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Definitions

• the present invention is directed to providing, preparing and using compounds which inhibit the enzyme cytochrome P450RAI. More particularly, the present invention is directed to selecting and preparing compounds which inhibit the enzyme cytochrome P450RAI, many of which are derivatives of phenylacetic or heteroarylacetic acid, and using said compounds for treatment of diseases and conditions which are normally treated by retinoids .
• retinoid-like activity Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals ofthe mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions.
• compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hype ⁇ roliferative disorders ofthe skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin.
• skin-related diseases including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hype ⁇ roliferative disorders ofthe skin, ec
• Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers ofthe breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas ofthe mucous membranes and in the treatment of Kaposi's sarcoma.
• premalignant and malignant hyperproliferative diseases such as cancers ofthe breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas ofthe mucous membranes and in the treatment of
• retinoid compounds can be used as agents to treat diseases ofthe eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other comeopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA).
• PVR proliferative vitreoretinopathy
• TPA tissue plasminogen activator
• retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil R , diseases associated with the immune system, including use ofthe present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rej ection and facilitation of wound healing, including modulation of chelosis.
• HPV human papilloma virus
• various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's
• Retinoid compounds have relatively recently been also discovered to be useful for treating type II non-insulin dependent diabetes mellitus (NIDDM).
• NIDDM non-insulin dependent diabetes mellitus
• Several compounds having retinoid-like activity are actually marketed under appropriate regulatory approvals in the United States of America and elsewhere as medicaments for the treatment of several diseases responsive to treatment with retinoids.
• Retinoic acid (RA) itself is a natural product, biosynthesized and present in a multitude of human and mammalian tissues and is known to play an important rule in the regulation of gene expression, tissue differentiation and other important biological processes in mammals including humans.
• a catabolic pathway in mammals, including humans, of natural retinoic acid includes a step of hydroxylation of RA catalyzed by the enzyme Cytochrome P450RAI (retinoic acid inducible).
• Cytochrome P450RAI retinoic acid inducible
• novel compounds of Formulas 1 through 8 are used as inhibitors of the enzyme cytochrome P450RAI to treat diseases and conditions which are normally responsible to treatment by retinoids, or which are prevented, treated, ameliorated, or the onset of which is delayed by administration of retinoid compounds or by the mammalian organism's naturally occurring retinoic acid. These novel compounds are shown by Formulas 1
• A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups;
• X is O, S or NR where is H, alkyl of 1 to 6 carbons or benzyl;
• Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
• Z is -C ⁇ C-, where
• A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, ftiryl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups;
• X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl; Z is -C ⁇ C-, where n' is an integer having the value 1 - 5,
• Rj is independently H or alkyl of 1 to 6 carbons;
• p is an integer having the values of 0 to 4;
• R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
• R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
• m is an integer having the values 0 to 4;
• R 5 is H, alkyl of 1 to 6 carbons, fluorosubstituted alkyl of 1 to 6 carbons, benzyl, or lower alkyl or halogen substituted benzyl;
• n is an integer having the values of 0 to 4, and
• A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, f ⁇ ryl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups;
• Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 1 to 6 carbons, Cl, Br, or I;
• Z is -C ⁇ C-, -(CR ⁇ CR !
• R j is independently H or alkyl of 1 to 6 carbons;
• p is an integer having the values of 0 to 5;
• R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
• R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
• m is
• A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups;
• X j is 1 -imidazolyl, or lower alkyl or halogen substituted 1 -imidazolyl, OR, SR, NRRg where R is H, alkyl of 1 to 6 carbons or benzyl; Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzy
• Z is -C ⁇ C-, where n' is an integer having the value 1 - 5,
• Rx is independently H or alkyl of 1 to 6 carbons
• R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons
• R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl
• m is an integer having the values 0 to 2
• 4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen
• o is an integer having the values of 0 to 4
• R 6 is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloal
• A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups;
• X is O, S or NR where R is H, alkyl of 1 to 6 carbons, C g-trialkylsilyl or benzyl;
• Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
• Ri is independently H or alkyl of 1 to 6 carbons;
• R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
• R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
• m is an integer having the values 0 to 3 ;
• R 7 is H
• A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups;
• X 2 is 1 -imidazolyl, lower alkyl or halogen substituted 1 -imidazolyl, OR 7 , SR 7 or NRR 7 where R is H, alkyl of 1 to 6 carbons or benzyl; Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substitute
• R j is independently H or alkyl of 1 to 6 carbons;
• R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
• R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
• m is an integer having the values 0 to 3;
• R 7 is H
• n is an integer having the values of 0 to 4
• R 8 is H, alkyl of 1 to 6 carbons, -CH 2 0(Ci. 6 -alkyl), or a cation of a pharmaceutically acceptable base.
• the novel compounds used in the method of treatment ofthe present invention are also shown in Formula 7
• A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups;
• Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, F, Cl, Br, or I;
• Z is -C ⁇ C-, where n' is an integer having the value 1 - 5, -CO-NR r , NR r CO-,
• A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups;
• X 3 is S, or O, C(R j ) 2 , or CO;
• Yj is H, lower alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, benzyl, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
• Z is -C ⁇ C-, where n' is an integer having the value 1 - 5
• R ! is independently H or alkyl of 1 to 6 carbons
• R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons
• R 3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl
• m is an integer having the values 0 to 2
• Y j is cycloalkyl, when Y 1 is not cycloalkyl then X 3 is O or S and n is 1 , when Y 1 is not cycloalkyl then X 3 is CO, and n is 1, when Y l is not cycloalkyl then X 3 is CO and the moiety A is substituted with at least one F group.
• novel compounds of Formula 1 through Formula 8 as well as the previously known compounds disclosed below in the specification are used for the prevention or treatment of diseases and conditions in mammals, including humans, those diseases or conditions that are prevented, treated, ameliorated, or the onset of which is delayed by administration of retinoid compounds or by the mammalian organism's naturally occurring retinoic acid. Because the compounds act as inhibitors of the breakdown of retinoic acid, the invention also relates to the use ofthe compounds of Formula 1 through Formula 8 in conjunction with retinoic acid or other retinoids.
• retionoids are useful for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders ofthe skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin.
• the retinoids are also useful for the prevention and treatment of metabolic diseases such as type II non- insulin dependent diabetes mellitus (NIDDM) and for prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers ofthe breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas ofthe mucous membranes and in the treatment of Kaposi's sarcoma.
• metabolic diseases such as type II non- insulin dependent diabetes mellitus (NIDDM)
• cancerous and precancerous conditions including, premalignant and malignant hyperproliferative diseases such as cancers ofthe breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, laryn
• Retinoids can also be used as agents to treat diseases ofthe eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other comeopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA).
• PVR proliferative vitreoretinopathy
• TPA tissue plasminogen activator
• retinoids include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil R , diseases associated with the immune system, including use ofthe present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rej ection and facilitation of wound healing, including modulation of chelosis.
• HPV human papilloma virus
• various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease
• This invention also relates to a pharmaceutical formulation
• a pharmaceutical formulation comprising one or more compounds of Formula 1 through Formula 8 or one or more of the previously known compounds disclosed below in the specification, in admixture with a pharmaceutically acceptable excipient, said formulation being adapted for administration to a mammal , including a human being, to treat or alleviate the conditions which were described above as treatable by retinoids, or which are controlled by or responsive to the organism's native retinoic acid.
• These formulations can also be co-administered with retinoids to enhance or prolong the effects of medications containing retinoids or ofthe organism's native retinoic acid.
• the present invention also relates to a method of providing a compound which is an inhibitor ofthe enzyme cytochrome P450RAI, wherein the method of providing the cytochrome P450RAI inhibitory compound comprises: identifying a compound that has activity as a retinoid in any ofthe art recognized assays which demonstrate retinoid-like activity, the retinoid compound having a formula such that it includes a benzoic acid, benzoic acid ester, naphthoic acid, naphthoic acid ester or heteroaryl carboxylic acid or ester moiety, with a partial structure of -A(R 2 )-(CH 2 ) n -COOR 8 where the symbols are defined as in Formulas 1 through 8, and where n is 0, and selecting a compound that is a homolog of the previously identified retinoid compound where in the formula of the homolog n is 1 or 2, preferably 1.
• Said homolog if it is not a previously known compound can be prepared by homologation procedures well known to the synthetic organic chemist, such as for example the well known Arndt-Eistert synthesis.
• said homologs can be prepared by any of the applicable synthetic processes illustrated below for the preparation of the novel compounds of Formulas 1 through 8 wherein the symbol n represents the integral 1 (one).
• BRIEF DESCRIPTION OF THE DRAWING FIGURE Figure 1 is a schematic representation ofthe P450RAI cell based assay utilized to evaluate the ability ofthe compounds ofthe invention to inhibit the Cytochrome P450RAI enzyme.
• Figure 1 shows a schematic diagram ofthe P450RAI-1 cell based assay.
• P45 ORAL 1 stably transfected HeLa cells are maintained in 100 millimolar tissue culture dishes in Modified Eagle's Medium (MEM) containing 10 % Fetal Bovine Serum (FBS) and 100 ⁇ g/ml hygromycin. Exponentially growing cells are harvested by incubating in trypsin.
• MEM Modified Eagle's Medium
• FBS Fetal Bovine Serum
• IC 50 values obtained in this assay for several previously known compounds the cythochrome P450RAI inhibitory activity of which has been discovered in accordance with the present invention are disclosed in Table 1A below.
• Assays of Retinoid-like or Retinoid Antagonist and Inverse Agonist-like Biological Activity Assays described below measure the ability of a compound to bind to, and/or activate various retinoid receptor subtypes. When in these assays a compound binds to a given receptor subtype and activates the transcription of a reporter gene through that subtype, then the compound is considered an agonist of that receptor subtype.
• a compound is considered an antagonist of a given receptor subtype if in the below described co-tranfection assays the compound does not cause significant transcriptional activation of the receptor regulated reporter gene, but nevertheless binds to the receptor with a K d value of less than approximately 1 micromolar.
• the ability ofthe compounds to bind to RAR ⁇ , RAR ⁇ , RAR ⁇ , RXR ⁇ , RXR ⁇ and RXR y receptors, and the ability or inability ofthe compounds to activate transcription of a reporter gene through these receptor subtypes can be tested.
• Table # refers to Table 2 through 9 provided below where the compound is identified with reference to a corresponding specific formula of Formulas 9 through 16.
• Table 1A below provides data similar to those provided in Table 1, for certain previously known compounds which have been discovered in accordance with the present invention to be useful as inhibitors of cytochrome P450RAI. These compounds are shown by Formula A through O and have compounds numbers 201 through 247. TABLE 1A
• TOPICAL SKT-N IRRITATION TESTS As is known the topical retinoid all-trans-retinoic acid (ATRA) and oral retinoids such as 13-cis RA and etretinate are known to induce substantial skin irritation in humans. This irritation is a direct result of activation of the RAR nuclear receptors. Analysis of retinoid topical irritation is also a highly reproducible method of determining in vivo retinoid potency.
• the SKH1- hrBR or hairless mouse provides a convenient animal model of topical irritation, since retinoid-induced skin flaking and abrasion can be readily scored by eye (Standeven et al, "Specific antagonist of retinoid toxicity in mice.” Toxicol. Appl.
• mice Female hairless mice (Crl:SKHl-ArBR), 5-7 weeks old, were obtained from Charles River Breeding Labs (Wilmington, MA). Animals were about 6 weeks old at the start ofthe experiments. Food (Purina Rodent Chow 5001) and reverse osmosis water were provided ad libitum. Mice were housed individually throughout the dosing period. In some experiments, mice that fit within a defined weight range, e.g. , 21 -25g, were selected from the available stock and then randomly assigned to the various treatment groups, using body weight as the randomization variable. The compounds to be tested were dissolved in acetone for application o the backs of the mice.
• mice were treated topically on the back in a volume of 4.0 ml/kg (0.07- 0.12ml) adjusted daily so as to deliver a fixed dose of test compound per g body weight. Doses are disclosed as nmol/25g. Unless indicated otherwise, mice were treated with retinoids once daily on days 1 through 5 and observed on days 2, 3, 4, 5, 6, 7 and 8. The mice were weighed daily and the dorsal skin was graded daily using separate semi-quantitative scales to determine flaking and abrasion. These flaking and abrasion scores were combined with weight change (if any) to create a cutaneous toxicity score (Blackjack score). Cutaneous Toxicity Score A visual grading scale was used for characterizing topical irritation on a daily basis. The grading scale used is as follows:
• Topical Toxicity Score The flaking and abrasion observations were combined with body weight observations to calculate a single, semiquantitative topical or cutaneous "toxicity score" as detailed below.
• the toxicity score also known as “blackjack score” since the theoretical maximum is 21) takes into account the maximal severity, and the time of onset of skin flaking and abrasions and the extent of weight between the first and last days ofthe experiment. Below are listed the seven numerical components ofthe toxicity score and an explanation of how those values are combined to calculate the toxicity score. 1. Flaking-Maximal Severity: Highest flaking score attained during observation period. 2.
• Flaking-Day of Onset of grade 2 or worse 0 - > 8 days 1 - day 8 2 - day 6 or 7 3 - day 4 or 5 4 - day 2 or 3 3.
• Flaking- Average Severity Flaking severity scores are summed and divided by the number of observation days. 4.
• Abrasion-Maximal Severity Highest abrasion score attained during observation period. 5.
• Abrasion- Average Severity Abrasion severity scores are summed and divided by the number of observation days . 7.
• Flaking onset score (2) and average severity score (3) are summed and divided by two. The quotient is added to the maximal severity score (1).
• Composite flaking scores are calculated for each individual animal in a group, averaged, and rounded to the nearest integer. Values can range from 0-9.
• Calculation of Composite Abrasion Score Abrasion onset score (5) and average severity score (6) are summed and divided by two. The quotient is added to the maximal severity score (4).
• Composite abrasion scores are calculated for each individual animal in a group, averaged and rounded to the nearest integer. Values can range from 0- 8.
• Toxicity Score Composite flaking score, composite abrasion score, and systemic toxicity score are summed to give the "toxicity score.” Toxicity scores are calculated for each individual animal in a group, averaged, and rounded to the nearest integer. Values can range from 0-21 and are expressed in Table IB below as the mean ⁇ SD ofthe values for a group. Calculation of Percentage Change in Body Weight The body weight at the time ofthe last weighing (day 8, 11, or 12) was subtracted from the initial body weight. The difference was divided by the initial body weight, multiplied by 100%>, and rounded to the nearest integer. Values were calculated for each individual animal and the mean and standard deviation for each group are shown. TABLE IB
• the compounds used in the methods of treatment of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and numerous other considerations.
• it will generally be preferred to administer the drug topically though in certain cases such as treatment of severe cystic acne or psoriasis, oral administration may also be used.
• Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, by Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania.
• the compounds could also be administered as a powder or spray, particularly in aerosol form.
• the drug may be confected as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration.
• the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.
• medicaments can be added to such topical formulation for such secondary pu ⁇ oses as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing infection, reducing irritation, inflammation and the like.
• Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds, or to control by naturally occurring retinoic acid will be effected by administration ofthe therapeutically effective dose of one or more compounds used in accordance with the instant invention.
• a therapeutic concentration will be that concentration which effects reduction ofthe particular condition, or retards its expansion.
• the compound potentially may be used in prophylactic manner to prevent onset of a particular condition.
• a useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per milliliter of formulation will constitute a therapeutically effective concentration for total application. If administered systemically, an amount between 0.01 and 5 mg per kg of body weight per day would be expected to effect a therapeutic result in the treatment of many diseases for which these compounds are useful.
• alkyl refers to and covers any and all groups which are known as normal alkyl and branched-chain alkyl. Unless specified otherwise, lower alkyl means the above-defined broad definition of alkyl groups having 1 to 6 carbons in case of normal lower alkyl, and 3 to 6 carbons for lower branch chained alkyl groups.
• a pharmaceutically acceptable salt may be prepared for any compound used in accordance with the invention having a functionality capable of forming a salt, for example an acid functionality.
• a pharmaceutically acceptable salt is any salt which retains the activity ofthe parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
• Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium.
• Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules.
• salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri- acid may also be used. Some compounds used in accordance with the present invention may have trans and cis (E and Z) isomers.
• a bond drawn with a wavy line indicates that the carbon to which the bond is attached can be in any ofthe applicable possible configurations.
• General Synthetic Methodology The novel compounds used in accordance with the invention are encompassed by the general Formulas 1 through 8 provided above.
• the previously known compounds the cytochrome P450RAI activity of which has been discovered in accordance with the present invention are identified below, and references are provided which enable their preparation by one of ordinary skill in the art of synthetic organic chemistry.
• a linker or tethering group designated Z covalently connects an aromatic or heteroaromatic moiety designated A(R 2 )-(CH 2 ) n -COOR 8 and another cyclic moiety which in accordance with these formulas is a substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety.
• the group X 4 represents a reactive group, which is suitable for coupling the X 4 .A(R 2 )-(CH 2 ) n -COOR 8 compound to a derivative ofthe substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety so that as a result ofthe coupling the linker or tether moiety Z is formed.
• the group X 4 is a leaving group such as halogen, or trifluoromethanesulfonyloxy, or a group capable of participating in a Wittig or Homer Emmons reaction.
• the group X 4 is an ethynyl group capable of undergoing a coupling reaction with a leaving group (such as a halogen or a trifluoromethanesulfonyloxy group) attached to the substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety.
• a leaving group such as a halogen or a trifluoromethanesulfonyloxy group
• the group X 4 can also represent an OH or an NH 2 group that forms an ester (COO) or amide (CONH) linker, respectively, when reacted with an activated carboxyl derivative ofthe substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety.
• Examples for the compounds of formula X 4 A(R 2 )-(CH 2 ) n -COOR 8 are provided in the specific examples below.
• X 4 group is halogen
• ethyl 4-iodobenzoate ethyl 6-iodonicotinate, ethyl 5-iodoruran-3 -carboxylate, ethyl 5-iodothio ⁇ hen-3-earboxylate, ethyl 5-iodofuran-2-carboxylate, ethyl 5- iodothiophen-2-carboxylate, and analogous halogenated derivatives ofthe respective pyridazine, pyrazine and other heteroaryl carboxylic acid esters.
• analogous aryl and and heteroaryl hydroxyl compounds and amines wherein the halogen ofthe above-listed compounds is replaced by OH or NH 2 respectively, also serve as additional examples for the reagents ofthe formula X 4 -A(R 2 )-(CH 2 ) ⁇ -COOR 8 .
• X 4 is OH or NH 2 , respectively.
• a derivative ofthe substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety is synthesized first, having a covalently attached X 5 group.
• the X s group reacts with the X 4 group of the reagent X 4 -A(R 2 )-(CH 2 ) n -COOR 8 to form the linker designated Z in Formulas 1 through 8.
• the X 5 group is one that is capable of participating in a catalyzed coupling reaction, (such as an ethynyl group when X 4 is a leaving group), or a leaving group (such as halogen or trifluoromethanesulfonyloxy when X 4 is an ethynyl group) , or an activated carboxylic acid function (when X 4 is OH or NH 2 ).
• the X 5 group can also be an OH, SH or NH 2 group when the X 4 group is an activated carboxylic acid function.
• substituted phenyl substituted tetrahydronaphthalene
• substituted chroman substituted thiochroman
• tetrahydroquinoline substituted thiochroman
• tetrahydroquinoline substituted thiochroman
• tetrahydroisoquinoline intermediates having an X 5 functionality are provided below, and are also available in the chemical scientific and patent literature.
• the substituted phenyl, tetrahydronaphthalene, chroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety ofthe novel compounds used in accordance with the invention are derivatized in a manner to include the specific substituents (such as for example the cycloalkyl substituents) encompassed within the scope ofthe invention, either before or after the - A(R 2 )-(CH 2 ) n -COOR 8 moiety has been attached and the linker Z has formed, as illustrated by the below described specific examples.
• the -(CH 2 ) n -COOR 8 moiety ofthe compounds of Formulas 1 through 8 can be modified in order to obtain still further novel compounds.
• One such modification is saponification of compounds where the R 8 group is an alkyl or -CH 2 0(C 1 . 6 -alkyl) group.
• Another modification is esterification of the carboxylic acid function when the R 8 group is H or a cation.
• Such saponification and esterification reactions are well known in the art and within the skill ofthe practicing organic chemist.
• Still another modification ofthe compounds used in accordance with the invention (or of the intermediates X 4 - A(R 2 )-(CH 2 ) n -COOR 8 , or of precursors to these intermediates) is the homologation ofthe (CH 2 ) n group.
• the synthetic procedure of homologation that may be utilized for providing a compound having the partial structure of -A(R 2 )-(CH 2 ) n -COOR 8 where n is 1, or 2 (one or two), preferably 1 (one), can be one of the several known procedures of homologation of carboxylic acids or esters, such as the Arndt-Eistert procedure that is described inter alia in March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, pages 809-810, McGraw-Hill Publishers, 1968, inco ⁇ orated herein by reference.
• the homologs ofthe partial structure of -A(R 2 )-(CH 2 ) complicat-COOR 8 are synthesized in accordance with the synthetic schemes disclosed herein in connection with the preparation of the novel compounds .
• SPECIFIC EMBODIMENTS With reference to the symbol A in Formulas 1 through 8, the preferred novel compounds used in accordance with the present invention are those where A is phenyl, naphthyl, pyridyl, thienyl or furyl. Even more preferred are compounds where A is phenyl. As far as substitutions on the A (phenyl) and A (pyridyl) groups are concerned, compounds are preferred where the phenyl group is 1,4 (para) substituted and where the pyridine ring is 2,5 substituted.
• R 8 group H lower alkyl of 1 to 3 carbons, and -CH 2 0(C 1 . 6 -alkyl) groups are preferred, as well as the pharmaceutically acceptable salts ofthe free acids when R 8 is H.
• the lower alkyl and -CH 2 0(C 1 . 6 -alkyl) groups ethyl and OCH 2 CH 3 , respectively, are presently most preferred.
• the linker Z is attached to the 6 position in Formula 1, to the 4 position in Formula 2, to the 6 position in Formula 3, to the 6 position in Formula 4, to the 4 position in Formula 5, to the 4 position in Formula 6, to the 6 position in Formula 7, and to the 6 position in Formula 8.
• the Rj group substituting the non-aromatic rings in Formulas 1, 3, 4, 7 and 8 is preferably alkyl, more preferably alkyl of 1 to 3 carbons, and most preferably methyl.
• the R x group substituting the cyclopropane ring in Formulas 1, 2, 3 and 7 is preferably non-existent (p is 0), or is alkyl of 1 to 3 carbons, even more preferably methyl.
• the X group in Formulas 1 and 5 is preferably O, and in Formula 2 X is preferably O or NR.
• the Xj group in Formula 4 is preferably 1 -imidazolyl, substituted 1- imidazolyl, or NRR 6 , where R 6 is preferably cyclopropyl or branched-chain alkyl.
• the X 2 group in Formula 6 is preferably 1 -imidazolyl or substituted 1 -imidazolyl.
• the Y group is preferably H, lower alkyl of 1 to 3 carbons, cycloalkyl, lower alkyl substituted cycloalkyl, or halogen. Among these, H, Cl, and cyclopropyl are most preferred.
• the Y j group of Formula 8 is preferably H, lower alkyl of 1 to 3 carbons, cycloalkyl, or lower alkyl substituted cycloalkyl. Among these H, ethyl and cyclopropyl are presently most preferred.
• the most preferred novel compounds used in accordance with the invention are disclosed in Tables 2 through 9 with reference to Formulas 9 through 16.
• the preferred compounds shown in Table 3 with reference to the more specific Formula 10 are within the scope of Formula 2; the preferred compounds shown in Table 4 with reference to the more specific Formula 11 are within the scope of Formula 3; the preferred compounds shown in Table 5 with reference to the more specific Formula 12 are within the scope of Formula 4; the preferred compounds shown in Table 6 with reference to the more specific Formula 13 are within the scope of Formula 5; the preferred compounds shown in Table 7 with reference to the more specific Formula 14 are within the scope of Formula 6; the preferred compounds shown in Table 8 with reference to the more specific Formula 15 are within the scope of Formula 7, and the preferred compounds shown in Table 9 with reference to the more specific Formula 16 are within the scope of Formula 8.
• the compounds used in accordance with the invention can be synthesized by applying the general synthetic methodology described above, and by such modifications of the hereinafter described specific synthetic routes which will become readily apparent to the practicing synthetic organic chemist in light of this disclosure and in view of general knowledge available in the art.
• the hereinafter disclosed specific reaction schemes are directed to the synthesis of exemplary and preferred compounds used in accordance with the invention. Whereas each ofthe specific and exemplary synthetic routes shown in these schemes may describe specific compounds only within the scope of one or two ofthe general Formulas 1 through 8, the synthetic processes and methods used therein are adaptable within the skill ofthe practicing organic chemist and can be used with such adaptation for the synthesis of compounds used in accordance with the invention which are not specifically described herein as examples.
• Reaction Scheme 1 discloses a presently preferred synthetic route to certain intermediates or reagents having the general formula X 4 -A(R 2 )-CH 2 ) n - COOR 8 , where the symbol A represents a di-, or tri-substituted phenyl moiety. These intermediates are utilized in the synthesis ofthe novel compounds used in accordance with the invention.
• Reaction Scheme 3 discloses presently preferred synthetic routes to obtain exemplary and preferred novel tetrahydronaphthalene compounds within the scope of Formula 4 where X j represents a dialkyl substituted nitrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• Reaction Scheme 4 discloses presently preferred synthetic routes to obtain exemplary and preferred novel isoquinoline compounds within the scope of Formula 3 where the symbol Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• Reaction Scheme 5 discloses presently preferred synthetic routes to obtain exemplary and preferred novel chroman compounds within the scope of Formula 8 where the symbol Yj represents hydrogen, Z is an ethynyl moiety or an ester (COO) fimction, and A is a substituted phenyl moiety.
• TPAP tetrarn-propyl ammonium peruthenate
• Reaction Scheme 6 discloses presently preferred synthetic routes to obtain other exemplary and preferred novel chroman compounds within the scope ofFormula 8 where the symbol Y x represents a cyclopropyl group, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• Reaction Scheme 7 discloses presently preferred synthetic routes to obtain exemplary and preferred novel chroman compounds within the scope of Formula 1 where the symbol X represents oxygen (O), Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• Reaction Scheme 8 discloses presently preferred synthetic routes to obtain other exemplary and preferred novel chroman compounds within the scope ofFormula 1 where the symbol X represents oxygen (O), Y represents a cyclopropyl group, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• Reaction Scheme 9 discloses presently preferred synthetic routes to obtain exemplary and preferred novel tetrahydroquinoline compounds within the scope ofFormula 1 where the symbol X represents an alkyl substituted nitrogen (alkyl-N), Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• Reaction Schemes 10 and 11 disclose presently preferred synthetic routes to obtain exemplary and preferred novel phenyl compounds within the scope of Formula 2 where the symbol X represents oxygen (O), Rg is alkyl or benzyl, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• Reaction Scheme 12 discloses presently preferred synthetic routes to obtain exemplary and preferred novel phenyl compounds within the scope of Formula 2 where the symbol Rs-X represents an alkyl, dialkyl, benzyl or dibenzyl substituted nitrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• Reaction Schemes 13 and 14 disclose presently preferred synthetic routes to obtain exemplary and preferred novel phenyl compounds within the scope ofFormula 6 where the symbol X 2 represents a (1 -imidazolyl) moiety, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• R i-propyl intermediate 97
• R i-propyl intermediate 104
• R t-butyl intermediate 106
• R t-butyl
• TBS t-butyldimethylsilyl
• Reaction Scheme 16 discloses presently preferred synthetic routes to obtain exemplary and preferred novel tetrahydronaphthalene compounds within the scope ofFormula 4 where the symbol X x represents a (1- imidazolyl) moiety, Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• Reaction Scheme 17 discloses presently preferred synthetic routes to obtain exemplary and preferred novel phenyl compounds within the scope of Formula 6 where the symbol X 2 represents a 1-methyl-cyclopropoxy moiety, Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• Reaction Scheme 18 discloses presently preferred synthetic routes to obtain exemplary and preferred novel phenyl compounds within the scope of Formula 5 where the symbol X represents oxygen (O), Y represents a tertiar -buty ] group, Z is an ethynyl moiety and A is a substituted phenyl moiety.
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C 1 . 6 -alkyl), or a cation of a pharmaceutically acceptable base, and where the other variables have the following specific values:
• Compound 201 is described as compound 4 in United States Patent No. 4,980,369 inco ⁇ orated herein by reference.
• Compounds 202, 210, and 215 are described in United States Patent No. 4,810,804 inco ⁇ orated herein by reference.
• Compound 215 is example 12 of Patent No. ,4810,804.
• Compound 238 is described in United States Patent No. 5,089,509 inco ⁇ orated herein by reference (see Claim 5 of Patent No. 5,089,509).
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C 1 . 6 -alkyl), or a cation of a pharmaceutically acceptable base.
• R 8 is H or a cation of a pharmaceutically acceptable base.
• Compound 240 is described and can be made in accordance with the teachings of United States Patent Nos. 5,089,509, ,5,602,130 or 5,348,972 all of which are inco ⁇ orated herein by reference.
• Still other known compounds which have been discovered in accordance with the present invention to be useful as inhibitors of cytochrome P450RAI are shown by Formula C where R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C 1 . 6 -alkyl), or a cation of a pharmaceutically acceptable base, and where the other variables have the following specific values:
• R 10 CH 3j
• R ⁇ CF 3
• R 12 F
• X 6 CH.
• Compound 206 R 8 is H or a cation of a pharmaceutically acceptable base
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 10 CH 3j
• n CH 3j
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 10 CH 3>
• R ⁇ Cl
• R 12 F
• X 6 N.
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 10 CH 3
• R ⁇ H
• R 10 CH 3
• R 10 CH 3
• R n CF 3 CF 2
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 10 CH 3
• R n CF 3 CF 2
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 10 CH 3)
• R ⁇ CH 3 CH 2
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 10 F and X 6 CH
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 10 CH 3j
• X 6 CH.
• Compounds 203 - 206, 220, 221, 224 - 228 and 247 - 254 are described and can be made in accordance with the teachings of United States Patent No. 5,675,024 which is inco ⁇ orated herein by reference.
• Compound 205 is compound or example 14
• Compound 225 is compound or example 10
• Compound 228 is compound or example 32 in Patent No. 5,675,024.
• Compound 220 is also described in United States Patent No. 5,965,606, inco ⁇ orated herein by reference.
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C 1 . 6 -alkyl), or a cation of a pharmaceutically acceptable base, and where the other variables have the following specific values:
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 12 H
• R 14 CH 3 .
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 12 H
• R 12 F
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 12 H
• Compound 207 is described (as compound 7) in United States Patent No. 5,489,584 inco ⁇ orated herein by reference.
• Compound 232 is described (as compound 42) in United States Patent No.
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C ⁇ 6 -alkyl), or a cation of a pharmaceutically acceptable base, and where the other variables have the following specific values:
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 12 H
• R 15 tertiary-butyl
• R 16 OH
• R 17 Cl
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 12 H
• R 15 tertiary-butyl
• R 16 OCH 3
• R 17 tertiary-butyl
• R 12 H
• R 15 1-adamantyl
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 12 H
• R 15 tertiary-butyl
• R 16 OH
• R 17 tertiary-butyl
• R 12 F
• R 15 tertiary-butyl
• R 16 OH
• R 17 H.
• Compound 211 is described and can be made in accordance with the teachings of United States Patent No. 5,202,471
• Compound 235 is described and can be made in accordance with the teachings of United States Patent No. 5,498,795. The specification of Patent Nos.
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 12 F
• R 15 tertz ⁇ ry-butyl
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 12 F
• R 15 tertiary-butyl
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 ⁇ (C ⁇ 6 -alkyl), or a cation of a pharmaceutically acceptable base, and where the other variables have the following specific values:
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 8 is H or a cation of a pharmaceutically acceptable base
• R 8 is H or a cation of a pharmaceutically acceptable base
• Compounds 217 is described (as example or compound 4) and can be made in accordance with the teachings of United States Patent Nos. 4,739,098 the specification of which is inco ⁇ orated herein by reference.
• Compounds 219 is described (as compound 2) and can be made in accordance with the teachings of United States Patent Nos. 5,688,957, the specification of which is inco ⁇ orated herein by reference.
• Compound 212 and Compound 229 can be made in accordance with the teachings of United States Patent Nos. 4,739,098 and in case of Compound 212 also in accordance with United States Patent No. 5,426,118, with such modifications ofthe synthetic procedures which will be readily apparent to those skilled in the art.
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C 1 - 6 -alkyl), or a cation of a pharmaceutically acceptable base.
• R 8 is H or a cation of a pharmaceutically acceptable base.
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C 1 . 6 -alkyl), or a cation of a pharmaceutically acceptable base.
• R 8 is H or a cation of a pharmaceutically acceptable base.
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C ⁇ 6 -alkyl), or a cation of a pharmaceutically acceptable base, and where the other variables have the following specific values:
• R 8 is H or a cation of a pharmaceutically acceptable base
• Compounds 237 and 246 are described and can be made in accordance with the teachings of United States Patent Nos. 5,675,024 and 5,856,490.
• Compound 237 is compound or example 2 of Patent No. 5,675,024.
• the specification of United States Patent No. 5,856,490 is inco ⁇ orated herein by reference.
• Additional known compounds which have been discovered in accordance with the present invention to be useful as inhibitors of cytochrome P450RAI are shown by Formula K where R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C
• R 8 is H or a cation of a pharmaceutically acceptable base.
• Compound 231 is described (as compound 2) in United States Patent No , 5,006,550, the specification of which is inco ⁇ orated herein by reference.
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C 1 . 6 -alkyl), or a cation of a pharmaceutically acceptable base.
• R 8 is H or a cation of a pharmaceutically acceptable base.
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C 1 . 6 -alkyl), or a cation of a pharmaceutically acceptable base, and where the other variables have the following specific values:
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C I . 6 -alkyl), or a cation of a pharmaceutically acceptable base.
• R 8 is H or a cation of a pharmaceutically acceptable base.
• R 8 generally represents H, alkyl of 1 to 6 carbons, -CH 2 0(C 1 . 6 -alkyl), or a cation of a pharmaceutically acceptable base.
• R 8 is H or a cation of a pharmaceutically acceptable base.
• Compound 247 is described in the publication by Winum et al. II Farmaco, 1997, Vol. 52, 1, ⁇ 39-42, inco ⁇ orated herein by reference.
• the P450RAI inhibition data of this compound are provided in Table 1A, and the cutaneous toxicity score (blackjack score) ofthe compound in the topical skin irritation tests provided above, are disclosed in Table IB.
• Methyl-2-fluoro-4-iodo benzoate (Reagent G) A solution of 2-fluoro-4-iodo toluene (5g, 26.6mmol) in pyridine (2mL) and water (20mL) was treated with potassium permanganate (16.6g, 105mmol) and heated at 150°C overnight. The reaction mixture was then cooled to room temperature and filtered and the filtrate was extracted with hexane. The aqueous phase was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo.
• Ethyl-2-fluoro-4-trifluoromethylsulfonyloxy-benzoate (Intermediate 6)
• a stirred, cooled (ice bath) solution of ethyl-2-fluoro-4-hydroxy- benzoate (Intermediate 5, 0.368g, 2mmol) and 2,6-di-tert-butyl-4-methyl- pyridine (0.81 g, 8mmol) in 8mL of dichloromethane was treated with trifluoromethanesulfonic anhydride (O.lg, 4mmol). The reaction mixture was allowed to warm to ambient temperature and stirred overnight.
• Ethyl-2-fluoro-4-trimethylsilanylethynyl-benzoate (Intermediate 7)
• a solution of ethyl-2-fluoro-4- trifluoromethylsulfonyloxy-benzoate (Intermediate 6, 1.82g, 6mmol) in triethyl amine (12mL) and anhydrous tetrahydrofuran (30mL) was treated with copper(I)iodide (0.12g, 0.6mmol) and sparged with argon.
• GENERAL PROCEDURE A 7-Methoxy- 1.1 -dimethyl- 1.2.3.4- tetrahydronaphthalene (Intermediate 8)
• IM titanium tetrachloride
• IM dimethyl zinc
• 2M dimethyl zinc
• 5mL a solution of 7-methoxy- 1 - tetralone (1.76g, lOrnmol) in anhydrous dichloromethane (5mL) was cannulated into the reaction mixture and the resulting solution was allowed to warm to ambient temperature and stirred overnight.
• reaction mixture was then cooled to -40°C and cautiously quenched with methanol (1 lmL). It was diluted with dichloromethane and saturated aqueous ammonium chloride solution. The phases were separated and the aqueous phase was extracted with dichloromethane (x2mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to the title compound (1.75g, 92%) as an oil.
• GENERAL PROCEDURE B 6-Methoxy-4.4-dimethyl-1.2.3.4- tetrahydronaphthalene- 1 -one (Intermediate 9)
• a solution of 7-methoxy- 1 , 1 -dimethyl- 1 ,2,3 ,4-tetrahydronaphthalene (Intermediate 8, 1.65g, 8.7 mmol) in 7.5mL of glacial acetic acid was cooled to 0°C and treated with a solution of chromium trioxide (2g, 20mmol) in 8mL of acetic acid and 7mL of water. The reaction mixture was then allowed to warm to ambient temperature and stirred overnight. It was diluted with water and extracted with diethyl ether (x2).
• 6-Hydroxy-4.4-dimethyl- 1.2.3.4-tetrahvdronaphthalene- 1 -one (Intermediate 10)
• a stirred, cooled (-78°C) solution of 6-methoxy-4,4-dimethyl-l ,2,3,4- tetrahydronaphthalene- 1 -one (Intermediate 9, 0.8, 3mmol) under argon was treated with a IM solution of boron tribromide (lOmL).
• the reaction mixture was allowed to warm to ambient temperature and stirred overnight.
• the reaction mixture was cooled to -78°C, quenched and diluted with saturated aqueous sodium bicarbonate solution and the aqueous phase was extracted with dichloromethane (x2).
• GENERAL PROCEDURE C 4.4-Dimethyl-6-trifluoromethylsulfonyloxy- 1.2.3.4-tetrahvdronaphthalene- 1 -one (Intermediate 11)
• GENERAL PROCEDURE D 4.4-Dimethyl-6-trimethylsilanyl-ethvnyl- 1,2.3.4-tetrahydronaphthalene-l-one (Intermediate 12)
• Trimethylsilyl acetylene (0.85mL, 6mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (0.25g, 0.36mmol).
• the resulting reaction mixture was heated at 70°C for 17h. It was then cooled to ambient temperature, diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound (0.28g, 72%).
• GENERAL PROCEDURE E 6-Ethynyl-4.4-dimethyl- 1.2.3.4- tetrahydronphthalene- 1 -one (Intermediate 13)
• a solution of 4,4-dimethyl-6-frimethylsilanylethynyl- 1 ,2 ,3 ,4- tetrahydronaphthalene-1-one (Intermediate 12, 0.28g, 1.03mmol) in methanol (lOmL) was treated with potassium carbonate (0.74g, 5.35mmol) and stirred at ambient temperature for 4h. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with diethyl ether (x2).
• GENERAL PROCEDURE F 4-(8.8-Dimethyl-5-oxo-5.6.7.8-tetrahvdro- naphthalene-2-yl-ethynyl)-benzoic acid ethyl ester (Intermediate 14)
• a solution of 6-ethynyl-4,4-dimethyl- 1 ,2,3 ,4-tetrahydronaphthalene- 1 - one (Intermediate 13, 0.23g, l.lmmol) and ethyl-4-iodo benzoate (Reagent A, 0.36g, 1.3mmol) in triethyl amine (7mL) and anhydrous tetrahydrofuran (3mL) was treated with copper(I)iodide (0.114g, 0.6mmol) and sparged with argon for 5 minutes.
• GENERAL PROCEDURE I 4-[f5-Cyclopropyl-methyl-aminoV8.8-dimethyl- 5.6.7.8-tetrahydro-naphthalene-2yl-ethynyl1-benzoic acid (Compound 3, General Formula 4)
• a solution of 4-[(5-cyclopropyl-methyl-amino)-8,8- dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-benzoic acid ethyl ester (Compound 2, 0.065g, 0.158mmol) in ethanol (ImL) and tetrahydrofuran (ImL) was treated with IM aqueous sodium hydroxide solution (ImL) and heated at 80°C for lh.
• GENERAL PROCEDURE J 4-[f8.8-Dimethyl-5-oxo-5.6.7.8-tetrahvdro- na ⁇ hthalene-2-yl-ethynv - ⁇ henyl]-acetic acid (Compound 5, General Formula 8)
• a solution of 4-[(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-na ⁇ hthalene- 2-ylethynyl)-phenyl]-acetic acid methyl ester (Compound 4, 0.1 g, 0.28mmol) in a mixture of methanol (2mL), tetrahydrofuran (3.5mL) and water (1.5mL) was treated with lithium hydroxide monohydrate (0.1 lg, 2.62mmol) and the resulting reaction mixture was stirred at ambient temperature for 3h.
• GENERAL PROCEDURE K 8.8-Dimethyl-5.6.7.8-tetrahydro-naphthalene-l- one-2-carboxylic acid-4-( ⁇ ert-butoxycarbonylmethyDphenyl ester Compound 19, General Formula 8)
• a solution of 4,4-dimethyl-6-trifluoromethylsulfonyloxy- 1 ,2,3 ,4- tetrahydronaphthalene- 1 -one (Intermediate 11, 0.14g, 0.434mmol), t-butyl-4- hydroxy-phenyl acetate (Reagent E, 0.14g, 0.673mmol), palladium acetate (0.054g, 0.24mmol) and l,3-bis(diphenyl ⁇ hos ⁇ hino)propane (0.082g, 0.2mmol) in a mixture of dimethylsulfoxide (ImL), 1,2-dichloroethane (1.5mL) and triethyl amine (
• 6-Methoxy-4,4-dimethyl- 1.2.3.4-tetrahvdro-isoquinoline (Intermediate 18)
• a solution of 6-methoxy-4,4-dimethyl- 1 ,2,3 ,4-tetrahydro-isoquinoline- 1-one (Intermediate 17, 3.5g, 17mmol) in lOOmL of anhydrous tetrahydrofuran was treated with lithium aluminum hydride (1.3g, 34.25mmol) in small portions and the resulting suspension was refluxed for 3 hours under argon.
• reaction mixture was then cooled in an ice bath and cautiously quenched with saturated aqueous sodium sulfate solution and the resulting slurry was filtered and the filter-cake washed well with ethyl acetate.
• the filtrate and washings were evaporated in vacuo to a brown oil which was dissolved in chloroform, the solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (3.2g, -100%).
• 6-Methoxy-4.4-dimethyl- 1.2.3.4-tetrahydro-isoquinoline-2-carbaldehvde (Intermediate 19)
• a solution of 6-methoxy-4,4-dimethyl- 1 ,2,3 ,4-tetrahydro-isoquinoline (Intermediate 18, 3.2g, 16.7mmol) in anhydrous dichloromethane (40mL) was treated with formic acid (ImL, 26.5mmol) followed l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.9g, 20.34mmol) and the resulting solution was stirred at ambient temperature overnight.
• 6-Hydroxy-4.4-dimethyl- 1.2.3 ⁇ 4-tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 20) A stirred, cooled (-78°C) solution of 6-methoxy-4,4- dimethyl- 1,2, 3, 4-tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 19, 3.26g, 15mmol) in anhydrous dichloromethane (15mL) was treated with IM solution of boron tribromide in dichloromethane (50mL) stirred at ambient temperature for 3h.
• reaction mixture was allowed to warm to -20°C over 1.5h, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as an oil (O.lg, 94%).
• GENERAL PROCEDURE L [4-f2.2.4.4-Tetiamethyl-chroman-6-yl-ethvnyr) phenyl] acetic acid (Compound 28, General Formula 8)
• 6-Bromo-4.4-dimethyl-chroman-2-one A solution of 3-methyl-but-2-enoic acid 4-bromo-phenyl ester (7g, 27.6mmol) in anhydrous dichloromethane (200mL) was cooled (ice bath) and treated with aluminum chloride (6.6g, 49.6mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with diethyl ether (x2).
• 6-Bromo-2.2.4.4-tetramethyl-chroman A solution of 4-bromo-2-(3-hydroxy- 1 , 1 ,3-trimethyl-butyl)-phenol (l .lg, 3.92mmol) and ⁇ -toluene sulfonic acid (0.744g, 3.92mmol) in benzene (20mL) was refluxed overnight. The reaction mixture cooled to ambient temperature, filtered on silica gel and washed with 10% ethyl acetate in hexane.
• GENERAL PROCEDURE M 6-Bromo-2.2.4.4-tetramethyl-chroman-8- carbaldehyde (Intermediate 30)
• a stirred, cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethyl chroman, (0.5g, 1.865mmol) in anhydrous dichloromethane (5mL) was treated with a IM solution (1.86mL, 1.86mmol) of titanium tetrachloride in dichloromethane followed by ⁇ , ⁇ -dichloro methyl ether (0.214g, 1.865mmol) .
• the reaction mixture was allowed to warm to ambient temperature for 4h.
• GENERAL PROCEDURE N 6-Bromo-8-vinyl -2.2.4.4-tetramethyl- chroman (Intermediate 31)
• a solution of methylidene triphenyl phosphorane [generated from methyl triphenylphosphonium bromide (7g, 20mmol) and (11.8mL, 19mmol) of a 1.6M solution of n-butyl lithium in hexanes ] was added 6-bromo-2,2,4,4- tetramethyl chroman- 8-carbaldehyde (Intermediate 30, 0.52g, 1.75mmol).
• GENERAL PROCEDURE O 6-Bromo-8-cvclopropyl-2.2.4.4-tetramethyl chroman (Intermediate 32) A stirred, cooled (-30°C) solution of 6-bromo-8-vinyl-2,2,4,4- tetramethyl chroman (Intermediate 31, 0.37g, 1.26mmol) in diethyl ether was treated with a solution of diazomethane in diethyl ether and catalytic amount of palladium (I ⁇ )acetate ( ⁇ 30mg).
• GENERAL PROCEDURE P 6-Bromo-4.4-dimethyl-2-methylene chroman (Intermediate 35)
• a stirred, cooled (ice bath) solution of 6-bromo-4,4-dimethyl-chroman- 2-one available in accordance with U.S. Patent No. 5,399,561 inco ⁇ orated herein by reference (lg, 3.92mmol) in 8mL of anhydrous tetrahydrofuran was treated with a 0.5 M solution of ⁇ -chloro- ⁇ -methylene- [bis(cyclopentadienyl)titanium]dimethylaluminum (Tebbe reagent) in toluene (8.23mL, 4.12mmol).
• reaction mixture was poured into ice-water mixture containing 50mL of IM sodium hydroxide and extracted with hexane.
• the hexane extract was washed with brine (xl), filtered over a bed of celite and evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent to afford the title compound (0.74g, 74%) as a clear oil.
• GENERAL PROCEDURE R 2.2.4.4-Tetramethyl-chroman-6-carboxylic acid (Intermediate 39)
• a stirred, cooled (-78°C) solution of 6-bromo-2,2,4,4-tetramethyl chroman ( 1.2g, 4.47mmol) in 15mL of anhydrous tetrahydrofuran was treated with a 1.7M solution of tert-butyl lithium solution in pentane ( 5.27mL, 8.9mmol).
• carbon dioxide generated from dry ice was bubbled into the reaction mixture. The reaction mixture was allowed to warm to ambient temperature.
• reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using ethyl acetate as the eluent to afford the title compound as a white solid (l.lg, 92%) .
• reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent to afford the title compound (O.lg, 55%).
• 6-Bromo-8-ethyl-2.2.4.4-tetramethyl chroman (Intermediate 46) A stirred, cooled (ice bath) solution of 8-acetyl-6-bromo-2,2,4,4- tetramethyl chroman (Intermediate 45, 0.95g, 3. lmmol) in trifluoroacetic acid ( 1 OmL) was treated with triethy lsilane ( 1 OmL) and the resulting reaction mixture was allowed to warm to ambient temperature and stirred overnight. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with hexane (x2).
• 6-Bromo-4,4-dimethyl- 1.2.3.4-tetrahydro-quinoline- 1 -carbaldehyde (Intermediate 50)
• a solution of 6-bromo-4,4-dimethyl- 1 ,2,3 ,4-tetrahydroquinoline, available in accordance with United States Patent No. 5,089,509, the specification of which is inco ⁇ orated herein by reference (1.8g, 7.5mmol) in 1 OmL of formic acid was refluxed for 3h.
• the reaction mixture was then cooled to ambient temperature and poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted with diethyl ether (x2).
• 6-Bromo- 1 -cyclo ⁇ ropyl-4.4-dimethyl- 1.2.3.4-tetrahvdroquinoline (Intermediate 51)
• a stirred, cooled (0°C) solution of 6-bromo-4,4-dimethyl- 1 ,2,3 ,4- tetrahydro-quinoline-1-carbaldehyde (Intermediate 50, 21.8, 6.7mmol) in anhydrous tetrahydrofuran (20mL) under argon was treated with titanium tetra--5O- ⁇ ropoxide (2.15mL, 7.39mmol) followed by 3M solution of ethyl magnesium bromide in diethyl ether (5.6mL, 16.8mmol) and the reaction mixture was then heated at 50°C overnight.
• reaction mixture was stirred for 1 hour at the same temperature and then cooled to room temperature. Ice was added cautiously to the solid, followed by ⁇ 200mL of iced water. The reaction mixture was then extracted with ether (x2) and dichloromethane (xl) and the combined organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo to yield a brown solid. The solid was treated with hexane-dichloromethane and filtered to afford 1.7g of product. The mother liquor was evaporated and purified by flash column chromatography on silica gel (230-400 mesh) to afford 2.9g of the title compound as a solid (total 72%).
• Method A The carboxylic acid was combined with a solution ofthe desired alcohol and concentrated sulfuric acid (20 to 1 v/v) and the resulting mixture or solution (0.75 to 1.0 M) heated to reflux overnight. The solution was cooled to room temperature, diluted with EtjO, and washed with H 2 0, saturated aqueous NaHC0 3 , and saturated aqueous NaCl before being dried over MgS0 4 . Concentration ofthe dry solution under reduced pressure afforded the desired carboxylic ester of sufficient purity to be used directly in the next reaction.
• Method B To a solution (0.67 to 1 ,0M) ofthe carboxylic acid in acetone was added 1.1 equivalents of the desired alkyl halide and 1.0 equivalents of solid potassium carbonate. The resulting mixture was heated to reflux for 2h and then allowed to stir at room temperature overnight. The mixture was filtered and the filtrate concentrated under reduced pressure. The product was isolated from the residue by column chromatography using silica gel as the solid phase.
• Method C A solution (IM) ofthe carboxylic acid in thionyl chloride was heated at reflux until analysis of a reaction aliquot by IR spectroscopy showed the absence ofthe aryl carboxylic acid carbonyl band ( 1705 - 1680 cm "1 ).
• the solution was cooled to room temperature and concentrated under reduced pressure to give the crude acyl chloride.
• the acyl chloride was dissolved in CH 2 C1 2 and the resulting solution (0.5 to 0.75M) treated with 1.1 equivalents the desired alcohol and 2.0 equivalents of pyridine. After stirring overnight at room temperature the solution was diluted with Et ⁇ O and washed with H 2 0, 10% aqueous HCl, saturated aqueous NaHC0 3 , and saturated aqueous NaCl before being dried over Na 2 S0 4 . Concentration ofthe dry solution under reduced pressure followed by column chromatography afforded the desired ester.
• GENERAL PROCEDURE 1 preparation of Enol ethers : A solution (0.35 M) ofthe aryl ester in anhydrous THF was cooled to 0 °C and treated with 1.0 equivalents of Tebbe's Reagent ([ ⁇ -chloro- ⁇ - methylene[bis(cyclopentadienyl)titanium]-dimethylaluminum] 0.5 M in toluene). After 30 minutes the solution was warmed to room temperature and stirred for 30 minutes before being carefully added to a 0.1 N NaOH solution at 0 °C. This mixture was treated with hexanes and the solids removed by filtration through a pad of Celite.
• GENERAL PROCEDURE 2 (cvclopropanation ofthe enol ethers): To a solution (0.3 M) ofthe enol ether in anhydrous Et 2 0 was added 2.0 equivalent of Et 2 Zn (as a solution in hexanes) and 2.0 equivalents of CH 2 I 2 .
• Ethyl 4-[4-(l-methoxycyclo ⁇ ro ⁇ yl)-phenylethynyl]-benzoate (Compound 67, General Formula 2) Using General Procedure F; l-ethynyl-4-(l-methoxycyclopropyl)- benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 141.0 mg, 0.51 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes.
• Methyl 4-[4-(l-methoxycvclo ⁇ ro ⁇ yl)- ⁇ henylethvnyl]- ⁇ henyl -acetate (Compound 68, General Formula 2) Using General Procedure F; 1 -ethynyl-4-( 1 -methoxycyclopropyl)- benzene (Intermediate 61, 120.0 mg, 0.56 mmol) and methyl-(4-iodo ⁇ henyl)- acetate (Reagent B, 154.0 mg, 0.56 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (35.0 mg, 0.19 mmol) and sparged with argon for 5 minutes.
• Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenyl ⁇ hosphine)palladium(II) (66.0 mg, 0.094 mmol).
• the resulting reaction mixture was heated to 70 °C for 5 days.
• the title compound (250.0 mg, 98%) was isolated by chromatography (0 - 3% EtOAc - hexanes) as an orange oil.
• Ethyl 4-[4-( 1 -isopropoxycyclopropyl)-phenylethynyl]-benzoate (Compound 71, General Formula 2) Using General Procedure F; l-ethynyl-4-(l-isopropoxycyclopropyl)- benzene (Intermediate 66, 114.0 mg, 0.57 mmol) and ethyl-4-iodo benzoate (Reagent A, 731.0 mg, 0.63 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (36.0 mg, 0.19 mmol) and sparged with argon for 5 minutes.
• Methyl ⁇ 4-[4-(l-iso ⁇ ro ⁇ oxycvclopropylV ⁇ henylethvnyll- ⁇ henyll-acetate (Compound 72, General Formula 2) Using General Procedure F; l-ethynyl-4-(l -isopropoxy cyclopropyl)- benzene (Intermediate 66, 95.0 mg, 0.45 mmol) and methyl-(4-iodophenyl)- acetate (Reagent B, 131.0 mg, 0.45 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes .
• Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (37.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70 °C for 5d. The title compound (150.0 mg, 83%) was isolated by chromatography (0 - 3% EtOAc - hexanes) s a pale-yellow oil.
• ⁇ NMR (CDC1 3 ) ⁇ : 7.21 (3H, m), 7.09 - 7.01 (6H, m), 4.18 (2H, s), 1.07 (2H, m), 0.79 (2H, m), 0.02 (9H, s).
• Ethyl 4- [4-( 1 -benzyloxycyclopropylVphenylethynyl] -benzoate (Compound 75, General Formula 2) Using General Procedure F; 1 -ethynyl-4-(l -benzyloxycyclopropyl)- benzene (Intermediate 71, 60.0 mg, 0.24 mmol) and ethyl-4-iodo benzoate (Reagent A, 72.0 mg, 0.26 mmol) in triethylamine (4 mL) was treated with cop ⁇ er(I)iodide (17.0 mg, 0.09 mmol) and sparged with argon for 5 minutes.
• Methyl ⁇ 4- [4-( 1 -benzyloxy cyclopropylVphenylethynyl] -phenyl ⁇ -acetate (Compound 76, General Formula 2) Using General Procedure F; l-ethynyl-4-(l -benzyloxy cyclopropyl)- benzene (Intermediate 71, 60.0 mg, 0.20 mmol) and methyl-(4-iodophenyl)- acetate (Reagent B, 66.0 mg, 0.24 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (15.0 mg, 0.08 mmol) and sparged with argon for 5 minutes.
• Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (70.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70 °C for 5d. The title compound (300.0 mg, 89%) was isolated by chromatography (0 - 2% EtOAc - hexanes). ⁇ NMR (CDC1 3 ) ⁇ : 7.34-7.13 (8H, m), 4.24 (2H, s), 2.52 (3H, s), 1.20 (2H, m), 0.88 (2H, m), 0.25 (9H, s).
• Ethyl 4-[4-(l-benzyloxycvclopropylV3-methyl-phenylethynyl]-benzoate (Compound 79, General Formula 2) Using General Procedure F; l-ethynyl-4-(l -benzyloxy cyclopropyl)-3- methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and ethyl-4-iodo benzoate (Reagent A, 95.0 mg, 0.34 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (23.0 mg, 0.12 mmol) and sparged with argon for 5 minutes.
• Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenyl ⁇ hosphine) ⁇ alladium(II) (70.0 mg, 0.1 mmol). The resulting reaction mixture was heated to 70 °C for 5d. The title compound (250.0 mg, 91%) was isolated by chromatography (0 - 3% EtOAc - hexanes).
• Ethyl 4-[4-( 1 -isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 83, General Formula 2) Using General Procedure F; 4-ethynyl- 1 -( 1 -isopropoxy cyclopropyl)-3 - methyl-benzene (Intermediate 81, 80.0 mg, 0.13 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes.
• Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis- (triphenylphosphine)palladium(II) (63.0 mg, 0.09 mmol). The resulting reaction mixture was heated to 70 °C for 5d. The title compound (220.0 mg, 81%) was isolated by chromatography ( 1 -2% EtOAc - hexanes) .
• Eth y l 4-[4-[l-(2.2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]- benzoate (Compound 87, General Formula 2) Using General Procedure F; 4-ethynyl-l-[l-(2,2-dimethylpropyloxy)- cyclopropyl]-3-methyl-benzene (Intermediate 85, 75.0 mg, 0.31 mmol) and ethyl-4-iodo benzoate (Reagent A, 86.0 mg, 0.31 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes.
• Methyl l4- 4-ri-(2.2-dimethylpropyloxyVcyclopropyll-3-methyl- phenylethynyl]-phenyl ⁇ -acetate (Compound 88, General Formula 2) Using General Procedure F; 4-ethynyl- 1 -[ 1 -(2,2-dimethylpropyloxy)- cyclo ⁇ ropyl]-3-methyl-benzene (Intermediate 85, 75.0 mg, 0.31 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 86.0 mg, 0.31 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes.
• Ethyl 4-[4-(l-benzyloxycyclopro ⁇ ylV3-ethyl-phenylethynyl]-benzoate (Compound 91, General Formula 2) Using General Procedure F; l-ethynyl-4-(l -benzyloxy cyclopropyl)-3- ethyl-benzene (Intermediate 90, 90.0 mg, 0.33 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes.
• Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(tri ⁇ henyl ⁇ hos ⁇ hine) ⁇ alladium(II) (75.0 mg, 0.11 mmol). The resulting reaction mixture was heated to 70 °C for 5d. The title compound (320.0 mg, 99%) was isolated by chromatography (0 - 2% EtOAc - hexanes) as an orange oil.
• Ethyl 4-[4-(l-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound 95, General Formula 2) Using General Procedure F; 4-ethynyl- 1 -( 1 -isopropoxy cy clopropyl)-3 - ethyl-benzene (Intermediate 95, 108.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 130.0 mg, 047 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes .
• Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (38.0 mg, 0.05 mmol).
• the resulting reaction mixture was heated to 95 °C for 5d.
• the title compound 200.0 mg (99%), was isolated by chromatography (0 - 2% EtOAc - hexanes) as an orange oil.
• Ethyl 4-r4-(l-ethoxycyclopro ⁇ y -3-isopropyl- ⁇ henylethvnvn-benzoate (Compound 99, General Formula 2) Using General Procedure F; l-(l-ethoxycyclopropyl)-4-ethynyl-2- isopropylbenzene (Intermediate 103, 50.0 mg, 0.22 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (14.0 mg, 0.07 mmol) and sparged with argon for 5 minutes.
• Meth y l 4-r4- ( l-ethoxycvclopropyl -3-isopro ⁇ yl-phenylethvnyl]-phenyl ⁇ - acetate (Compound 100, General Formula 2) Using General Procedure F; l-(l-ethoxycyclopropyl)-4-ethynyl-2- isopropylbenzene (Intermediate 103, 120.0 mg, 0.52 mmol) and methyl-(4- iodophenyl)-acetate (Reagent B, 150.0 mg, 0.52 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (32.0 mg, 0.17 mmol) and sparged with argon for 5 minutes.
• Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (40.0 mg, 0.06 mmol).
• the resulting reaction mixture was heated to 95 °C for 18 hours.
• Ethyl 4- 4-(l-ethoxycyclo ⁇ ropylV3-tert-butyl-phenylethynyll-benzoate (Compound 103, General Formula 2) Using General Procedure F; l-(l-ethoxycyclopropyl)-4-ethynyl-2-tert- butylbenzene (Intermediate 112, 70.0 mg, 0.30 mmol) and ethyl-4-iodo benzoate (Reagent A, 85.0 mg, 0.30 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (19.0 mg, 0.01 mmol) and sparged with argon for 5 minutes.
• Methyl ( 4-r4- ( l-ethoxycvclopropylV3-tert-butyl- ⁇ henylethynyl]-phenyll- acetate (Compound 104, General Formula 2) Using General Procedure F; l-(l-ethoxycyclopropyl)-4-ethynyl-2-tert- butylbenzene (Intermediate 112, 95.0 mg, 0.39 mmol) and methyl-(4- iodophenyl)-acetate (Reagent B, 108.0 mg, 0.39 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes.
• Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenyl ⁇ hosphine) ⁇ alladium(II) (48.0 mg, 0.06 mmol).
• the resulting reaction mixture was heated to 70 °C for 5days.
• the title compound (80.0 mg, 75%) was isolated by chromatography (0 - 10% EtOAc - hexanes) as an orange oil.
• Ethyl 4-[4-(l-propylamino-cyclopropyl)-phenylethvnyl]-benzoate (Compound 107, General Formula 2) Using General Procedure F; [l-(4-ethynyl ⁇ henyl)-cyclo ⁇ ro ⁇ yl]- propylamine (Intermediate 120, 38.0 mg, 0.19 mmol) and ethyl-4-iodo benzoate (Reagent A, 58.0 mg, 0.21 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 5 minutes.
• Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (35.0 mg, 0.05 mmol).
• the resulting reaction mixture was heated to 70 °C for 5d.
• the title compound was isolated by chromatography (0 - 3% EtOAc - hexanes).
• Ethyl 4-[4-(l-dipropylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 109, General Formula 2) Using General Procedure F; [l-(4-ethynylphenyl)-cyclopropyl]- dipropylamine (Intermediate 123, 34.0 mg, 0.16 mmol) and ethyl-4-iodo benzoate (Reagent A, 59.0 mg, 0.21 mmol) in triethyl amine (6 mL) was treated with cop ⁇ er(I)iodide (13.0 mg, 0.07 mmol) and sparged with argon for 5 minutes.
• Ethyl 4- [4-( 1 -benzylamino-cyclopropyl)-phenylethynyl] -benzoate (Compound 111, General Formula 2) Using General Procedure F; benzyl-[l-(4-ethynylphenyl)-cyclopropyl]- amine (Intermediate 127, 65.0 mg, 0.27 mmol) and ethyl-4-iodo benzoate (Reagent A, 68.0 mg, 0.27 mmol) in triethyl amine (8 mL) was treated with copper(I)iodide (16.0 mg, 0.08 mmol) and sparged with argon for 5 minutes.
• Ethyl 4T4-( 1 -dibenzylamino-cvclo ⁇ ropylVphenylethvnyl]-benzoate (Compound 113, General Formula 2) Using General Procedure F; dibenzyl-[l-(4-ethynyl ⁇ heny ⁇ )- cyclopro ⁇ yl]-amine (Intermediate 129, 40.0 mg, 0.12 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with co ⁇ per(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 5 minutes.
• Benzyl- 1 -(4-ethvnyl ⁇ henylV cyclopropyl]-methylamine (Intermediate 132) Using General Procedure E; benzyl- [ 1 -(4-trimethylsilanylethynyl- ⁇ henyl)-cyclopropyl]-methylamine (Intermediate 131, 80.0 mg, 0.24 mmol) in methanol (5 mL) was treated with potassium carbonate (80.0 mg, 0.59 mmol) and stirred overnight at ambient temperature. The crude alkyne (60 mg, 99%) was used directly in the next reaction.
• Ethyl 4- ⁇ 4-f 1 -(benzyl-methylamino -cyclopropyl]- ⁇ henylethynyl ⁇ -benzoate (Compound 115, General Formula 2) Using General Procedure F; benzyl-[l -(4-ethynyl ⁇ henyl)-cyclopropyl]- methylamine (Intermediate 132, 70.0 mg, 0.28 mmol) and ethyl-4-iodo benzoate (Reagent A, 77.0 mg, 0.28 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (18.0 mg, 0.10 mmol) and sparged with argon for 5 minutes.
• Ethyl 4-(4-hydroxymethyl-3-methyl-phenylethynyl -benzoate (Compound 117, General Formula 6) Using General Procedure F; (4-ethynyl-2-methyl-phenyl)-methanol (Intermediate 136, 100.0 mg, 0.44 mmol) and ethyl-4-iodo benzoate (Reagent A, 125.0 mg, 0.45 mmol) in triethyl amine (4 mL) was treated with copper(I)iodide (29 mg, 0.15 mmol) and sparged with argon for 5 minutes.
• Eth y l 4- 4-bromomethyl-3-methyl-phenylethynylVbenzoate (Intermediate 137)
• a solution of ethyl 4-(4-hydroxymethyl-3-methyl-phenylethynyl)- benzoate (Compound 117, 130.0 mg, 0.44 mmol) and triphenylphosphine (150.0 mg, 0.57 mmol) in 5 mL CH 2 C1 2 was cooled to 0 °C and N- bromosuccinimide (101.0 mg, 0.57 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25 °C and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHC0 3 .
• Ethyl 4-(4-imidazol- 1 -yl-methyl-3-methyl-phenylethynyl -benzoate (Compound 118, General Formula 6)
• a solution of imidazole (30.0 mg, 0.44 mmol) in 2 mL DMF was treated with NaH (11.0 mg, 0.44 mmol) and heated to 90 °C.
• a solution of ethyl 4-(4-bromomethyl-3 -methyl-phenylethynyl)-benzoate (Intermediate 137, 120.0 mg, 0.34 mmol) in 2 mL DMF was added and stirring at 90 °C continued for 1 hour.
• the solution was cooled to room temperature and concentrated under reduced pressure.

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