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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

• This invention relates to biologically active vitamin D compounds, and more particularly to vitamin D compounds with hydrolyzable groups at one or more of the 1 , 3 and 25 carbon positions, such as esters of l ⁇ ,25-dihydroxyvitamin D 3 or esters of 1 ,25-dihydroxyvitamin D 3 analogs, and their use to regulate over time the function of l ,25(OH) 2 D 3 (or of l ,25(OH) 2 D 3 analogs) during the treatment of a variety of diseases such as osteoporosis, renal osteodystrophy, hypoparathyroidism or proliferative skin disorders.
• diseases such as osteoporosis, renal osteodystrophy, hypoparathyroidism or proliferative skin disorders.
• the l ⁇ -hydroxylated metabolites of vitamin D -- most importantly l ⁇ ,25-dihydroxyvitamin D 3 and l ⁇ ,25- dihydroxyvitamin D 2 -- are known as highly potent regulators of calcium homeostasis in animals and humans.
• D 3 as the active form of the vitamin has come an intense investigation of analogs of this hormonal form of vitamin D with the intent of finding analogs that have selective biological activity.
• many structural analogs of these metabolites such as compounds with different side chain structures, different hydroxylation patterns, or different stereo chemistry, have been prepared and tested.
• l ⁇ -hydroxyvitamin D3 l ⁇ -hydroxyvitamin D 3
• l -hydroxyvitamin D 2 various side chain fluorinated derivatives of l ⁇ ,25-dihydroxyvitamin D 3
• 19-nor-vitamin D compounds and side chain homologated analogs.
• Several of these known compounds exhibit highly potent activity in vivo or in vitro, and some of these have been found to exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity provides these compounds with advantageous therapeutic activity profiles and thus some of these compounds are in use, or have been proposed for use, in the treatment of variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
• osteoporosis Various forms of osteoporosis are known, e.g. , postmenopausal, senile and steroid-induced osteoporosis, one of the characteristics of which is the loss of bone mass.
• Females at the time of menopause suffer a marked loss of bone mass giving rise ultimately to osteopenia, which in turn gives rise to spontaneous crush fractures of the vertebrae and fractures of the long bones.
• This disease is generally known as postmenopausal osteoporosis and presents a major medical problem, both in the United States and most other countries where the life-span of females reaches ages of at least 60 and 70 years.
• the disease which is often accompanied by bone pain and decreased physical activity, is diagnosed by one or two vertebral crush fractures with evidence of diminished bone mass. It is known that this disease is accompanied by diminished ability to absorb calcium, decreased levels of sex hormones, especially estrogen and androgen, and a negative calcium balance.
• a conventional treatment is to administer a calcium supplement to the patient.
• calcium supplementation by itself has not been successful in preventing or curing the disease.
• Another conventional treatment is the injection of sex hormones, especially estrogen, which has been reported to be effective in preventing the rapid loss of bone mass experienced in postmenopausal women. This technique, however, has been complicated by the fear of its possible carcinogenicity.
• Other treatments for which variable results have been reported have included a combination of vitamin D in large doses, calcium and fluoride.
• Calcitriol treatment has also been found to be effective in reducing bone loss in women with postmenopausal osteoporosis by increasing intestinal calcium absorption and reducing bone resorption. Aloria et al, "Calcitriol In The Treatment Of Postmenopausal Osteoporosis", Amer. Jour, of Med., Vol.
• in vivo calcitriol is produced slowly and continuously by the kidney and thus is available throughout the day and night. When given by mouth or by injection, large amounts are available to the tissues initially but little is left after 2-4 hours due to metabolism and excretions.
• a process whereby calcitriol can be made available in vivo more slowly and more continuously would avoid peaks and valleys in the availability of calcitriol thereby providing an effective in vivo level of the compound over a more prolonged period of time and also avoiding or substantially reducing episodes of hypercalcemia that often result from the sudden availability of excessive amounts of the substance.
• the present invention provides a method for modulating and regulating the in vivo activity of biologically active vitamin D compounds, such as calcitriol or analogs of calcitriol. More specifically, this invention provides modified vitamin D compounds that exhibit a desirable and highly advantageous pattern of biological acitivity in vivo, namely, the more gradual onset and more prolonged duration of activity. As a consequence of such advantageous properties, these compounds represent novel therapeutic agents for the treatment of all diseases where vitamin D compounds have been shown effective, such as metabolic bone diseases or proliferative skin disorders (e.g.
• the modified vitamin D compounds having these desirable biological attributes are derivatives of l ⁇ ,25-dihydroxyvitamin D 3 , or derivatives of l ⁇ ,25-dihydroxyvitamin D 3 analogs, in which a hydrolyzable group is attached to the hydroxy group at carbon 25 and, optionally, to any other of the hydroxy groups present in the molecule.
• a hydrolyzable group is attached to the hydroxy group at carbon 25 and, optionally, to any other of the hydroxy groups present in the molecule.
• these derivatives are thought to hydrolyze to l ⁇ ,25-dihydroxyvitamin D 3 , or to a l ⁇ ,25-dihydroxyvitamin D 3 analog, at different rates in vivo, thus providing for the "slow release" of the biologically active vitamin D compound (i.e. 1 ,25-dihydroxyvitamin D 3 , or an analog thereof) in the body.
• the “slow release" in vivo activity profiles of such compounds can, of course, be further modulated by the use of mixtures of derivatives (e.g. mixtures of different derivatives of 1 ,25-dihydroxyvitamin D 3 , or different derivatives of 1 ,25- dihydroxyvitamin D 3 analogs) or the use of mixtures consisting of one or more vitamin D derivative together with underivatized vitamin D compounds.
• mixtures of derivatives e.g. mixtures of different derivatives of 1 ,25-dihydroxyvitamin D 3 , or different derivatives of 1 ,25- dihydroxyvitamin D 3 analogs
• mixtures consisting of one or more vitamin D derivative together with underivatized vitamin D compounds e.g. mixtures of different derivatives of 1 ,25-dihydroxyvitamin D 3 , or different derivatives of 1 ,25- dihydroxyvitamin D 3 analogs
• the critical structural feature of the vitamin derivatives identified above is the presence of a hydrolyzable group attached to the hydroxy group at carbon 25 of the molecule.
• a hydrolyzable group at that position imparts on the resulting derivatives the desirable "slow- release" biological activity profile mentioned above.
• Other hydroxy functions occurring in the molecule e.g. hydroxy functions at carbons 1 or 3 may be present as free hydroxy groups, or one or more of them may also be derivatived with a hydrolyzable group.
• the fact that the introduction of a hydrolyzable group at carbon 25 of the vitamin D molecule markedly modulates the in vivo biological activity pattern of the resulting derivative was not appreciated previously. The realization of the importance of this specific modification, and the demonstration of its marked and highly beneficial biological effects form the basis of this invention.
• the "hydrolyzable group" present in the above-mentioned derivatives is preferably an acyl group, i.e. a group of the type Q1CO-, where Q - represents hydrogen or a hydrocarbon radical of from 1 to 18 carbons that may be straight chain, cyclic, branched, saturated or unsaturated.
• the hydrocarbon radical may be a straight chain or branched alkyl group, or a straight chain or branched alkenyl group with one or more double bonds, or it may be an optionally substituted cycloalkyl or cycloalkenyl group, or an aromatic group, such as substituted or unsubstituted phenyl, benzyl or naphthyl.
• acyl groups are alkanoyl or alkenoyl groups, of which some typical examples are forrnyl, acetyl, propanoyl, hexanoyl, isobutyryl, 2-butenoyl, palmito i or oleoyl.
• Another suitable type of hydrolyzable group is the hydrocarbyloxycarbonyl group, i.e. a group of the type Q2-O-CO-, where Q 2 is a Ci to Ci ⁇ hydrocarbon radical as defined above.
• hydrocarbon radicals are methyl, ethyl, propyl, and higher straight chain or branched alkyl and alkenyl radicals, as well as aromatic hydrocarbon radicals such as phenyl or benzoyi.
• an especially important and preferred class are certain acyl ester derivatives of calcitriol, i.e. the calcitriol derivatives characterized by the following general structure:
• X 1 and X 2 independently represent hydrogen or an acyl group
• X3 represents an acyl group as previously defined.
• Two other very important groups of modified vitamin D compounds are the corresponding acyl esters of the calcitriol side chain homologs, and the acyl derivatives of the 19-nor- l,25- dihydroxyvitamin D analogs.
• the present invention therefore, provides a series of modified vitamin D compounds that are useful for the treatment of metabolic bone disease (such as the various forms of osteoporosis, osteomalacia, osteodystrophy, etc.) or of differentiative diseases such as psoriasis or malignancies. More specifically, a method of treating such diseases comprises the administration of an effective amount of the above-indicated acyl ester derivatives of l ⁇ ,25-dihydroxyvitamin D 3 or of the corresponding derivatives of l ⁇ ,25-dihydroxyvitamin D 3 analogs.
• the above compounds may be administered alone or in combination with other pharmaceutically acceptable agents. Dosages of from not less than about 0.5 ⁇ g per day to not more than about lO ⁇ g per day of the individual compound per se, or in combinations, are generally effective. This method has the distinct advantage that it will restore bone mass due to the conversion of these compounds to calcitriol which has been proven to be effective in the treatment of osteoporosis. Further, these compounds advantageously will be less likely to cause hypercalcemia or hypocalcemia then the underivatized compounds even if the compound is administered continuously on a daily basis, as long as the appropriate compounds and dosages are used, it being understood that the compounds and the dosage levels will be adjusted dependent upon the response of the subject as monitored by methods known to those skilled in the art.
• Fig. 1 is a graph illustrating the activity of di- and tri- acetates of D 3 on serum calcium, and particularly illustrates the milligrams percent calcium found in blood over time;
• Fig. 2 is a graph similar to Fig. 1 except illustrating the activity of a 25-mono-acetate of l ⁇ ,25-dihydroxyvitamin D 3 on serum calcium . Disclosure of the Invention
• the present invention provides novel modified vitamin D compounds which are useful in the treatment of metabolic bone diseases, such as osteoporosis, as well as other disease states.
• modified vitamin D compounds are hydrolyzable in vivo to calcitriol, or analogs of calcitriol, over a period of time following administration, and as a consequence regulate the in vivo availability of active calcitriol, or analogs of calcitriol, thereby also modulating their activity profile in vivo.
• the term "activity profile” refers to the biological response over time of vitamin D compounds such as calcitriol or analogs of calcitriol. Individual modified compounds, or mixtures of such compounds, can be administered to "fine tune" a desired time course of response.
• vitamin D compound encompasses compounds which have the C-ring, D-ring and 3 - hydroxycyclohexane A-ring of vitamin D interconnected by the 5,7 diene double bond system of vitamin D together with any side chain attached to the D-ring.
• the vitamin D compounds encompassed herein include those having a "vitamin D nucleus” comprising substituted or unsubstituted A-, C-, and D- rings interconnected by a 5, 7 diene double bond system typical of vitamin D together with a side chain attached to the D-ring.
• modified vitamin D compound encompasses any vitamin D compound in which one or more of the hydroxy functions present in such a compound are modified by derivatization with a hydrolyzable group.
• a “hydrolyzable group” is a hydroxy-modifying group that can be hydrolyzed in ⁇ i ⁇ o, so as to regenerate the free hydroxy functions.
• hydrolyzable group preferably includes acyl and hydrocarbyloxycarbonyl groups, i.e. groups of the type Q! CO- and Q 2 -O-CO, respectively, where Q 1 and Q 2 have the meaning defined earlier.
• modified vitamin D compounds encompassed may be represented by the formula:
• R5 and R6 each represent hydrogen, or taken together R5 and R 6 represent a methylene group.
• the side chain group R in the above-shown structure represents a steroid side chain of the structure below:
• Ri is selected from hydrogen, OX 4 , fluoro, trifluoromethyl, and C 1 - 5 - alkyl, which may be straight chain or branched and, optionally, bear a hydroxy substituent
• R 2 is selected from hydrogen, fluoro, trifluoromethyl and C 1 - 5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy substituent
• R 3 and R 4 independently represent trifluoromethyl or C 1 - 5 alkyl, which may be straight chain or branched and, optionally, bear a hydroxy substituent
• X- , X 2 and X 4 independently represent hydrogen, an acyl group or a hydrocarbyloxycarbonyl group, and X3 represents an acyl group or a hydrocarbyloxycarbonyl group, as previously defined herein.
• modified vitamin D compounds include calcitriol derivatives such as:
• Preparative thin layer chromotography (p. I.e.) was carried out with Merk 1-mm F-254 silica gel plates and E. Merk 0.25 mm F-254 silica gel plates.
• This example illustrates the serum calcium response of rats over time to three compounds, namely, l ⁇ ,25(OH) 2 D 3 -
• FIG. 1 is a graph illustrating the data of Table 1. Because calcium is present in the diet and hence their intestine, the rise in serum calcium largely represents intestinal calcium absorption.
• This example illustrates the serum calcium response of rats over time to two compounds, namely, l ⁇ ,25(OH) 2 D 3 (unesterified) and l ⁇ ,25(OH) 2 D 3 -25-acetate, administered by three different methods, namely, orally (oral), intramuscularly (I.M.), and subcutaneously (Sub. Cu.).
• Serum Calcium (mg/ 100 ml)
• modified vitamin D compound or combinations thereof can be readily administered as sterile parenteral solutions by injection or intravenously, or by alimentary canal in the form of oral dosages, or trans-dermally, or by suppository.
• Doses of from about 0.5 micrograms to about 10 micrograms per day or modified vitamin D compound per se, or in combination with other modified vitamin D compounds, the proportions of each of the compounds in the combination being dependent upon the particular disease state being addressed and the degree of bone mineralization and/or bone mobilization desired, are generally effective to practice the present invention. In all cases sufficient amounts of the compound should be used to restore bone mass.
• the higher doses are used where therapeutic treatment of a disease state is the desired end while the lower doses are generally used for prophylactic purposes, it being understood that the specific dosage administered in any given case will be adjusted in accordance with the specific compounds being administered, the disease to be treated, the condition of the subject and the other relevant medical facts that may modify the activity of the drug or the response of the subject, as is well known by those skilled in the art.
• either a single daily dose or divided daily dosages may be employed, as is well known in the art.
• Dosage forms of the various compounds can be prepared by combining them with non-toxic pharmaceutically acceptable carriers to make either immediate release or slow release formulations, as is well known in the art.
• suitable carriers may be either solid or liquid such as, for example, com starch, lactose, sucrose, peanut oil, olive oil, sesame oil and propylene glycol. If a solid carrier is used, the dosage form of the compounds may be tablets, capsules, powders, troches or lozenges. If a liquid carrier is used, soft gelatin capsules, or syrup or liquid suspensions, emulsions or solutions may be the dosage form.
• the dosage form may also contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, etc. They may also contain other therapeutically valuable substances.
• the modified vitamin D compounds may also include any of the following compounds in which one or more hydroxy functions that may be present are modified by derivatization with a group hydrolyzable in vivo.
• - P stands for hydrogen, alkyl or acyl
• 5 - X represents part of the side-chain of vitamin D or of one of its established analogues
• o - Y and V which may be the same or different, stand for hydrogen or alkyl or, when taken together, represent an alky ⁇ dene group, or form a carbocyclic ring
• o - W and W which may be the same or different, stand for hydrogen or alkyl or, when taken together, represent an alkylidene group, or form a carbocyclic ring
• one of the carbon atoms of the central part corresponding to positions 14, 13, 17 or 20, together with the R and R' substituents connected to it, may be 5 replaced by an oxygen (O), a sulfur (S) or a nitrogen bearing an R substituent (NR).
• R and R' i.e., R, R 1 r R 2 . R'2- R3. R ' 3. R4. ' , R ⁇ - R' ⁇ ) -
• lower alkyl group indicates a straight or branched saturated or unsaturated carbon chain containing from 1 to 7 carbon atoms
• “iower alkylidene group” indicates a straight or branched saturated or unsaturated carbon chain containing from 1 to 7 carbon atoms, which is connected to one of the main chain atoms 14, 13, 17 and/or 20 through a double bond.
• part of the side-chain of vitamin D or of one of its established analogues stands for a 2 to 15 carbon atom substituted alkyl chain especially as present in vitamin D2 (C-22 to C-28) or D3 (C-22 to C-27) or partially modified as shown below with the vitamin D numbering, especially :
• the ring can be saturated, unsaturated or aromatic and may optionally be substituted at any possible position(s) with the substituent mentioned above and/or - cyclized between the carbon atoms 26 and 27 by 1 to 4 atoms to form a heterocyclic ring, including aromatic, which may optionally be substituted at any possible pos ' rtion with the substituent mentioned above and/or
• these unsaturated chains may be substituted at any possible position by the substituents mentioned above and/or
• - epoxide function can be present between carbon atoms 22,23 or 23,24 or 24,25 or 25,26; these epoxidized chains can be saturated or unsaturated and may be substituted at any possible positions with the substituents mentioned above and/or
• the invention relates to a series of analogues with widely varying structures . Most often the compounds of the invention are represented by one of the formulas
• - Z represents a saturated or unsaturated hydrocarbon chain consisting of zero (hence Z represents a bond between two 1 ,3-related carbon atoms of the central chain), one, two, three or four atoms, which may all be substituted and/or replaced by a heteroatom such as oxygen, sulfur and nitrogen.
• R ' 5 o which may be the same or different, stand for hydrogen or lower alkyl, such as methyl, ethyl or n-propyl.
• - n is a ⁇ integer equal to 2 or 3;
• R2 R'2. R3. R'3. . R'4. 5 and R'5, which may be the same or different, stand for hydrogen or methyl.

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