Pyrazoline derivatives, their preparation and application as...

Details Pyrazoline derivatives, their preparation and application as... Pyrazoline derivatives, their preparation and application as...

2000-11-28

2002-03-05

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S379700, C514S403000

Reexamination Certificate

active

06353117

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new pyrazoline derivatives, of general formula (I), and to physiologically acceptable salts thereof, to the procedures for their preparation, to their application as medicaments in human and or veterinary therapy and to the pharmaceutical composition that contain them.
The new compounds object of the present invention can be used in the pharmaceutical industry as intermediates and for the preparation of medicaments.
BACKGROUND OF THE INVENTION
Non-steroid anti-inflammatory drugs (NSAIDS) are traditionally classified as anti-inflammatory, antipyretic and analgesic agents for the symptomatic alleviation of inflammation, fever and light to moderate pain. The main indications for these drugs are osteoarthritis, rheumatoid arthritis and other inflammatory diseases of articulations, as well as for the treatment of inflammations associated with small lesions and as analgesics of broad use. The NSAIDS are essentially inhibitors of acute inflammatory response, but in rheumatic disorders they have little effect on the underlying degenerative changes occurring in tissue.
The discovery of the main mechanism of action of the NSAIDS by inhibition of cyclooxygenase (COX) [J. R. Vane,
Nature,
1971, 231, 232] provided a satisfactory explanation of their therapeutic action and established the importance that certain prostaglandins have as mediators in inflammatory disease [R. J. Flower, J. R. Vane,
Biochem. Pharm.,
1974, 23, 1439; J. R. Vane, R. M. Botting,
Postgrad Med. J.,
1990, 66(Suppl 4), S2]. The gastric toxicity of the classic NSAIDS, as well as their beneficial effects, is due to the suppression of prostaglandin synthesis by inhibition of the COX enzyme. Although several strategies have been followed (enteral Coating to prevent adsorption in the stomach, parenteral administration, pro-drug formulation, etc) to reduce the gastrointestinal lesions provoked by the NSAIDS, none of these modifications have provided a significant impact on the incidence of serious adverse reactions such as perforation and haemorrhaging.
The discovery of an induced prostaglandin-synthetase, denominated cyclooxygenase-2 (COX-2), different from the constitutive enzyme, currently denominated cyclooxygenase-1 (COX-1) [J. Sirois, J. R. Richards,
J. Biol. Chem.,
1992, 267, 6382], has renewed the interest in the development of new anti-inflammatory drugs. The identification of the isoform COX-2 has led to the hypothesis that it could be responsible for the production of prostaglandins in places where inflammation occurs. As a result, selective inhibition of this isoenzyme would reduce the inflammation without producing the side effects of gastric and renal toxicity. The COX-1 isoenzyme is essentially expressed in most of tissues with the function of synthesising prostaglandins which regulate the normal cell activity. On the other hand, the isoenzyme COX-2 is not normally present in cells but in chronic inflammation the levels of the protein COX-2 increase in parallel with the over-production of prostaglandins [J. R. Vane, R. M. Botting,
Infalmm. Res.,
1995, 44, 1]. Therefore, a selective COX-2 inhibitor has the same anti-inflammatory, antipyretic and analgesic properties as a conventional non-steroid anti-inflammatory agent and also inhibits the uterine contractions induced by hormones and presents potential anti-carcinogenic effects and beneficial effects in the prevention of the development of Alzheimer disease. On the other hand, a selective COX-2 inhibitor reduces the potential gastrointestinal toxicity, reduces the potential renal side effects and reduces the effects of bleeding time.
The tri-dimensional structure of COX-1 has been determined by x-ray diffraction [D. Picot, P. J. Loll, R. M. Garavito,
Nature,
1994, 367, 243]. Three of the helixes of the structure form the entrance to the cyclooxygenase channel and its insertion in the membrane allows the arachidonic acid to access the active site from inside the bilayer. The active site of cyclooxygenase is a large hydrophobic channel and the authors argue that the NSAIDS inhibit COX-1 by excluding arachidonic acid from the upper part of the channel. Recently [R. S. Service,
Science,
1996, 273, 1660], the three-dimensional structure of COX-2 has been described, which allows comparison of the similarities and differences between the two isoforms and therefore study of new drugs that selectively inhibit COX-2. The structures of COX-1 and COX-2 show that the sites where the anti-inflammatory agents bind to the enzymes are very similar but there is a difference of at least one important amino acid. A voluminous isoleucine present in the active site of COX-1 is replaced by a valine in COX-2. The isoleucine blocks the lateral cavity that is separated from the principle bond of both isoenzymes. The blocked cavity of COX-1 does not impede the binding of classic NSAIDS, but an inhibitor that needs the extra support point supplied by the lateral cavity will bind more easily to COX-2 than to COX-1. As a result, a model for a new generation of anit-inflammatory agents is one where the inhibitors of cyclooxygenase have a large preference for the lateral cavity of COX-2.
In the chemical literature derivatives of nitrogenated heterocyclic aromatics of five members have been described with COX-2 inhibitory activity. Within these azole derivatives are the pyrrols [W. W. Wilkerson, et al,
J. Med. Chem.,
1994, 37, 988; W. W. Wilkerson, et al,
J. Med. Chem.,
1995, 38, 3895; I. K. Khanna, et al,
J. Med. Chem.,
1997, 40, 1619], pyrazoles [T. D. Penning, et al,
J. Med. Chem.,
1997, 40, 1347; K. Tsuji, et al,
Chem. Pharm. Bull.,
1997, 45, 987; K. Tsuji, et al,
Chem. Pharm. Bull.,
1997, 45, 1475], or imidazoles [Khanna, et al,
J. Med. Chem.,
1997, 40, 1634].
We have now discovered that the novel compounds derived from pyrazolines of general formula (I) show interesting biological properties and these make them particularly useful for their employment in human and/or veterinary therapy. The compounds object of this invention are useful as agents with anti-inflammatory activity and for other diseases in which cyclooxygenase-2 plays a part, without having the gastric and renal toxicity of the classic NSAIDS.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides new pyrazolines that inhibit the enzyme cyclooxygenase-2, with application in human and/or veterinary medicine as anti-inflammatories and for other diseases in which cyclooxygenase-2 plays a part, and that have low or no gastric and renal toxicity. These anti-inflammatories therefore have a better safety profile. The new compounds object of the present invention are derivatives of &Dgr;
2
-pyrazolines, also known as 4,5-dihydro-1H-pyrazoles. They are therefore nitrogenated heterocyclic compounds. As a result the pyrazoline rings are not planar as opposed to the azoles described previously. The compounds object of the present invention have the general formula (I)
wherein
R
1
represents a hydrogen atom, a methyl, fluoromethyl, difluormethyl, trfluoromethyl, carboxylic acid, lower carboxylate of 1 to 4 carbon atoms, carboxamide or cyano group,
R
2
represents a hydrogen or methyl group,
R
3
, R
4
, R
7
and R
8
, identical or different, represent an atom of hydrogen, chlorine, fluorine, a methyl, trifluoromethyl or methoxy group,
R
5
represents an atom of hydrogen, chlorine, fluorine, a methyl, trifluoromethyl or methoxy group, provided that—in all cases—R
6
represents a methylsulphonyl, aminosulphonyl or acetoaminosulphonyl group,
R
6
represents an atom of hydrogen, chlorine, fluroine, a methyl, trifluromethyl or methoxy group, provided that —in all cases—R
5
represents a methylsulphonyl, aminosulphonyl or acetoaminosulphonyl group.
For the case that R
1
represents a methyl group
R
2
represents a hydrogen atom or a methyl group,
R
3
y R
8
, identical or different, represent an atom of hydrogen, chlorine, fluorine, a methyl or trifluorome

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