Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-01-17
2001-04-17
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S221000, C514S970000, C514S973000, C536S103000
Reexamination Certificate
active
06218375
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a ras-farnesyltransferase inhibitor complex having improved water-solubility and stability, which is formed from ras-farnesyltransferase inhibitors, such as (R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine and sulfobutylether-7-&bgr;-cyclodextrin or to (R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine and 2-hydroxypropyl-&bgr;-cyclodextrin, and to methods of forming such complex. The ras-farnesyltransferase inhibitors are useful as anti-tumor agents. The complex is also useful as an anti-tumor agent.
BACKGROUND OF THE INVENTION
Cyclodextrins are cyclic oligosaccharides obtained from starch, formed of six glucose units (&agr;-cyclodextrin), seven glucose units (&bgr;-cyclodextrin) or eight glucose units (&ggr;-cyclodextrin). They are known to form inclusion compounds with smaller molecules which fit entirely or at least partially into the 5-8 A cyclodextrin cavity, Saenger, W., “Cyclodextrin Inclusion Compounds in Research and Industry,” Angew. Chem. Int. Ed. Engl. 19, 344-362 (1980). On page 351, Saenger indicates that &agr;-cyclodextrin forms complexes with water, methanol, polyiodide, iodine, krypton, n-propanol, p-iodoaniline, dimethyl sulfoxide and methanol, m-nitrophenol, methyl orange, prostaglandin E, potassium acetate; &bgr;-cyclodextrin forms complexes with water, n-propanol, p-iodophenol, 2,5-diiodobenzoic acid, p-nitroacetanilide; and &ggr;-cyclodextrin forms complexes with propanol/water and water.
In addition, Saenger indicates on page 357 that &bgr;-cyclodextrin increases stabilization of benzocaine, procaine, atropine, aspirin, nitroglycerin, allicin, phenylbutazone, salicyclic acid, ascaridole, the ether ester of chaulmoogric acid, linoleic acid and indomethacin, and cyclodextrins increase water-solubility of fatty acids, amines such as procaine, lidocaine, meperdine, adipherine, steroids such as cortisone acetate and testosterone, hydroxybenzoic acid, benzocaine, aspirin, p-aminobenzoic acid, tetracycline, sulfadiazine, morphine, vanillin, ephedrine, sorbic acid, phenyl-substituted carbonic acids, ketoprofen, other antipyretic agents, vitamin D
3
, coumarin anticoagulants, sulfonamides and barbiturates.
However, &bgr;-cyclodextrin shows nephrotoxicity and membrane destabilizing properties. Because of the safety concerns with &bgr;-cyclodextrins, numerous chemical modifications of the cyclodextrins have been made. The different types of &bgr;-cyclodextrins are alkylated cyclodextrins, hydroxyalkylated cyclodextrins, carboxymethyl cyclodextrins and the sulfoalkylether cyclodextrins which include sulfobutylether (SBE) &bgr;-cyclodextrins with degrees of substitution on 4 and 7 positions of &bgr;-cyclodextrin. The specific product in the last group includes Captisol®, an SBE 7-&bgr;-cyclodextrin (SBE-CD). The specific product in the hydroxyalkylated cyclodextrins include 2-hydroxypropyl-&bgr;-cyclodextrin (HPCD).
U.S. Pat. No. 4,371,673, issued Feb. 1, 1983, discloses two types of water soluble cyclodextrin complexes of retinoid-polymers and complexes of retinoids with ether type derivatives of cyclodextrins.
U.S. Pat. No. 4,596,795, issued Jun. 24, 1986, discloses the administration of sex hormones, particularly testosterone, progesterone and estradiol in the form of their complexes or inclusions with specific derivatives of cyclodextrins by the sublingual or buccal route resulting in effective transfer of these hormones into the systemic circulation, followed by only gradual elimination. The derivatives of cyclodextrins must carry one or several substituents, each containing one or several hydroxy group. Specially preferred are the complexes of hydroxypropylbetacyclodextrin and poly-beta-cyclodextrin.
U.S. Pat. No. 4,727,064, issued Feb. 23, 1988, is directed to the method of conversion of drug compositions which themselves are crystalline and of low water-solubility into intrinsically amorphous complexes which have improved pharmaceutical properties. This conversion is achieved by inclusion of the above drug compositions into water-soluble, multi-component mixtures of cyclodextrin derivatives. The cyclodextrin derivatives which are used are hydroxypropyl-beta-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, etc.
U.S. Pat. No. 5,134,127, issued Jul. 28, 1992, discloses sulfoalkyl ether cyclodextrin derivatives and their use as solubilizing agents for water insoluble drugs for oral, intranasal or parenteral administration. It also discloses a pharmaceutical composition wherein a drug is complexed to a sulfobutylether-&bgr;-cyclodextrin. The drug is selected from the group consisting of amobarbital, ampicillin, aspirin, beclomethasone, benzocaine, testosterone, etc.
U.S. Pat. No. 5,376,645, issued Dec. 27, 1994, also discloses sulfoalkylether cyclodextrin derivatives and their use as solubilizing agents for water insoluble drugs for oral, intranasal or parenteral administration. It also discloses a composition wherein a drug is complexed to a sulfobutyl ether-&bgr;-cyclodextrin. The drugs used are identical to the drugs disclosed in U.S. Pat. No. 5,134,127.
Ras-farnesyltransferase inhibitors of the formula I
are potential anti-tumor agents having poor water-solubility and stability. Accordingly, ras-farnesyltransferase inhibitors which have improved water-solubility and stability would be a desirable addition to the anti-tumor field.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, a new ras-farnesyltransferase inhibitor complex or inclusion compound is provided which is formed of ras-farnesyltransferase inhibitors of formula I or their pharmaceutically acceptable salts
and a sulfobutylether-7-&bgr;-cyclodextrin or 2-hydroxypropyl-&bgr;-cyclodextrin. In formula I, n is 0 or 1; R
1
is Cl, Br, phenyl, pyridyl or cyano; R
2
is aralkyl; R
3
is lower alkyl, aryl, substituted aryl or heterocyclo; Z
1
is CO, SO
2
, CO
2
, SO
2
NR
5
wherein R
5
is hydrogen, lower alkyl or substituted alkyl.
The term “alkyl” refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression “lower alkyl” refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The term “substituted alkyl” refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. SO
2
NH
2
, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. CONH
2
, substituted carbamyl e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
The term “aralkyl” refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term “substituted aryl” refers to an aryl group substituted by, for example, one to four substituents such as alkyl, substituted alkyl, halo, trifluoromethoxy, t
Malloy Timothy M.
Raghavan Krishnaswamy S.
Varia Sailesh A.
Babcock Timothy J.
Bristol--Myers Squibb Company
Krass Frederick
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