WO1987007895A1 - Aminoesters corticaux et du type androstane - Google Patents

Aminoesters corticaux et du type androstane Download PDF

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Publication number
WO1987007895A1
WO1987007895A1 PCT/US1987/001304 US8701304W WO8707895A1 WO 1987007895 A1 WO1987007895 A1 WO 1987007895A1 US 8701304 W US8701304 W US 8701304W WO 8707895 A1 WO8707895 A1 WO 8707895A1
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Prior art keywords
piperazinyl
taken together
aminoester
cortical
bis
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PCT/US1987/001304
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English (en)
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Donald E. Ayer
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The Upjohn Company
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
    • C07J5/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom

Definitions

  • U.S. Patent 4,456,602 discloses steroidal 21-esters in which there is an amino function in the non-steroidal portion of the ester.
  • ANDERSON links a secondary amine to a corticosteroid at C 21 with an ester linkage to form a prodrug which produces as the active pharmacological agent the parent corticosteroid.
  • the prodrug contains additional functional groups between the ester and the amine.
  • the amine function is attached to the carbonyl carbon atom of the ester linkage only by a -CH 2 - (acetyl) or -C(CH 3 )H- propionyl.
  • the amine function is part of the active compound, not just part of a prodrug.
  • U.S. Patent 3,998,829 discloses 21- aminomethyl steroids and U.S. Patent 3,983,111 discloses 21-amino steroids where the amino group is cyclized. These patents also disclose reduced A-ring steroids as well as steroids with a hydrogen atom at C 17 and two hydrogen atoms at C lt .
  • 20-Amino steroids are known in the ⁇ l ⁇ A -3-keto series with an 11/9-hydroxyl substitution, see Steroids, supra, as well as with ll£,17 ⁇ -dihydroxy substitution, see Protides Biol. Fluids, 29, 393 (1982); J. Clin. Chem. Clin. Biochem., 22, 209 (1984); Eur. J. Biochem., 108, 47 (1980); J. Steroid Biochem. , 14, 697 (1981), Nature (London) 279, 158 (1979) and Eur. J. Biochem., 131, 333 (1983) and with ll ,17 ⁇ -dihydroxy substitution, see J. Clin. Chem. Clin. Biochem., 21, 69 (1983).
  • US Patent 4,191,759 discloses 20-amino- ⁇ 1, 4 -3-keto steroids without any substitution at the 11 position where the amine substituent is morpholine or piperazine.
  • 21-Amino steroids are known in the ⁇ 4 -3-keto series with no sub ⁇ stitution at C ll t see J. Org. Chem., 45, 3084 (1980); J. Org. Chem., 26, 1223 and 5052 (1961); J. Chem. Soc, Perkin Trans. 1, 502 (1972); Great Britain Patent 954,146; Austrian Patent 249,883; Arch. Biochem. Biophys., 182, 197 (1977) and Khim.-Farm. 2, 26 (1968).
  • 21-amino steroids are known in the ⁇ 1, 4 -3-keto series substituted with lLS-hydroxyl, .see Arch. Biochem. Biophys., 182, 197 (1977); Int. Conf. Chem.
  • Hungarian Patent 150,350 discloses dipersolone, 1 9,17 ⁇ -dihydroxy-21-(4-methyl-l-piperazinyl)- pregna-l,4-diene-3,20-dione.
  • U.S. Patent 3,705,150 dis- closes 21-N-(N' -methyl)piper zinyl prednisolone.
  • the amine function was substituted with simple alkyl (methyl, propyl, dimethyl, diethyl, dipropyl) , simple aralkyl (benzyl) , substituents containing hetero atoms (sulfur), esters, acids, amino substituted alkyl, alcohols, ethynyl groups and complex combinations and substituents.
  • These amines include 4- [hydroxyethyl] -1-piperidine, 4- [hydroxyethyl] -1- ⁇ i- perazine, 4-methylpiperazine, 4-acetylpiperazine and 4-formyl- piperazine.
  • Japanese patent J8 5043068 discloses azepino-(1,2,3-lh)-/3-car- boline derivatives which inhibit lipid peroxidation and are useful in inhibiting the aging of living bodies.
  • a number of 20-amino steroids are known where the 20-amino group is of the general type -NH-(CH 2 ) ⁇ -N(R 1 ) (R 2 ) where x is 2 or 3 and R ⁇ and R 2 are methyl or ethyl.
  • the 20-amino group is of the general type -NH-(CH 2 ) ⁇ -N(R 1 ) (R 2 ) where x is 2 or 3 and R ⁇ and R 2 are methyl or ethyl.
  • 20-amino steroids are known where the amino group is a simple amine including very simple cyclic and heterocyclic amines, see US Patents 3,523,942 and 4,191,759.
  • 21-amino substituted steroids where the amine is a simple (substituted) cyclic amine such as 4-(2-hydroxyethyl)-l-piperazinyl [CA 65;20189g]; 4-(2-hydroxy- ethyl)-l-piperidinyl [83544-11-0]; 4,4-dimethyl-l-piperazinyl, 3- hydroxyethyl-1-piperidinyl, 4-hydroxy-l-piperidinyl, 4-carboxy-l- piperidinyl, 3-hydroxy-l-piperidinyl, 3-carboxy-l-piperidinyl, piperazinyl, bis(hydroxyethyl)amino, 4-acetyl-l-piperazinyl, 4- carboxaldehyde-1-pipe
  • amino steroids of the prior art above with the exception of ANDERSON do not have an ester group between the amine function and the steroid. Further, in the amino steroids of the prior art above the steroids were generally of the corticoid type whereas the steroids of the present invention are of the androstane (17 -hydroxy) type.
  • R 10 is ⁇ -R 101 :/3-R 102 , where R 102 is -CH 3 , R 10 1 and 5 taken together are -CH 2 -CH 2 -C0-CH-, R g is o-H: / 9-H,
  • R 10 is ⁇ -R 103 : ⁇ -R 104 , where R ⁇ 0 is -CH 3 , R 10 3 and R 3 taken together are -CH-CH-C0-CH-, R g is ⁇ -H: -H,
  • R 5 is a-R 5 5 : ⁇ -R 5 6
  • R g is ⁇ -R ⁇ : ⁇ -R 6 6
  • R 10 is a " R 10 5 : ⁇ - R 106 , where R 106 is -CH 3 , where one of R 65 and R gg is ! -H and the other taken together with one of R 55 and R 56 forms a second bond between C 5 and C 6 and R 105 and the other of R 55 and ⁇ taken together are
  • X ⁇ is phenyl optionally substituted with 1 through 2 -Cl, -Br, C 1 -C 3 alkoxy, -COOH, -NH 2 , C j ⁇ -C 8 alkylamino, di(C ⁇ -C 3 )alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl- , 1-piperidinyl, 1-hexamethyl- enimino-, 1-hep amethylenimino-, C 2 -C 4 acylamino and -NH-CHO or with 1 -F or -CF 3 ,
  • R 21 and R 2X0 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of
  • R 5 is ⁇ -R 57 .-jfl-Rjg and R ⁇ 0 is ⁇ -R ⁇ o7 •' / S-Rio ⁇ • wl ⁇ ere or *e of R 57 and R 58 is -H
  • R 107 and the other of R 57 and 58 taken together are -CH 2 -CH 2 -C( « R 3 )-CH 2 - , where R 3 is as defined above, R 108 is -CH 3 , g is ⁇ -H: -H; where:
  • R l ⁇ is ⁇ -R ⁇ :j8-R 112 , where one of R X11 and R 1X2 is taken together with R g to form a second bond between C g and C ⁇ x and the other of R ⁇ x ⁇ and R l ⁇ 2 is -H,
  • (D-I) AE is as defined above, and pharmaceutically acceptable salts thereof; and hydrates thereof; with the following overall provisos that
  • R xx is ⁇ -AE:,8-H only when R ⁇ o is c.-R 10 ⁇ : _R io 2 or ⁇ " R i 03 :
  • R X05 and the other of R 55 and R 56 taken together are -CH 2 -CH 2 -C(-R 3 )-CH 2 - only when R X1 is ⁇ -R ll ⁇ :j9-R ⁇ x2 , -0 or ⁇ -H:/3-H and
  • X ⁇ is -0, ⁇ -H: -H or ⁇ -X ⁇ '. ⁇ -X ⁇ i2
  • X g is -H or taken together with one of X ⁇ xx and X ⁇ X2 to form a second bond between C g and C ⁇ and the other of X XX1 and X 112 is -H.
  • R 105 and one of R 55 and R 56 or R ⁇ o7 and one of R 57 and R 58 taken together are -CH 2 -CH 2 -C ⁇ )-CH 2 - and R ⁇ is ⁇ -R lxl : -R ⁇ 2 , -0 or - H: -H; which is the 3-aminoester of formula (III) where - indicates the AE group is in either the ⁇ or ⁇ configuration, ....
  • X ⁇ is -0, -H:/3-H or c.
  • X g is -H or taken together with one of X ⁇ xx and X X12 to form a second bond between C g and C ⁇ and the other of X X1X and X X12 is -H.
  • R xo is ⁇ -R xox : / 9-R 102 , where R 102 is -CH 3 , R ⁇ 01 and R 5 taken together are -CH 2 -CH 2 -C0-CH-, R g is ⁇ -R g ⁇ : -H where R gX is -H, -F and -CH 3 ,
  • R ⁇ o is ⁇ -R ⁇ 03 :0-R 104 , where R ⁇ ot is -CH 3 , R ⁇ 03 and R 5 taken together are -CH-CH-C0-CH-, R g is ⁇ -R g3 : ⁇ -H where R g3 is -H, -F and -CH 3 ,
  • R 5 is ⁇ -R 5S :0-R s ⁇
  • R 6 is ⁇ -R g5 :0-Rg 6
  • R 10 is a-R 10S : ⁇ - R ⁇ 06 , where R ⁇ 06 is -CH 3 , where one of R g5 and R 66 is -H and the other taken together .
  • one of R 55 and R 56 forms a second bond between C 5 and C 6 and R ⁇ 05 and the other of R 55 and R 56 taken together are -CH 2 -CH 2 -C(R 3 ) -CH 2 -
  • R 3 is a-E: ⁇ -AE or ⁇ -AE:/3-H
  • AE is -0-C0-C(X 5 )H-NR 2 ⁇ R 2 ⁇ o
  • R 2X is (1) -(CH 2 ) m -NR 2 ⁇ -X 2 , where is 2, 3 or 4, where R 2 ⁇ is -H or C ⁇ -C 3 alkyl, where X 2 is:
  • R 223 is -X ⁇ or -X 2 as defined above, or R 222 an( R 223 are ta ⁇ en together with the attached nitrogen atom to form a saturated mono-nitrogen C 3 -C 8 heterocyclic ring and where m is as defined above, (6) -(CHCH 3 ) b -(CH 2 ) f -R 22A , where b is 0 and f is 1 through 3 or b is one and f is 0 through 3, where R 22A is phenyl optionally substituted with 1 through 3 -OH, C ⁇ -C 3 alkoxy, where R 225 and R 226 being the same or different and are -H, C ⁇ -C 3 alkyl or are taken together with the attached nitrogen atom to form a saturated mononitrogen C A _C 7 heterocyclic ring,
  • (C) R ⁇ is (1) -H, (2) C 5 -C 7 cycloalkyl,
  • R 21 and R 210 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of (1) 2-(carboxy)-l-pyrrolidinyl optionally as the C ⁇ -C 3 alkyl ester or as a pharmaceutically acceptable salt, (F-24)
  • R 8 is a-R S 5 : ⁇ -H where R 65 is -H, -F and -CH 3 ;
  • A-IV R 5 is -R 57 : ⁇ -R 58 and R ⁇ o is ⁇ -R ⁇ 07 :0-R ⁇ 08 , where one of R 57 and R 58 is -H, R 107 and the other of R 57 and R 58 taken together are -CH 2 -CH 2 -C(R 3 )-CH 2 - , where R 3 is as defined above, R X08 is -CH 3 , R 6 is ⁇ -R 57 : ⁇ 3-H where R 67 is -H, -F and -CH 3 ,
  • R ⁇ 0 is c.-R 109 : - X0X0 , where R X010 is -CH 3 , R ⁇ 09 taken together with R 5 are -CH 2 -CH 2 -C(R 3 )-CH-, where R 3 is ⁇ -H: ⁇ -AE or ⁇ -AE:9-H, where AE is as defined above, where:
  • R ⁇ is ot-R xll :j9-R XX2 , where one of R ⁇ xl and R 112 is taken together with R g to form a second bond between C g and C ⁇ and the other of R 11X and R ⁇ l2 is -H,
  • R ⁇ is -AE: ⁇ -H where AE is as defined above and R g is -H;
  • R ⁇ 6 is .-R 16X : / S-R x62 where one of R ⁇ gl and R X62 is -H and the other is -H or CH 3 ;
  • R ⁇ 7 is c--R X71 :/3-R ⁇ 72 , where R ⁇ 7 ⁇ is -H, -OH, -0-C0-R X73 where R ⁇ 73 is -H or C ⁇ -C 5 alkyl, where R ⁇ 72 is (A) -CO-CH 2 -0-CO-C(X 5 )H-NR 21 R 2 ⁇ o , where X 5 , R 2 ⁇ and R 2 ⁇ o are as defined above,
  • R ⁇ is ⁇ -AE: -H only when R ⁇ o is ⁇ -R ⁇ o ⁇ : -R X02 or ⁇ -R 103 :0-R ⁇ 0A and
  • R 5 and R x0 are -CH 2 -CH 2 -C(R 3 )-CH 2 - only when R X1 is ⁇ -R ⁇ xl : -R 112 . -0 or ⁇ -H:0-H.
  • X ⁇ 0, -H:3-H or ⁇ -X ⁇ x : -X xl2
  • X 9 is -H or taken together with one of X ⁇ xx and X 1X2 to form a second bond between C g and C ⁇ and the other of X ⁇ x and X ⁇ l2 is -H.
  • cortical aminoester where R ⁇ ox and R 3 taken together are -CH 2 -CH 2 -CO-CH- or R ⁇ 03 and R 5 taken together are -CH-CH-CO-CH-, R ⁇ is ⁇ -AE:y3-H; which is the 11-aminoester of formula (VI) where .... is a single or double bond, where X ⁇ is -AE, -H and -NR 2 ⁇ R 210 .
  • X ⁇ is -0, a-H.- ⁇ -H or ⁇ :-X ⁇ :j8-X ⁇ 2
  • X 9 is -H or taken together with one of X ⁇ xx and X ⁇ x2 to form a second bond between C 9 and C ⁇ and the other of X ⁇ x ⁇ and X XX2 is -H
  • X ⁇ is -AE, -NR 2 ⁇ R 2;L0 and -H.
  • the androstane-type aminoesters (IV) encompass the 17-aminoester (I), the 11,17-diaminoester (II) and the 3,17-diaminoester (III).
  • the cortical aminoesters (VIII) encompass the 21-aminoester (V) , the 11,21-diaminoester (VI) and the 3,21-diaminoester (VII).
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are produced from steroids well known to those skilled in the art by methods well known to those skilled in the art.
  • the andros- tane-type aminoesters (IV) and cortical aminoesters (VIII) are prepared from known steroids containing one or two acylable hydroxyl groups (la, Ila, Ilia, Va, Via and Vila, respectively) by reaction with with with an acylating agent (IXA or IXB) .
  • an acylating agent (IX) be an ⁇ -halo acid halide (IXA) or an ⁇ -halo acid anhydride (IXB) .
  • Suitable acylating agents include ⁇ -chloroacetyl chloride, chloroacetic acid anhydride, bromoacetylbromide and 2- chloropropionyl chloride, preferred is ⁇ -chloroacetyl chloride.
  • a solution of the steroid with the acylable hydroxyl group (la, Ila, Ilia, Va, Via or Vila) in a basic organic solvent such as pyridine is cooled to about 0" to about 20° and the acylating agent (IX) is added slowly.
  • the reaction is quenched in the usual manner, with ice and water, and the ⁇ -halo ester (lb, lib, Illb, Vb, VIb or Vllb, respectively) is isolated by extraction and purified by means well known to those skilled in the art such as chromatography and/or crystallization.
  • the acylable steroid la, Ila, Ilia, Va, Via or Vila
  • an inert solvent such as methylene chloride or chloroform
  • the ⁇ -halo ester (lb, lib, Illb, Vb, VIb or Vllb) is then reacted with the appropriate amine in an aprotic solvent containing a base, as is well known to those skilled in the art, to produce the desired androstane-type aminoester (IV) or cortical aminoester (VIII) respectively.
  • the steroid A-ring be ⁇ *-3-keto.
  • R 9 be -H or with R ⁇ be A 9 i l l ) , more preferably ⁇ 9 l l l ) .
  • X 5 be -H.
  • R 2 ⁇ and R 2X0 be taken together with the attached nitrogen atom to form 1- piperazinyl substituted in the 4- position with X 2 (CH 2 ) j - and X 1 (CH 2 ) j -. It is preferred that j is 0.
  • X 2 be selected from the group consisting of l,3,5-triazin-4-yl substituted in the 2- and 6- position with -CH 2 -CH-CH 2 , pyrimidin-4-yl sub ⁇ stituted in the 2- and 6- position with 1-pyrrolidinyl, pyrimidin-4- yl substituted in the 2- and 6- position with 4-morpholinyl, 1,3,5- triazin-4-yl substituted in the 2- and 6- position with 1-pyr- rolidinyl and pyridinyl substituted in the 3- position with -NR 2 ⁇ 3 R 2X3 where one of ⁇ is -H and the other is C 2 alkyl with the cortical aminoesters (VIII).
  • the substitution at C ⁇ 5 be methyl and it is preferred that it be in the ⁇ configuration. It is preferred that the substituent at the C ⁇ 7 ⁇ position (R 17X ) be -H. It is preferred that the substituent at the C 1 7 ⁇ position (R ⁇ 72 ) he -C0-CH 2 -0-C0-C(X 5 )H-NR 2X R 2X0 . It is prefer- red that X 5 be -H.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) of the present invention are reacted with acids to form amine salts as is well known to those skilled in the art to prepare compounds which are much more water soluble and therefore preferable to use when an aqueous formulation is desired such as a solution for IV use.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) possess one or more basic nitrogen atoms to be converted to an acid addition salt.
  • the pharmaceutically acceptable salt forms of the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are generally preferred over the free base form since the salts have greater water solubility and form crystals more suitable for pharmaceutical purposes.
  • an acid addition salt of the androstane-type aminoesters (IV) and cortical aminoesters (VIII) can be converted to the free base, which can be converted to any desired pharmaceutically acceptable acid addition salt by methods well known to those skilled in the art. It is preferred that the acid addition salt be prepared by reacting the free base of the androstane-type aminoesters (IV) and cortical aminoesters (VIII) with a stoichiomet- ric amount of an acid, such as hydrochloric, hydrobromic, hydrogen iodidic, sulfuric, phosphoric, acetic, lactic, citric, succinic, benzole, salicyclic, pamoic, cyclohexanesulfamic, methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, maleic, fumaric, oxalic acid and the like. It is preferred that the acid be selected from the group consisting of hydrochloric,
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) and acid addition salts can be isolated as hydrates or solvates, and such forms are regarded as equivalent to the cor- responding androstane-type aminoesters (IV) and cortical aminoesters (VIII) not containing water or solvent.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) of the present invention are useful pharmaceutical agents in treating a number of different medical conditions in humans and useful warm blooded animals.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) of the present invention are useful in treating spinal trauma, mild and/or moderate to severe head injury, subarach- noid hemorrhage and subsequent cerebral vasospasm, ischemic (throm- boembolic) stroke excess, mucous secretion, asthma, muscular dystro ⁇ phy, adriamycin cardiac toxicity, Parkinsonism, Alzheimer's disease, other degenerative neurological disorders, multiple sclerosis, organ damage during reperfusion after transplant, skin graft rejection, hemorrhagic, traumatic and septic shock, and conditions such as severe burns, ARDS, inflammatory diseases such as osteo- or rheumat ⁇ oid arthritis, nephrotic syndrome (immunological) , systemic lupus erythematosis, allergic reactions, atherosclerosis, inflammation (for example, dermatological, inflammatory and psoriasis conditions), em
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in preventing damage following car- diopulmonary resuscitation, neurological or cardiovascular surgery and cardiac infarction.
  • androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in the same way as glucocorticoid pharmaceuticals ' for the treatment of above human conditions as well as the animal conditions listed below. While the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in both humans and animals in treating many . of the same conditions and preventing damage from the same problems as .the glucocorticoids, the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in treating a number of conditions and preventing damage from conditions where the glucocorticoids are not useful.
  • the androstane- type aminoesters (IV) and cortical aminoesters (VIII) have diminished glucocorticoid activity and therefore, unlike the glucocorticoids, they can be given daily for long periods of time (used chronically) without the side effects associated with the glucocorticoids. This is a distinct advantage.
  • each of the androstane-type amino ⁇ esters (IV) and cortical aminoesters (VIII) is useful for a number of the above conditions but not each and every compound is useful for each and every condition. It is well within the ability of those skilled in the art to easily determine which particular androstane- type aminoesters (IV) and cortical aminoesters (VIII) are useful for each particular condition without undue experimentation.
  • the fertile egg or chick embryo assay of Folkman discloses an assay to determine antiangiogenic activity which is indicative of inhibition of tumor growth and anti-cancer utility.
  • the compounds which are active in the Folkman embryo test are useful in the treatment of various diseases and conditions, especially various forms of cancer. Accordingly, they are administered to animals and humans to prolong survival or reduce pain and/or discomfort secondary to tumor growth and the alike.
  • the arachidonic acid LD 50 test of Kohler, Thrombosis Res., 9, 67 (1976) identifies compounds which are antioxidants, which inhibit lipid peroxidation, and/or which inhibit the pros- taglandin cascade and are useful in treating spinal trauma, mild and/or moderate to severe head injury, degenerative neurological disorders, etc.
  • Neurol., 79, 488 (1983) discloses a routine assay from which one skilled in the art can readily determine which particular androstane-type aminoesters (IV) are useful in treating chronic degenerative neurological disorders such as Parkinsonism, AlzheimerTMs disease etc. H. Johnson in Int. Arch. Allergy Appl. Immunol., 70, 169 (1983) has described the ascarias sensitized rhesus monkey assay for anti-asthma drugs.
  • the standard conditions for treatment are to give the andros- tane-type aminoesters (IV) and cortical aminoesters (VIII) orally or parenterally, e.g. IV (that is by injection, infusion or continuous drip) or IM, with a dose of about 0.05 to about 100 mg/kg/day, one to four times daily for oral or IM administration and continuously for IV infusion.
  • the standard conditions are used for treating spinal trauma, mild and moderate to severe head injury, damage following cardiopulmonary resuscitation, or cardiac infarction, organ damage during reperfusion after transplant, hemor ⁇ rhagic, traumatic and septic shock, severe burns, ARDS, nephrotic syndrome and preventing skin graft rejection.
  • Typical treatment will involve an initial IV loading dose of 0.01 to 1 mg/kg followed by IV infusion for a day to a week depending on the particular condition of the patient and particular compound used. This may be supplemented with IM or oral dosing for days, weeks or months to prevent delayed neuronal degeneration in neurological applications (eg spinal trauma, head injury).
  • ischemic thromboembolic
  • the androstane- type aminoesters (IV) and cortical aminoesters (VIII) are adminis- tered orally, IV, and by inhalation in the standard dose.
  • the frequency of administration is according to the standard conditions.
  • the oral administration of the androstane-type aminoesters (IV) and cortical aminoesters (VIII) to treat excess mucous secretions may go on for months or even years.
  • the susceptible individuals can be pre- treated a few hours before an expected problem.
  • the IV dose is about 0.05 to about 50 mg/kg/day.
  • the aerosol formulation contains about 0.05 to about 1.0% of the androstane-type aminoesters (IV) and cortical aminoesters (VIII) and is administered or used about three times daily.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are adminl- stered orally using a dose of about 0.05 to about 100 mg/kg/day, administered or used one to four times a day. The treatment may go on for years.
  • the androstane- type aminoesters (IV) and cortical aminoesters (VIII) are adminis ⁇ tered orally or IV using a dose of about 0.05 to about 100 mg/kg/day (orally) or (IV).
  • the androstane-type aminoesters "(IV) and cortical aminoesters (VIII) are preferably given concomitantly with IV adriamycin or the individual is pre-treated with the androstane-type aminoesters (IV) and cortical aminoesters (VIII) .
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are given orally or IM in doses of about 0.05 to about 100 mg/kg/day, one to four times daily. Orally the drug will be given over a period of months or years alone or with other steroidal agents.
  • the initial dose with some severe rheumatoid patients may be given IV and followed with an IV drip for up to 24 hr or more.
  • intra-articular administration may be employ ⁇ ed.
  • the androstane-type aminoesters (IV) and cortical amino- esters (VIII) are given orally in a dose of about 0.05 to about 100 mg/kg/day, one to four times daily or applied topically as a cream, ointment or lotion or equivalent dosage form in a concentration of about 0.05 to about 5% as long as needed.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) can be used with other steroidal agents.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are given orally or IV in a dose of about 0.05 to about 100 mg/kg/day administered one to four times daily orally and IV.
  • Typical treatment would be an initial IV loading dose of 0.01 to 1 mg/kg followed by oral dosing for a few days.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in the prevention and treatment of stress ulcers and of gastric intolerance caused by drugs such as nonsteroidal anti- inflammatory compounds (NOSAC) .
  • Stress ulcers are ulcers that develop after exposure to severe conditions such as trauma, burns, sepsis, extensive surgery, acute illnesses, and the like. Patients in intensive care units are particularly prone to develop stress ulcers. Stress ulcers also include lesions that can lead to upper gastrointestinal bleeding; such bleeding is likely to be prevented or stopped by these compounds.
  • NOSAC includes drugs such as aspirin, indomethacin, naproxen, piroxicam and the like that are usually taken for analgesia, and that are often associated with gastrointestinal intolerance characterized by pain and lesions that may lead to bleeding.
  • the androstane-type aminoesters (IV) and cortical amino ⁇ esters (VIII) will be administered preferentially by the oral route either as tablets, capsules or liquids, in doses ranging from 5 to 500 mg, two to four times a day.
  • the treatment would be either preventive, i.e., starting before ulcers have formed in patients at risk of developing such lesions, or therapeutic, i.e., once the ulcers have formed.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) would be given either thru a nasogastric tube, or parenterally, i.e., IV or IM.
  • the parenteral doses would range from about 1 to about 100 mg and be administered one to four times a day or by IV.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in treating head and spinal trauma, intervertebral diseases (slipped disk) , traumatic shock, flea bite and other allergies.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in treating endotoxic or septic shock which follows colic, pretreatment before surgery for colic and treatment of Founder (laminitis) .
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in treating acute coliform mastitis, bovine mastitis and acute allergic reaction to feed lot vaccination.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in treating porcine stress syndrome and thermal stress syndrome.
  • treatment or treating as used in this patent is used broadly and includes both treatment of an existing condition as well as preventing the same condition from occurring where such is possible as is well known to those skilled in the art.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) can be used to treat existing asthma conditions and to prevent future ones from occurring.
  • the androstane-type aminoesters (IV) and cortical aminoesters (VIII) treat spinal trauma and prevent rejection of skin grafts.
  • the exact dosage and frequency of administration depends on the particular androstane-type aminoesters (IV) and cortical aminoesters (VIII) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condi ⁇ tion of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentra ⁇ tion of the androstane-type aminoester (IV) and cortical aminoesters (VIII) in the patient's blood and/or the patients response to the particular condition being treated.
  • variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, "Z” or "R ⁇ " where "i" is an integer. These variable substituents are either monovalent or bivalent, that is represent a group attached to the formula by one or two chemical bonds. For example, a group Z would represent a bivalent variable if attached to the formula CH 3 -C(-Z)H.
  • R ⁇ and R j would represent monovalent variable substituents If attached to the formula CH 3 -CH 2 -C(R i )(R j )H 2 .
  • hen chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis.
  • each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses.
  • both R L and R ⁇ are bonded to the preced ⁇ ing carbon atom.
  • C i represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry.
  • R 6 represents a variable substituent (either monovalent or biva- lent) at the C 6 position.
  • Chemical forumlas of cyclic (ring) compounds or molecular frag ⁇ ments can be represented in a linear fashion.
  • the compound 4- chloro-2-methylpyridine can be represented in linear fashion by N*-C(CH 3 )-CH-CC1-CH-C * H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring.
  • the cyclic molecular fragment, 4- (ethyl)-1-piperazinyl can be represented by -N * -(CH 2 ) 2 -N(C 2 H 5 )-CH 2 - C * H 2 .
  • a cyclic (ring) structure for any compound herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the cyclic compound.
  • a substituent attached to a carbon atom below the plane of the ring is identified as being in the alpha ( ⁇ ) configuration and is indicated by a broken line attachment to the carbon atom, i.e., by the symbol "- - -”.
  • the corresponding sub ⁇ stituent attached above the plane of the ring is identified as being in the beta ( ⁇ ) configuration.
  • the valences may be taken together or separately or both in the definition of the variable.
  • a variable R attached to a carbon atom as -C(-R ⁇ )- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monvalent variable substituents ct- j . and jS-R ik .
  • R A is defined to consist of two monovalent variable substituents
  • the convention used to define the bivalent variable is of the form " ⁇ -R ⁇ : -R ik .. or some variant thereof. In such a case both ⁇ - j .
  • bivalent variable may be defined as two separate monovalent variable substituents
  • two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable.
  • R ⁇ and R may be defined to be taken together to form (1) a second bond between C ⁇ and C 2 or (2) a bivalent group such as oxa (-0-) and the formula thereby describes an epoxide.
  • the carbon atom content of variable substituents is indicated in one of two ways.
  • the first method uses a prefix to the entire name of the variable such as "C ⁇ -C ", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable.
  • the prefix is separated from the variable by a space.
  • C ⁇ -C A alkyl represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given) .
  • the prefix indicates the entire carbon atom content of the variable being defin ⁇ ed.
  • C2-C4 alkoxycarbonyl describes a group CH 3 -(CH 2 ) n -0-CO- where n is zero, one or 2.
  • the carbon atom content of only each portion of the definition is Indicated separate ⁇ ly by enclosing the "Ci-Cj" designation in parentheses and placing it immediately (no intervening space) before the portion of the defini ⁇ tion being defined.
  • this optional convention (C1-C3)alkoxycar ⁇ bonyl has the same meaning as C2-C4 alkoxycarbonyl because the "Cl- C3"refers only to the carbon atom content of the alkoxy group.
  • C2-C6 alkoxyalkyl and (Cl-C3)alkoxy(Cl-C3)alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms
  • the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
  • the claims contain a (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be the notation (F-##) , formula-number, which will correspond to the same name/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent.
  • TLC thin-layer chromatography
  • Saline refers to an aqueous saturated sodium chloride solution.
  • Ether refers to diethyl ether.
  • NMR nuclear (proton) magnetic resonance spectroscopy
  • chemical shifts are reported in ppm (5) downfield from tetramethyl- silane.
  • dec refers to decomposition.
  • the steroids of the Examples were chromatographed on 63-200 micron silica gel by gravity chromatography.
  • Alcohol refers to ethyl alcohol.
  • Allyl refers to 2-propen-l-yl.
  • ARDS refers to acute/adult respiratory distress syndrome.
  • IV refers to intravenous, including injection, infusion and continuous drip.
  • IM refers to intramuscular.
  • compositions and/or substances which are acceptable to the patient from a pharmacologi- cal/toxicological point of view including bioavailability and patient acceptance or to the manufacturing chemist from a physical-chemical point of view regarding composition, formulation, stability and isolatability.
  • solvent pairs When solvent pairs are used, the ratios of solvents used are volume/volume (v/v) .
  • NNNNN-NN-NJ refers to Chemical Abstracts Service (CAS) registry numbers where each N is an integer from 0 thru 9, but deleting leading zeros in the 6-digit portion of the number. Registry numbers are assigned to a particular chemical compound by CAS only when there is sufficient proof according to CAS criteria that the compound has been found to exist and it has been charac ⁇ terized in some way. Compounds published from approximately 1967 to the present are registered publicly and the registry numbers is the key to finding references in the CAS data base for such a registered compound.
  • the CAS database is publicly available from several database vendors such as STN International, System Development Corporation (SDC) , Orbit Search Service, Lockheed Dialog, Bibliogra- phic Retrieval Systems, Questel, etc. CAS registry numbers are included in the EXAMPLES for some of the compounds which have been registered.
  • Aldrich item refers to an item listed for sale by Aldrich Chemical Co., P.O. Box 355, Milwaukee, Wisconsin, 53201, USA in their
  • AE is (aminoester) -0-C0-C (X 5 ) H-NR 2 ⁇ R 2 ⁇ o .
  • Q ⁇ is -Cl or -Br .
  • Q 2 is -Cl or -Br .
  • X ⁇ is -0, ⁇ -H:/3-H or ⁇ -X l ⁇ : ⁇ -X ⁇ 2
  • X 9 is -H or taken together with one of X ⁇ xl and X 112 to form a second bond between C g and C ⁇ and the other of X lxl and X X12 is -H.
  • the extracts are washed with aqueous potassium carbonate, 50% saline and saline and dried over magnesium sulfate and concentrated to give a gum.
  • Chromatography on silica gel (400 g) and elution (200 ml fractions) with 20% acetone-methylene chloride gives the formamide.
  • the formamide (9.2 g) in 200 ml of methanol is heated to reflux, then cooled under nitrogen and mixed with 4 ml of 45% potassium hydroxide solution. The mixture is heated under reflux for about 20 hours, then cooled and concentrated. The residue is partitioned between ethyl acetate and water.
  • a solution of pyrrolidine (80 g) in THF (500 ml) is chilled in an ice water bath and stirred mechanically under nitrogen. With a syringe pump of 2,4,6-trichloropyrimidine (50 g) is added over 35 minutes. The reaction is stirred in the ice bath for 1 hour and is then warmed to 20-25° over 4 h. Pyridine (100 ml) is added to the reaction and the mixture stirred at 20-25° overnight. The reaction is concentrated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate.
  • the organic phase is concentrated and the residue chromatographed on silica gel (10% ethyl acetate/hexane) to yield 51 g of crystalline 2,4-bis[pyrrolidino] - -6-chloropyrimidine.
  • silica gel 10% ethyl acetate/hexane
  • two spots are seen with 25% ethyl acetate on a silica gel plate. These are the 2- and the 4- adducts.
  • the bis product forms over time. It moves between these first two spots.
  • the 51 g of product is reacted with piperazine (40 g) in 100 ml of dry pyridine at 100° for 50 h.
  • the reaction is concentrated.
  • the residue is partitioned between methylene chloride and sodium bicarbonate solution.
  • a solution of 160 g of morpholine in 1000 ml of methylene chloride is treated dropwise with 100 g of 2,4,6-trichloropyrimidine.
  • the reaction is immersed in an Ice water bath. After 1 h, 300 ml of pyridine is added. The reaction is stirred for two days and con ⁇ centrated.
  • the residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The residue is chromatographed on silica gel (10% ethyl acetate/hexane to 25% to methylene chloride) to give 2,4- [bis-morpholino] -6-chloropyrimidine.
  • PREPARATION A-47 4- [3-(Ethylamino) -2-pyridinyl]piperazine 2-(1-piperazinyl)-3-nitropyridine (24.50 g) , ethanol (445 ml) and hydrochloric acid (1.2 N, 44 ml) are combined and hydrogenated over night at 40 psi, refilling when necessary.
  • the mixture is filtered thru celite, washed with ethanol, chloroform, ethanol and water.
  • the organic solvents are removed with heat and reduced pressure.
  • the remaining material is partitioned betweened methylene chloride (3 x 250 ml) and sodium bicarbonate.
  • 3-Amino-2-(l-piperazinyl)pyridine (19.58 g) , methylene chloride 600 ml), triethylamine (17.2 ml) are combined and cooled to 6°.
  • Di- t-butyl-dicarbonate (24.34 g) in methylene chloride (50 ml) is added to the pyridine mixture over 30 min and permitted to stand at 0° for 1 hr, then allowed to warm to 20 - 25°. After 30 min, TLC indicates no starting material remains.
  • reaction mixture is partitioned between sodium bicarbonate (500 ml) and methylene chloride (3 x 250 ml) .
  • the organic phases are combined, dried over potassium car ⁇ bonate, filtered and concentrated under reduced pressure and heat to give a solid which is recrystallized from ethyl acetate to give 3- amino-2- [(4-t-butyldicarbonate)-l-piperazinyl]piperidine.
  • the concentrate is column chromatographed on silica gel 60 (40 63 ⁇ ) eluting with hexane/ethyl acetate (2/1) containing triethylamine (1%). The appropriate fractions are pooled and concentrated to give 3-ethylamino-2- [(4-t-butyldicarbonate)-1- piperazinyl]piperidine.
  • PREPARATION A-48 4- [3-(Diethylamino)-2-pyridinyl]piperazine Following the general procedure of PREPARATION A-47 and making non-critical variations but reacting the protected ethylamine compound with additional acetaldehyde and again reducing the title compound is obtained.
  • PREPARATION S-22 21-Hydroxy-16 ⁇ -methylpregna-l,4,9(11)-triene-3,20 dione
  • reaction is quenched with 375 ml of 25% concentrated hydrochloric acid in methan- ol.
  • the reaction is partitioned between water and toluene.
  • the organic phase is washed with water, filtered through sodium sulfate and concentrated.
  • the residue is crystallized from ether and hexane. The crystals are triturated with ether to give the desired (16 ⁇ - methyl) Michael addition product.
  • the mixture Is slowly permitted to warm to 20-25° over a period of 2 hours and then is washed with hydrochloric acid (0.1 N) and potassium bicarbonate (1 N) .
  • the extract is filtered through sodium sulfate and concentrated.
  • the concentrate is chromatographed on silica gel (200 g) and eluted with acetone/methylene chloride (5/95). The appropriate fractions are pooled and concentrated.
  • the concentrate is crystallized from acetone-hexane. These crystals are rechromatographed on silica gel eluting with acetone/methylene chloride (2/98) .
  • EXAMPLE 4 ll ⁇ ,17j8-Dihydroxyandrost-4-en-3-one ll,17-bis[4-(2- pyridinyl)-1-piperazinyl]acetate tetrahydrochloride
  • EXAMPLE 3 A mixture of ll ⁇ ,17 ⁇ -dihydroxyandrost-4-en-3-one ll,17-di(chlo- roacetate) (EXAMPLE 3, 0.9 g) and 4-(2-pyridinyl)piperazine (PREPARA- TION A-6, 0.64 ml) in acetonitrile (16 ml) is heated under reflux for about 18 hours. The reaction mixture is concentrated and the residue partitioned between methylene chloride and aqueous potassium bi ⁇ carbonate.
  • the phases are separated, the organic phase is con- centrated.
  • the concentrate is chromatographed on silica gel (120 g) eluting with acetone/methylene chloride (20/80 - 30/70).
  • the ap ⁇ basementte fractions (50 ml) are pooled and concentrated to obtain the free amine of the title compound.
  • EXAMPLE 5 ll ⁇ ,17 ⁇ -Dihydroxyandrost-4-en-3-one 11,17-bis[4-[4,6- bis(2-propenylamino)-1,3,5-triazin-2-yl] -1-piperazin ⁇ yl]acetate tetrahydrochloride
  • a mixture of ll ⁇ ,17/3-dihydroxyandrost-4-en-3-one ll,17-di(chlo- roacetate) (EXAMPLE 3, 0.69 g) and l-(4,6-bispropenylamino-l,3,5- triazin-2-yl)piperazine (PREPARATION A-14, 1.65 g) in acetonitrile (30 ml) is heated under reflux for 6.5 hours.
  • the crude product is chromatographed on silica gel (120 g) eluting with acetone/methylene chloride (0.5 liters 20/80 and 4 liters 30/70 - 60/40).
  • the ap ⁇ basementte fractions (50 ml) are pooled and concentrated to give the free amine of the title compound, NMR (CDC1 3 ) 2.58, 3.16, 3.24, 3.7- 4.2, 4.75, 5.0-5.5, 5.8 and 5.7-6.3 6 .
  • EXAMPLE 6 ll ⁇ ,17 ⁇ ,21-Trihydroxypregn-4-ene-3,20-dione 11,17- di(chloroacetate) Following the general procedure of EXAMPLE 3 and making non- critical vaiations but starting with ll ⁇ ,17 ⁇ ,21-trihydroxypregn-4- ene-3,20-dione the title compound is obtained.
  • EXAMPLE 7 ll ⁇ ,17 ⁇ ,21-Trihydroxypregn-4-ene-3,20-dione 11,21- bis[4- [4,6-bis(2-propenylamino)-l,3,5-triazin-2-yl] -1- piperazinyl]acetate tetrahydrochloride
  • a mixture of ll ⁇ ,17 ⁇ ,21-trihydroxypregn-4-ene-3,20-dione 11,17- di(chloroacetate) (EXAMPLE 6, 0.37 g) , 1- [4,6-bis(2-propenylamino)-
  • EXAMPLE 8 ll ⁇ ,17 ⁇ ,21-Trihydroxypregn-4-ene-3,20-dione 11,21- bis[4-(2-pyridinyl)-1-piperazinyl]acetate tetrahydro ⁇ chloride Following the general procedure of EXAMPLE 7 and 2(B) and making non-critical variations but starting with 4-(2-pyridinyl)piperazine (PREPARATION A-6) the title compound is obtained, mp 185° dec.
  • EXAMPLE 9 ll ⁇ -Hydroxy-16 ⁇ -methylprogesterone 11-chloroacetate
  • EXAMPLE 11 ll ⁇ -Hydroxy-16 ⁇ -methylprogesterone 11- [4- [2,6-bis(mor- pholino)-4-pyrimidinyl] -1-piperazinyl]acetate dihydro- chloride Following the general procedure of EXAMPLE 2(A) and making non- critical variations but starting with a mixture of ll ⁇ -hydroxy-16 ⁇ - methylprogesterone 11-chloroacetate (EXAMPLE 9, 0.43 g) , and 4- [2,6- bis(morpholino)-4-pyrimidinyl]piperazine (PREPARATION A-23, 0.56 g) the free amine of the title compound is obtained, NMR (CDC1 3 ) 0.76, 0.97, 1.25, 2.1, 2.65, 3.18, 3.4-3.7, 3.75, 5.12, 5.35 and 5.8 ⁇ .
  • EXAMPLE 14 21-Hydroxypregn-4-ene-3,20-dione 21-[4- [2,6-bis(l-pyr ⁇ rolidinyl) -4-pyrimidinyl ] -1-piperazinyl]acetate dihydrochloride Following the general procedure of EXAMPLE 2(A) and making non- critical variations but starting with a mixture of 21-hydroxypregn-4- ene-3,20 dione 21-chloroacetate (EXAMPLE 13, 0.4 g) , and 4- [2,6- 5 bis(l-pyrrolidinyl)-4-pyrimidinyl]piperazine (PREPARATION A-22, 0.45 g) the free amine of the title compound is obtained, NMR (CDC1 3 ) 0.72, 1.20, 2.65, 3.35-3.8, 4.73, 4.88 and 5.8 S .
  • EXAMPLE 17 ll ⁇ -Hydroxy-21- [4- [2,6-bis(l-pyrrolidinyl)-4-pyrimi ⁇ dinyl] -1-piperazinyl] -16 ⁇ -methylpregna-l,4-diene-3,20- dione 11-[4-[2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl] 1-piperazinyl]acetate tetrahydrochloride 5 Following the general procedure of EXAMPLE 2(A) and making non- critical variations but starting with a mixture of ll ⁇ -hydroxy-21- iodo-16 ⁇ -methylpregna-l,4pdiene-3,20 dione 11-chloroacetate (EXAMPLE 16, 0.3 g) , and 4-[2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl]piperazine f i
  • EXAMPLE 18 3/9,17 ⁇ -Dihydroxy-6 ⁇ -methylpregn-4-en-20-one 17-acetate 3- [4-(2-pyridinyl)-l-piperazinyl]acetate dihydrochlo- ride Following the general procedure of EXAMPLES 1, 3, 6, 9, 13, and 16 and making non-critical variations but starting with 3 ,17 ⁇ - dihydroxy-6 ⁇ -methylpregn-4-en-20-one 17-acetate (J. Med. Chem. 7, 355 (1964) *3.89 g) , 3/3,17 ⁇ -dihydroxy-6 ⁇ -methylpregn-4-en-20-one 17- acetate 3-chloroacetate is obtained.
  • EXAMPLE 20 21-Hydroxy-16 ⁇ -methylpregna-l,4,9(11)-triene-3,20-- dione 21- [4- [2,6-bis(morpholino) -4-pyrimidinyl] -1-pi ⁇ perazinyl] -acetate dihydrochloride Following the general procedure of EXAMPLE 18 and making non- critical variations but starting with a mixture of 21-hydroxy-16 ⁇ - methylpregna-1,4,9(11)-triene-3,20-dione (PREPARATION S-22, reference*), and 4- [2,6-bis(morpholino)-4-pyrimidinyl]piperazine (PREPARATION A-23, 0.56 g) the free amine of the title compound is obtained
  • EXAMPLE 22 21-Hydroxy-16 ⁇ -methylpregna-l, ,9(11)-triene-3,20-- dione 21-[4- [4,6-bis(2-propenylamino)-l,3,5-triazin-2- yl] -1-piperazinyl]acetate dihydrochloride Following the general procedure of EXAMPLE 18 and making non- critical variations but starting with a mixture of 21-hydroxy-16 ⁇ - methylpregna-1,4,9(11)-triene-3,20-dione and 4- [(4,6-bis(2-propenyl- amino)-l,3,5-triazin-2-yl)]piperazine (PREPARATION A-14), the free amine of the title compound is obtained Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 159°. EXAMPLE A Conjugated Diene Formation Assay
  • conjugated dienes as assayed by Braughler, J. Neurochem. , 44, 1282 (1985), Bucher, Fund. Applied Tox. , 3, 222 (1983) and Tein, Arch. Biochem. Biophy. , 216, 142 (1982) is a standard pharmacological laboratory procedure useful for identifying compounds which inhibit lipid peroxidation. Since lipid peroxidation is involved in the pathophysiology of central nervous system trauma, compounds which inhibit conjugated diene formation are useful in treating the conditions listed below.
  • Inhibition of conjugated diene formation as measured by any of the above procedures or the modified procedure below demonstrates usefulness in treating spinal trauma, mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent cerebral vaso- spasm, ischemic (thromboembolic) stroke, muscular dystrophy, adriamy ⁇ cin cardiac toxicity, Parkinsonism, Alzheimer's disease, other degenerative neurological disorders, multiple sclerosis, organ damage during reprefusion after transplant, skin graft rejection, hemor ⁇ rhagic, traumatic, or septic shock, severe burns, ARDS, allergic reactions, emphysema and post burn pulmonary complication. Further, an inhibition of conjugated diene formation also demonstrates usefulness in preventing damage following cardiopulmonary resuscita ⁇ tion, neurological or cardiovascular surgery and cardiac infarction.
  • rat brain synap- tosomes are prepared according to the procedure described in J. Neurochem. 44, 1282 (1985). Synaptosomal suspension (10 ⁇ l) is added to 1 ml of physiological (normal) saline containing 1 % Lubrol PX (Sigma Chemical Co. St. Louis, Mo.), 100 ⁇ M hydrogen peroxide and 100 ⁇ M (or less) of the drug to be tested prepared in either absolute ethanol or water depending upon solubility. The reaction is started by the rapid addition of 200 ⁇ M ferrous ammonium sulfate prepared in argon-purged water.
  • the sample is rapidly mixed and the change in absorbance at 232nm is followed in a Gilford Response Spectrophoto- eter equipped with a rapid sampler. Due to the rapidity of the reaction, rapid addition of the iron, rapid mixing and sampling are obligatory to the accuracy of the assay. For best results absorbance readings of one/sec should be started within 5 sec following the addition of iron.
  • the initial linear rate of absorbance change during the first 30 sec of reaction are compared with the rate of a reaction containing all reagents except synaptosomes. The difference in rates is the rate of conjugated diene formation. Rates with drug are compared to rates obtained in the absence of drug and the % inhibition is calculated. A compound that inhibits conjugated diene formation by 50% or more is considered to be "active".
  • the Arachidonic Acid Antagonism Assay (AAAA) as set forth in Thrombosis Res., 9, 67 (1976) is a standard laboratory procedure for demonstrating antagonism of the effects of arachidonic acid metabol ⁇ ites. Since these metabolites contribute to the pathological problems associated with stroke, spinal trauma and head injury, compounds which antagonize arachidonic acid are useful in treating stroke, spinal trauma and head injury. Compounds which significantly elevate the LD 50 of arachidonic acid in amimals a re considered to be useful for the traatment of these conditions.
  • MDA formation as measured by any of the above procedures or the modified procedure below demonstrates usefulness in treating spinal trauma, mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent cerebral vasospas , ischemic (thrombo- embolic) stroke, muscular dystrophy, adriamycin cardiac toxicity, Parkinsonism, Alzheimer's disease, other degenerative neurological disorders, multiple sclerosis, organ damage during reprefusion after transplant, skin graft rejection, hemorrhagic, traumatic and septic shock, severe burns, ARDS, allergic reactions, emphysema and post burn pulmonary complication. Further, MDA formation also demon ⁇ strates usefulness in preventing damage following cardiopulmonary resuscitation, neurological or cardiovascular surgery and cardiac infarction.
  • rat brain synaptosomes are prepared as described in the Example about the conjugated diene assay, except that the final wash of the synaptosomes and final suspension are in physiological (normal) saline in which the pH has been adjusted to 7.0.
  • the synaptosomes are incubated for 10 min at 37° in physiologi ⁇ cal (normal) saline pH 7.0 (total volume - 100 ul) containing; 10 ul synaptosomal suspension, 10% DMSO plus or minus drug, 150 uM Fe +++ and 50 uM Fe++.
  • the incubation is started by the rapid addition of iron to the otherwise complete reaction.
  • the iron solutions are prepared fresh as ferric chloride and ferrous ammonium sulfate in argon-purged water. Following the 10 min incubation, the reaction is stopped by the addition of 500 ul ice-cold 12% trichloroacetic acid prepared in 0.5 N hydrochoric acid. Water (300 ul) is then added along with 100 ul of freshly prepared thiobarbituric acid (3.3% in 0.5N sodium hydroxide) and 10 ul of 5mM desferrioxamine. The sample is then heated in a boiling water bath for 20 minutes. The samples are cooled and centrifuged for 15 minutes at 1500 xg and the absor ⁇ nadoe of the supernatant fraction is read at 532 nm.
  • the % inhibi- tion of MDA formation is calculated by dividing the absorbance of sample containing drug by the absorbance of samples incubated without drug. Reaction blanks are samples incubated in the absence of iron. A compound that inhibits MDA formation by 50% or more at a concentra ⁇ tion of 200 ⁇ M or less is considered "active". The compounds of Example 5 demonstrates such activity by inhibition of MDA formation.
  • ACAT AcylCoA:Cholesterol Acyltransferase Inhibition Assay ACAT esterifies arterial cholesterol which is a key reaction in the development of atherosclerosis.
  • the procedure of Bell, Can. J. Biochem. 60, 967 (1982) provides a standard procedure for demonstrat ⁇ ing which compounds inhibit ACAT and therefore inhibit formation of esterified arterial cholesterol thereby preventing atherosclerosis.
  • Fu5AH cells see Lipids 9, 526 (1974). According to this procedure, compounds which inhibit ACAT activity equal to, or greater than, that of chlorpromazine are considered "active".
  • Demonstration of antiatherosclerotic activity of a compound in SEA Japanese Quail is done by showing that the compound reduces the serum and arterial cholesterol in quail fed an atherogenic diet.
  • This suspension is incubated for 10 min at 45° to dissolve the material.
  • This solution as well as the diluted serum samples are analyzed for cholesterol by standard clinical chemistry analyzer methods. According to the above procedure compounds which decrease serum or arterial cholesterol > 30 % are considered to be "active" .
  • EXAMPLE F Inhibition of Interleukin-1
  • the inhibition of interleukin-1 induced T cell proliferation assay, Proc. Nat. Acad. Sci. USA, 78, 1133 (1981) is a standary laboratory procedure for demonstrating inhibition of interleukin-1 bioactivities. Since people with arthritis make excess interleukin 1, compounds which inhibit the activity of interleukin 1 are useful in the treatment of arthritis. According to this procedure com ⁇ pounds which inhibit the activity of interleukin 1 greater that 30% at 10 " s M are considered to be "active”.
  • EXAMPLE G Inhibition of Mucous Secretion
  • ovalbumin sensitized guinea pig test Brit. J. Pharm. 78, 67 (1983) is a standard laboratory procedure for demonstrating inhibi- tion of bronchoconstriction and therefore use in treating/preventing asthma. While not necessary the above test has been modified as follows. Male guinea pigs (500-700 g at the time of antigen chal ⁇ lenge) are sensitized by IM injection of ovalbumin (5%, 0.35 ml) into each hind limb and repeated 6 days later.
  • Heart rate is derived from the blood pressure signal using a Grass 7P4F tachograph.
  • a jugular vein is catheterized for injection of drugs and antigen.
  • the amimals are pretreated with the following: indomethacin (10 mg/kg, 15 min prior to antigen), pyrilamine maleate (2 mg/kg, 10/11 min before antigen), and propranolol (0.25 mg/kg, 5 min prior to antigen).
  • Antigen challenge consists of ovalbumin (0.3 mg/kg) given IV.
  • the compounds to be tested are administered by either IV (compound precedes the antigen challenge by four minutes) , orally (fasted animals are dosed at either 2 or 4 hr prior to challenge) or by areosol (the compound is nebulized thru the Harvard respirator and directly into the tracheal cannula 180 sec four min prior to the IV antigen challenge) .
  • Vehicles include IV (saline) , oral (emulphor or 0.1% Tween 80) or for aerosol (DMSO) .
  • the antigen provocation produces a slowly developing broncho ⁇ constriction which lasts at least 15 min.
  • the percent inhibition at various times points after antigen challenge compares the test compound to control animals (vehicle only) . According to this procedure compounds which give 50% or greater inhibition at 10 mg/kg are considered to be "active".
  • N ⁇ -oxide thereof optionally (F-9) substituted at the 2- and/or 6- position

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Sont décrits des aminoesters du type androstane (IV) et des aminoesters corticaux (VIII), plus particulièrement des 17-aminoesters (I), 11,17-diaminoesters (II), 3,17-diaminoesters (III), 21-aminoesters (V), 11-aminoesters (VI), et 3-aminoesters (VII) qui sont utiles à titre d'agents pharmaceutiques pour traiter un certain nombre d'états, et notamment des traumatismes crâniens et des traumatismes spinaux allant d'une faible gravité à une gravité importante.
PCT/US1987/001304 1986-06-23 1987-06-09 Aminoesters corticaux et du type androstane WO1987007895A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US87741386A 1986-06-23 1986-06-23
US87741486A 1986-06-23 1986-06-23
US877,414 1986-06-23
US877,413 1986-06-23

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WO1987007895A1 true WO1987007895A1 (fr) 1987-12-30

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AU (1) AU7580187A (fr)
WO (1) WO1987007895A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0389368A1 (fr) * 1989-03-22 1990-09-26 Roussel Uclaf Nouveaux dérivés de la 6-(1-pipérazinyl) 2,5-pyridine diamine N,N,N',N'-substituée, leur procédé de préparation et les intermédiaires de ce procédé, leur application comme médicaments et les compositions pharmaceutiques les renfermant
EP0389370A1 (fr) * 1989-03-22 1990-09-26 Roussel-Uclaf Nouveaux stéroides 19-Nor 3-céto comportant une chaîne en 17 aminosubstituée, leur procédé de préparation et les intermédiaires de ce procédé,leur application comme médicaments et les compositions pharmaceutiques les contenant
EP0389369A1 (fr) * 1989-03-22 1990-09-26 Roussel-Uclaf Nouveaux stéroides 3-céto comportant une chaîne en 17 aminosubstituée, leur procédé de préparation et les intermédiaires de ce procédé, leur application comme médicaments et les compositions les contenant
WO1991011453A2 (fr) * 1990-01-26 1991-08-08 The Upjohn Company 2,4,6-triaminopyrimidines oxygenees en position 5
EP0574906A2 (fr) * 1992-06-17 1993-12-22 Nisshin Flour Milling Co., Ltd. Dérivés de pipérazine et homopipérazine, compositions pharmaceutiques les contenant et procédé pour leur préparation
WO1994024146A1 (fr) * 1993-04-13 1994-10-27 Jenapharm Gmbh Des androgenes et anaboliques nouveaux
LT3071B (en) 1992-06-09 1994-11-25 Richter Gedeon Vegyeszet Novel steroids with pregnane skeleton,pharmaceutical compositions containing them and process for preparing thereof
LT3118B (en) 1992-06-09 1994-12-27 Richter Gedeon Vegyeszet Novel, biologically active eburnamenine derivatives and a process for preparing the same
US5502187A (en) * 1992-04-03 1996-03-26 The Upjohn Company Pharmaceutically active bicyclic-heterocyclic amines
WO1996021648A1 (fr) * 1995-01-11 1996-07-18 Samjin Pharmaceutical Co., Ltd. Nouveaux derives piperazines, leurs procedes de preparation, et compositions les contenant
US8207151B2 (en) 2008-05-28 2012-06-26 Validus Biopharma Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US9198921B2 (en) 2010-04-05 2015-12-01 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US10799514B2 (en) 2015-06-29 2020-10-13 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kappa beta for treatment of disease
US11382922B2 (en) 2019-03-07 2022-07-12 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions

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US3005836A (en) * 1956-08-31 1961-10-24 Pfizer & Co C Salts of steroidal amino acid esters
GB966060A (en) * 1961-08-17 1964-08-06 Searle & Co Aminoalkyl esters of 3ª‰-hydroxypregn-5-en-20-one
GB2028336A (en) * 1978-08-14 1980-03-05 Kureha Chemical Ind Co Ltd Steroid hormone-antitumour drug conjugates
FR2459249A1 (fr) * 1979-06-14 1981-01-09 Fabre Sa Pierre Derives de steroides azotes sur l'atome de carbone en positio n 21 de la chaine laterale et leur application comme anti-inflammatoires

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
US3005836A (en) * 1956-08-31 1961-10-24 Pfizer & Co C Salts of steroidal amino acid esters
GB966060A (en) * 1961-08-17 1964-08-06 Searle & Co Aminoalkyl esters of 3ª‰-hydroxypregn-5-en-20-one
GB2028336A (en) * 1978-08-14 1980-03-05 Kureha Chemical Ind Co Ltd Steroid hormone-antitumour drug conjugates
FR2459249A1 (fr) * 1979-06-14 1981-01-09 Fabre Sa Pierre Derives de steroides azotes sur l'atome de carbone en positio n 21 de la chaine laterale et leur application comme anti-inflammatoires

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0389368A1 (fr) * 1989-03-22 1990-09-26 Roussel Uclaf Nouveaux dérivés de la 6-(1-pipérazinyl) 2,5-pyridine diamine N,N,N',N'-substituée, leur procédé de préparation et les intermédiaires de ce procédé, leur application comme médicaments et les compositions pharmaceutiques les renfermant
EP0389370A1 (fr) * 1989-03-22 1990-09-26 Roussel-Uclaf Nouveaux stéroides 19-Nor 3-céto comportant une chaîne en 17 aminosubstituée, leur procédé de préparation et les intermédiaires de ce procédé,leur application comme médicaments et les compositions pharmaceutiques les contenant
EP0389369A1 (fr) * 1989-03-22 1990-09-26 Roussel-Uclaf Nouveaux stéroides 3-céto comportant une chaîne en 17 aminosubstituée, leur procédé de préparation et les intermédiaires de ce procédé, leur application comme médicaments et les compositions les contenant
FR2644789A1 (fr) * 1989-03-22 1990-09-28 Roussel Uclaf Nouveaux steroides 19-nor, 3-ceto comportant une chaine en 17 aminosubstituee, leur procede de preparation et les intermediaires de ce procede, leur application comme medicaments et les compositions pharmaceutiques les contenant
FR2644787A1 (fr) * 1989-03-22 1990-09-28 Roussel Uclaf Nouveaux steroides 21 aminosubstitues, leur procede de preparation et les intermediaires de ce procede, leur application comme medicaments et les compositions pharmaceutiques les contenant
FR2644788A1 (fr) * 1989-03-22 1990-09-28 Roussel Uclaf Nouveaux steroides 3-ceto comportant une chaine en 17 amino-substituee, leur procede de preparation et les intermediaires de ce procede, leur application comme medicaments et les compositions pharmaceutiques les contenant
WO1991011453A2 (fr) * 1990-01-26 1991-08-08 The Upjohn Company 2,4,6-triaminopyrimidines oxygenees en position 5
WO1991011453A3 (fr) * 1990-01-26 1991-11-14 Upjohn Co 2,4,6-triaminopyrimidines oxygenees en position 5
US5502187A (en) * 1992-04-03 1996-03-26 The Upjohn Company Pharmaceutically active bicyclic-heterocyclic amines
LT3071B (en) 1992-06-09 1994-11-25 Richter Gedeon Vegyeszet Novel steroids with pregnane skeleton,pharmaceutical compositions containing them and process for preparing thereof
LT3118B (en) 1992-06-09 1994-12-27 Richter Gedeon Vegyeszet Novel, biologically active eburnamenine derivatives and a process for preparing the same
EP0574906A3 (fr) * 1992-06-17 1994-04-13 Nisshin Flour Milling Co
US5380724A (en) * 1992-06-17 1995-01-10 Gyogyszerkutato Intezet Kft Piperazine and homopiperazine derivatives, pharmaceutical compositions containing them and process for preparing same
EP0574906A2 (fr) * 1992-06-17 1993-12-22 Nisshin Flour Milling Co., Ltd. Dérivés de pipérazine et homopipérazine, compositions pharmaceutiques les contenant et procédé pour leur préparation
WO1994024146A1 (fr) * 1993-04-13 1994-10-27 Jenapharm Gmbh Des androgenes et anaboliques nouveaux
US5795883A (en) * 1993-04-13 1998-08-18 Jenapharm Gmbh Androgens and anabolic agents
WO1996021648A1 (fr) * 1995-01-11 1996-07-18 Samjin Pharmaceutical Co., Ltd. Nouveaux derives piperazines, leurs procedes de preparation, et compositions les contenant
US8673887B2 (en) 2008-05-28 2014-03-18 Reveragen Biopharma, Inc Non-hormonal steroid modulators of NF-kB for treatment of disease
US8334279B2 (en) 2008-05-28 2012-12-18 Validus Genetics Non-hormonal steroid modulators of NF-κB for treatment of disease
US8207151B2 (en) 2008-05-28 2012-06-26 Validus Biopharma Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US9649320B2 (en) 2008-05-28 2017-05-16 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US10206933B2 (en) 2008-05-28 2019-02-19 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kB for treatment of disease
US10857161B2 (en) 2008-05-28 2020-12-08 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kB for treatment of disease
US11833159B2 (en) 2008-05-28 2023-12-05 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kB for treatment of disease
US9198921B2 (en) 2010-04-05 2015-12-01 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US10000525B2 (en) 2010-04-05 2018-06-19 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US10799514B2 (en) 2015-06-29 2020-10-13 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kappa beta for treatment of disease
US11690853B2 (en) 2015-06-29 2023-07-04 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κβ for treatment of disease
US11382922B2 (en) 2019-03-07 2022-07-12 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions
US11471471B2 (en) 2019-03-07 2022-10-18 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions

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