyspepsia or others associated with disorders of motility or secretion, urogenital tract disorders such as incontinence, as analgesics for treating pain including non-somatic pain, or as immunosuppressants to prevent rejection in organ transplant and skin graft. Thus the invention provides compounds of the formula:
and their pharmaceutically acceptable salts; wherein
R
1
is H, C
2
-C
6
alkanoyl, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
3
-C
7
cycloalkyl, (C
3
-C
7
cycloalkyl)-(C
1
-C
4
alkyl), (C
1
-C
4
alkoxy)-(C
1
-C
4
alkyl), carboxy-(C
1
-C
4
alkyl), aryl-(C
1
-C
4
alkyl) or heteroaryl-(C
1
-C
4
alkyl);
R
2
and R
3
are each independently H or C
1
-C
4
alkyl;
R
4
is selected from (i) H, (ii) a group of the formula R
6
—(CH
2
)
m
—Z—(CH
2
)
n
—, where m is 0, 1, 2 or 3, n is 1, 2 or 3, Z is a direct link or O, and R
6
is —CO
2
H or —CO
2
(C
1
-C
4
alkyl), and (iii) a group of the formula
where R
7
is H or C
1
-C
4
alkyl;
and R
5
is hydroxy, C
1
-C
4
alkoxy or —NHSO
2
(C
1
-C
4
alkyl);
with the proviso that when Z is O, m is 1, 2 or 3 and n is 2 or 3.
Where appropriate, the alkyl alkanoyl, alkoxy, alkenyl and alkynyl groups can be straight or branched chain.
Preferred aryl groups are phenyl and naphthyl, both optionally substituted by up to three substituents each independently selected from halo, trifluoromethyl, C
1
-C
4
alkyl and C
1
-C
4
alkoxy.
More preferably, “aryl” is phenyl optionally substituted by one or two substituents as defined above.
“Halo” means F, Cl, Br or I.
Preferred heteroaryl groups include 5- or 6-membered aromatic heterocyclic groups such as thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl and pyrazolyl.
Thiazol-2-yl is the most preferred heteroaryl group.
The preferred alkyl groups are methyl and ethyl. The preferred alkoxy groups are methoxy and ethoxy The preferred alkanoyl group is acetyl. The preferred alkenyl group is allyl. The preferred alkynyl group is vinyl. The preferred cycloalkyl group is cyclopropyl.
The tetrazole group is preferably attached to the 3- or 4- position of the adjacent phenyl ring.
R
1
is preferably H, allyl, benzyl, C
1
-C
4
alkyl, or (C
3
-C
7
cycloalkyl)methyl; most preferably allyl.
R
2
and R
3
are preferably each independently H or methyl; more preferably both methyl or both H; most preferably both methyl.
R
5
is preferably hydroxy, methoxy or —NHSO
2
Me; most preferably hydroxy.
R
4
is preferably H or a group of the formula (a) —(CH
2
)
p
CO
2
H or —(CH
2
)
p
CO
2
(C
1
-C
4
alkyl) where p is 1, 2, 3 or 4, (b) —(CH
2
)
2
—O—CH
2
CO
2
H, (c) —(CH
2
)
2
—O—CH
2
CO
2
(C
1
-C
4
alkyl) or (d),
where R
7
is H or C
1
-C
4
alkyl.
In R
4
, the preferred alkyl group is ethyl.
Preferred individual compounds are those of Examples 1, 4, 24, 27, 36, 42, 94, 96, 104 and 107.
The preferred stereo chemistry of the compounds of the formula (i) is as follows:
Such compounds are most readily prepared by using starting materials with the appropriate stereochemistry.
The compounds of the formula (I) can be prepared by conventional routes such as those set out in the following Examples and Preparations and in WO-A-9315062.
Route A
Compounds of the formula (I) in which R
5
is hydroxy can be prepared by the reaction of the corresponding methoxy compounds of the formula (I) with boron tribromide. Preferably boron tribromide in dichloromethane is added to a solution of the methoxy starting material in dichloromethane and the mixture is stirred at room temperature for a few hours. The product can then be isolated and purified by conventional techniques.
Removal of a hydroxy-protecting group from the corresponding hydroxy-protected compound is also possible, typified by the conversion of t-butyldimethylsilyloxy to hydroxy using tetraethylammnonium fluoride.
Route B
The compounds (I) in which R
4
is H, can be prepared by the reaction of a corresponding nitrile of the formula:
where R
1
, R
2
, R
3
and R
5
are as defined for formula (I), with dibutyltin oxide and trimethylsilyl azide.
The reaction is typically carried out in a suitable organic solvent such as dry toluene at from about 50° C. to the reflux temperature. If necessary, a hydroxy group represented by R
5
can be protected prior to reaction, e.g. by a t-butyldimethylsilyl protecting group, and the protecting group can be removed subsequently by a conventional technique.
Route C
Compounds (I) in which R
4
is either (i) R
6
—(CH
2
)
m
—Z—(CH
2
)
n
— where R
6
is —CO
2
(C
1
-C
4
alkyl) and Z, m and n are as defined for formula (I) or (ii)
where R
7
is C
1
-C
4
alkyl can be prepared by the alkylation of the corresponding compounds in which R
4
is H with an alkylating agent of the formula, respectively,
R
6
—(CH
2
)
m
—Z—(CH
2
)
n
—Q
1
(IIIA)
or
where Z, m and n are as defined for formula (I), R
6
and R
7
are defined in this method and Q
1
is a leaving group, preferably Br.
The reaction is typically carried out in the presence of a base such as potassium or cesium carbonate in a suitable organic solvent, e.g. acetonitrile, under gentle reflux.
This reaction generally produces a mixture of compounds in which the group R
4
is attached to the 1- and 2- positions of the tetrazole ring.
When a compound in which R
5
is hydroxy is required, it may be necessary to protect the hydroxy group before reaction, such as by a t-butyldimethylsilyl group, which can be removed conventionally after reaction, e.g. by the use of tetraethylammonium fluoride.
In an alternative alkylation procedure, the corresponding compound in which R
4
is H is reacted firstly with a strong base such as sodium ethoxide (prepared by adding sodium metal to ethanol) and then with the compound III, no additional base being necessary.
Route D
Compounds (I) in which R
6
is —CO
2
H can also be prepared by the hydrolysis, preferably alkaline hydrolysis, of the corresponding esters in which R
6
is C
1
-C
4
alkyl.
The reaction is typically carried out with aqueous sodium hydroxide in methanol or a mixture of dioxane and methanol at room temperature.
Route E
Compounds (I) in which R
6
is —CO
2
H can also be prepared by the hydrolysis of the corresponding compounds in which R
4
is NC—(CH
2
)
m
—Z—(CH
2
)
n
— where Z, m and n are as defined for formula (I). Acidic hydrolysis using hydrogen chloride gas in ethanol is preferred.
Route F
Compounds (I) in which R
4
is 1-[CH
2
CO
2
(C
1
-C
4
alkyl)] and R
5
is —OH can be prepared by ring closure by the reaction of a compound of the formula:
where R
1
, R
2
and R
3
are as defined for formula (I) and Q
2
is a hydroxy-protecting group such as t-butyldimethylsilyl, with diethyl acidodicarboxylate, triphenyl phosphine and trimethylsilyl azide in a suitable organic solvent such as toluene. Generally the protecting group Q
2
is removed under t
Benson Gregg C.
Bernhardt Emily
Pfizer Inc
Richardson Peter C.
Ronau Robert T.
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