Exhibit
        10.21

    

     

    OMNIBUS
      AMENDMENT TO JOINT VENTURE AGREEMENT AND ADDITIONAL
      AGREEMENTS

     

    THIS
      OMNIBUS AMENDMENT TO JOINT VENTURE AGREEMENT AND ADDITIONAL AGREEMENTS (this
      “Amendment”)
      is
      entered into as of June 9, 2008
      by and
      among Manhattan Pharmaceuticals, Inc., a Delaware corporation (“MHA”),
      Hedrin Pharmaceuticals K/S,
      a
      Danish limited liability partnership (“Newco”),
      Hedrin
      Pharmaceuticals General Partner ApS, a Danish private limited company
      (“Hedrin
      GP”)
      and
      Nordic
      Biotech Venture Fund II K/S, a Danish limited liability partnership
      (“Nordic”).

     

    WITNESSETH:

     

    WHEREAS,
      MHA and Nordic previously entered into that certain Joint Venture Agreement
      dated as of January 31, 2008 (as previously amended, the “Joint
      Venture Agreement”).
      Capitalized terms not otherwise defined herein shall have the meanings assigned
      to them in the Joint Venture Agreement;

    


    WHEREAS,
      pursuant
      to the Joint Venture Agreement, (i) MHA agreed to assign certain assets to
      Newco
      in accordance with the terms of that certain Assignment and Contribution
      Agreement dated as of February 21, 2008 (as amended from time to time, the
      “Contribution
      Agreement”),
      (ii)
      MHA, Nordic and Hedrin GP entered into a Limited Partnership Agreement dated
      as
      of February 21, 2008 (as amended from time to time, the “Partnership
      Agreement”),
      and
      (iii) MHA and Nordic entered into a Shareholders Agreement dated as of February
      21, 2008 (as amended from time to time, the “Shareholders
      Agreement”)
      with
      respect to Hedrin GP; and

    


    MHA,
      Newco, Hedrin GP and Nordic wish to recognize that substantial progress has
      been
      made toward achieving the Payment Milestone so as to justify a current partial
      Milestone Payment and that more specificity is appropriate in the definition
      of
      the Payment Milestone that will result in the payment of the remaining Milestone
      Payment, all in accordance with the terms hereof, and that the Joint Venture
      Agreement, Contribution Agreement, Partnership Agreement and Shareholders
      Agreement should be appropriately modified, in each case on the terms and
      conditions set forth in this Amendment. 

    


    NOW,
      THEREFORE, for good and valuable consideration, the receipt and sufficiency
      of
      which is hereby acknowledged, the parties hereto hereby agree as
      follows:

    


    1. Amendments
      to Joint Venture Agreement.
      

     

    (a) Section
      1
      of the Joint Venture Agreement is hereby amended by deleting the defined term
      “Milestone Payment” in its entirety and adding the following two new defined
      terms in alphabetical sequence in Section 1:

     

    “Initial
      Milestone Payment” means the payment by Nordic of an additional $1,250,000 to
      Newco after the satisfaction of the Initial Payment Milestone (as defined in
      the
      Contribution Agreement).


    
      
        
        

      

      
        1

        
          

        

      

      
        
        

      

    

     

    “Second
      Milestone Payment” means the payment by Nordic of an additional $1,250,000 to
      Newco after the satisfaction of the Second Payment Milestone (as defined in
      the
      Contribution Agreement).

     

    (b) Section
      1
      of the Joint Venture Agreement is hereby amended by deleting the defined term
      “Investment Amount” in its entirety and replacing it with the following:


     

    “Investment
      Amount”
means
      (i) $2,500,000 if neither the Initial Milestone Payment nor the Second Milestone
      Payment has occurred, (ii) $3,750,000 if, prior to June 30, 2009, the Initial
      Milestone Payment has occurred but the Second Milestone Payment has not
      occurred, (iii) $3,500,000 if (A) on or after June 30, 2009, the Initial
      Milestone Payment has occurred but the Second Milestone Payment has not
      occurred, or (B) if
      prior
      to June 30, 2009, the U.S.
      Food
      and Drug Administration (“FDA”)
      formally designates the Licensed Products (as defined in the Contribution
      Agreement) as a drug and refers regulation thereof to the FDA Center for Drug
      Evaluation and Research, and (iv) $5,000,000 if both the Initial Milestone
      Payment and the Second Milestone Payment have occurred.

     

    2. Amendments
      to Contribution Agreement.

     

    (a) Section
      5.3 of the Contribution Agreement is hereby deleted in its entirety and replaced
      with the following:

     

    “5.3 Definition
      of Initial Payment Milestone and Second Payment Milestone

    


    For
      purposes of this Agreement, (i) the term “Initial
      Payment Milestone”
shall
      mean a preliminary determination from the U.S. Food and Drug Administration
      received prior to September 30, 2008 that the Licensed Products will be
      regulated as a medical device, and (ii) the term “Second
      Payment Milestone”
shall
      mean (A) a determination by the U.S. Food and Drug Administration (“FDA”)
      that a
      Licensed Product is substantially equivalent to a predicate device in accordance
      with Section 513(f)(1) or 510(k) of the Federal Food, Drug, and Cosmetic Act
      (as
      amended, the “FDC
      Act”)
      or any
      other marketing authorization of a Licensed Product by the FDA as a medical
      device, (B) the issuance of a “Classification Decision” as such term is used in
      Attachment 1 of the FDA Guidance for Industry and CDRH Staff titled “New Section
      513(f)(2) - Evaluation of Automatic Class III Designation” issued by the FDA on
      February 19, 1998, with respect to a Licensed Product, or (C) the receipt of
      a
      formal response to a “Request for Designation” from the Office of Combination
      Products that designates a Licensed Product as a device, in each of cases (A)
      through (C) prior to June 30, 2009.”

    


    (b) Section
      5.1(a)(ii) of the Contribution Agreement is hereby deleted in its entirety
      and
      replaced with two new subsections as follows:

    


    “(ii) within
      21
      days after the achievement of the Initial Payment Milestone (as defined below):
      (A) pay to MHA an additional US$1,000,000.00 in cash (the “Second
      Cash Payment”)
      and
      (B) if necessary to maintain MHA’s 50% ownership of outstanding Partnership
      Shares, issue to MHA, and deliver a certificate representing, a number of
      additional Partnership Shares of Newco that will constitute, together with
      the
      Initial Equity Issuance, 50% of all outstanding Partnership Shares (the
“Second
      Equity Issuance”).


    
      
        
        

      

      
        2

        
          

        

      

      
        
        

      

    

    


    (iii) within
      30
      days after the achievement of the Second Payment Milestone (as defined below):
      (A) pay to MHA an additional US$500,000.00 in cash (the “Third
      Cash Payment”
and
      together with the First Cash Payment and the Second Cash Payment, the
“Cash
      Payments”)
      and
      (B) if necessary to maintain MHA’s 50% ownership of outstanding Partnership
      Shares, issue to MHA, and deliver a certificate representing, a number of
      additional Partnership Shares of Newco that will constitute, together with
      the
      Initial Equity Issuance and Second Equity Issuance, 50% of all outstanding
      Partnership Shares (the “Third
      Equity Issuance”)
      and,
      together with the Initial Equity Issuance and Second Equity Issuance, the
“Equity
      Issuances”).”

    


    (c) Section
      5.1(c) of the Contribution Agreement is hereby deleted in its entirety and
      replaced with the following:

    


    “Upon
      the
      Initial Equity Issuance, MHA shall own 50% of the outstanding Partnership Shares
      of Newco. Upon the Second Equity Issuance, MHA shall own 50% of the outstanding
      Partnership Shares of Newco (after giving effect to the issuance of additional
      Partnership Shares, if any, to Nordic pursuant to the Partnership Agreement).
      Upon the Third Equity Issuance, if any, MHA shall own 50% of the outstanding
      Partnership Shares of Newco (after giving effect to the issuance of additional
      Partnership Shares, if any, to Nordic pursuant to the Partnership
      Agreement).”

    


    (d) Section
      5.2(b) of the Contribution Agreement is hereby deleted in its entirety and
      replaced with the following:

    


    “(b) (i)
      The
      authorized capital of Newco, immediately after the Second Equity Issuance,
      if
      any, consists of 2,000 Partnership Shares, 700 of which are owned, beneficially
      and of record, by Nordic, and 700 of which are owned, beneficially and of record
      by MHA, and (ii) the authorized capital of Newco, immediately after the Third
      Equity Issuance, if any, consists of 2,000 Partnership Shares, 1,000 of which
      are owned, beneficially and of record, by Nordic, and 1,000 of which are owned,
      beneficially and of record by MHA.

    


    3. Amendments
      to Partnership Agreement.
      

     

    (a) Section
      1.1 of the Partnership Agreement is hereby amended by deleting the defined
      term
“Payment Milestone” in its entirety and adding the following two new defined
      terms in alphabetical sequence in Section 1.1:


    
      
        
        

      

      
        3

        
          

        

      

      
        
        

      

    

     

    “Initial
      Payment Milestone” means such term as defined in the Contribution Agreement.


     

    “Second
      Payment Milestone” means such term as defined in the Contribution Agreement.


     

    (b) Section
      3.6 of the Partnership Agreement is hereby deleted in its entirety and replaced
      with the following:

     

    “(a)
      Not
      later than 21 days after satisfaction, if any, of the Initial Payment Milestone,
      Nordic shall pay to the Partnership an additional $1,250,000 by wire transfer
      to
      a bank account designated by the Partnership as payment for an additional 200
      Partnership Shares. The satisfaction of the Initial Payment Milestone shall
      constitute payment by MHA for an additional 200 Partnership Shares, subject
      to
      subsection (c) below. Accordingly, after satisfaction of the Initial Payment
      Milestone, the Partnership Shares shall be distributed among the Parties as
      follows (all amounts in DKK):

     

    
      	 	 	
              Number of Partnership Shares

            	 
	
              Nordic
                

            	 	 	
              700

            	 
	
              MHA

            	 	 	
              700

            	 
	
              General
                Partner

            	 	 	
              0

            	 
	
              Total

            	 	 	
              1,400

            	 


    

    


    (b)
      Not
      later than 30 days after satisfaction, if any, of the Second Payment Milestone,
      Nordic shall pay to the Partnership an additional $1,250,000 by wire transfer
      to
      a bank account designated by the Partnership as payment for an additional 300
      Partnership Shares. The satisfaction of the Second Payment Milestone shall
      constitute payment by MHA for an additional 300 Partnership Shares. Accordingly,
      after satisfaction of the Second Payment Milestone, the Partnership Shares
      shall
      be distributed among the Parties as follows (all amounts in DKK):

     

    
      	 	 	
              Number of Partnership Shares

            	 
	
              Nordic
                

            	 	 	
              1,000

            	 
	
              MHA

            	 	 	
              1,000

            	 
	
              General
                Partner

            	 	 	
              0

            	 
	
              Total

            	 	 	
              2,000

            	 


    

    


    (c)
      If
      the Second Payment Milestone is not achieved by June 30, 2009, or if prior
      to
      June 30, 2009, the U.S.
      Food
      and Drug Administration (“FDA”)
      formally designates the Licensed Products (as defined in the Contribution
      Agreement) as a drug and refers regulation thereof to the FDA Center for Drug
      Evaluation and Research,
      (i)
      Nordic shall not be obliged to make any payment to the Partnership pursuant
      to
clause
      3.6(b), (ii) MHA shall forfeit to the Partnership 400 Partnership Shares, and
      (iii) Nordic shall be entitled to, and the Partnership shall make, a return
      of
      capital of $250,000, with no corresponding reduction in Nordic’s Partnership
      Shares. Accordingly,
      after June 30, 2009, if the Second Payment Milestone has not been achieved,
      or
      if
      prior to June 30, 2009, the FDA
      formally designates the Licensed Products as a drug and refers regulation
      thereof to the FDA Center for Drug Evaluation and Research, the Partnership
      Shares shall be distributed among the Parties as follows (all amounts in
      DKK):


    
      
        
        

      

      
        4

        
          

        

      

      
        
        

      

    

    


    
      	 	 	
              Number of Partnership Shares

            	 
	
              Nordic
                

            	 	 	
              700

            	 
	
              MHA

            	 	 	
              300

            	 
	
              General
                Partner

            	 	 	
              0

            	 
	
              Total

            	 	 	
              1,000

            	 


    

    


    (c) Section
      11.1(ii) of the Partnership Agreement is hereby deleted in its entirety and
      replaced with the following:

    


    From
      any
      amount available for distribution in excess of the amount referred to under
      sub-clause 11.1(i) the holder(s) of the MHA Partnership Shares shall before
      any
      distribution is made to other Limited Partners be entitled to receive an amount
      equal to the proceeds distributed to the holders of the Nordic Partnership
      Shares under sub-clause 11.1(i) multiplied by a fraction the numerator of which
      is MHA’s number of Partnership Shares at the time of such distribution, and the
      denominator of which is the total number of outstanding Partnership Shares
      at
      the time of such distribution.

    


    4. Amendments
      to Shareholders Agreement.
      

     

    (a) Section
      1.1 of the Shareholders Agreement is hereby amended by deleting the defined
      term
“Payment Milestone” in its entirety and adding the following two new defined
      terms in alphabetical sequence in Section 1.1:

     

    “Initial
      Payment Milestone” means such term as defined in the Contribution Agreement.


     

    “Second
      Payment Milestone” means such term as defined in the Contribution Agreement.


     

    (b) Section
      4.3 of the Shareholders Agreement is hereby deleted in its entirety and replaced
      with the following: 

     

    “Irrespective
      of clause 4.2, if the Second Payment Milestone has not been achieved by 30
      March
      2009, Nordic shall - in addition to any board members appointed by Nordic
      pursuant to clause 4.2 and as long as Nordic is the owner of the Nordic
      Partnership Shares - immediately be entitled to appoint one additional board
      member, in which case the board of directors may consist of up to five members
      elected at the general meeting.”


    
      
        
        

      

      
        5

        
          

        

      

      
        
        

      

    

     

    5. Satisfaction
      of Initial Payment Milestone.
      The
      parties hereto acknowledge and agree that the Initial Payment Milestone is
      deemed to be achieved as of the date of this Amendment and that payment of
      the
      Nordic capital contribution to Newco pursuant to Section 3.6(a) of the
      Partnership Agreement, as amended hereby, and payment by Newco of the Second
      Cash Payment pursuant to Section 5.1(a)(ii) of the Contribution Agreement,
      as
      amended hereby, will each occur on or before the twenty-first day after the
      date
      of this Amendment.

     

    6. Representations
      and Warranties; Ratification.
      

     

    (a) Each
      of
      MHA, Nordic, Newco and Hedrin GP represents and warrants to the other parties
      hereto that this Amendment has been duly executed and delivered by such party
      and constitutes a legal, valid and binding obligation of such party enforceable
      against it in accordance with its terms, subject to laws of general application
      relating to bankruptcy, insolvency and the relief of debtors and rules of law
      governing specific performance, injunctive relief or other equitable remedies,
      and to limitations of public policy. 

     

    (b) Each
      of
      Nordic, MHA, Newco and Hedrin GP represents and warrants to the others that
      each
      of the representations and warranties of such party in each of the Joint Venture
      Agreement and the Additional Agreements to which such company is a party is
      true
      and correct in all material respects on the effective date of this Amendment
      (except as set forth on Schedule
      A
      hereto
      and except for representations and warranties limited as to time or with respect
      to a specific event, which representations and warranties shall continue to
      be
      limited to such time or event).

    


    (c) Except
      as
      hereby amended, the Joint Venture Agreement and each provision thereof, and
      each
      Additional Agreement (as the same may be amended in connection with this
      Amendment) and each provision thereof, are hereby ratified and confirmed in
      every respect and shall continue in full force and effect. 

     

    7. Conditions
      Precedent.
      The
      agreements set forth in this Amendment are conditional and this Amendment shall
      not be effective until receipt by each party of a fully-executed counterpart
      of
      this Amendment (which may be a facsimile or .pdf copy thereof).

     

    8. Miscellaneous.

     

    (a) Entire
      Agreement.
      This
      Amendment, the Joint Venture Agreement and the Additional Agreements, as amended
      hereby, contain the entire understanding of the parties hereto and supercedes
      all prior or contemporaneous negotiations, promises, covenants, agreements
      and
      representations of every nature whatsoever with respect to the matters referred
      to in this Amendment, the Joint Venture Agreement and the Additional Agreements.
      

     

    (b) Headings.
      The
      headings herein are for convenience only, do not constitute a part of this
      Agreement and shall not be deemed to limit or affect any of the provisions
      hereof. The language used in this Agreement will be deemed to be the language
      chosen by the parties to express their mutual intent, and no rules of strict
      construction will be applied against any party.


    
      
        
        

      

      
        6

        
          

        

      

      
        
        

      

    

     

    (c) Successors
      and Assigns.
      This
      Amendment shall be binding upon and inure to the benefit of the parties and
      their successors and permitted assigns.

     

    (d) Expenses.
      Notwithstanding any provision to the contrary in the Agreement or the Additional
      Agreements, MHA will reimburse Nordic for all legal, due diligence and advisory
      fees and expenses incurred by Nordic or its advisors in connection with this
      Amendment and the transactions contemplated by this Amendment, the Agreement
      and
      the Additional Agreements. MHA has made on or before the date of this Amendment,
      or shall make within five (5) days of the date of this Amendment, a payment
      to
      Nordic of $30,000, and thereafter shall make additional advances and payments
      to
      Nordic necessary to reimburse Nordic for its fees and expenses in excess of
      amounts previously advanced under this Section 8(d). 

     

    (e) Governing
      Law.
      

     

    (i) All
      questions concerning the construction, validity, enforcement and interpretation
      of this Amendment, as it relates to the amendments to the Joint Venture
      Agreement and Contribution Agreement, shall be governed by and construed and
      enforced in accordance with the internal laws of the State of New York, without
      regard to the principles of conflicts of law thereof, except to the extent
      that
      the application of the General Corporation Law of the State of Delaware is
      mandatorily applicable. 

     

    (ii) All
      questions concerning the construction, validity, enforcement and interpretation
      of this Amendment, as it relates to the amendments to the Partnership Agreement
      and Shareholders Agreement, shall be governed by and construed and enforced
      in
      accordance with Danish law. 

     

    (iii) Each
      Party hereby irrevocably submits to the exclusive jurisdiction of the federal
      and state courts sitting in the state of New York in any action or proceeding
      arising out of or relating to this Amendment. Each Party hereby irrevocably
      agrees, on behalf of itself and on behalf of such Party’s successors and
      permitted assigns, that all claims in respect of such action or proceeding
      shall
      be heard and determined in any such court and irrevocably waives any objection
      such person may now or hereafter have as to the venue of any such suit, action
      or proceeding brought in such a court or that such court is an inconvenient
      forum. If either party shall commence an action or proceeding to enforce any
      provision of this Amendment, then the prevailing party in such action or
      proceeding shall be reimbursed by the other party for its reasonable attorneys’
fees and other costs and expenses incurred with the investigation, preparation
      and prosecution of such action or proceeding. 

     

    (f) Counterparts.
      This
      Amendment may be executed in two or more counterparts, all of which when taken
      together shall be considered one and the same agreement and shall become
      effective when counterparts have been signed by each party and delivered to
      the
      other party, it being understood that both parties need not sign the same
      counterpart. In the event that any signature is delivered by facsimile
      transmission, such signature shall create a valid and binding obligation of
      the
      party executing (or on whose behalf such signature is executed) with the same
      force and effect as if such facsimile signature page were an original
      thereof.


    
      
        
        

      

      
        7

        
          

        

      

      
        
        

      

    

     

    (g) Severability.
      If any
      provision of this Amendment is held to be invalid or unenforceable in any
      respect, the validity and enforceability of the remaining terms and provisions
      of this Amendment shall not in any way be affected or impaired thereby and
      the
      parties will attempt to agree upon a valid and enforceable provision that is
      a
      reasonable substitute therefore, and upon so agreeing, shall incorporate such
      substitute provision in this Amendment.

     

    [Signature
      page follows]


    
      
        
        

      

      
        8

        
          

        

      

      
        
        

      

    

     

    IN
      WITNESS WHEREOF, the parties hereto have executed this Amendment under seal
      as
      of the day and year first above written.

     

    
      	
              MHA:

            
	 
	
              MANHATTAN
                PHARMACEUTICALS, INC.

            
	 	 
	
              By:

            	
              /s/
                Douglas Abel

            
	
              Name:

            	
              /s/
                Douglas Abel

            
	
              Title:

            	
              President
                and Chief Executive Officer

            
	 	 
	
              NORDIC:

            
	 
	
              NORDIC
                BIOTECH VENTURE FUND II K/S

            
	 	 
	
              By:

            	
              /s/
                Florian Schonharting

            
	 	
              Florian
                Schonharting, Partner

            
	 	 
	
              By:

            	
              /s/
                Christian Hansen

            
	 	
              Christian
                Hansen, Partner

            


    

     

    HEDRIN
      PHARMACEUTICALS K/S:

    


    BY: HEDRIN
      PHARMACEUTICALS GENERAL PARTNER APS

     

    
      
        	
                By:

              	
                /s/
                  Florian Schonharting 

              	 	
                By:

              	
                /s/
                  Douglas Abel

              
	Florian
                Schonharting, Director	 	 	
                Douglas
                  Abel, Director

              


      

    

     

    HEDRIN
      PHARMACEUTICALS GENERAL PARTNER APS:

    


    
      	
              By:

            	
              Florian
                Schonharting

            	 	
              By:

            	
              /s/
                Douglas Abel

            
	 	
              Florian
                Schonharting, Director

            	 	 	
              Douglas
                Abel, Director

            


    

     

    Signature
      Page to Omnibus Amendment to Joint Venture Agreement and Additional
      Agreements


    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    SCHEDULE
      A

    June
      9,
      2008

    


    1. Update
      to Capitalization Representation and Warranty (Section
      8.2).

    


    As
      of May
      31, 2008, there were 11,001,308 shares of Common Stock reserved for issuance
      pursuant to outstanding options and 8,683,853 shares of Common Stock reserved
      for issuance pursuant to outstanding warrants.

    


    2. Update
      to Schedule 8.6.

    


    Swiss
      Pharma Contract LTD, or Swiss Pharma, a clinical site that MHA used in one
      of
      its obesity trials, gave notice to MHA that Swiss Pharma believes it is entitled
      to receive an additional payment of $322,776 for services in connection with
      that clinical trial. While the contract between MHA and Swiss Pharma provides
      for additional payments if certain conditions are met, Swiss Parma did not
      specify which conditions they believed have been achieved and MHA does not
      believe that Swiss Pharma is entitled to additional payments and had not accrued
      any of these costs as of March 31, 2008 and December 31, 2007. The contract
      between MHA and Swiss Pharma provides for arbitration in the event of a dispute,
      such as this claim for an additional payment. On March 10, 2008, Swiss Pharma
      filed for arbitration with the Swiss Chamber of Commerce. On April 2, 2008,
      MHA
      filed its statement of defense and counterclaim for recovery of costs incurred
      by MHA as a result of Swiss Pharma’s failure to meet agreed upon deadlines under
      the contract. On June 3, 2008 an arbitration hearing was held. As MHA does
      not
      believe that Swiss Pharma is entitled to additional payments, MHA has defended
      its position in arbitration. The arbitrator expects to render his decision
      on or
      about August 31, 2008.

    


    3. Update
      to Schedule 8.22.

    


    MHA's
      cash balance as of May 31, 2008, was approximately $72,000; and its receivable
      from the Hedrin JV was $69,000.